Histamine and H1-Antihistamines in Allergic Disease, Second Edition, (Clinical Allergy and Immunology)

Histamine and H1-Antihistamines in Allergic Disease Second Edition Revised and Expanded

edited by

F. Estelle R. Simons University of Manitoba Winnipeg, Manitoba, Canada

Marcel Dekker, Inc.

New York • Basel

TM

Copyright © 2002 by Marcel Dekker, Inc. All Rights Reserved.

The first edition was published as Histamine and H1-Receptor Antagonists in Allergic Disease (Marcel Dekker, 1996). ISBN: 0-8247-0628-5

This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http:/ /www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above.

Copyright  2002 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA

Dedicated with deepest gratitude to my father, Francis Raymond Edward Davies (1910–1995)

Series Introduction

Although 60 years have passed since antihistamines were first developed, new and exciting observations are still coming forward, new antihistamines are still being developed, and new uses for existing products are still being established. Thus, it is timely to produce the second edition of this very successful volume by F. Estelle R. Simons, M.D. Dr. Simons is widely considered the clinical expert in the use of antihistamines, and she warrants being the creator and editor of this useful book. This revised edition contains new chapters, new concepts, and information about new products. This book will be exciting reading for those interested in the study of allergy. Michael A. Kaliner, M.D.

v

Preface ‘‘Yet all experience is an arch wherethro’ Gleams that untravell’d world . . .’’ Tennyson

Since the first edition of this successful medical textbook was published in 1996, high-level interest in histamine as a chemical mediator of inflammation has continued, and H1-antihistamines such as cetirizine, fexofenadine, and loratadine remain the most widely used medications worldwide for allergic disorders, particularly for allergic rhinoconjunctivitis and urticaria. Several new second-generation, nonsedating H1-antihistamines have been approved for use during the past few years. These medications include ebastine, mizolastine, desloratadine, and levocetirizine, soon to be followed by epinastine, tecastemizole, and others. New topical H1-antihistamine formulations such as azelastine, levocabastine, ketotifen, emedastine, and olopatadine have also been introduced for intranasal and ocular use. Two H1-antihistamines, astemizole and terfenadine, which are no longer approved by regulatory agencies due to their potential cardiac toxicity, have now almost entirely disappeared from the scene. Histamine and H1-Antihistamines in Allergic Disease, Second Edition, Revised and Expanded, reflects these important developments. It provides an upto-date, comprehensive analysis of the benefits of this important class of medications, including their broad antiallergic effects, and it contrasts the excellent safety profiles of the relatively nonsedating second-generation H1-antihistamines with those of the sedating first-generation H1-antihistamines. We sincerely thank the scientists and clinician scientists who have helped to make this new edition a reality—not only for their contributions to the book, but also for their sustained contributions to improving the evidence base for H1antihistamine use in the treatment of allergic disease. F. Estelle R. Simons University of Manitoba Winnipeg, Manitoba, Canada vii

Contents

Series Introduction Preface Contributors Introduction

v vii xi xiii

Part I. Histamine and Histamine Receptors 1. Histamine in Health and Disease M. Susana Repka-Ramirez and James M. Baraniuk 2. Histamine Receptors: Specific Ligands, Receptor Biochemistry, and Signal Transduction Remko A. Bakker, Hendrik Timmerman, and Rob Leurs

1

27

Part II. H1-Antihistamines: Basic Science 3. Structure and Classification of H1-Antihistamines and Overview of Their Activities Giovanni Passalacqua, G. Walter Canonica, and Jean Bousquet 4. Antiallergic Anti-Inflammatory Effects of H1-Antihistamines in Humans Paraya Assanasen and Robert M. Naclerio 5. Clinical Pharmacology of H1-Antihistamines F. Estelle R. Simons and Keith J. Simons

65

101

141 ix

x

Contents

Part III. H1-Antihistamines: Clinical Science 6.

Antihistamines in Rhinoconjunctivitis Peter Howarth

179

7.

H1-Antihistamines in Asthma James L. Lordan and Stephen T. Holgate

221

8.

Antihistamines in Urticaria and Angioedema Anne Kobza Black and Malcolm W. Greaves

249

9.

Histamine and Antihistamines in Anaphylaxis Stephen L. Winbery and Philip L. Lieberman

287

Cost-Effectiveness of H1-Antihistamines Michael S. Blaiss

319

10.

Part IV. H1-Antihistamines: Potential Adverse Effects 11.

H1-Antihistamines and the Central Nervous System Michael J. Welch, Eli O. Meltzer, and F. Estelle R. Simons

337

12.

Potential Cardiac Toxicity of H1-Antihistamines Yee Guan Yap and A. John Camm

389

Part V. H1-Antihistamines: Special Populations 13.

H1-Antihistamines in Pregnancy and Lactation Michael Schatz

421

14.

H1-Antihistamines in Children F. Estelle R. Simons

437

15.

H1-Antihistamines in the Elderly Michael A. Kaliner

465

Index

483

Contributors

Paraya Assanasen, M.D.

University of Chicago, Chicago, Illinois

Remko A. Bakker, M.Sc. Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, Amsterdam, The Netherlands James N. Baraniuk, M.D.

Georgetown University, Washington, D.C.

Michael S. Blaiss, M.D. University of Tennessee Center for the Health Sciences College of Medicine, Memphis, Tennessee Jean Bousquet, M.D.

Montpellier University, Montpellier, France

A. John Camm, M.D., F.R.C.P., F.A.C.S., F.E.S.C. Medical School, London, England G. Walter Canonica, M.D.

St. George’s Hospital

Genoa University, Genova, Italy

Malcolm W. Greaves, M.D., Ph.D., F.R.C.P. sia, Kuala Lumpur, Malaysia

National University of Malay-

Stephen T. Holgate, B.Sc., M.D., D.Sc., F.R.C.P., F.R.C.Path., F.I. Biol., F.Med.Sci University of Southampton, Southampton, England Peter Howarth, B.Sc. (Hons.), D.M., F.R.C.P. Southampton, England Michael A. Kaliner, M.D. Chevy Chase, Maryland

University of Southampton,

Institute for Allergy and Asthma, Wheaton and xi

xii

Anne Kobza Black, M.D. London, England

Contributors

Guy’s, King’s & St. Thomas’ School of Medicine,

Rob Leurs, Ph.D. Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, Amsterdam, The Netherlands Philip L. Lieberman, M.D. Memphis, Tennessee

University of Tennessee College of Medicine,

James L. Lordan, M.B., M.R.C.P.I., B.Sc., D.C.H., D.M.E., D.Obs. sity of Southampton, Southampton, England

Univer-

Eli O. Meltzer, M.D. Allergy and Asthma Medical Group and Research Center, University of California, San Diego, San Diego, California Robert M. Naclerio, M.D.

University of Chicago, Chicago, Illinois

Giovanni Passalacqua, M.D.

Genoa University, Genoa, Italy

M. Susana Repka-Ramirez, M.D.

Georgetown University, Washington, D.C.

Michael Schatz, M.D., M.S. Kaiser-Permanente Medical Center, San Diego, California F. Estelle R. Simons, M.D., F.R.C.P. itoba, Canada Keith J. Simons, M.Sc., Ph.D. Canada

University of Manitoba, Winnipeg, Man-

University of Manitoba, Winnipeg, Manitoba,

Hendrik Timmerman, Ph.D. Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, Amsterdam, The Netherlands Michael J. Welch, M.D. Allergy and Asthma Medical Group and Research Center, University of California, San Diego, San Diego, California Stephen L. Winbery, M.D., Ph.D. tice, Memphis, Tennessee

Methodist Central Hospital Teaching Prac-

Yee Guan Yap, B. Med. Sci., M.B.B.S., M.R.C.P. ical School, London, England

St. George’s Hospital Med-

Introduction

Histamine and H1-Antihistamines in Allergic Disease, Second Edition, Revised and Expanded, like the first edition, reviews the basic science of histamine, histamine receptors, and antihistamines, and the clinical science—the benefits and risks—of antihistamine use in allergic disease. It has been expanded to include new chapters on ‘‘Cost-Effectiveness of Antihistamines,’’ ‘‘H1-Antihistamines in Pregnancy and Lactation,’’ and ‘‘H1-Antihistamines in the Elderly.’’ The book can be read in its entirety from cover to cover, since there is consistency and minimal overlap among the chapters; or, individual chapters can be perused as free-standing reviews of a particular aspect of histamine or H1-antihistamines. In Chapter 1, ‘‘Histamine in Health and Disease,’’ the authors introduce the concept that histamine is released in large amounts during the immediate hypersensitivity response in the airways, skin, and other organs, where it upregulates a wide range of cellular responses and plays a primary role in allergic inflammation. In Chapter 2, ‘‘Histamine Receptors: Specific Ligands, Receptor Biochemistry, and Signal Transduction,’’ exciting new information about selective ligands for the histamine receptors, including the recently discovered H3- and H4-receptors, is introduced. Clinically relevant aspects of receptor biochemistry, molecular biology, and signal transduction are presented. The constitutive nature of H1- and H2-receptor signaling is described. In Chapter 3, ‘‘Structure and Classification of H1-Antihistamines and Overview of Their Activities,’’ the authors review the history and chemistry of H1antihistamines, and provide an overview of their specific beneficial and adverse effects. Second-generation H1-antihistamines that have been introduced during the past few years are discussed in depth. In Chapter 4, ‘‘Antiallergic Anti-Inflammatory Effects of H1-Antihistamines in Humans,’’ these wide-ranging activities are described in detail. Although some antiallergic effects such as suppression of mediator release from mast cells and basophils occur independently of the H1-receptor and may not be xiii

xiv

Introduction

clinically relevant, others, such as down-regulation of transcription by nuclear factor kappa B and generation of cytokines and adhesion molecules, appear to be H1-receptor-dependent and are probably of considerable clinical importance. In Chapter 5, ‘‘Clinical Pharmacology of H1-Antihistamines,’’ the authors focus on the second-generation medications, including cetirizine, desloratadine, ebastine, fexofenadine, loratadine, and mizolastine. They explain how the differences in pharmacokinetics and pharmacodynamics among H1-antihistamines directly influence recommendations for dose and dose interval, and facilitate H1antihistamine use in children, the elderly, and other special groups. New clinical pharmacology concepts, for example, population pharmacokinetics of H1-antihistamines, and correlation of tissue H1-antihistamine concentrations with pharmacodynamic activity, are introduced. In Chapter 6, ‘‘Antihistamines in Rhinoconjunctivitis,’’ the important contribution of histamine to allergic inflammation in the mucosa of the upper airways and the conjunctivae, and the strong clinical evidence base for the use of H1antihistamines in treatment of allergic rhinoconjunctivitis, are covered in depth. In this chapter, both oral second-generation H1-antihistamines and topical H1antihistamines for intranasal and/or ocular use are reviewed. In Chapter 7, ‘‘H1-Antihistamines in Asthma,’’ the authors describe the scientific rationale for the beneficial effects of H1-antihistamines in asthma, which is due in large part to down-regulation of inflammatory cell recruitment. The evidence supporting the beneficial effects of the second-generation H1-antihistamines in mild seasonal asthma in patients with concomitant allergic rhinoconjunctivitis is presented. Combined H1-antihistamine and antileukotriene treatment is discussed. The timely issue of the potential preventative effect of antihistamines on the development of asthma in high-risk atopic infants is addressed. In Chapter 8, ‘‘Antihistamines in Urticaria and Angioedema,’’ H1-antihistamine use in acute urticaria, chronic idiopathic urticaria, and the physical urticarias is reviewed. The evidence base for the efficacy of various H1-antihistamines, including the second-generation H1-antihistamines in urticaria, is presented in tabular form for easy reference. The relatively minor role of H2-antihistamines in the treatment of urticaria is also discussed. In Chapter 9, ‘‘Histamine and Antihistamines in Anaphylaxis,’’ the authors contrast the secondary adjunctive role of H1-antihistamines in the treatment of anaphylaxis and anaphylactoid reactions, with their primary and very important role in prevention of iatrogenic anaphylaxis and anaphylactoid reactions in patients at risk for reactions to radiocontrast media, drugs, anesthetics, and other substances. The rationale for concurrent administration of H1- and H2-antihistamines in anaphylaxis and anaphylactoid reactions is reviewed. In Chapter 10, ‘‘Cost-Effectiveness of Antihistamines,’’ the author con-

Introduction

xv

firms that it no longer suffices to assess a medication’s clinical efficacy. It is also necessary to evaluate cost-effectiveness and to perform comparative analyses of the improvement in quality of life provided by the medication relative to other options available. In Chapter 11, ‘‘H1-Antihistamines and the Central Nervous System,’’ the authors highlight the neurotransmitter effect of histamine in the central nervous system (CNS) and review the evidence that first-generation H1-antihistamines, even in low doses, cross the blood-brain barrier and can be identified on brain H1-receptors by using positron emission tomography. More than 50 objective and comprehensive studies contrasting the sedation and other adverse CNS effects produced by first-generation sedating H1-antihistamines with the lack of CNS effects of second-generation H1-antihistamines are summarized. The authors conclude that the first-generation H1-antihistamines are no longer medications of choice for the outpatient treatment of allergic disorders, due to their common, often subclinical, CNS adverse effects. In Chapter 12, ‘‘Potential Cardiac Toxicity of H1-Antihistamines,’’ the mechanisms underlying drug-induced QT interval prolongation and arrhythmias, including torsade de pointes, are outlined. The physicochemical properties and potassium ion channel blockade properties of H1-antihistamines leading to QT prolongation and, occasionally, to torsade de pointes are reviewed. Fortunately, these are not class effects. Most second-generation H1-antihistamines, such as cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, and mizolastine, have a well-documented low potential for cardiac toxicity. The regulatory agency perspective on cardiac safety testing of H1-antihistamines and other new chemical entities (new active substances) in development is presented. In Chapter 13, ‘‘H1-Antihistamines in Pregnancy and Lactation,’’ the author provides a general overview of potential drug effects on the fetus, and discusses the risks of uncontrolled allergic disease during pregnancy and lactation in the context of H1-antihistamine use during these important life stages. Clear recommendations for choice of drugs are made based on the best evidence available. The concept of obtaining informed consent for H1-antihistamine treatment during pregnancy is introduced. In Chapter 14, ‘‘H1-Antihistamines in Children,’’ the challenges of studying these medications in infants and young children are outlined, and recent studies of the second-generation H1-antihistamines in infants and children are reviewed. In the landmark randomized, placebo-controlled, double-blind Early Treatment of the Atopic Child (ETAC) Study, the H1-antihistamine cetirizine, given for 18 months to high-risk 1-year-olds with atopic dermatitis, delayed asthma development in dust mite– and grass pollen–sensitized children, had a topical steroid-sparing effect in atopic dermatitis, and reduced acute urticaria. As the new nonsedating H1-antihistamines become more widely available in pediatric

xvi

Introduction

formulations, the old sedating H1-antihistamines, which are still an important cause of toxicity and fatality in the vulnerable pediatric population, will eventually disappear from outpatient use. Finally, in Chapter 15, ‘‘H1-Antihistamines in the Elderly,’’ the author explores the use of these medications in elderly patients with allergic disorders, who comprise another vulnerable population. He describes the anticholinergic effects and alpha-adrenergic blockade produced by first-generation H1-antihistamines when given in usual doses to elderly individuals, potentially leading to urinary problems, supraventricular tachycardia, peripheral vasodilation, postural hypertension, reflex tachycardia, sedation, confusion, memory loss, and falls. He also discusses polypharmacy and drug–drug interactions in the elderly. Throughout the book, the terms ‘‘H1-antihistamine’’ and ‘‘H1-receptor antagonist’’ are used interchangeably, although the former is perhaps more appropriate due to recent discovery of the constitutive nature of H1-receptor signaling. Also, the terms ‘‘second-generation,’’ ‘‘new generation,’’ ‘‘nonsedating,’’ and ‘‘low-sedating’’ are used interchangeably to refer to the H1-antihistamines introduced since the early 1980s which do not cross the blood-brain barrier to a significant extent and do not cause sedation or psychomotor impairment. In summary, Histamine and H1-Antihistamines in Allergic Disease, Second Edition, Revised and Expanded, again provides a unique, global perspective on histamine, histamine receptors, and H1-antihistamines. We thank all our contributors who are advancing research in the areas of histamine, histamine receptors, and H1-antihistamines. We also gratefully acknowledge the support of Dr. Janet R. Roberts and Lori L. McNiven at the University of Manitoba, and of Elyce Misher and her colleagues at Marcel Dekker, Inc. F. Estelle R. Simons The University of Manitoba Winnipeg, Manitoba, Canada

1 Histamine in Health and Disease M. Susana Repka-Ramirez and James N. Baraniuk Georgetown University, Washington, D.C.

I.

INTRODUCTION

Histamine, by far the most important mediator of acute allergic symptoms, and the earliest recognized mediator of the immediate hypersensitivity response, was discovered as a potent vasodilator substance by Dale and Laidlaw in 1910 (1). In 1953 it was associated with tissue mast cells by Riley and West (2). Human mast cells contain 2–5 pg histamine per cell. It is unclear if there are differences in histamine content in different mast cell subsets (Table 1). Rapid advances in molecular biology have led to the discovery of H 1-, H 2-, and H 3-receptors that mediate the complex histamine-induced actions. In this chapter we discuss concepts of the synthesis and metabolism, localization, receptors, effects, and the role of histamine in various syndromes in which basophil and mast cell degranulation occurs.

II. HISTAMINE A. Histamine Synthesis and Catabolism Histamine, 2-(4-imidazolyl)ethylamine or 5β-amino-ethylimidazole, is formed by decarboxylation of histidine by the pyridoxalphosphate-dependent enzyme 1Although the research described in this chapter has been funded wholly or in part by the United States Environmental Protection Agency through grant number R825814 to James N. Baraniuk, M.D., it has not been subjected to the agency’s required peer and policy review and therefore does not necessarily reflect the views of the Agency and no official endorsement should be inferred.

1

2 Table 1

Repka-Ramirez and Baraniuk Distribution of Human Mast Cell Subtypes Human mast cell subtypes in various tissues (%)

Skin Small intestine mucosa submucosa Lung bronchi/bronchioles subepithelium alveoli dispersed cells

MCT

MCTC

12

88

98 13

2 87

77 93 90

23 7 10

Source: Data from Ref. 5. T, tryptase; C, chymase.

histidine decarboxylase (3). It is stored preformed in cytoplasmic granules of mast cells and basophils, and within platelets of some species. Intracellular production of histamine is necessary for human platelet aggregation. Histamine synthesis occurs in other cells, such as histaminocytes in rat gastric mucosa (4). Mast cells are generally found in mucosal linings, or deeper in tissues around vessels, nerves, and lymphatics. High densities have been measured in the conjunctiva, skin (3–12 ⫻ 103 mast cells/mm3), upper and lower airway mucosa (0.1–0.5% of all cells), the gastrointestinal mucosa (up to 20 ⫻ 103 /mm3), and the reproductive tract (5). Subsets of tryptase-positive ‘‘mucosal’’ mast cells (MCT ) and tryptase and chymase-double-positive ‘‘connective tissue’’ mast cells (MCCT ) may have different amounts of stored histamine (Table 1). In the heart, the histamine is localized in mast cells of the right atrium and in walls of coronary blood vessels (6). Plasma histamine levels following tissue mast cell degranulation rise between 2.5 and 5 min, and return to baseline by 15–30 min. Histamine is also elevated in tears (5 ng/mL), and in nasal and bronchoalveolar lavage fluids after challenge provocations. Urinary histamine is elevated in patients with idiopathic hypereosinophilia, mastocytosis, and occasionally in Zollinger-Ellison syndrome and pregnancy (7). Histamine can also be generated in cell culture systems of lymphocytes, tumor cells, and embryological tissues. Plasma histamine is rapidly and extensively metabolized (Fig. 1). Between 50 and 70% is metabolized to N-methylhistamine and N-methylimidazoleacetic acid, and 30 and 50% to imidazole acetic acid (7). Only 2–3% of urine histamine is in a nonmetabolized state.

Histamine in Health and Disease

3

Figure 1 Histamine synthesis and catabolism. Percentage recovery was calculated following intradermal administration of [14C]histamine in human males. (Reprinted from Ref. 3.)

4

B.

Repka-Ramirez and Baraniuk

Central Nervous System

Central nervous system (CNS) sources of histamine include the lateral hypothalamic nuclei projecting to the telencephalon, diencephalon, and lower brainstem. Histaminergic neurons are present homogeneously throughout all laminar and interlaminar zones of the pregeniculate nucleus and dorsolateral geniculate nucleus (8). Their axons branch infrequently, and possess varicosities along their length that do not form conventional synapses with other neurons. This suggests that the histamine may be released into the interstitial space, where it may modulate state-dependent thalamic activity without necessarily producing neurotransmission to specific neural pathways. Histamine receptors are found throughout the human frontal cortex by positron emission tomography (PET) (9). H 1-receptor occupancy by H 1-antagonists is significantly correlated with sleepiness and impaired cognitive performance. This is consistent with the slow wave sleep-inducing effects of first-generation H 1-antagonists, which show a rank potency of promethazine ⬎ chlorpheniramine ⬎ diphenhydramine ⫽ pyrilamine (10). The ranking for increase in sleep duration is chlorpheniramine ⬎ promethazine ⬎ diphenhydramine ⫽ pyrilamine. These activities are at odds with the effects of long-term intraventricular infusion of chlorpheniramine in aged Brown-Norway rats, in which this drug improves maze performance and reduces fear-related behaviors (11). Proposed explanations for these results include the anticholinergic effect of chlorpheniramine (12) or hyperactivation of the central histaminergic neural system during senescence that leads to an increase in hypomnesia and hyperanxiety (11). Histamine H 1-receptor knock-out mice have changes in arousal, sleep–wake patterns, locomotion, nociception, and aggressive behavior compared to healthy littermates, suggesting roles for histamine and/or the histaminergic neural systems in these activities (9). In assessing the issue of sedation, it is important to remember that allergic rhinitis (AR) itself leads to sedation, inattentiveness, and loss of vigilance that is readily improved by administration of second-generation antihistamines (13). Thus, it may be important to test the effects of antihistamines on these CNS symptoms in subjects with active AR rather than in healthy subjects in order to assess AR-specific fatigue vs. drug-related effects. These findings are consistent with an ‘‘allergic fatigue’’ syndrome that has been postulated but poorly characterized to date (14).

C.

IgE-Mediated Histamine Release

A variety of stimuli may induce mast cells and basophil degranulation and exocytosis which may or may not be IgE-dependent. For IgE-dependent triggers, cross-linking of at least two IgE molecules bound to high-affinity IgE receptors

Histamine in Health and Disease

5

(FCεRIαβγ) by multivalent antigens is necessary. IgE binds to the α subunit, while the βγ subunits form a tyrosine kinase that leads to activation of additional enzymes including other tyrosine kinases, serine proteases, phospholipase C (PLC), methyltransferases, and adenylate cyclase. PLC begins the hydrolysis of membrane inositol phospholipids and the release of inositol-1,4,5-triphosphate (IP3 ) and 1,2-diacylglycerol (DAG). IP3 functions as a second messenger for the mobilization of intracellular calcium. The DAG and Ca2⫹, in turn, activate protein kinase (PKC) (15). Changes in intracellular calcium are thought to initiate the transport of preformed granules to the cell surface, their hydration, and the exocytosis of their contents. D. Non-IgE-Mediated Histamine Release Non-IgE-mediated histamine release can be initiated by highly charged or amphipathic molecules including opioids such as morphine and codeine, and by intravenous contrast media, calcium ionophore, anaphylatoxins (C3a, C4a, C5a), substance P, vancomycin, quinolones, and numerous cytokines (Table 2). Substances that inhibit histamine release include cromolyn, nedocromil, transforming growth factor-β1(TGF-β1), antisense oligonucleotides to TGF-β1 and FcεR1α, and β2adrenergic agonists.

Table 2

IgE-Independent Histamine-Releasing Factors

Direct agonists IL-1 MCP-1 MCP-3 MIP-1α

C3a, C5a Opioids Vancomycin Intravenous contrast dye High dosages of substance P Mast cell degranulating peptide

Augment histamine release

Inhibit histamine release

IL-1α, IL-1β IL-3 IL-5 IL-6 IL-7 c-kit ligand

Cromolyn Nedocromil TGF-β1 TGF-β1 antisense oligonucleotides FcεR1α antisense oligonucleotides β-agonists isoprenaline ⬎ salmeterol ⬎ albuterol ‘‘Sainte’’ and ‘‘Val d’Orb’’ waters H 1-antihistamines

IL, interleukin; MCP, monocyte chemotactive protein; MIP, monocyte inhibitory protein; C, complement; TGF, transforming growth factor; FcεR1α, high-affinity IgE receptor.

6

Repka-Ramirez and Baraniuk

III. HISTAMINE RECEPTORS A.

H 1-Receptors

The H 1-histamine receptor was identified pharmacologically in 1966 (Chap. 2). After being cloned, the deduced protein of 487 amino acids showed similarity to G-protein-coupled receptors (16). Members of this ‘‘rhodopsin receptor family’’ have seven transmembrane segments, an extracellular N-terminal, two extracellular loops, two intracellular loops, and a C-terminal tail. These receptors generate intracellular messages by activating guanosine triphosphate (GTP)-binding protein (G-proteins). Binding of histamine to the H 1-receptor has been studied by site-directed mutagenesis and three-dimensional (3D) computer modeling of the receptor (17). The histamine binding site consists of five amino acids. There may be two separately defined components of the binding site, with one region responsible for rewinding the α-helix of the fifth transmembrane region. This, in turn, has been postulated to lead to subsequent conformational changes resulting in intracellular G-protein activation, and cellular activation. This mechanism is different from both β 2-adrenergic receptor and H 2-receptor interactions. H 1-receptor activation leads to rapid, transient effects, suggesting that continued release of histamine is required for prolonged histamine-induced symptom production. H 1-receptor mRNA is upregulated in allergic rhinitis (18). H 1-receptors are present on endothelial cells, where they act to induce vascular permeability and the watery rhinorrhea of allergic rhinitis (19; see Table 3). Consistent with this finding, allergic sensitization of guinea pigs increases H 1-receptor density and vasodilator responses to histamine provocation (20). Histamine has been thought to stimulate mucus production directly; however, histamine does not induce exocytosis of mucus in human nasal mucosal explants in vitro (21). B.

H 2-Receptors

Stimulation of H 2-receptors leads to a slower but more sustained response (3). Burimamide, the first H 2-receptor ligand, has been used to define the difference between H 1- and H 2-receptors (22). H 2-receptor stimulation induces a rise in cyclic adenosine 3′,5′,monophosphate (cAMP) and secondary rise in intracellular calcium concentrations in the gastric mucosa, vascular smooth muscle, brain, adipocytes, basophils, neutrophils, and other tissues (23). H 2-receptor stimulation plays a minor role in vasodilation, but may mediate a substantial portion of the chronotropic and inotropic cardiac effects of histamine in conditions such as anaphylaxis. H 2-receptor stimulation has also been related to tracheobronchial airway mucus secretion, inhibition of basophil histamine release, stimulation of suppressor T cells, and inhibition of neutrophil chemotaxis and enzyme release (3). The

Histamine in Health and Disease

7

Table 3 Summary of Actions of Histamine at H 1-, H 2-, and H 3-Receptors H 1-receptor

H 2-receptor

Vasodilation ↑ Vascular permeability ↑ Leukocyte adhesion through multiple mechanisms Contraction

Vasodilation No ↑ permeability

No effect

No effect

Possible bronchial mucus secretion No effect

No effect

Neurons

No effect on exocytosis of mucus Activate nociceptive ‘‘itch’’ nerves

Atrioventricular node conduction

↓ Conduction time (tachycardia)

Positive chronotropic and inotropic effectsa

Transduction

PLC, guanylyl cyclase, cGMP, NO

Adenylyl cyclase and cAMP

Vessels

Adhesion

Bronchial smooth muscle Glands

No significant effect

H 3-receptor Vasodilation? Indirect ↓ permeability No effect

Inhibit neural activation leading to reduced neurotransmitter release Potential inhibitory autoreceptor effects on cardiac innervation Modulation of hyperpolarizing potassium channels?

a

Rapid infusion of cimetidine or ranitidine can lead to bradycardia, hypotension, and asystole. PLC, phospholipase C; cGMP, cyclic guanosine 3′,5′monophosphate; cAMP, cyclic adenosine 3′,5′monophosphate; NO, nitric oxide.

H 2-receptor plays a major role in stomach parietal cell hydrogen ion production and in esophageal contraction. Both H 1- and H 2-receptor mRNA have been identified by reverse transcriptase polymerase chain reaction (RT-PCR) in the human nasal mucosa (24). Even though histamine plays little or no role in the control of vasomotor tone under normal conditions, a synergy between H 1- and H 2-antagonists has been demonstrated in the cardiovascular system. The combination significantly blunts the fall in diastolic blood pressure and pulse pressure associated with infusion of low-dosage histamine (25). H 2-antagonists alone do not affect results of allergy skin tests, but concomitant administration with an H 1-antagonist may augment the inhibitory effect of the H 1-antagonist.

8

Repka-Ramirez and Baraniuk

A further interaction is seen in cultured endothelial cells. Histamine causes a transient decrease in H 1-receptor mRNA and a rapid and prolonged decrease in H 2-receptor mRNA (26). The latter effect may occur via an H 1-receptor-mediated transduction pathway. This interaction has relevance to tachyphylaxis of H 1- and H 2-receptors, since continuous exposure to histamine, as in ongoing mast cell degranulation states, may lead to tachyphylaxis of H 2-receptor-mediated events but continued expression of H 1-receptor mRNA. These preliminary studies on gene expression must be followed by an examination of the function of H 1- and H 2-receptors, since uncoupling from G-protein transducing systems may still occur for H 1-receptors despite the continued generation of H 1-receptor mRNA. C.

H 3-Receptors

In 1983, Arrang et al. defined a new histamine receptor (H 3) in rat cerebral cortex (27). The H 3-receptor also belongs to the G-protein-coupled receptor superfamily (28). The localization and pharmacology of this H 3-receptor are distinct from H 1and H 2-receptors. It has a presynaptic localization and is an autoreceptor mediating inhibition of histamine release and biosynthesis in histaminergic nerve terminals in CNS (29). H 3-receptors have been observed in neurons of the cerebral cortex, amygdala, hippocampus, striatum, thalamus, and hypothalamus (30), where they appear to act as ‘‘inhibitory autoreceptors’’ that reduce neural activity (31). Presynaptic H 3-receptors may participate in the pathophysiology of headache and cardiac ischemia. Post-synaptic H 3-receptors on peripheral neurons of the gastrointestinal and respiratory tracts may regulate the release of a variety of neurotransmitters (28). H 3-receptors have been detected in several vascular beds and may cause vasodilation. H 3-receptor activity is currently subject to intense investigation in humans. In 1998, Hey et al. demonstrated that histamine may cause nasal congestion through activation of inhibitory prejunctional H 3-receptors on sympathetic nerves, leading to decreased norepinephrine release and subsequent ‘‘default’’ vasodilation with nasal vascular engorgement. They demonstrated that a combination of H 1- and H 3-receptor antagonists could reduce nasal airflow resistance and increase nasal cavity airspace volumes (measured by acoustic rhinometry) in several feline models. They proposed that a dual H 1-/H 3-antagonist could provide relief for allergic nasal congestion (32).

IV. HISTAMINE PRODUCTION BY BACTERIA The bacterial enzyme histidine decarboxylase catalyzes the conversion of histidine into histamine. Bacterial infection of food can lead to excessive levels of histamine that can be a cause of food poisoning (scombroid) (33). Histamine

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generated at sites of infection may modulate local inflammatory reactions. Chlamydia pneumoniae induce or enhance histamine release from basophil leukocytes (34). Helicobacter pylori may trigger mast cell degranulation and promote gastric mucosal inflammation (35). Nasal inoculation of hamsters with Mycoplasma pneumoniae potentiates the contractile responses to histamine in the bronchi, possibly through a reduction of endogenous histamine N-methyltransferase activity (36). Other respiratory bacterial species that produce significant amounts of histamine include Moraxella catarrhalis, Haemophilus parainfluenzae, and Pseudomonas aeruginosa.

V.

HISTAMINE IN ALLERGIC DISEASES

A. General Principles After its release, histamine contributes to the pathophysiology of asthma, allergic rhinitis and conjunctivitis, anaphylactic shock, and urticaria. Histamine participates in both the early- and late-phase allergic responses (37), playing important and prominent roles in cytokine release and in the adhesion process. The immediate- or early-phase reaction begins with the explosive degranulation of mast cells that follows exposure to allergen (Fig. 2). In the nose, histamine and other mediators rapidly lead to itching, sneezing, nasal discharge, and mucosal swelling with increased nasal airway resistance (21, 38).

Figure 2 Mast cell degranulation.

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Endothelial Cell Interactions

Histamine-induced contraction of postcapillary venule endothelial cells opens gaps, which permits the hydrostatic intravascular pressure to force plasma into the interstitial space. These effects are mediated by phosphorylation of vascular endothelial (VE) cadherin with dissociation of VE-cadherin from the actin cytoskeleton (39). The rapid and transient (⬍3 min) increase in endothelial permeability also involves calcium ion release, calmodulin, and phosphorylation of myosin light chains (40). Thrombin accentuates this transepithelial flux by activation of a tyrosine kinase activity, RhoA, and by increasing the sensitivity of calcium release to low levels of histamine. Under these conditions of reduced endothelial barrier function, a hydrostatic vascular pressure of 5 cm H 2O is capable of driving fluid from vessels through the interstitium, across the epithelial basement membrane, and between epithelial cells and their tight junctions into the nasal lumen (41). This is a nondamaging reversible event driven by the increase in hydrostatic pressure. Plasma exudation may occur without significant tissue edema. Histamine causes plasma extravasation by at least two mechanisms. First, it may cause increased leukocyte adhesion and infiltration that can be inhibited by exogenous nitric oxide (NO) and 9-Br-cGMP (42). Second, there may be an adhesion-independent mechanism that can be blocked only by NO. Both of these potential mechanisms offer novel targets for future therapeutic drugs. Histamine also acts synergistically with bradykinin, leukotrienes, and platelet-activating factor (PAF) to activate the endothelial cells of postcapillary venules, inducing vasodilation, vascular permeability, and cellular adhesion. These and other immediate consequences of histamine release are greater than the combined immediate effects of tryptase, prostaglandin D2 (PGD2 ), prostaglandin F2 (PGF2 ), mast cell kininogenase-mediated bradykinin, tumor necrosis factor α (TNF-α), interleukin 4 (IL-4), IL-5, IL-6, TGF-β, and IL-13 production (43). This is clear from antihistamine studies, since H 1-antagonists reduce early allergic response symptoms by 50–60% (44). Leukotrienes and chymase stimulate glandular exocytosis and mucus secretion during the early allergic response, yet this is outweighed by the mucus secretion induced via H 1-receptor-stimulated nociceptive nerve recruitment of parasympathetic reflexes and cholinergic glandular secretion (21, 45, 46).

C.

Recruitment Phase

In allergen provocation models, the early allergic response phase is self-limited, and followed by a relatively symptom-free period. During this ‘‘recruitment phase’’ the cytokines and chemokines released as part of the early phase stimulate endothelial cell adhesion marker expression and the diapedesis of the unique set of inflammatory leukocytes that characterize atopic inflammation. Increased lev-

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els of IL-4 and expression of vascular cell adhesion molecule 1 (VCAM-1) are critical for the late-phase response (47). Histamine stimulates endothelial cell production of IL-6 and IL-8 that increases the adhesion of leukocytes to the endothelium and epithelium (48). Histamine increases IL-8 mRNA expression sixfold and monocyte chemotactic protein (MCP)-1 mRNA twofold by stimulating transcription of the endothelial cell transcription factor nuclear factor of activated T cell (NFAT) (49). These effects are potentiated by TNF-α that is also stimulated during the immediate and late phases. In vitro, both H 1- and H 2-, but not H 3-, receptors participate in neutrophil adhesion of human umbilical cord endothelial cells (50). Second messengers appear to include PLC-derived IP3, DAG, calcium ions, NO, and cGMP. Increases in cAMP may counter this adhesion event. Diesel exhaust particulates may also potentiate these effects, since they can upregulate H 1-receptor mRNA and histamine-induced IL-8 and granulocyte macrophage colony-stimulating factor (GM-CSF) production from cultured human nasal epithelial and endothelial cells in vitro (51). The recruited eosinophils, basophils, and other leukocytes in turn perpetuate the inflammatory process by the liberation of their own mediators (late-phase response). Upregulation of leukocyte–endothelial cell interactions is not a universal consequence of histamine, however. In rat models, only Brown-Norway rats demonstrate upregulation of leukocyte adhesion after histamine exposure (52). It is curious that Brown-Norway rats are a preferred model for allergen-induced eosinophilia and bronchial hyperresponsiveness. It will be of interest to determine if mast cells, histamine release, eosinophil–endothelial binding, and tissue eosinophilia are uniquely linked by a single underlying molecular mechanism that is present in this, but not other, rat strains. Antihistamines may exert their anti-inflammatory effects by decreasing histamine-induced adhesion and thereby reducing inflammatory cell influx into the tissues (53). This, in turn, would mean a reduction in mediator release from these cells, and so a diminution in symptoms. While an attractive hypothesis, it is still unclear if these effects are sufficient to alter the long-term outcomes of chronic allergic diseases. Competition between versus in PLC, nitric oxide synthase (NOS), and GC activity induced by histamine and β2-adrenergic agonist induced increases in cAMP may represent one anti-inflammatory action of β2-agonists on histamine-induced inflammation (50). Intranasal glucocorticoids can also reduce histamine-related hyperresponsiveness in chronic allergic rhinitis, perhaps by interfering with many of these transcription pathways, normalizing endothelial and leukocyte adhesion marker expression, and reducing mediator release (54, 55). D. Late-Phase Response During the late-phase response, histamine is released without a change in tryptase, suggesting release from basophils rather than a secondary degranulation of

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mast cells (45, 46, 56, 57). Histamine’s effects in the late phase are likely to be essentially the same as those described above for the early allergic response.

VI. HISTAMINE AND ASTHMA Atopic subjects with asthma experience an immediate allergic response caused by allergen-specific IgE-mediated histamine release (58). Histamine and leukotrienes are the major mediators of allergen-induced contraction in the human airways. Passive sensitization with IgE in vitro induces an increase in histamine and leukotriene release and responsiveness (59). Histamine and leukotriene C4 (LTC4 ) participate in the initiation mechanism of atopic asthma, but apparently only LTC4 plays a role in nonatopic asthma (60). Plasma histamine concentrations are elevated during early and late responses to inhaled allergens, and may also increase during spontaneous acute asthma episodes (61). Asthma is characterized by smooth muscle spasm, mucosal edema, inflammation, and mucus hypersecretion. Bronchospasm and mucosal edema can be caused by H 1-receptor stimulation, while H 2- and possibly H 1-activation may contribute to mucus secretion. Histamine interacts directly with the endothelial cells to induce permeability and increase IL-6, IL-8, and lipid mediators (PGI2, PAF, and LTB4) (62). Antihistamines have some beneficial effects on airflow obstruction in allergic asthma, but are not as effective as low-dosage inhaled glucocorticoids for long-term therapy (Chap. 7). More interesting is the recent finding that a combination of an H 1-antagonist (loratadine) and LTD4-receptor antagonist (zafirlukast) in high doses could block both early- and late-phase bronchial obstruction following allergen inhalation (63). This suggests that histamine and leukotrienes, or mediators secondarily generated by them, are largely responsible for changes in airway caliber after allergen inhalation. This combination of medications did not have a synergistic effect in blocking exercise-induced bronchospasm (64). It remains to be seen if it would be effective throughout a pollen season in persistent atopic asthma as it is in seasonal allergic rhinitis (65), or if it would prevent airway remodeling and irreversible airway changes over the longer term. Histamine is a potent bronchoconstrictor, and is commonly used to assess bronchial hyperresponsiveness. This appears to be a direct effect of inhaled histamine on the smooth muscle; however, in other model provocation systems, such as hypertonic saline, mast cell degranulation and histamine release have been postulated to play central roles in bronchoconstriction, based largely on studies with first-generation antihistamines that have significant anticholinergic activity. Recent evidence indicates that inhalation of hypertonic saline is associated with a decrease in bronchoalveolar lavage endothelin levels with no changes in histamine, tryptase, or PGD2 (66). These data suggest that hypertonic saline does not

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directly stimulate epithelial production of the potent bronchoconstrictor endothelin, and does not lead to mast cell degranulation. Rather, other mechanisms must be postulated, such as direct activation of sensory afferent nerves that may lead to bronchoconstriction via axon response release of neuropeptides such as neurokinin A and substance P (67), and recruitment of local parasympathetic reflexes and cholinergically mediated smooth muscle contraction. This is further suggested by the effects of β2-agonists on mast cell degranulation and bronchodilation. Isoproterenol, but not formoterol, terbutaline, or salbutamol, inhibits human bronchial mast cell degranulation in vitro, while all of these drugs can overcome histamine-induced bronchoconstriction in vivo (68).

VII. HISTAMINE, SINUSITIS, AND NASAL POLYPS The response of the sinus mucosa to histamine is lower in magnitude than that of the nose. Sinus challenge with histamine resulted in significant increases in vascular permeability within the sinus cavity, but no significant change in parasympathetic reflex-mediated nasal secretions (69). This indicates the presence of H 1-receptors on sinus mucosal vessels; however, this mucosa is much thinner than that covering the inferior or middle turbinates, hence less vascular leak would be anticipated. The levels of histamine in aspirin-induced, asthma-related polyps were significantly lower than in nasal polyps related to allergy and infection (70). This argues against a strong role for mast cells in nasal polyposis unless there is concomitant atopic disease.

VIII. HISTAMINE AND ALLERGIC RHINITIS To appreciate best the many effects of histamine in human nasal mucosa, it is important to understand how the nose runs, and what runs in a runny nose (71). The epithelium lies above the region of postcapillary venules, the site of vascular leak and leukocyte diapedesis. Submucosal glands form the next ‘‘layer’’ and contain both seromucous and mucous cells. Seromucous cells secrete many nonspecific antimicrobial factors, neutral mucins such as MUC7, and hyaluronan. Mucus and goblet cells secrete acid mucins such as MUC5B and MUC5/AC (72). MUC5/5AC mRNA levels are 5–10-fold higher than those of MUC1 and MUC2 in patients with allergic rhinitis, cystic fibrosis, and normal subjects. MUC2 mRNA levels are similar in all subjects, while MUC5/5AC levels are significantly reduced in patients with cystic fibrosis. The venous sinusoids are the erectile machinery that regulates the thickness of the nasal lining. They are located deep in the mucosa. Dilation of arteriovenous

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anastomoses combined with closure of venous outlet vessels increases the blood flow into the sinusoids, causing them to swell. This thickens the mucosa, and reduces nasal air flow. Sympathomimetic drugs contract both the arteriovenous anastomoses and sinusoid wall myoepithelial cells to decrease blood flow, reduce the volume of swollen sinusoids, thin the mucosa, and restore nasal patency. The components of nasal secretions have three major sources: vascular leak via the postcapillary venules, glandular exocytosis, and leukocyte infiltration. Vascular leak accounts for about one-third of nasal secretion protein in healthy subjects, and is increased in patients with allergic rhinitis and rhinovirus infections. Glandular exocytosis accounts for about two-thirds of the total protein in nasal secretions in healthy subjects, with half this amount from seromucous cells and half from mucous cells. Glandular products are increased in nasal secretions from patients with allergic rhinitis, rhinovirus infections, cystic fibrosis, and acute sinusitis. It has been proposed that the relative proportions of seromucous and mucous cells in glands are modulated in inflammatory states, but as yet there is little experimental evidence from human diseases. In models of ovalbuminimmunized mice, IL-4 appears to promote goblet cell hyperplasia and mucus hypersecretion. IL-13 stimulated goblet cell hyperplasia in an IL-13-overexpression murine model (73). Leukocyte infiltration from the epithelium into the nasal lumen is prominent in allergic (eosinophils) and infectious (neutrophils) rhinitis. The effects of histamine on these processes have been widely studied. Histamine induces prominent vascular leakage after nasal provocation. This appears to be a direct effect on endothelial cells, since histamine H 1-receptors are densely localized to these cells. Histamine induces itching by activating type C nociceptive nerves. These may generate axon responses with the release of substance P, calcitonin gene-related peptide, and other neuropeptides (74). Activation of these trigeminal neurons recruits parasympathetic reflexes that release acetylcholine, which is responsible for the glandular exocytosis that follows histamine provocation in vivo (75). In vitro, histamine does not stimulate glandular exocytosis from nasal explants. In contrast, histamine H 2-receptors may be responsible for exocytosis from bronchial explants in humans and other species. Histamine may activate epithelial and inflammatory cells based upon in vitro experiments, but effects on these cells are difficult to appreciate in vivo because of the overwhelming vascular permeability and nociceptive nerve events. Based on this framework, the effects of H 1-antihistamines should be clear. They will reduce vascular leak, itch, and recruitment of parasympathetic glandular secretion. Antihistamines account for amelioration of 50–60% of the symptoms of immediate allergic reactions, explaining their widespread popularity, but also their inability to block all allergic rhinitis symptoms. These other effects are mediated by bradykinin, leukotrienes, prostaglandins, neuropeptides, and, in the chronic situation, cytokines and other mediators. H 1-antagonists and leukotriene

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modifiers have a synergistic effect in allergic rhinitis treatment (65). As other mediators are identified, additional antagonists may be developed. Adjunctive treatments include α-adrenergic agonists that reduce the thickness of the nasal mucosa and improve nasal patency, but apparently they have no effect on vascular leak in allergic rhinitis or rhinovirus infections. Anticholinergic agents reduce glandular hypersecretion.

IX. HISTAMINE AND VERNAL CONJUNCTIVITIS The classic clinical symptoms of allergic conjunctivitis, itching and lacrimation, are caused by histamine, and the histamine levels in tears can be monitored along with the clinical symptoms in this disorder (76). Histamine may affect extracellular matrix production and cell growth in vernal conjunctivitis (VC), increasing proliferation, migration, and collagen production in VC fibroblasts, so histamine may be at least partially responsible for fibroblast stimulation (77). The enzymatic degradation of histamine in tears and plasma is significantly decreased in patients with VC compared with control subjects, suggesting that this dysfunction may be an important factor in the pathophysiology of VC (78). Tear histaminase activity is different during the early and late phases of allergen conjunctival provocation tests. Greater histaminase activity occurs during the late-phase reaction, while the lower enzymatic activity during the immediate phase may contribute to the observed surge of histamine release (79). Histamine-stimulated cytokine secretion by conjunctival epithelial cells is attenuated by compounds with H 1antagonist activity. Topical ocular drugs with antihistaminic activity offer therapeutic improvement by inhibiting proinflammatory cytokine secretion. Olopatadine, emedastine, and levocabastine seem to be more potent than pheniramine and antazoline (80).

X.

HISTAMINE AND OTITIS MEDIA

Evidence has accumulated for the role of immunological mechanisms in the pathogenesis of otitis media with effusion. Infection and eustachian tube obstruction play an important role. Viruses and bacterial infections increase mast cell numbers and histamine release into the middle ear fluid (81). Higher histamine levels are observed in effusions positive for Haemophilus influenzae (82), suggesting that both mast cells and the organisms generate the histamine. Histamine concentrations are also increased in the adenoids of children with otitis media, and lymphoid hyperplasia or mast cell degranulation in the nasopharynx may contribute to edema with occlusion of the medial eustachian tube (83).

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Histamine induces mucociliary dysfunction of the tubotympanum that contributes to the increased negative pressure in the middle ear, improper ventilation, and resulting eustachian tube insufficiency (84). Injection of histamine into the guinea pig middle ear produces dilation and endothelial disjunction in capillaries, leading to mucosal edema (85). Within the endothelial cells, this has been associated with an increased density of cytoplasmic vesicle-like structures that may represent pinocytotic vesicles (86). Histamine and bradykinin (BK) work in parallel through H 1- and BK B 2receptors, respectively, to activate intracellular calcium-dependent mechanisms that lead to apical chloride secretion in a cultured gerbil middle ear epithelium model (85). The release of these mediators can both initiate tissue destruction and stimulate tissue repair (87). An imbalance or prolongation of these processes may lead to chronic middle ear dysfunction.

XI. HISTAMINE AND ANAPHYLAXIS A dramatic and devastating form of atopic disease is this systemic manifestation of immediate hypersensitivity. All of the symptoms of anaphylaxis can be reproduced by histamine. Histamine promotes increased vascular permeability and vascular smooth muscle relaxation, which leads to vasodilation, reduction of circulating blood volume, and fall in blood pressure, leading to hypovolemic shock. Laryngeal edema is due in large part to vascular leak with occlusion of the glottic airway. Bronchial smooth muscle contraction, airway edema, neurogenic and direct bronchorrhea contribute to airway plugging and bronchospasm with asphyxia. Stimulation of gastrointestinal smooth muscle along with plasma extravasation and glandular secretion lead to vomiting, tenesmus, and diarrhea. In anaphylaxis H 1-antagonists are useful adjunctive treatment for itching and the urticarial component of the reaction, but systemic vasodilator and bronchoconstrictor reactions require the vasoconstricting and bronchodilating effects of epinephrine (3) (Chap. 9).

XII. ANAPHYLACTOID REACTIONS Anaphylactoid reactions are clinically similar to anaphylaxis, but they are not initiated by allergen–IgE interactions. They are generally caused by highly charged or amphipathic molecules such as intravenous contrast dye and vancomycin (red man syndrome). A wide range of peptides, drugs, complement factors (e.g., C3a and C5a released by immune complex formation as in serum sickness), and other IgE-independent mechanisms can trigger histamine, arachidonic acid metabolite, or cytokine release (Table 2). The role of histamine and

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of H 1- and H 2-antagonists in anaphylactoid reactions is similar to their role in anaphylaxis (Chap. 9).

XIII. HISTAMINE AND URTICARIA Histamine is the best known chemical mediator that arises from the activation of mast cells and basophils to elicit the classic triple response of Lewis (88). Drawing a probe across the skin leads to very transient local endothelial cell swelling, leading to a sudden decrease in superficial blood flow (‘‘white line’’), local increased vascular permeability (edema, ‘‘tumor’’), and nociceptive nerve stimulation resulting in a local axon response with the release of calcitonin generelated peptide (CGRP) that causes local erythema (rubor), heat (calor), and centrally mediated pain/itch (‘‘dolor’’) (89). Other vasoactive mediators that may contribute to vasodilation are PGD 2 , LTC 4 , LTD 4 , PAF, and bradykinin (3). For decades this model of cutaneous histamine release has shaped therapy for urticaria; however, a variety of mechanisms may initiate the histamine release in physical, solar, cold-induced, and other types of urticaria. The central role of histamine in urticaria and angioedema is demonstrated clinically by the beneficial responses that occur when treated exclusively with H 1-antihistamines. Old, sedating, first-generation H 1-antagonists that have ‘‘nonspecific’’ pharmacological properties (e.g., cyproheptadine, diphenhydramine, or hydroxyzine) are still sometimes used in urticaria despite their poor benefit-to-risk ratio. While the vascular leak (edema) and itch (neurogenically mediated itch ⫹ flare) are mediated primarily by H 1-receptors, other factors also contribute. The histamine release may be only a marker of mast cell degranulation. Neither old nor new antihistamines are likely to modify the primary pathogenesis of the urticaria, although they effectively relieve symptoms and signs (Chap. 8). Recently, an autoimmune hypothesis of chronic idiopathic urticaria has emerged. IgG 1 and IgG 3 autoantibodies that bind to the Fcε–RI–α subunit may fix complement and activate the classic cascade (90). The autoimmune nature is further suggested by the frequent coexistence of autoantibodies to thyroglobulin and/or thyroid peroxidase. This hypothesis offers the potential for future innovative therapies for this common clinical disorder, which may frustrate patients and physicians alike.

XIV. HISTAMINE AND THE COMMON COLD Human rhinoviruses account for the majority of common colds, although parainfluenza virus, adenovirus, respiratory syncytial virus, influenza, and other viruses may also be causative factors. Viral replication may occur in the adenoidal

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tissue and spread anteriorly and posteriorly. Until recently, bradykinin was the only mediator found to be consistently elevated in nasal secretions in upper respiratory tract infections (91). Vascular leak and symptom severity parallel each other over the first 3 days of infection, only to subside as glandular secretion becomes more prominent. Additional mediators such as histamine, interleukins and prostaglandins, and stimulation of parasympathetic reflexes exacerbate the vasodilation of nasal blood vessels, plasma transudation, glandular secretion, and other pathophysiological processes (92). Nociceptive nerve stimulation triggers sensations of irritation, sore throat, nasal congestion and obstruction, and sneeze and cough reflexes (93). Computed tomography scans demonstrate the accumulation of secretions in the maxillary and other paranasal sinuses after 4 days. This may represent a sterile transudate. It generally resolves completely within 6 weeks. Rhinovirus infection has been causally linked with changes in lower airways physiology and asthma exacerbations. Rhinoviral colds are associated with a bronchial mucosal lymphocytic and eosinophilic infiltrate that may be related to changes in airway responsiveness and asthma exacerbations (94). Trigg et al. compared bronchial inflammation and the common cold in atopic and nonatopic subjects. They found that lower airways inflammation was present in allergic and nonallergic normal subjects with colds, but atopic subjects were less likely to have positive results of virological tests and more likely to show activated eosinophilia in the lower airway, even though they had similar symptoms (95). The increased severity in atopic subjects suggested a potential role for histamine in this process; however, studies of antihistamines in this setting have produced mixed results. First-generation antihistamines do appear to decrease rhinorrhea, but this may be because of their anticholinergic properties (96), which also contribute to their adverse effects.

XV. SUMMARY Histamine is a potent vasoactive agent, bronchial smooth muscle constrictor, and stimulant of nociceptive itch nerves. Activation of H 1-receptors plays a central role in the immediate allergic reaction, but has less of an impact in chronic allergic disorders where inflammatory infiltrates, additional mediators such as LTC 4 / D 4 /E 4 and cytokines, and structural remodeling occur. Histamine, through its H 1-receptor-mediated activities, appears to be primarily a proinflammatory agent, yet it does have some homeostatic functions in gastric acid production (H 2-receptors) and the central nervous system (predominantly H 3-receptors) (97, 98). The realization that first-generation antihistamines often had mixed pharmacological properties (e.g., anticholinergic actions) and crossed the blood–brain barrier led to the development of the second-generation drugs, which are more selective for H 1-receptors, have less access to the central

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nervous system, and, therefore, a more favorable benefit-to-risk ratio (therapeutic index). The potential for combined H 1 –H 3-antagonists remains to be fully explored, but offers another exciting opportunity for this ever-expanding family of beneficial drugs. ACKNOWLEDGMENTS This work was supported by U.S. Public Health Service Award AI42403 and Environmental Protection Agency Award R825814. REFERENCES 1. Dale HH, Laidlaw PP. The physiologic action of B-imidazolylethylamine. J Physiol 1910; 41:318–344. 2. Riley JF, West DB. Histamine and tissue mast cells. J Physiol 1953; 120:528–537. 3. White MV, Kaliner MA. Histamine in allergic diseases. In: Simons FER, ed. Histamine and H 1-Receptor Antagonists in Allergic Disease. New York: Marcel Dekker, 1996:61–90. 4. Soll AH, Lewin KJ, Beaven MA. Isolation of histamine-containing cells from rat gastric mucosa: biochemical and morphologic differences from mast cells. Gastroenterology 1981; 80:717–727. 5. Metcalfe DD. Effector cell heterogeneity in immediate hypersensitivity reactions. Clin Rev Allergy 1983; 1:311–325. 6. Wolff AA, Gross SS, Levi R. Histamine receptors: Involvement in cardiac function and dysfunction. In: Settipane GA, ed. H 1 and H 2 Histamine Receptors. Providence, RI: Ocean Side Publications, 1988–1989:61–64. 7. White MV, Slater JE, Kaliner MA. Histamine and asthma. Am Rev Respir Dis 1987; 135:1165–1176. 8. Wilson JR, Manning KA, Forestner DM, Counts SE, Uhlrich DJ. Comparison of cholinergic and histaminergic axons in lateral geniculate complex of the macaque monkey. Anat Rec 1999; 255:295–305. 9. Yanai K, Okamura N, Tagawa M, Itoh M, Watanabe T. New findings in pharmacological effects induced by antihistamines: from PET studies to knock-out mice. Clin Exp Allergy 1999; 29(suppl 3):29–36. 10. Saitou K, Kaneko Y, Sugimoto Y, Chen Z, Kamei C. Slow wave sleep-inducing effects of first generation H 1-antagonists. Biol Pharm Bull 1999; 22:1079–1082. 11. Hasenohrl RU, Weth K, Huston JP. Intraventricular infusion of the histamine H(1) receptor antagonist chlorpheniramine improves maze performance and has anxiolytic-like effects in aged hybrid Fischer 344xBrown Norway rats. Exp Brain Res 1999; 128:435–440. 12. Fang S-Y, Druce HM, Baraniuk JN. Anticholinergic properties of brompheniramine, chlorpheniramine and atropine in human nasal mucosa in vitro. Am J Rhinol 1998; 12:131–133.

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31. Rozneicki JJ, Letourneau R, Sugiultzoglu M, Spanos C, Gorbach J, Theoharides TC. Differential effect of histamine 3 receptor-active agents on brain, but not peritoneal, mast cell activation. J Pharmacol Exp Ther 1999; 290:1427–1435. 32. McLeod RL, Mingo GG, Herczku C, DeGennaro-Culver F, Kreutner W, Egan RW, Hey JA. Combined histamine H 1- and H 3-receptor blockade produces nasal decongestion in an experimental model of nasal congestion. Am J Rhinol 1999; 13:391–399. 33. Actis LA, Smoot JC, Barancin CE, Findlay RH. Comparison of differential plating media and two chromatography techniques for the detection of histamine production in bacteria. J Microbiol Methods 1999; 39:79–90. 34. Larsen FO, Norn S, Mordhorst CH, Skov PS, Milman N, Clementsen P. Chlamydia pneumoniae and possible relationship to asthma. Serum immunoglobulins and histamine release in patients and controls. APMIS 1998; 106:928–934. 35. Yamamoto J, Watanabe S, Hirose M, Osada T, Ra C, Sato N. Role of mast cells as a trigger of inflammation in Helicobacter pylori infection. J Physiol Pharmacol 1999; 50:17–23. 36. Tamaoki J, Araake M, Chiyotani A, Isono K, Nagai A. Airway hyperresponsiveness to histamine in mycoplasmal infection: role of histamine N-methyltransferase. Eur J Pharmacol 1998; 347:257–260. 37. Pietrzkowicz M, Grzelewska-Rzymowska I. Histamine as a mediator of allergic inflammation. Pol Merkuriusz Lek 1999; 6:232–235. 38. Baraniuk JN. Pathogenesis of allergic rhinitis. J Allergy Clin Immunol 1997; 99: S763–S772. 39. Andriopoulou P, Navarro P, Zanetti A, Lampugnani MG, Dejana E. Histamine induces tyrosine phosphorylation of endothelial cell-to-cell adherens junctions. Arterioscler Thromb Vasc Biol 1999; 19:2286–2297. 40. van Nieuw Amerongen GP, Draijer R, Vermeer MA, van Hinsbergh VW. Transient and prolonged increase in endothelial permeability induced by histamine and thrombin: role of protein kinases, calcium, and RhoA. Circ Res 1998; 83:1115–1123. 41. Erjefalt I, Persson CGA. Allergen, bradykinin, and capsaicin increase outward but not inward macromolecular permeability of guinea-pig tracheobronchial mucus. Clin Exp Allergy 1991; 21:217–224. 42. Johnston B, Gaboury JP, Suematsu M, Kubes P. Nitric oxide inhibits microvascular protein leakage induced by leukocyte adhesion-independent and adhesion-dependent inflammatory mediators. Microcirculation 1999; 6:153–162. 43. Naclerio RM, Baroody FM, Kagey-Sobotka A, Lichtenstein LM. Basophils and eosinophils in allergic rhinitis. J Allergy Clin Immunol 1994; 94:1303–1309. 44. Togias A, Naclerio RM, Proud D, Pipkorn U, Bascom R, Iliopoulos O, Kagey-Sobotka A, Norman PS, Lichtenstein LM. Studies on the allergic and nonallergic nasal inflammation. J Allergy Clin Immunol 1988; 81:782–790. 45. Sommerhoff CP, Caughey GH, Finkbeiner WE, Lazarus SC, Basbaum CB, Nadel JA. Mast cell chymase: a potent secretagogue for airway gland serous cells. J Immunol 1989; 142:2450–2456. 46. Holgate ST, Bradding P, Sampson AP. Leukotriene antagonists and synthesis inhibitors: new directions in asthma therapy. J Allergy Clin Immunol 1996; 98:1–13. 47. Fernvik E, Hallden G, Lundahl J, Raud J, Alkner U, van Hage-Hamsten M, Gronneberg R. Allergen-induced accumulation of eosinophils and lymphocytes in skin cham-

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2 Histamine Receptors: Specific Ligands, Receptor Biochemistry, and Signal Transduction Remko A. Bakker, Hendrik Timmerman, and Rob Leurs Vrije Universiteit, Amsterdam, The Netherlands

I.

INTRODUCTION

The monoamine histamine is an important chemical messenger that regulates a wide variety of physiological responses in the brain and peripheral organs. In the central nervous system (CNS) this amine is synthesized in a restricted population of neurons located in the tuberomammillary nucleus of the posterior hypothalamus. These neurons project diffusely to most cerebral areas and have been implicated in various functions of the brain of mammalian species (e.g., sleep/ wakefulness, hormonal secretion, cardiovascular control) (1–3). In various peripheral tissues histamine is stored in mast cells, basophils, enterochromaffin cells, and probably also in specific neurons. In the gastric mucosa, histamine release from enterochromaffin cells stimulates the gastric acid secretion by parietal cells, whereas histamine release after mast cell degranulation leads to various allergic phenomena conditions in skin and airway preparations (3, 4). Initially, research in the histamine field focused completely on the role of histamine in allergic diseases. This intensive research resulted in the development of several potent ‘‘antihistamines’’ (e.g., mepyramine), which were useful in inhibiting many symptoms of allergic disorders. The observation that these ‘‘antihistamines’’ could not antagonize all histamine effects led Ash and Schild in 1966 to hypothesize the existence of at least two distinct receptor subtypes (5). In 1972 this hypothesis became generally accepted, when Black and his co-workers succeeded in synthesizing a series of new compounds (e.g., burimamide), which antagonized the effects of histamine on the stomach and heart (6). These H 227

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receptor antagonists proved to be useful in the therapy of gastric ulcers. The identification of the presynaptic H 3-receptor as a new receptor subtype in 1983 by Arrang and colleagues (7) gave rise to a new field of interest. The H 3-receptor is now regarded as a general regulatory system and a potential target for new therapeutic interventions (8). The use of genomic databases has recently resulted in the identification of a new histamine receptor, the histamine H 4-receptor (8a). In view of its expression profile, this receptor is suggested to be a new target in the regulation of immune function. In this chapter we will review the molecular pharmacological properties of the various histamine receptor subtypes. Attention will be given to the specific pharmacological tools used, the biochemical aspects of the receptor proteins, and the different biochemical processes triggered in various target cells/tissues after receptor activation.

II. SELECTIVE LIGANDS FOR THE HISTAMINE RECEPTORS In this section we will describe the various histaminergic agents that can be used for the study of the four histamine receptor subtypes. For a detailed description of the medicinal chemistry of the histamine receptor ligands, the reader is referred to recent reviews (9–14). A.

Histamine H 1-Receptor Ligands

Many pharmacological tools are available for the study of the H 1-receptor, although highly potent receptor agonists are not yet available. For many years the substituted 2-phenylhistamines (e.g., 2-(3-trifluoromethylphenyl)histamine) (Fig. 1) have been the best choice. These agonists show relatively high affinity for the H 1-receptor, but appear to possess only limited potency (11). Recently, however, Schunack’s laboratory introduced histaprodifens as a new class of highly active H 1-agonists (15), which are clearly more potent than histamine (Fig. 1). Many potent and selective receptor antagonists are available for the study of H 1-receptors (9); however, one should be aware of the possible antagonistic properties at muscarinic and serotoninergic receptors and of the local anesthetic properties of several classic H 1-receptor antagonists at concentrations usually much higher than those needed for blocking the H 1-receptor. Currently, mepyramine (pyrilamine) (Fig. 1) is the most commonly used H 1-receptor antagonist (pA 2 ⫽ 9) for pharmacological studies. The d- and l-enantiomers of chlorpheniramine are also very useful for receptor classification. These compounds penetrate the brain readily and can thus be used for in vivo CNS studies. New H 1-receptor antagonists have been developed (e.g., cetirizine and loratadine) (Fig. 1), which do not cross the blood–brain barrier and are of therapeutic importance in allergic disorders (9).

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Figure 1 Structures of various selective histamine H 1-receptor agonists and antagonists.

Classification of the H 1-antagonists has recently been changed. As described in the section on signal transduction, the H 1-receptor shows considerable constitutive activity, which can be inhibited by most H 1-antagonists, thus acting as inverse agonists (16). [ 3 H] mepyramine is the best available radioligand for labeling H 1-receptors, although the compound might be taken up in cells (17) and has been shown to label various non-H 1-receptor binding sites (e.g., in rat liver) (18). If a very high sensitivity is required, the iodinated ligand [125l] iodobolpyramine (24) is of interest. [ 3 H]doxepin (19) and the quaternary radioligand [ 3 H] (⫹)N-methyl-4methyldiphenhydramine, have also been used to label H 1-receptors, although not to a large extent (20, 21). [11C]Doxepin has been used successfully to label H 1receptors in the human brain in positron emission tomographic (PET) studies (22). Finally, [ 3 H](⫺)trans-phenyl-3-aminotetralin has recently been reported as a novel H 1-receptor radioligand (23, 24). This ligand binds with high affinity to binding sites with H 1-receptor pharmacology, but for still unknown reasons the number of [ 3 H](⫺)trans-phenyl-3-aminotetralin binding sites is much lower than the number labeled with [ 3 H]mepyramine. B. Histamine H 2-Receptor Ligands For the histamine H 2-receptor, both agonists and antagonists are available for a proper pharmacological characterization. Amthamine (2-amino-5-(2-aminoethyl)-4-methylthiazole) (Fig. 2) is the best choice for a selective H 2-agonist. It combines a high H 2-receptor selectivity with a potency slightly higher than that of

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Figure 2 Structures of various selective histamine H 2-receptor agonists and antagonists.

histamine (25). Many compounds with potent H 2-receptor antagonistic properties have been described (see 12, 26, 27 for extensive reviews). Nowadays, compounds such as cimetidine, ranitidine, and tiotidine are usually applied as selective tools for functional studies of the H 2-receptor (Fig. 2). As in the case of the H 1-antagonists, the recognition of constitutive activity of the H 2-receptor (see the signal transduction section) resulted in the reclassification of cimetidine, ranitidine, and tiotidine as inverse agonists and burimamide as a neutral antagonist (28) or a weak partial agonist (29). Although [ 3 H]tiotidine has been used for labeling H 2-receptors in various tissues, the high level of nonspecific binding has led to the development of [ 125 I]iodoaminopotentidine (30). This iodinated H 2-receptor radioligand labels H 2-receptors with high affinity and provides a sensitive method for the detection of H 2-receptor expression. C.

Histamine H 3-Receptor Ligands

Soon after the initial description of the H 3-receptor (17), Arrang et al. described highly potent and selective ligands for this receptor subtype (31); (R)α-methylhistamine and thioperamide, an H 3-receptor agonist and an antagonist, respectively, are valuable tools for receptor identification (Fig. 3), although they have recently been reported to interact with the H 4-receptor as well. The use of (R)-α-methylhistamine in combination with its less active enantiomer (S)-αmethylhistamine is very effective for the characterization of H 3-receptor-mediated effects. Recently, the dimethylated histamine analog (R)-α,β-dimethylhistamine has also been shown to be a potent H 3-receptor agonist (32). In addition, isothiourea analogs of histamine resulted in the development of potent H 3-receptor agonists and antagonists (33). The unsubstituted isothiourea analog S-[2-(4(5)-imidazolyl)ethyl]isothiourea (VUF 8325 or imetit) (Fig. 3) is a very potent agonist (34–36). In addition, immepip (4(5)-1H-imidazolylmethylpiperidine) (Fig. 3) with the side chain

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31

Figure 3 Structures of various selective histamine H 3-receptor agonists and antagonists.

incorporated in a piperidine ring was shown to possess high H 3-agonistic potency (38). In contrast to immepip, (R)-α-methylhistamine shows some α 2- and H 1-agonistic activity, whereas imetit shows reasonable 5-HT 3-agonistic activity (37, 39). Yet immepip acts as an H 4-receptor agonist as well. A wide variety of potent H 3-antagonists have been described to date (13). Thioperamide (Fig. 3) (pA 2 ⫽ 8.4) (31) and clobenpropit (Fig. 3) (pA 2 ⫽ 9.9) (35), developed some years ago, are often considered to be the standard H 3antagonists. Thioperamide also acts as an H 4-receptor antagonist, whereas clobenpropit surprisingly acts as an H 4-receptor agonist. One should be aware that clobenpropit does not easily penetrate the blood–brain barrier in rats (40) and mice (41), whereas thioperamide also interacts with cytochrome P-450 (42, 43) and 5-HT 3 and sigma receptors (39). It is also important to mention that GT-2331 (Fig. 3) (K i ⫽ 0, 15 nM), also known as Perceptin (13), is currently under clinical evaluation and might be the first clinically useful drug to target the H 3-receptor. Due to the availability of various compounds with a very high H 3-receptor affinity, it is not surprising that currently a variety of radioligands for the H 3receptor are also available. With the initial description of (R)-α-methylhistamine as a selective ligand for the H 3-receptor (31), the tritiated compound was reported as a suitable radioligand for the H 3-receptor (31). To overcome the low specific activity of [ 3 H](R)-α-methylhistamine, [ 3 H]Nα-methylhistamine was labeled to a threefold higher specific activity and has been used successfully to label H 3receptors (44). [ 125 I]Iodoproxyfan can be used as a highly sensitive agonist radioligand, although it was originally introduced as an iodinated antagonist (45). A variety of radiolabeled H 3-antagonists have been reported in the literature. [ 3 H]Thioperamide (43) and [ 3 H]S-methylthioperamide (46) have been used to probe the H 3-receptor, but exhibit complex behavior which is probably related to the interaction of the radioligand with cytochrome P-450 isoenzymes (43). In con-

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trast, the guanidine analog of thioperamide, [ 3 H]GR168320 (47), and [ 3 H]clobenpropit (48) are quite well validated and function as high-affinity radioligands for H 3-receptors in the brain or intestine. [ 125 I]Iodophenpropit, a clobenpropit analog, can be used as a highly sensitive H 3-receptor radioligand (49). D.

Histamine H 4-Receptor Ligands

Heterologous expression of the H 4-receptor in cells confers the ability to bind [ 3H]histamine with high affinity (KD ⫽ 5 nM). Pharmacologically the H 4-receptor resembles to some extent the histamine H 3-receptor in that it binds many of the known H 3-agonists and antagonists, albeit with a different rank order of affinity and potency. Oda and colleagues have shown that the histamine H 4-receptor can bind and be activated by histamine, but also by the H 3-receptor ligands as R-(α)methylhistamine, N-(α)-methylhistamine, clozapine, imetit, immepip, and interestingly also by the H 2-receptor antagonist burimamide and the H 3-receptor antagonist clobenpropit (49a). The H 4-receptor does not bind H 1- and H 2-receptor antagonists such as diphenhydramine, loratadine, ranitidine, and cimetidine, but has modest affinity for the H 2-receptor agonist, dimaprit (377 nM) (49b). III. MOLECULAR ASPECTS OF THE HISTAMINE RECEPTORS In this section we describe the three histamine-receptor subtypes that were traditionally characterized by pharmacological techniques, and subsequently, with the availability of modern molecular biological approaches, have also been identified by gene cloning. We now have a detailed understanding of the receptor proteins and their function at the molecular level. A.

The H 1-Receptor

1. Receptor Biochemistry Using [ 125 I]iodoazidophenpyramine, Ruat et al. irreversibly labeled H 1-receptor proteins in rat, guinea pig, and mouse brain (50, 51). Following sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the labeled proteins, two main polypeptides (56 and 41–47 kDa) were found to be specifically labeled (51). Based on experiments with protease inhibitors, it was suggested that the H 1-receptor is a 56 kDa peptide, whereas the other labeled peptide was probably a result of protease action (51). Using [ 3 H]azidobenzamide, Yamashita et al. recently found receptor peptides of similar size (53–58 kDa) to be labeled in bovine adrenal medulla membranes (52). Whereas the 56 kDa peptide was also found in guinea pig lung and ileum, a peptide with a substantially higher

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molecular weight (68 kDa) was labeled in guinea pig heart tissue (50). Although at present no pharmacological differences have been observed between the H 1receptors from guinea pig heart and brain tissue, these results suggest the occurrence of several isoforms for the H 1-receptor. Also, the molecular weight found for the H 1-receptor after photoaffinity labeling is in sharp contrast with the reported weight (38–40 kDa) of a purified [ 3 H]mepyramine-binding protein from DDT1-MF2 smooth muscle cells (53, 54). Since several highly potent H 1-receptor antagonists possess only a moderate affinity for this binding protein, it is not yet clear whether the binding of [ 3 H]mepyramine to these cells really represents H 1receptor binding (53). 2. Molecular Biology of the H 1-Receptor Recently, Yamashita et al. cloned the gene encoding the bovine H 1-receptor (55) by expression cloning. The H 1-receptor cDNA encodes for a 491 amino acid receptor protein (apparent molecular weight 56 kDa) with all of the structural features of a G-protein-coupled receptor (GPCR), 7 transmembrane domains (TMs), N-terminal glycosylation sites, and phosphorylation sites for protein kinase A and C (55). Based on biochemical studies, it is known that the H 1-receptor protein from guinea pig brain is glycosylated (56). Therefore, the predicted molecular weight of 56 kDa is almost certainly an underestimate. Using the sequence information of the bovine H 1-receptor gene, the genes for the rat (57), guinea pig (58), mouse (59), and human (60–63) H 1-receptor have now also been cloned. De Backer et al. recently identified a previously unknown intron of approximately 5.8 kb in the 5′ untranslated region immediately upstream of the start codon (64). Several groups have individually mapped the H 1-receptor gene to chromosome 3, and have localized the gene on bands 3p14– p21 (65), or band 3p25 (61, 64). In the promotor region of the H 1-receptor, several potential transcription factor binding sites were identified, including glucocorticoid response element (GRE), Sp1, AP1, AP2, and NF-κB. Several of these transcription factors are involved in the regulation of inflammatory genes as well as in pathophysiological conditions that induce the expression of the H 1-receptor (64). In this respect, the observed effect of dexamethasone on H 1-receptor function (66) and expression (67) is clearly of interest as well. The expression of the histamine H 1-receptor gene is repressed by binding of the human TR2 orphan receptor, a member of the steroid/thyroid hormone receptor family, to the 3′ flanking region of the receptor (68). The H 1-receptor protein is encoded by a single exon and contains 486 (rat [57]), 488 (guinea pig [58, 69], mouse [59]), 491 (bovine [55]), or 487 (human [61–63]) amino acids. The homology among the several receptor proteins is quite high in the transmembrane domains (90%), but is significantly lower in the intracellular and extracellular domains. The various cloned genes are real species homologs, although some small changes in pharmacology are evident (55, 58, 63).

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Figure 4 Molecular model of histamine docked into the guinea pig histamine H 1-receptor according to information from site-directed mutagenesis studies using AMBER 4.1 molecular dynamics simulations (15). Five of seven helices (II–VI) in the transmembrane region of the histamine H 1-receptor are shown in yellow (see color plate). In this model, three residues in the ligand-binding pocket (Asp116 in helix III [71], Lys200 in helix V [74, 75], and Asn207 in helix V [72]) contribute to the binding of histamine via intermolecular hydrogen bonds.

With the availability of the cloned genes, detailed information on the receptor–ligand interaction can now be obtained. From site-directed mutagenesis studies of various other aminergic receptors, it is generally accepted that the binding of biogenic amines mainly occurs within the transmembrane (TM) domains (70). The H 1-receptor also binds agonists and antagonists within the TM domains. Figure 4 shows the current concepts regarding the interaction of histamine with the TM domains 3 and 5. The protonated amine function of histamine interacts with the aspartate residue in the TM domain TM3 (71, 72), whereas the imidazole ring makes hydrogen bond contacts with an asparagine and lysine residue in TM5 (73, 74). The asparagine residue appears to be very important for the interaction with histamine and 2-methylhistamine (73), but seems to be only of minor importance for 2-(3-bromophenyl) histamine. As was already suggested on the basis of pharmacochemical studies (33), the aromatic 2-substituent apparently interacts in a

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specific way with the H 1-receptor (15), and this interaction results in high-affinity binding to the receptor protein. More detailed studies should identify the amino acid residues of the H 1-receptor protein involved in the interaction with the aromatic ring of the 2-phenylhistamines and/or histaprodifens. The binding site of the H 1-antagonists was recently investigated in detail (71, 75). The H 1-agonists, like the antagonists, use the conserved aspartate residue in TM3 as a counterion for their protonated amine function (71). The combination of this information and a pharmacophore model derived for a variety of rigid H 1antagonists (76) led to the prediction that the binding site of the H 1-antagonists is located between TMs 3, 4, and 6 (75). Mutagenesis studies revealed tryptophane167 (TM4) and phenylalanine433 and phenylalanine435 to be involved in the binding of the aromatic rings of mepyramine. In addition, using the same model, an additional recognition site (lysine200 in TM5) was found for the acidic side chain in the relatively nonsedating H 1-antagonists acrivastine and cetirizine (75). Since the acid group was previously thought to be responsible only for limiting brain penetration (and thus sedation), these results illustrate nicely the impact of molecular biology. The ultimate example of the power of molecular biology is exhibited in the generation of histamine H 1-receptor knockout mice by the method of gene targeting (77, 78). Targeted disruption of the H 1-receptor gene leads to a loss of both [ 3 H]mepyramine (77, 78) and [ 3 H]doxepin (77) binding in the brain. The knock-out mice are very useful for clarification of the role of the H 1-receptors in behavior. The initial studies confirmed results obtained with classic pharmacological studies: histamine modulates various neurophysiological functions such as locomotor activity, emotion, memory and learning, nociception, and aggressive behavior through histamine H 1-receptors (79).

B. The H 2-Receptor Protein 1. Receptor Biochemistry Detailed biochemical information about the H 2-receptor has been obtained by photoaffinity labeling studies. Using [ 125 I]iodoazidopotentidine, Ruat et al. (30) showed that the H 2-receptor binding peptide is probably a 59 kDa protein, although the purification of a [ 3 H]tiotidine binding protein from human gastric tumor HGT-1 cells resulted in the identification of a 70 kDa protein (80). The H 2-receptor nature of the [ 3 H]tiotidine-binding protein from these cells has not, however, been defined clearly. Although it was once generally accepted that Gprotein-coupled receptors (GPCRs) function as monomeric entities, a growing body of evidence suggests that receptor dimers form and play a role in receptor function. H 2-receptor oligomer formation has been observed after overexpression in Sf9 cells (81, 82); however, further detailed investigations are required to

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determine whether these oligomers arise from receptor aggregation (82) or represent true receptor dimers. 2. Molecular Biology of the H 2-Receptor The gene and cDNA encoding the H 2-receptor have been identified in several species including humans (83–85). Using the polymerase chain reaction with degenerate oligonucleotides based on the known sequence homology of various G-protein-coupled receptors, and canine gastric parietal cDNA, Gantz et al. obtained the intronless gene encoding the canine H 2-receptor (83). Based on information about the canine cDNA, the nucleotide sequence encoding the rat and human H 2-receptor were rapidly identified (84, 85). The various sequences show considerable homology (80–90%) and are probably real species homologs (83– 85). In parallel with recent advances in the understanding of the genetic makeup of the histamine H 1-receptor gene, the location of the human histamine H 2-receptor gene has also been characterized (86). The H 2-receptor gene has been assigned to human chromosome 5 (86) and is regulated in a complex manner. The proximal promoter region lacks an apparent TATA box (87, 88), and multiple transcription-initiation sites of the human histamine H 2-receptor have been identified that may be important for tissue-specific receptor expression (88). Also, the promoter region of the human H 2-receptor gene contains several sites for potential transcriptional regulation, including AP2 and CRE sites, and GATA motifs (87). The H 2-receptor genes encode for a histamine receptor protein of 359 amino acids in the dog (83), human (85), and guinea pig (86) or 358 in the rat (84) and mouse (89), with many of the structural features of G-protein-coupled receptors and an apparent molecular weight of approximately 40 kDa. Since in the N-terminal extracellular tail a consensus sequence for N-linked glycosylation is present, the actual molecular weight of the receptor will be significantly higher. With respect to receptor recognition, the H 2-receptor uses the conserved aspartate residue in TM3 for the binding of histamine and H 2-receptor antagonists (90). Initial studies indicate that the threonine and aspartate residues in TM5 of the H 2-receptor are likely to interact with histamine and the antagonist [ 3 H]tiotidine. Based on studies of other biogenic amine receptors, however, the interaction of the two residues with the antagonist is rather unexpected and certainly deserves future attention. C.

The H 3-Receptor Protein

1. Receptor Biochemistry Detailed biochemical studies of the histamine H 3-receptor have been hampered by the low abundance of this receptor protein and the lack of highly sensitive radioligands. Using [ 3 H]histamine, the H 3-receptor was solubilized from bovine

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brain tissue, and size-exclusion chromatography revealed an apparent molecular weight of 220 kDa (91). Due to the protein-associated digitonin, this value is clearly overestimated. Recently, a value of 70 kDa has been reported as the molecular weight for a putative human H 3-receptor (92), purified from human gastric tumoral cell line HGT-1; however, no clear pharmacological profile of this putative receptor protein was obtained. 2. Molecular Biology Although the intronless genes encoding the H 1- and H 2-receptors were cloned in 1991 (55, 83), the molecular architecture of the H 3-receptor was unknown until recently, when Lovenberg et al. showed that, like the H 1- and H 2-receptor, the H 3-receptor belongs to the large superfamily of GPCRs (93). A potential GPCRrelated expressed sequence tag (EST)-sequence was identified in silico in a search for orphan GPCRs and used to clone a full-length cDNA from a human thalamus cDNA library. The cDNA contained an open reading frame (ORF) of 445 amino acids with all the features of a GPCR for a small biogenic amine (93, 94), which turned out to be the H 3-receptor. The H 3-receptor protein shows very low homology with other GPCRs. Overall homology between the H 3-receptor and the H 1and H 2- receptor amounts to only 22% and 20%, respectively. Within the transmembrane (TM) domains the homology is somewhat higher (H 1, 27%; H 2 33%), although still not very high. This remarkable divergence probably explains why the H 3-receptor gene was not cloned by homology screening with H 1- or H 2receptor-specific probes. Using the information on the human H 3-receptor cDNA, the rat (445 amino acids) and guinea pig (445 amino acids) cDNAs have been identified recently (95, 96). For the human, rat, and guinea pig H 3-receptor, various isoforms have been identified. The various H 3-isoforms are generated as a result of alternative splicing and show differential brain expression (96a–96d) and signaling properties (96a, 96d), in addition, also non-functional truncated receptors have been identified (96a–96d). So far, no data are available on the ligand-binding site or the generation of knock-out mice; however, in view of the growing interest in the therapeutic potential of H 3-ligands, these studies will certainly be performed in the near future. D. The H 4-Receptor Protein As part of a directed effort to discover novel G-protein-coupled receptors through homology searching of genomic databases, a novel orphan G-protein-coupled receptor gene was identified on chromosome 18 that has significant homology to the recently identified histamine H 3-receptor cDNA (8a, 49a, 49b, 96e–96g). Although the H 4-receptor shows little overall sequence homology to any of the other histamine receptors cloned to date, it exhibits an approximately 60% homol-

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ogy within the transmembrane domains of the H 3-receptor. The human H 4-receptor gene exhibits an exon/intron arrangement nearly identical to that of the H 3-receptor gene (49b). In view of several reports on the existence of multiple H 3-receptor isoforms (96a–96d), the recent report on H 4-receptor isoforms is perhaps not surprising (96h). By means of RT-PCR low expression of the H 4-receptor is reported in a wide variety of peripheral tissues (8), and expression is predominantly found in eosinophils (8a, 49a, 49b, 96) and in tissues likely to contain high concentrations of blood cells, such as bone marrow and lung (49b, 96e, 96f ). In contrast to the H 3-receptor, expression was not detected in the brain, although in situ hybridization analysis showed that mouse H 4-receptor mRNA is selectively expressed in the hippocampus (96f ). The unique expression profile of the H 4-receptor suggests it may be a therapeutic target for the regulation of immune function.

IV. TRANSMEMBRANE SIGNALING In this section we describe the signal transduction pathways activated by the histaminergic receptor subtypes. Along with the identification of an increasing number of G-proteins and effector systems, histamine receptors have been shown to activate a variety of signal transduction systems. Detailed knowledge of the intracellular pathways activated by histamine is indispensable for a proper understanding of the action of histamine in (patho)physiological processes. A.

Signal Transduction of the H 1-Receptor

The histamine H 1-receptor is, among other G-protein-coupled receptors, a Ca 2⫹mobilizing receptor. It is widely accepted that activation of Ca 2⫹-mobilizing receptors is associated with the phospholipase C-(PLC) catalyzed hydrolysis of membrane inositide phospholipids. Activation of the histamine H 1-receptor (Fig. 5) leads to the hydrolysis of phosphatidyl 4,5-biphosphate (Pl(4,5)P 2) resulting in the formation of inositol (1,4,5)triphosphate (Ins(1,4,5)P 3) and 1,2-diacylglycerol (DAG). Ins(1,4,5)P 3-receptors in the endoplasmic reticulum (ER) mediate the subsequent release of Ca 2⫹ from the ER, thereby raising [Ca 2⫹ ] i , whereas the released DAG activates protein kinase C (PKC). For a detailed description of the various functions of the second messengers Ins(1,4,5)P 3, Ca 2⫹, DAG, and their downstream effectors, the interested reader is referred to comprehensive reviews (99–101). Recent advances in molecular biology have led to the discovery of a plethora of previously unknown signaling proteins, and rapid progress in the understanding of mechanisms of signal transduction has been made. In parallel with this progress, the H 1-receptor is also found to couple to G-proteins other than members of the G q/11 family, and the βγ subunits that are released upon receptor activation are suggested to be involved in the H 1-receptor-mediated responses.

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Figure 5 Histamine activates various signal transduction pathways via interaction with the G-protein-coupled histamine receptors (H 1-, H 2-, H 3-, and H 4-). Activated histamine H 1-receptors will activate the phosphoinositide pathway by activating G-proteins belonging to the G q/11 family of G-proteins, which will result in the activation of PLC and the subsequent formation of DAG and InsP 3. Histamine H 2-, H 3-, and H 4-receptor activation will affect the adenylyl cyclase cascade. Adenylyl cyclase is activated upon H 2-receptor activation to generate cAMP from ATP. Activation of the H 3-receptor will inhibit adenylyl cyclase and lower cAMP levels.

1. Stimulation of Phospholipase C Histamine has been shown to induce production of inositol phosphates in several tissues, including brain, airway smooth muscle, intestinal smooth muscle, vascular smooth muscle, and heart (2, 102–106). Guinea pig brain regions with the highest density of H 1-receptors display the largest phosphoinositide response (107, 108); however, in some tissues (guinea pig ileum and neonatal brain) the H 1-response to histamine itself appeared to be masked by an H 1-antagonist-insensitive component (109, 110). In membrane preparations of rat cerebral cortex and 1321N1 astrocytoma cells, H 1-receptor-stimulated phospholipid hydrolysis was found to be dependent on the presence of guanine nucleotides (103, 106). Studies in 1321N1 astrocytoma cells (106), HeLa cells (111), and CHO cells stably expressing H 1-receptors (112) showed the inositol phosphate response to be mediated by a pertussis toxininsensitive G-protein. Furthermore, histamine increased the incorporation of [α-

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P]GTP azidoanilide into G q/11-like proteins in H 1-receptor-expressing Sf9 cells (113) as well as in membranes prepared from guinea pig heart (114). In addition, antibodies to the α q subfamily of G-proteins have been shown to inhibit the histamine stimulation of Pl(4,5)P 2 hydrolysis in 1321N1 cells (115), implicating the involvement of Gα q/11 in the H 1-receptor response. Activation of PLC will not only generate Ins(1,4,5)P 3 and result in the release and cellular influx of Ca 2⫹, but will also result in the formation of DAG. DAG in turn will activate other effectors such as isoforms of PKC and protein kinase D (PKD). Activated PKC has many cellular functions, including desensitization of the H 1-receptor by receptor phosphorylation (116, 117) and transcriptional downregulation of histamine H 1-receptor expression (118). More recently, the histamine H 1-receptor-mediated production of diacylglycerol has been shown to mediate an influx in [Ca 2⫹ ] i by activating transient receptor potential (TRPC) channels, homologs of Drosophila TRP proteins (119), which are thought to mediate capacitative Ca 2⫹ entry (120). Histamine activated the human TRPC6, a nonselective cation channel that is activated in a Ca 2⫹-store-depletion-independent mechanism by diacylglycerol, independently of protein kinase C in cotransfected Chinese hamster ovary (CHO)-K1 cells (119). 2. Calcium Signaling One of the physiological consequences of the production of inositol phosphates is the elevation of intracellular Ca 2⫹. The histamine H 1-receptor has been widely used to study the mechanism of Ca 2⫹ release from intracellular stores and the extracellular Ca 2⫹ influx. The histamine-induced Ca 2⫹ response is characterized by a rapid transient rise of the intracellular Ca 2⫹ concentration, which is followed by a sustained elevation of the Ca 2⫹ concentration. Experiments in Ca 2⫹-free medium and with inorganic Ca 2⫹ antagonists suggest that the sustained response is highly dependent on the influx of extracellular calcium, whereas the transient increase is caused by the release of Ca 2⫹ from intracellular Ca 2⫹ stores (112, 121– 129). In addition, histamine H 1-receptor stimulation has been shown to result in a slight increase in the amplitude of the [Ca 2⫹ ] i transient rise due to H 1-receptormediated inhibition of the outward K⫹ current (130). The Ca 2⫹ signal exhibits a high degree of spatiotemporal complexity in which intracellular organelles play a key role. Ca 2⫹-signal compartmentalization after histamine stimulation (131) has been described for various intracellular compartments, including the cytosol (132–135), the endoplasmic reticulum (136, 137), the mitochondria (133, 138, 139), the Golgi apparatus (140), and the nucleus (141, 142). Histamine not only results in the rise of intracellular Ca 2⫹ in various compartments but also influences Ca 2⫹ oscillations (143, 144). Ins(1,4,5)P 3-receptors in the ER bind Ins(1,4,5)P 3 and release calcium from the lumen. Repetitive phosphorylation/dephosphorylation of the Ins(1,4,5)P 3-receptor by calmodulin-

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dependent kinase II (CaMKII) in histamine-stimulated HeLa cells has been shown to control sustained Ca 2⫹ oscillation in these cells (143). In addition, Ins(1,3,4,5)P 4, a metabolite of Ins(1,4,5)P 3, modulates Ca 2⫹ entry across the plasma membrane, is known to alter frequency and amplitude of intracellular Ca 2⫹ oscillations in HeLa cells (145, 146), and was recently found to regulate calcium oscillations in histamine-stimulated HeLa cells (147). These [Ca 2⫹ ] i oscillations, rather than an increase in amplitude of the [Ca 2⫹ ] i transient (148), have been implicated in the regulation of gene expression (143, 149–151), which may depend on the phosphorylation/dephosphorylation of transcription factors that vary specifically according to distinct Ca 2⫹ frequency. Histamine has been shown to activate the transcription factor nuclear factor of activated T cells (NFAT) in a cyclosporin-A-sensitive manner in human umbilical vein endothelial cells (152). Furthermore, histamine has also been shown to activate the transcription factor nuclear factor kappa B (NF-κB) in human aortic endothelial cells (143) and in epithelial cells (153). Although activation of NF-κB in endothelial cells appears to occur secondarily to PLC-mediated [Ca 2⫹ ] i oscillations (143), the H 1-receptor mediated activation of NF-κB in epithelial cells seems to involve the generation of arachidonic acid metabolites (153). 3. Other H 1-Receptor Signaling Pathways Since Ca 2⫹ is involved in the regulation of many cellular functions, the increase of intracellular Ca 2⫹ concentration can explain a wide variety of pharmacological responses induced after stimulation of the H 1-receptor. First, elevation of intracellular Ca 2⫹ levels leads to further stimulation of PLC, most likely the PLC-β subtype, since it is known to be sensitive to Ca 2⫹ (154). Correspondingly, the histamine-induced production of inositol phosphates in both brain and tracheal slices (155, 156) and CHO cells stably expressing the guinea pig H 1-receptor (112) has been shown to be highly dependent on the influx of extracellular Ca 2⫹. In addition to the effects on the inositol phospholipid-signaling systems, histamine H 1-receptor activation also leads to the activation of other signaling pathways, many of which appear to be secondary to changes in intracellular calcium concentration or the activation of protein kinase C. Yet it appears that PLC-independent pathways can also regulate responses, such as the modulation of cAMP and phospholipase A 2 activity. How H 1-receptor activation leads to these responses will be discussed in detail below. 4. Activation of Nitric Oxide Synthase Histamine-induced increase of Ca 2⫹ can elevate nitric oxide synthase activity to induce nitric oxide production via a Ca 2⫹ /calmodulin-dependent pathway, with subsequent activation of soluble guanylyl cyclase in a variety of cell types. In various vascular preparations, the endothelium-dependent relaxation observed upon H 1-receptor activation is found to be related to the production of nitric oxide

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(157–161). In cultured bovine aortic cells the actual generation of nitric oxide could be measured after stimulation with histamine (162). In a variety of airway and heart preparations, H 1-receptor activation was shown to induce the production of cGMP, which may be ascribed to generation of nitric oxide (163–168). More recently, histamine was found to induce the association of heat-shock protein 90 with endothelial nitric oxide synthase (eNOS) and subsequently to activate eNOS in human umbilical vein endothelial cells (HUVEC) (169). Thus, vascular responses to histamine may be explained by the generation of nitric oxide, which appears to be highly dependent on the mobilization of intracellular Ca 2⫹. 5. Activation of Phospholipase A 2 and Subsequent Arachidonic Acid Release Another consequence of the histamine-induced mobilization of Ca 2⫹ is the release of arachidonic acid and the generation of arachidonic acid metabolites such as prostacyclin and thromboxane A 2 (112, 170, 171). The formation of arachidonic acid metabolites has been implicated in the regulation of NF-κB-mediated gene transcription by the H 1-receptor (153). In HeLa cells endogenously expressing the human H 1-receptor as well as in CHO-K1 transfected with the guinea pig H 1-receptor, the release of arachidonic acid appeared to be phospholipase-A 2-dependent (112). In contrast to the phospholipase-A 2-dependent, pertussis toxin-insensitive release of arachidonic acid in HeLa cells (112), histamine stimulation of the transfected CHO cells resulted in a partially sensitive phospholipase A 2 activation (112). Murayama et al. (172) reported the histamine-induced, pertussis toxin-sensitive release of arachidonic acid in the absence of inositol phosphate generation in both human and rabbit platelets. Therefore, the H 1-receptor-mediated activation of phospholipase A 2 in transfected CHO cells may be ascribed to elevation of the intracellular Ca 2⫹ concentration (as in HeLa cells) and, via interaction of phospholipase A 2, with a pertussis toxin-sensitive G-protein (as in platelets). 6. Stimulation of Phospholipase D Activation of phospholipase D (PLD) by the H 1-receptor may occur secondarily to the activation of PLC by the liberation of DAG and subsequent activation of PKC. PLD mediates the hydrolysis of phosphatidylcholine and other phospholipids, to generate phosphatidic acid. The activation of PLD is believed to serve diverse functions in signal transduction, membrane vesicle trafficking, and cytoskeletal dynamics, and to play an important role in the regulation of cell function and cell fate (see Ref. 173 for a recent review on PLD). Agonist-induced PLD activation involves PKC activation and is dependent on an increase in intracellular Ca 2⫹ (174); however, part of the histamine-stimulated PLD activity may occur in the absence of PKC activation (174, 175). In

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addition to binding to G q/11 proteins, the H 1-receptor has recently been shown to mediate PLD activation in 1321N1 human astrocytoma cells via the small Gprotein ARF (176). 7. Changes in Intracellular cAMP Levels The histamine H 1-receptor is also reported to mediate substantial changes in intracellular levels of cAMP. The H 1-receptor acts to amplify cAMP responses from histamine H 2-, adenosine A 2-, and vasoactive intestinal polypeptide receptors (177–182); however, in various carcinomas, the H 1-receptor was found to couple to elevation of cAMP in the absence of Ins(1,4,5)P 3 formation (183, 184). The exact mechanism involved in the elevation of cAMP remains to be determined; a role for both Ca 2⫹ and protein kinase C has been suggested (185). Neither protein kinase C nor Ca 2⫹ accounted for the observed elevation of cAMP levels in guinea-pig H 1-receptor-expressing CHO cells (112). The latter observations could possibly be explained by stimulation of adenylyl cyclase by G-protein βγsubunits. 8. Coupling to G i/o-Proteins In contrast to the H 1-receptor-mediated increase in intracellular levels of cAMP, a phenomenon generally associated with coupling to G-proteins, differentiated HL-60 cells have been found to express H 1-receptors coupled to both pertussistoxin (PTX)-insensitive G-proteins and PTX-sensitive G i-proteins (186, 187). PTX partially inhibited the stimulatory effect of histamine on [Ca 2⫹ ] i (187), indicating a role for G i/o-proteins in the Ca 2⫹ response. Modulation of a nonselective cation current through coupling of the H 1-receptor to G i/o-proteins has also been reported (188). 9. Constitutive H 1-Receptor Signaling Recently, we have found the human histamine H 1-receptor to be constitutively active (16). Overexpression of the receptor in SV40-immortalized African green monkey kidney (COS-7) cells results in an agonist-independent production of Ins(1,4,5)P 3, which can be inhibited by inverse H 1-agonists formerly known as H 1-antagonists (Fig. 6). Among these are well-known, clinically useful H 1-antagonists such as cetirizine, loratadine, and epinastine. The recognition of inverse agonism by H 1-antagonists provides an extremely important insight into the action of these drugs at the H 1-receptor. The (patho)physiological significance of basal H 1-receptor activity is as yet unknown, but in view of the reported regulatory mechanisms induced by inverse agonists (28, 189), one could speculate that neutral antagonists might have some therapeutic benefit. However, neutral H 1antagonists have not, as yet, been identified.

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Figure 6 Constitutive activity of the human histamine H 1-receptor and inverse agonism of H 1-antagonists. (A) Effect of mepyramine on the basal [ 3 H]inositolphosphate accumulation in COS-7 cells expressing the human histamine H 1-receptor (䊉) and on mock transfected cells (䊊). The stereoisomers of cetirizine, (R)- (■) and (S)-cetirizine (䊐), stereospecifically inhibit basal [ 3 H]inositolphosphate accumulation. (B) Correlation graph of the plC 50 values obtained for the inverse agonists in the [ 3 H]inositolphosphate accumulation assay vs. the pK 1 values obtained by [ 3 H]mepyramine displacement in COS-7 cells expressing the human histamine H 1-receptor. (Data from Ref. 16.)

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10. Conclusions The H 1-receptor is primarily coupled to a PLC-dependent inositol phosphate pathway via a G q/11-protein. In addition to binding to G q/11, the H 1-receptor can also couple to G i/o-proteins and has recently been shown to activate phospholipase D by activation of small G-proteins (176). B. Signal Transduction of the H 2-Receptor It is generally accepted that the histamine H 2-receptor is coupled to the adenylate cyclase system (Fig. 5). A large number of reports have shown that histamine increases the levels of cAMP in the brain, stomach, heart, and other tissues of several species, including humans (2, 166, 190–198). 1. Stimulation of Adenylyl Cyclase The H 2-receptor activates adenylyl cyclase in membrane fractions in a guanylnucleotide-sensitive manner (197). Direct evidence for the involvement a G sprotein in the H 2-receptor-mediated response comes from the observation of an enhanced GTP azidoanilide-labeling of G s-like proteins in H 2-receptor-expressing Sf9 cells (113). Ozawa and co-workers suggested that an H 2-receptor-stimulated phospholipid methylation is involved in the activation of adenylyl cyclase (191, 198). In both rat brain (191, 199) and guinea pig heart (198), histamine was shown to stimulate the phospholipid methylation rapidly. The cAMP response in both tissues was significantly slower and completely dependent on the presence of the methyl-donor S-adenosyl-L-methionine and reduced by an inhibitor of the phospholipid methyltransferases (191, 198). Moreover, in rat brain the regional distribution of histamine-induced phospholipid methylation closely paralleled the H 2receptor-mediated cAMP response (191). These data suggest the necessity of the phospholipid response for an effective G-protein-receptor coupling to adenylylcyclase activation. 2. Other H 2-Receptor Signaling Pathways Although the linkage of the H 2-receptor to the adenylate cyclase is well accepted, some findings argue against a universal role of cAMP. In guinea pig brain the regional distribution of H 2-receptor-binding sites does not parallel the observed H 2-receptor-mediated cyclase activation (30). Also, Haas et al. (200) observed a denervation hypersensitivity to histamine at the electrophysiological level, whereas under the same conditions the cAMP response was unaltered. In addition to the activation of adenylyl cyclase, presumably by activating G s-type G-proteins, there are reports of H 2-receptor coupling to other signaling

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systems. In differentiated HL-60 cells (201–203), parietal cells (204), human keratinocytes (205), and HEPA, COS-7, and HEK-293 cells transfected with the canine H 2-receptor (114, 206, 207), an H 2-receptor-mediated increase of the intracellular Ca 2⫹ concentration was observed. The increase of intracellular Ca 2⫹ was found to result from the release of Ca 2⫹ from intracellular stores (114, 202, 206). The H 2-receptor-dependent Ca 2⫹ mobilization is probably due to the activation of phospholipase C, since histamine was also found to increase the levels of Ins(1,4,5)P 3 (114, 183, 184, 206, 208–212), and activation of both PKCα and PKCβ (207). The physiological role of stimulation of PLC by the H 2-receptor is unknown; however, a role in H 2-receptor desensitization (213) and cell proliferation is suggested (207, 214). G-proteins are likely to be involved in the activation of PLC since the increase of Ins(1,4,5)P 3 levels in both HL-60 and HEPA cells lines were found to be inhibited by cholera toxin but not by pertussis toxin (202, 206). Reports in hamster DDT1 MF-2 cells and bovine trachea smooth muscle have demonstrated a cAMP-mediated inhibition of the production of inositol phosphates (215–217). The crosstalk between the cAMP cascade and phosphoinositide system could well explain the observed inhibitory effects induced by cholera toxin (206, 210); yet, in the HEPA cells, forskolin did not inhibit the histamine-induced effects, suggesting the involvement of another mechanism (206). H 2-receptormediated Ins(1,4,5)P 3 formation has also been observed in the absence of cAMP accumulation (209). A PTX-insensitive histamine-induced stimulation of PLC has also been observed in COS-7 cells transfected with cDNA encoding the H 2receptor (114). In addition, coexpression of G q/11-family members of G-proteins, but not G i- or G s-, lead to a further H 2-receptor-mediated increase in Ins(1,4,5)P 3 formation. Further, histamine stimulated the H 1- and H 2-receptor-mediated incorporation of [α-32P]GTP azidoanilide into G q/11-like proteins in membranes prepared from guinea pig heart (114). Therefore, in addition to elevation of cAMP levels, the H 2-receptor is thought to activate phospholipase-C-signaling pathways via a separate GTP-dependent mechanism (206, 211, 212). Although these results indicate a direct coupling of the H 2-receptor to both G s- and G q/11-proteins, histamine failed to elicit Ins(1,4,5)P 3 formation in CHO cells permanently expressing the rat H 2-receptor (112), raising the possibility that the coupling to G q/11 is cell-type-specific. Moreover, allelic variation of the human histamine H 2-receptor gene (218) may play a role in the observed atypical coupling to second messengers in transformed cells (183). Another cAMP-independent response was described for the cloned rat H 2receptor expressed in CHO cells (219). In addition to massive production of cAMP upon H 2-receptor activation, inhibition of the release of arachidonic acid induced by either constitutive purinergic receptors or a Ca 2⫹-ionophore was observed. At present, the actual mechanism for this response is unknown. One should, however, be aware that ambiguous receptor coupling might be due to the high level of receptor expression in these cells. In contrast, expression of the gene encoding the human

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H 2-receptor in CHO cells was shown to be functionally coupled to adenylate cyclase, but did not influence the inositol phosphate turnover or arachidonic acid release (220). The observed sequence differences, in particular in the intracellular domains between the rat and human receptor (84, 221) might also be a possible explanation for the observed differences in signal transduction. 3. Constitutive H 2-Receptor Signaling Preceding our findings concerning constitutive signaling by the histamine H 1receptor (16), we have shown constitutive activity of the histamine H 2-receptor (28, 29, 222, 223). Expression of the H 2-receptor in CHO cells results in agonistindependent elevation of cAMP levels (28, 29). In addition, constitutive H 2-receptor activity enhances forskolin-induced cAMP production (222). Various inverse H 2-receptor agonists have now been identified, and among these are well-known therapeutic agents. The (patho)physiological significance of constitutive H 2-receptor activity and the H 2-receptor upregulation resulting from prolonged inverse H 2-agonist treatment (28) are as yet unknown. 4. Conclusions As previously seen for the H 1-receptor, various intracellular mediators are likely to be involved in the H 2-receptor-mediated effects. The H 2-receptor is primarily coupled to the adenylyl-cyclase-dependent production of cAMP. It appears, however, that in some cell types the breakdown of phosphoinositides, the intracellular Ca 2⫹ levels, and phospholipase A 2 activity can be regulated by cAMP-independent pathways. C. Signal Transduction of the H 3-Receptor The recent cloning of the histamine H 3-receptor by Lovenberg and colleagues (93) has shown that the H 3-receptor indeed belongs to the family of G-proteincoupled receptors. Binding studies (49, 91, 92, 224–228), as well as inhibitory effects induced by pertussis toxin and cholera toxin (92, 229–231), had already supported the involvement of a G i/o-protein in the H 3-receptor-mediated responses (Fig. 5). In agreement with these observations, an inhibition of cAMP accumulation in response to histamine was observed in forskolin-stimulated mouse L cells, human SK-N-MC neuroblastoma cells, and rat C6 glioma cells expressing the human histamine H 3-receptor (93). The effect was mimicked by the selective H 3-agonist (R)-α-methylhistamine, unmasking the H 3-receptor as a G i-coupled GPCR, which confirms previous findings of a PTX-sensitive G-protein coupling of the H 3-receptor (227, 228, 230, 232). Availability of the H 3-receptor cDNA will allow a more detailed investigation of the signaling properties of this receptor. Recent studies have shown coupling of the H 3-receptor to MARK pathway (96b) and the Na⫹ /H⫹ exchanger (232a).

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Signal Transduction of the H 4-Receptor

Heterologous expression of the H 4-receptor in a variety of cells indicates this member of the histamine receptor family is also a G-protein-coupled receptor, and that it can couple to both G i/o- and to G 15/16-proteins. H 4-receptor-expressing cells respond to histamine and inhibit forskolin-induced cAMP accumulation (8a, 49b, 96e), potently stimulate [ 35S]GTPγS binding (49a), and result in a pertussis toxin-sensitive phosphorylation of MAP kinase (49a), indicating the involvement of G i/o proteins. Coexpression studies using either Gα 15 or Gα 16 (8a, 49a), or chimeric Gproteins Gα q/i1,2 or Gα q/i3 in which the last five C-terminal amino acids of Gα q have been replaced with those of the α-subunits Gα i1,2 or Gα i3 (49a), have shown activation of the H 4-receptor to mobilize [Ca 2⫹ ]i. As the receptor is predominantly expressed in leukocytes, coupling of the receptor to G 15/16-proteins, linking receptor-activation to the phospholipase C pathway to generate inositolphosphates, diacylglycerol and [Ca 2⫹ ]i, may also represent a natural second messenger pathway of the H 4-receptor (8a). V.

MISCELLANEOUS HISTAMINE RECEPTORS

Apart from the G-protein-coupled histamine H 1-, H 2-, and H 3-receptors, several other histamine receptors have been described. Patch-clamp studies on histamine receptors in invertebrate neurons have identified a ligand-gated chloride channel at a photoreceptor synapse of the housefly (233). Furthermore, similar histaminegated chloride channels have been detected in lobster olfactory neurons (234). The histamine-gated chloride channels in the large monopolar cell, a retinal neuron, have been utilized to estimate the metabolic cost of neural information (235). Recently, three histamine-binding proteins have been cloned from the tick Rhipicephalyus appendiculatus (236). These high-affinity histamine-binding proteins (HBPs) appear to possess two histamine-binding sites, as determined from the crystal structure of a histamine-bound HBP. They may sequester histamine at the wound site of the host to outcompete histamine receptors for histamine, thus overcoming their host’s inflammatory and immune responses (236). There is as yet no indication of the presence of mammalian counterparts for these ligand-gated ion channels or histamine-binding proteins. It therefore remains an intriguing possibility that the family of mammalian histamine receptors consists of ligand-gated ion channels, G-protein-coupled receptors, in addition to histamine-binding proteins. VI. SUMMARY During the past few years, there has been a tremendous increase in our understanding of the histamine receptors. Important progress has been made in the

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development of H 1-receptor agonists and the rationalization of H 1-receptor–ligand interaction. The recent observation of constitutive H 1- and H 2-receptor activity has led to a reclassification of H 1- and H 2-antagonists. For the H 3-receptor, a wide variety of selective and potent ligands are currently available and await clinical application. The recent cloning of the H 3-receptor gene and the anticipated generation of transgenic mice will facilitate this development. Within the field of signal transduction, a previously unanticipated complexity has been unravelled. With the cloning of the H 3-receptor gene, a similar complexity is to be expected. REFERENCES 1. Hough LB. Cellular localization and possible functions for brain histamine: recent progress. Prog Neurobiol 1988; 30:469–505. 2. Schwartz JC, Arrang JM, Garbarg M, Pollard H, Ruat M. Histaminergic transmission in the mammalian brain. Physiol Rev 1991; 71:1–51. 3. Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, Schunack W, Levi R, Haas HL. International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev 1997; 49:253–278. 4. Barnes PJ. Histamine receptors in the respiratory tract. In: Schwartz JC, Haas HL, eds. The Histamine Receptor. New York: Wiley-Liss, 1992:253–270. 5. Ash AS, Schild HO. Receptors mediating some actions of histamine. Br J Pharmacol 1966; 27:427–439. 6. Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM. Definition and antagonism of histamine H 2-receptors. Nature 1972; 236:385–390. 7. Arrang JM, Garbarg M, Schwartz JC. Auto-inhibition of brain histamine release mediated by a novel class (H 3) of histamine receptor. Nature 1983; 302:832–837. 8. Leurs R, Blandina P, Tedford C, Timmerman H. Therapeutic potentials of histamine H 3-receptor agonists and antagonists. Trends Pharmacol Sci 1998; 19:177–183. 8a. Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S. Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes. J Biol Chem 2000; 275:36781–36786. 9. Zhang M-Q, Leurs R, Timmerman H. Histamine H 1-receptor antagonists. In: Wolff ME, ed. Burger’s Medical Chemistry and Drug Discovery. New York: John Wiley & Sons, 1997:495–559. 10. van der Goot H, Timmerman H. Selective ligands as tools to study histamine receptors. Eur J Med Chem 2000; 35:5–20. 11. Zingel V, Leschke C, Schunack W. Developments in histamine H 1-receptor agonists. Prog Drug Res 1995; 44:49–85. 12. van der Goot H, Bast A, Timmerman H. Structural requirements for histamine H 2agonists and H 2-antagonists. In: Uvna¨s B, ed. Handbook of Experimental Pharmacology. Berlin: Springer-Verlag, 1991:573–748. 13. Phillips JG, Ali SM. Medicinal chemistry of histamine H 3-receptor antagonists. In: Leurs R, Timmerman H, eds. The Histamine H 3-Receptor: A Target for New Drugs. Amsterdam: Elsevier, 1998:197–222.

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205. Koizumi H, Ohkawara A. H 2-histamine receptor-mediated increase in intracellular Ca 2⫹ in cultured human keratinocytes. J Dermatol Sci 1999; 21:127–132. 206. Del Valle J, Wang L, Gantz I, Yamada T. Characterization of H 2 histamine receptor: linkage to both adenylate cyclase and [Ca 2⫹ ] i signaling systems. Am J Physiol 1992; 263:G967–972. 207. Wang LD, Hoeltzel M, Butler K, Hare B, Todisco A, Wang M, Del Valle J. Activation of the human histamine H 2-receptor is linked to cell proliferation and c-fos gene transcription. Am J Physiol 1997; 273:C2037–2045. 208. Legnazzi BL, Monczor F, Rivera E, Bergoc R, Davio C. Histamine receptors in human epithelial cells—characterization of the receptor G-protein-effector system. Inflamm Res 1998; 47(Suppl 1):S40–41. 209. Fitzsimons C, Duran H, Engel N, Molinari B, Rivera E. Changes in H 2-receptor expression and coupling during Ca 2⫹-induced differentiation in mouse epidermal keratinocytes. Inflamm Res 1999; 48(Suppl 1):S73–74. 210. Fitzsimons C, Dura´n H, Labombarda F, Molinari B, Rivera E. Histamine receptors signalling in epidermal tumor cell lines with H-ras gene alterations. Inflamm Res 1998; 47(Suppl 1):S50–51. 211. Wang LD, Hoeltzel M, Gantz I, Hunter R, Del Valle J. Characterization of the histamine H 2-receptor structural components involved in dual signaling. J Pharmacol Exp Ther 1998; 285:573–578. 212. Wang L, Gantz I, Del Valle J. Histamine H 2-receptor activates adenylate cyclase and PLC via separate GTP-dependent pathways. Am J Physiol 1996; 271:G613–620. 213. Fukushima Y, Asano T, Katagiri H, Aihara M, Saitoh T, Anai M, Funaki M, Ogihara T, Inukai K, Matsuhashi N, Oka Y, Yazaki Y, Sugano K. Interaction between the two signal transduction systems of the histamine H 2-receptor: desensitizing and sensitizing effects of histamine stimulation on histamine-dependent cAMP production in Chinese hamster ovary cells. Biochem J 1996; 320:27–32. 214. Del Valle J, Gantz I. Novel insights into histamine H 2-receptor biology. Am J Physiol 1997; 273:G987–996. 215. Dickenson JM, White TE, Hill SJ. The effects of elevated cyclic AMP levels on histamine-H 1-receptor-stimulated inositol phospholipid hydrolysis and calcium mobilization in the smooth-muscle cell line DDT1MF-2. Biochem J 1993; 292:409– 417. 216. Hall IP, Hill SJ. β-Adrenoceptor stimulation inhibits histamine-stimulated inositol phospholipid hydrolysis in bovine tracheal smooth muscle. Br J Pharmacol 1988; 95:1204–1212. 217. Hall IP, Donaldson J, Hill SJ. Inhibition of histamine-stimulated inositol phospholipid hydrolysis by agents which increase cyclic AMP levels in bovine tracheal smooth muscle. Br J Pharmacol 1989; 97:603–613. 218. Orange PR, Heath PR, Wright SR, Pearson RC. Allelic variations of the human histamine H 2-receptor gene. Neuroreport 1996; 7:1293–1296. 219. Traiffort E, Ruat M, Arrang JM, Leurs R, Piomelli D, Schwartz JC. Expression of a cloned rat histamine H 2-receptor mediating inhibition of arachidonate release and activation of cAMP accumulation. Proc Natl Acad Sci USA 1992; 89:2649–2653. 220. Leurs R, Smit MJ, Menge WM, Timmerman H. Pharmacological characterization of the human histamine H 2-receptor stably expressed in Chinese hamster ovary cells. Br J Pharmacol 1994; 112:847–854.

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221. Gantz I, Scha¨ffer M, Del Valle J, Logsdon C, Campbell V, Uhler M, Yamada T. Molecular cloning of a gene encoding the histamine H 2-receptor. Proc Natl Acad Sci USA 1991; 88:5937. 222. Alewijnse AE, Smit MJ, Rodriguez Pena MS, Verzijl D, Timmerman H, Leurs R. Modulation of forskolin-mediated adenylyl cyclase activation by constitutively active G s-coupled receptors. FEBS Lett 1997; 419:171–174. 223. Alewijnse AE, Timmerman H, Jacobs EH, Smit MJ, Roovers E, Cotecchia S, Leurs R. The effect of mutations in the DRY motif on the constitutive activity and structural instability of the histamine H 2-receptor. Mol Pharmacol 2000; 57:890–898. 224. Arrang JM, Roy J, Morgat JL, Schunack W, Schwartz JC. Histamine H 3-receptor binding sites in rat brain membranes: modulations by guanine nucleotides and divalent cations. Eur J Pharmacol 1990; 188:219–227. 225. West RE, Jr., Zweig A, Granzow RT, Siegel MI, Egan RW. Biexponential kinetics of (R)-α-[ 3 H]methylhistamine binding to the rat brain H 3-histamine receptor. J Neurochem 1990; 55:1612–1616. 226. Cumming P, Shaw C, Vincent SR. High affinity histamine binding site is the H 3receptor: characterization and autoradiographic localization in rat brain. Synapse 1991; 8:144–151. 227. Clark MA, Korte A, Egan RW. Guanine nucleotides and pertussis toxin reduce the affinity of histamine H 3-receptors on AtT-20 cells. Agents Actions 1993; 40:129– 134. 228. Clark EA, Hill SJ. Sensitivity of histamine H 3-receptor agonist-stimulated [ 35S]GTPγ[S] binding to pertussis toxin. Eur J Pharmacol 1996; 296:223–225. 229. Takeshita Y, Watanabe T, Sakata T, Munakata M, Ishibashi H, Akaike N. Histamine modulates high-voltage-activated calcium channels in neurons dissociated from the rat tuberomammillary nucleus. Neuroscience 1998; 87:797–805. 230. Nozaki M, Sperelakis N. Pertussis toxin effects on transmitter release from perivascular nerve terminals. Am J Physiol 1989; 256:H455–459. 231. Oike M, Kitamura K, Kuriyama H. Histamine H 3-receptor activation augments voltage-dependent Ca 2⫹ current via GTP hydrolysis in rabbit saphenous artery. J Physiol (Lond) 1992; 448:133–152. 232. Endou M, Poli E, Levi R. Histamine H 3-receptor signaling in the heart: possible involvement of G i /G o proteins and N-type Ca 2⫹ channels. J Pharmacol Exp Ther 1994; 269:221–229. 232a. Silver RB, Mackins CJ, Smith NC, Koritchneva IL, Lefkowitz K, Lovenberg TW, Levi R. Coupling of histamine H 3-receptors to neuronal Na⫹ /H ⫹ exchange: a novel protective mechanism in myocardial ischemia. Proc Natl Acad Sci USA 2001; 98: 2855–2859. 233. Hardie RC. A histamine-activated chloride channel involved in neurotransmission at a photoreceptor synapse. Nature 1989; 339:704–706. 234. McClintock TS, Ache BW. Histamine directly gates a chloride channel in lobster olfactory receptor neurons. Proc Natl Acad Sci USA 1989; 86:8137–8141. 235. Laughlin SB, de Ruyter van Steveninck RR, Anderson JC. The metabolic cost of neural information. Nat Neurosci 1998; 1:36–41. 236. Paesen GC, Adams PL, Harlos K, Nuttall PA, Stuart DI. Tick histamine-binding proteins: isolation, cloning, and three-dimensional structure. Mol Cell 1999; 3:661–671.

3 Structure and Classification of H 1-Antihistamines and Overview of Their Activities Giovanni Passalacqua and G. Walter Canonica Genoa University, Genoa, Italy

Jean Bousquet Montpellier University, Montpellier, France

I.

INTRODUCTION

Histamine, an ubiquitous cell-to-cell messenger, was identified in 1910 by Dale and Laidlaw (1) and has been recognized since the 1920s as a major mediator of allergic disorders such as rhinitis, asthma, urticaria, and anaphylaxis. The precise mechanism of action of histamine remained unknown until 1966, when the H 1histamine receptor was identified (2). Knowledge about the histaminergic system evolved with the subsequent discovery of the H 2-receptor (3), involved in gastric acid secretion, and the H 3-receptor (4) represented most prominently in the central nervous system (CNS) in humans. Histamine is released from basophils and mast cells following an IgE-mediated allergic reaction. The resulting inflammatory response is far more complex than previously thought, since many cell types and a wide array of inflammatory mediators including arachidonic acid metabolites, toxic proteins, cytokines, growth factors, and neuromediators are involved. Thus, it is difficult to explain why a drug that only acts on the H 1-receptor can be effective in controlling symptoms induced by an allergic reaction, unless additional anti-inflammatory properties are present. H 1-antihistamines (H 1-blockers or H 1-receptor antagonists) were discovered by Bovet and Staub at the Institut Pasteur in 1937 (5). Although the first 65

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compounds were too weak and too toxic for clinical use, their discovery led to further research and, in 1942, to the development of phenbenzamine (Antegan), the first H 1-antagonist used in the treatment of allergic diseases (6). Within a few years, three other H 1-antihistamines were synthesized: pyrilamine maleate (7), diphenhydramine (8), and tripelennamine (9), which are still in use today. Despite their pronounced side effects, these were the first really useful drugs for the symptomatic relief of allergic diseases. During the past 15 years, pharmacological research has produced several compounds with an improved benefit-to-risk ratio (therapeutic index) suitable for once-daily dosing: the so-called second-generation H 1-antihistamines, as opposed to the older first-generation H 1-antihistamines. This class of drugs has recently been the focus of considerable medical scientific interest, for two rather different reasons: its multiple antiallergic properties, and its potential cardiotoxic effects. These topics are the source of much current interest because of the widespread use of H 1-antihistamines in medical practice.

II. CHEMISTRY OF H1-ANTIHISTAMINES Histamine consists of a single heterocyclic ring (imidazole) connected directly to the ethylamine group. The unsubstituted amino-terminal H 1-antihistamines bear much less structural resemblance to histamine than do the H 2-antagonists. H 1antihistamines are nitrogenous bases containing an aliphatic side chain, sharing with histamine the common core structure of a substituted ethylamine (10). The ethylamine side chain is essential for H 1-antagonism. A methyl group in the 2 position increases, and the same group in the 4 position decreases, the relative affinity of a compound for H 1-receptors in contrast with H 2-receptors (3). The side chain is attached to one, or more often two, cyclic or heterocyclic rings that may be pyridine, piperidine, pyrrolidine, piperazine, phenothiazine, or even imidazole (AR1, AR2). These rings are connected via a nitrogen, carbon, or oxygen linkage (X) to the ethylamine group. Unlike that of histamine, the nitrogen of this ethylamine group is tertiary with two substituents (R1 and R2) (Fig. 1). A study of the structure–activity relationship indicates that not all compounds with an aliphatic side chain have antihistamine activity (11). Three features of H 1-antihistamines are of importance. First, the presence of multiple aromatic or heterocyclic rings and alkyl substituents in these antagonists results in their lipophilic properties, in contrast to histamine and H 2-antagonists, which are hydrophilic compounds. Second is the basicity of the nitrogen group as the nearer the pKa is to 8.6 the more potent the compound is. Third is the nature of the linkage atom X used to categorize the numerous H 1-antihistamines into six major classes (Fig. 2). The geometries of H 1-antagonists have been studied by x-ray crystallography and data have been compared with those obtained by minimizing the conformational energy of the molecules according to a simplified model of force

Figure 1 Structural comparison between histamine (top) and the general formula for H 1-antihistamines (bottom). (From Ref. 10.)

Figure 2 The six major groups of H 1-antihistamines.

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field. Both approaches agree in indicating unique stereochemical requirements for optimum H 1-antihistaminic activity (12). Some second-generation H 1-antihistamines have a chemical structure that differs considerably from that of old H 1-antihistamines, thereby explaining some of the properties of the new compounds (Fig. 3). Fexofenadine and levocabastine contain a piperidine ring but they cannot be directly ascribed to this class (13).

Figure 3 Structural formula of some new-generation H 1-antihistamines.

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Loratadine is related to azatadine, whereas cetirizine is a metabolite of hydroxyzine and acrivastine is structurally related to triprolidine. An additional group of compounds includes azelastine, ketotifen, and oxatomide. Although most H 1-antihistamines possess antiallergic properties, these compounds have been directly developed to be both H 1-antihistamines and inhibitors of mediator release from inflammatory cells. Tricyclic antidepressants have a common three-ring molecular core and are classified by the type of amine on the side chain into tertiary (doxepin, amitriptyline, and trimipramine) and secondary (protriptyline, nortriptyline, and desipramine) amine tricyclics (14). These compounds were initially developed for possible use as H 1-antihistamines but they were found to have potent moodelevating effects and have subsequently been used for the treatment of depression (15); however, they possess a potent inhibitory activity on histamineand allergen-induced skin tests (16).

III. PHARMACOLOGICAL EFFECTS OF H 1-ANTIHISTAMINES A. Effects Related to H 1-Receptor-Mediated Responses The pharmacological effects of H 1-antihistamines derive primarily from inhibition of histamine action at H 1-receptors. The major effects of histamine that are inhibited by H 1-antihistamines are smooth muscle contraction, increase in vascular permeability, possibly by direct action on endothelial cells (17), sensory nerve stimulation, and pruritus. H 1-antihistamines act by binding to H 1-histamine receptors. Unlike histamine, binding of the antagonists to the receptors does not elicit a tissue response. The presence of H 1-antihistamines at the receptor prevents histamine from binding and histaminic responses are therefore blocked. The firstgeneration classic H 1-antihistamines act competitively with histamine at the receptor level and their binding is readily reversible. They can be displaced by high levels of histamine or when they dissociate from the receptor. Doses of H 1-antihistamines must therefore be high enough to compete effectively with histamine for the H 1-receptor; however, the incidence and severity of side effects increase with dose, thus limiting the use of first-generation H 1-antihistamines (18). Second-generation H 1-antihistamines bind in a noncompetitive manner with the H 1-receptor (19, 20). These new compounds dissociate slowly from the histamine H 1-receptor, and are not displaced easily by histamine from the receptor site. Objective dose–response studies of H 1-receptor activity in the skin have been performed using suppression of the histamine-induced wheal and flare reactions. Results with second-generation H 1-antihistamines indicate a dosedependent increase in histamine skin test suppression. Few dose–response

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studies of H 1-antihistamines in allergic rhinitis or chronic urticaria have been published. Recommended doses for H 1-antihistamines appear to be optimal with regard to safety and should not be exceeded as, with the exception of fexofenadine, the incidence of adverse effects may increase when higher doses are used. Also, even if higher doses are given, complete symptom relief may not occur in all patients since total H 1-blockade still leaves the effects of other chemical mediators of inflammation unopposed (21). B.

Antiallergic Activities

Histamine is not the only mediator released during allergic reactions. The rank order of relative H 1-antagonism by H 1-antihistamines was studied by Simons et al. using skin tests with histamine. The order from the most effective to the least effective was found to be cetirizine, 10 mg; terfenadine, 120 mg; terfenadine, 60 mg; loratadine, 10 mg; astemizole, 10 mg; chlorpheniramine, 4 mg; and placebo (22). Other studies confirmed this ranking (23); however, when these drugs are compared in placebo-controlled clinical trials in which the outcomes are subjective relief of ocular, nasal or skin symptoms, it is usually impossible to differentiate their clinical efficacy (24–32). Skin test reactivity does not correlate with symptoms during nasal challenge (33) or the pollen season (34). This suggests that the clinical activity of these drugs involves other properties besides H 1blocking activity, or alternatively that an incomplete H 1-blockade is sufficient for clinical efficacy. Moreover, the blockade of the release of histamine by a synthesis inhibitor was unable to suppress symptoms significantly during nasal challenge (35). Thus, it appears that properties in addition to H 1-blockade are desirable for drugs that relieve the symptoms of the allergic reaction. Over the past 15 years, it has become clear that most first- and second-generation H 1-antihistamines have such antiallergic properties (36), although the properties differ depending on the H 1-antihistamine and the cells and experimental conditions used (37–41). In vitro, high concentrations of H 1-antihistamines are able to block mediator release from basophils and human mast cells (42–46) by mechanisms that are not yet completely understood (47). These antiallergic effects can also be seen in vivo in skin, nasal, lung, and ocular challenge studies. Using nasal challenge with allergen, it has been observed that azatadine, loratadine, and terfenadine reduce histamine, PGD2, and kinin release during challenge (48–51). Cetirizine was found to reduce tryptase levels in nasal secretions (52). Azelastine (53) and cetirizine (51) decrease release of leukotrienes. On the other hand, the effects of ketotifen were disappointing in this particular model since mediator release was not blocked as expected (54). Ebastine reduced cytokine production (37). Cetirizine, at least in some studies in the skin, reduced eosinophil chemotaxis after allergen challenge (55–59), but

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had no effect on eosinophils after allergen bronchial (60) or nasal challenge (61). Moreover, terfenadine, cetirizine, and loratadine decreased the expression of intracellular-adhesion molecule-1 (ICAM-1) on cells from conjunctival or nasal secretions during allergen challenge (62–66) or natural allergen exposure to pollens (67–72) or mites (73). The extent of these antiallergic effects is not completely understood, yet these studies have led to the concept of antiallergic drugs with H 1-blocking properties (36, 74). It would be premature to attempt to reclassify the H 1-antihistamines according to their antiallergic properties because these have not been fully investigated. Their relative contribution to the overall therapeutic effectiveness of each H 1-antihistamine is unknown (75). Due to their variable H 1-blocking activity and antiallergic effects and possibly due to differences in lipophilicity and tissue deposition, the various H 1antihistamines are not equally effective in reducing skin, nose, eye, or lung symptoms. Moreover, it appears that not all H 1-antihistamines have identical effects in various patients, since nonresponders to one may respond favorably to another (76). C. Adverse Effects Unrelated to H 1-Activity Most, if not all, first-generation H 1-antihistamines possess pharmacological effects that are not related to H 1-activity. Many H 1-antihistamines block cholinergic muscarinic receptors in a dose-dependent manner. Quantitative evaluation of antimuscarinic effects of antihistamines (H 1- and H 2-receptor antagonists) was carried out using a receptor-binding assay. Mequitazine, cyproheptadine, clemastine, diphenylpyraline, promethazine, homochlorcyclizine, and alimemazine had high affinities for the muscarinic receptors (Ki ⫽ 5.0–38 nM). Another group of H 1receptor antagonists (mepyramine, terfenadine, methapyralene, azelastine, hydroxyzine, and meclizine) exhibited low affinities for the muscarinic receptors (Ki ⫽ 3,600–30,000 nM) (77). Based on molecular cloning studies, five different muscarinic receptor subtypes exist: m1, m2, m3, m4, and m5. Stanton et al. (78) determined the affinity and selectivity of binding for three H 1-antihistamines using Chinese hamster ovarian cells (CHO-K1) transfected with genes for the human muscarinic receptor subtypes. The compounds studied showed no significant selectivity among the five cloned subtypes in vivo. The most common anticholinergic side effects at usual dosages consist of dryness of the mouth and of the mucous membranes of the nose and the throat. In susceptible individuals, urinary retention and blurred vision may occur. At higher doses, more severe anticholinergic effects may be observed. Some H 1-antihistamines have local anesthetic effects, possess membranestabilizing or quinidine-like effects on cardiac muscle, and are responsible for a prolongation of the refractory period in the myocardium and torsade de pointes

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(79). These effects have been highlighted recently by the potentially fatal cardiotoxicity of the H 1-antihistamines astemizole and terfenadine. The cardiac effects of H 1-antihistamines are reviewed in Chapter 12. Certain H 1-antihistamines, particularly promethazine, possess α-adrenergic receptor-blocking properties. Some H 1-antihistamines increase adrenergic effects by cocaine-like activity, decreasing transmitter reuptake. Other H 1-antihistamines possess antiserotonin (80) or antidopamine effects (phenothiazines) (81). Several but not all H 1-antihistamines are analgesic agents or adjuvants. They include diphenhydramine, hydroxyzine, orphenadrine, pyrilamine, phenyltoloxamine, promethazine, methdilazine, and tripelennamine. More than one mechanism of action exists for them. Considerable evidence suggests that histaminergic and serotoninergic central pathways are involved in nociception and that H 1-antihistamine drugs can modulate these responses. The evidence for a role for norepinephrine and dopamine and the effects of H 1-antihistamines on their pathways is less well established (82). Histamine H 1-receptors are involved in the development of the symptoms of motion sickness, including emesis. On provocative motion stimulus, a signal for sensory conflict activates the histaminergic neuron system and the histaminergic descending impulse then stimulates H 1-receptors in the emetic center of the brainstem. The histaminergic input to the emetic center via H 1-receptors is independent of dopamine D2-receptors in the chemoreceptor trigger zone and serotonin 5HT3-receptors in the visceral afferents that are also involved in the emetic reflex. H 1-antihistamines block emetic H 1-receptors to prevent motion sickness. Acetylcholine muscarinic receptors are involved in the generation of signals for sensory conflict. Anticholinergic drugs prevent motion sickness by modifying the neural store to facilitate habituation to provocative motion stimuli (83–85). D.

Central Nervous System Side Effects

In the CNS (86), histamine is considered to be both a local hormone and a neurotransmitter and is synthesized primarily by neurons and mast cells. The three types of receptors are present in the CNS but differ in their localization, biochemical machinery, function, and affinities for histamine. H 1-receptors, visualized by autoradiography, are widespread throughout the CNS. The most important physiological role of histamine at H 1-receptors in the CNS is to control vigilance in the waking state. The most common side effects of first-generation H 1-antihistamines are sedation, impaired coordination, dizziness, lassitude and inability to concentrate, and, occasionally, paradoxical stimulation. Sedation ranging from mild drowsiness to deep sleep can occur frequently, even at the usual therapeutic doses. The CNS side effects of H 1-antihistamines can be attributed either to the poor selectivity for the H 1-receptor or to the capacity to cross the blood–brain

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barrier (87). This latter concept involves a number of different factors: lipophilicity (88, 89), ionization, binding to serum proteins, and presence of active transportation. Second-generation relatively nonsedative H 1-antihistamines do not cross this barrier to the same extent as their predecessors. Moreover, there is a highly significant correlation between the sedation caused by H 1-antihistamines and the level of their binding to brain receptors (90). Nonsedative H 1-antihistamines may have a reduced affinity for CNS histamine receptors (91, 92). The second-generation H 1-antihistamines are mostly devoid of CNS side effects (93). A battery of cognitive and psychomotor tests has been used to assess both objective and subjective sedative effects of these medications. They include tests of psychomotor performance, sensorimotor coordination, speed, information processing, sensory skills, as well as physiological measures and subjective rating scales. At therapeutic doses, most of the new compounds are relatively free from sedative effects (for review see 94–99), and, unlike the first-generation H 1antihistamines (100), do not exacerbate the CNS effects of alcohol and vice versa (101–103). Elderly patients present a greater risk for CNS side effects and first-generation H 1-antihistamines should no longer be used in this population (104) (Chap. 15). E.

Cardiac Side Effects

During the past 15 years, arrhythmogenic effects and fatalities have been attributed to terfenadine and astemizole (96, 105, 106), which have been withdrawn in several countries due to their potential cardiotoxicity. This is not a class effect. It is a quinidine-like action that involves an abnormal prolongation of the QT interval (107), possibly leading to torsade de pointes, ventricular tachycardia, atrioventricular block, and cardiac arrest (79, 108–140). The molecular mechanism sustaining the cardiotoxic action is the blockade of some potassium channels on ventricular myocytes, namely Ikr and Ik1, which are responsible for the inward rectifier current (141–143). The proclivity to block ion channels depends upon the molecular structure of the drug and is maximal for terfenadine and astemizole. The blockade of these channels may occur, and become clinically significant, in the case of increased plasma concentration of the drug due to an overdose or to impaired metabolism. There is a dose-dependent effect on cardiac toxicity and this is of relevance for drugs metabolized by the P-450 cytochrome system. The concomitant administration of compounds that compete with the enzyme (macrolide antibiotics, imidazole antifungals) may reduce metabolism of the H 1-antihistamine and increase its plasma concentration. Loratadine (144–146) and ebastine (147, 148), although metabolized in the liver, do not appear to possess the intrinsic capacity to block

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ion channels. On the other hand, cetirizine (149) and fexofenadine (150, 151) are eliminated mostly unchanged. Mizolastine is extensively metabolized. In doses up to 40 mg (four times the therapeutic dose) there is no evidence of an effect on ventricular repolarization in healthy volunteers (153). F.

Gastrointestinal Disturbances

Gastrointestinal disturbances including nausea, vomiting, diarrhea, loss of appetite, and epigastric distress are produced by some members of the ethylenediamine class. G.

Tumor Promotion

The potential tumor-promoting effects of some H 1-antihistamines were reported in a single study in mice injected in the intraperitoneal space with melanoma or fibrosarcoma cells (154), but these results have not been confirmed. Moreover, results obtained in rodents are not directly applicable to humans because of the experimental conditions and the different cellular metabolic systems involved (155, 156). During 60 years of use there has been no clinical evidence of tumor-promoting effects of the commercially available H 1-antihistamines (157). Therefore, this should not be considered to be a possible side effect of H 1-antihistamines.

IV. FIRST-GENERATION H 1-ANTIHISTAMINES First-generation H 1-antihistamines are usually classified into six different groups based on their chemical structure. In addition to their H 1-antagonist effects, they have anticholinergic and antiserotonin effects that contribute to their adverse effect profiles. A.

Group I: Ethylenediamines

These include pyrilamine, antazoline, methapyrilene (158), and tripelennamine. These drugs have relatively weak CNS effects but gastrointestinal side effects are common. Methapyrilene was found to possess carcinogenic properties (159) and is no longer available for use. B.

Group II: Ethanolamines

These include diphenhydramine (8, 160), bromodiphenhydramine, carbinoxamine (161), clemastine (162), doxylamine, and phenyltoloxamine (163). These drugs have significant anticholinergic side effects and cause overt sedation in

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about half of users. The incidence of gastrointestinal side effects is relatively low. Diphenhydramine is sometimes used as a sedative (due to its antihistamine effects) or to improve voluntary movements in patients with Parkinson’s disease (due to its anticholinergic effects). C. Group III: Alkylamines These include chlorpheniramine (164, 165), brompheniramine (166), dexbrompheniramine, dexchlorpheniramine, dimethindene (167–169), pheniramine, and triprolidine (170), which cause overt sedation in about 40% of users. D. Group IV: Phenothiazines Among these are promethazine, mequitazine, methdilazine, and trimeprazine (171). Sedative and anticholinergic side effects are common with these drugs, which are now primarily used as antiemetics (172). Mequitazine is effective in the treatment of allergic rhinitis (26) but it is moderately sedative (173, 174) and possesses anticholinergic effects (175, 176). E.

Group V: Piperazines

These include cyclizine (170, 177), buclizine, chlorcyclizine, hydroxyzine (178, 179), and meclizine, and induce mild to moderate sedation and anticholinergic side effects in most users. Cyclizine, buclizine, and meclizine are used for treating motion sickness or vertigo. Hydroxyzine is used as an H 1-antagonist (180, 181) as well as a sedative, tranquilizer, and antiemetic. F.

Group VI: Piperidines

Among these are cyproheptadine (180, 181) and azatadine (182–184). These drugs possess sedative and anticholinergic side effects. Cyproheptadine is used as an appetite stimulant. Conflicting observations concerning the action of cyproheptadine on pituitary function have been reported in the literature. This may be a reflection of the diversity of pharmacological actions of this drug, which include a potent antiserotonin activity (185, 186). First-generation H 1-antihistamines should no longer be used for allergic rhinitis or chronic urticaria treatment owing to their side effects, among which sedation, impaired driving performance (187, 188), and anticholinergic activity are the most important. Tachyphylaxis in response to chlorpheniramine may occur (189–191), in contrast to the second-generation H 1-antihistamines, for which tachyphylaxis has not been reported (192, 193).

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SECOND-GENERATION H 1-ANTIHISTAMINES

Second-generation H 1-antihistamines have been developed over the last 15 years and can be differentiated from the first-generation H 1-antihistamines by many properties, two of which are of great importance: the kinetics of their binding to and dissociation from the H 1-receptor and their lack of appreciable CNS and anticholinergic side effects. Some of these drugs have been formulated for topical use on the nasal mucosa and conjunctiva. A.

General Properties

Ideally, second-generation H 1-antihistamines should incorporate the properties discussed below. 1. Pharmacological Properties Agents should provide potent and noncompetitive H 1-receptor blockade as well as antiallergic activities. 2. Side Effects Formulations should cause no or little sedation, have no anticholinergic effect, and cause neither weight gain nor cardiac side effects. 3. Pharmacokinetics The ideal agent should have a rapid onset of action and food should not interfere with its absorption. It should have a long duration of action (24 h) after oncedaily administration. It should not cause development of tachyphylaxis (192, 193) and should not interact with cytochrome P-450. All the newer H 1-antihistamines (except cetirizine and fexofenadine) undergo hepatic metabolism via the cytochrome P-450 system and most are transformed into active metabolites. Cytochrome P-450 (CYP3A) is involved in the metabolism of many chemically diverse drugs administered to humans (194, 195). Moreover, its localization in high concentrations both in the small intestinal epithelium and liver makes it a major contributor to presystemic first-pass elimination following oral drug administration. Drug interactions involving enzyme inhibition or induction are common following the coadministration of two or more CYP3A substrates (196). 4. Clinical Activities The new H 1-antihistamines are highly selective for H 1-receptors and therefore they are effective in reducing itching, sneezing, and watery rhinorrhea in allergic rhinitis (for review on clinical efficacy, see Refs. 197–202), but they are less

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effective in treating nasal congestion (203). It is important to note that an H 1antihistamine, when administered orally, also exerts its effects on nonnasal symptoms such as allergic conjunctivitis and the mild asthma which is often associated with allergic rhinitis. It has been shown that long-term continuous treatment with H 1-antihistamines is more advantageous and effective than ‘‘on demand’’ treatment (204). In addition to improving lower respiratory tract symptoms (205), these agents may delay asthma onset in a subset of infants with house dust mite or grass pollen sensitization (206). Some H 1-antihistamines (azelastine, ketotifen, levocabastine) can be administered locally to the nose or the eyes. The major advantage of delivering drugs directly to the nasal mucosa or the conjunctiva is that high concentrations can be delivered more effectively into the target organ. Topical H 1-antihistamines have a rapid onset of action (within 15 min) at low dosage, but their actions are limited to the treated organ. Topical H 1-antihistamines usually require twice-daily (bid) administration to maintain a satisfactory clinical effect. Their use may therefore be recommended for mild organ-limited disease and as an ‘‘on demand’’ treatment in addition to regular medication (207). B. Specific Properties Second-generation H 1-antihistamines have similar efficacy, but differ in their clinical pharmacology and safety profiles. Additional H 1-antihistamines in various stages of development at this time include desloratadine, emedastine, epinastine, levocetirizine, and tecastemizole (208). 1. Acrivastine Acrivastine is a side-chain-reduced relative of the first-generation antihistamine triprolidine. It is a very short-acting histamine H 1-receptor antagonist with a rapid onset of action. Randomized controlled trials have shown acrivastine (usually 8 mg three times daily) to be an effective antihistamine in the treatment of chronic urticaria (209) and allergic rhinitis (210). Acrivastine was found to cause less drowsiness than clemastine (211), but it does seem to have some sedative effects (212) and CNS interactions with alcohol have been observed (213). Because of its rapid onset of action, acrivastine is useful for ‘‘on demand’’ therapy in patients with intermittent symptoms (214). 2. Astemizole Astemizole [1-(4-fluorophenylmethyl)-N-1(2-(4-methoxyphenyl)ethyl)-4piperidinyl-1H-benzamidazole-2-amine] is a long-acting, highly selective H 1antagonist with no CNS or anticholinergic effects (20, 215, 216). Due to its

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potential cardiac toxicity, it has been withdrawn from the market in most countries. 3. Cetirizine Cetirizine, [2-[(4-chlorophenyl)phenylmethyl-1-piperazinyl)ethoxy] acetic acid dihydrochloride, a piperazine derivative and carboxylated metabolite of hydroxyzine, is a specific and long-acting histamine H 1-receptor antagonist. The H 1blocking activity of cetirizine is extremely potent (22). It also inhibits eosinophil chemotaxis during the allergic response in the skin (217–219) but not in the nose. Cetirizine is not extensively metabolized in the liver and no cardiac side effects have been reported. Randomized controlled trials indicate that cetirizine 10 mg daily is an effective treatment for seasonal and perennial allergic rhinitis (220– 230) and for allergic conjunctivitis (231, 232). It also has a role in the treatment of certain forms of physical urticaria, atopic dermatitis, and reactions to mosquito bites (233). It is associated with a significantly lower incidence of sedation than hydroxyzine; however, when sedation was subjectively assessed, cetirizine appeared to be more sedating than placebo or other second-generation H 1-antihistamine such as loratadine in some, but not all, double-blind studies (234). In contrast, when assessed objectively in pharmacodynamic comparisons, cetirizine rarely had more CNS effects than placebo or other second-generation histamine H 1-antagonists (197, 235). 4. Ebastine Ebastine, 4-diphenylmethoxy-1-[3-(4-ter-butylbenzoyl)-propyl piperidine, a piperidine derivative, and its active metabolite carebastine are selective H 1-receptor antagonists (236) devoid of any other noticeable receptor binding. Ebastine has less affinity for central than for peripheral H 1-receptors. Randomized controlled trial have shown that, administered at a dosage of 10 mg daily, ebastine was effective in the treatment of seasonal (237–239) and perennial allergic rhinitis (240, 241). However, a dosage of 20 mg daily was found to be more effective and a dual dosage has been suggested; 10 mg for seasonal (242) and 20 mg for perennial rhinitis (241, 243). Administered at a dosage of 10 or 20 mg daily, ebastine was not found to induce sedation (244). No interactions with alcohol (245) have been reported. Ebastine appears to be free from cardiovascular side effects at dosages of 10 mg or 20 mg daily (246). 5. Fexofenadine Fexofenadine is the pharmacologically active metabolite of terfenadine (247). It is a potent H 1-antihistamine in skin test models (198, 248, 249). Its pharmacokinetics have been studied in adults and children (250) and support once-daily

Structure and Classification

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dosing. Randomized controlled trials have found that fexofenadine is effective in seasonal allergic rhinitis and urticaria (151, 225, 251–253). Fexofenadine is nonsedating in dosages up to 240 mg daily (151, 225, 251, 252) and does not impair driving performance. It does not potentiate alcohol sedative effects or have any cardiac side effects in dosages up to 690 mg twice daily for 28 days (254). 6. Levocabastine Levocabastine (3S-(1(cis)-3α, 4β))-1[-[4-cyano-4(4-fluorophenyl)cyclohexyl]3-methyl-4-phenyl-4-piperidine carboxylic acid monochloride] is a cyclohexylpiperidine derivative shown to possess long-lasting H 1-antagonism and antiallergic properties (255). It has only been developed for nasal mucosal and conjunctival administration due to its sedative effects. In controlled trials, levocabastine was effective and well tolerated in the treatment of allergic rhinitis and allergic conjunctivitis. Randomized controlled trials have demonstrated that levocabastine is superior to placebo and at least as effective as sodium cromoglycate in alleviating symptoms of seasonal allergic rhinitis (256–261) and conjunctivitis (262–268); however, it is less effective than topical corticosteroids in relieving rhinorrhea and nasal congestion. The incidence of adverse effects associated with topical levocabastine therapy is low and similar to that observed with placebo or sodium cromoglycate (269). No sedation was observed after use of eye drops (270). 7. Loratadine Loratadine (ethyl-4 (8-chloro-5,6-dihydro-11H-benzo (5-6)-cyclo-hepta (1,2-b) pyridine 11-ylidene)-1 piperidine carboxylate) has high selectivity for peripheral histamine H 1-receptors (271). It is rapidly metabolized into an active metabolite, descarboethoxyloratadine. Although it is metabolized by the cytochrome CYP3A4 system in the liver, an alternative pathway CYP2D6 is available and no accumulation has been reported. Randomized controlled trials have shown that loratadine (10 mg daily) is a well-tolerated and effective H 1-antagonist in seasonal and perennial allergic rhinitis and chronic urticaria (24–28, 34, 272– 277). No sedative effect of loratadine is observed at recommended dosages (92, 188, 278, 279). No cardiac side effects have been observed. 8. Mizolastine Mizolastine, an H 1-antihistamine (153, 280) without anticholinergic effects (281, 282), has antiallergic and anti-inflammatory effects in animals (283–285) and healthy volunteers. Randomized controlled trials have shown that mizolastine is effective in the treatment of seasonal and perennial allergic rhinitis (200, 286– 289). Mizolastine 10 mg daily is generally well tolerated, with the most common

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adverse events, including sedation, being similar to those reported after placebo. The incidence of prolonged QTc interval was similar in mizolastine- and placebotreated subjects (153, 290), although mizolastine is contraindicated in those with cardiac disease or hepatic impairment or in those receiving erythromycin, ketoconazole, or class I or III antiarrhythmic agents. 9. Terfenadine Terfenadine (alpha-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1piperidinebutanol) is a selective histamine H 1-receptor antagonist devoid of CNS and anticholinergic activity (291). Due to its potential cardiac toxicity, terfenadine has been withdrawn from use in most countries (292).

VI. OTHER H 1-ANTIHISTAMINES A.

Azelastine

Azelastine [(4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)phthalazinone hydrochloride)] demonstrates H 1-receptor antagonist activity and also inhibits mediator release from mast cells and other cells involved in the allergic inflammation following antigenic and nonantigenic stimuli (293–300). Azelastine antagonizes histamine- and leukotriene-induced bronchospasm in animal studies and reduces airway responsiveness to inhaled antigen or distilled water and exercise challenge. Randomized controlled trials have shown that orally administered azelastine in dosages up to 4 mg daily significantly relieved symptoms in patients with seasonal (301) or perennial allergic rhinitis (302). In addition, azelastine administered as a topical intranasal (303–306) or ophthalmic formulation (307–310) is effective in alleviating symptoms of seasonal and perennial allergic rhinitis and conjunctivitis. As an antiasthmatic agent, azelastine 4 mg twice daily orally is superior to placebo and comparable to oral ketotifen 2 mg daily and sustained-release theophylline 700 mg daily. Azelastine is generally well tolerated: the most common adverse effects, altered taste perception and drowsiness, are less frequent after topical application than after oral administration (297). B.

Ketotifen

Ketotifen [(4-/1-methyl-4-piperidylidene/-4H-benzo[4,5]cyclohepta[1,2-b] thiophen-10(9H)-1-one hydrogen fumarate)] is an H 1-antagonist with antiallergic properties. After 6–12 weeks of administration, ketotifen significantly reduces respiratory symptoms and the need for concomitant antiasthmatic drugs in patients with mild to moderate bronchial asthma; however, improvement in lung

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function is generally minimal. Ketotifen has shown efficacy in patients with atopic dermatitis, seasonal or perennial rhinitis, allergic conjunctivitis, and chronic or acute urticaria. Side effects include sedation and weight gain (311). C. Oxatomide Oxatomide, ((diphenylmethyl-4-piperazinyl-1)-3 propyl)-1,3 H benzimidazolone-2, is an orally active H 1-histamine receptor antagonist that also inhibits mediator release (312). It is mostly used in the treatment of chronic urticaria. Some patients responding to oxatomide were said to have been unresponsive to previously administered antihistamines. Sedation is a common side effect, as is weight gain (313).

VII. SUMMARY: FUTURE OF H 1-ANTIHISTAMINES With cloning of the gene encoding the histamine H 1-receptor (314–316), a new area of histamine research has become reality. It seems feasible to study the target of the therapeutically important H 1-antihistamines. Expression of the genes in mammalian cells allows detailed investigations of the various signal transduction routes of the histamine H 1-receptor (317). Moreover, using molecular biological techniques, it is now possible to investigate ligand–receptor interaction at the molecular level (318, 319). It is expected that these new developments will provide fundamental information about ligand interaction with the H 1-receptor (320).

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Structure and Classification

84. 85. 86. 87.

88. 89. 90.

91. 92.

93.

94.

95.

96.

97.

98.

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194. 195. 196. 197.

198. 199. 200.

201. 202. 203.

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211.

212. 213.

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221. 222.

223.

224.

225.

226.

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227.

228.

229. 230.

231. 232. 233. 234.

235. 236. 237.

238.

239.

240.

241.

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4 Antiallergic Anti-Inflammatory Effects of H1-Antihistamines in Humans Paraya Assanasen and Robert M. Naclerio University of Chicago, Chicago, Illinois

I.

INTRODUCTION

There is increasing evidence that some H 1-receptor antagonists possess a variety of activities not explained by H 1-antagonism. These antiallergic, anti-inflammatory activities can be studied in vitro, in vivo, and ex vivo. In vivo (in humans) allergen challenge of the skin, nose, lung, and eye has been useful in studying the role of anti-inflammatory properties. The clinical significance of antiallergic, anti-inflammatory effects beyond H 1-receptor blockade is currently an important area of investigation. In this chapter, we begin by describing the pathophysiology of nasal allergic inflammation and a human nasal model for the study of the antiallergic antiinflammatory effects of antihistamines. Different H 1-antagonists and available human data on these effects of antihistamines are then reviewed.

II. PATHOPHYSIOLOGY OF ALLERGIC INFLAMMATION To understand the antiallergic, anti-inflammatory effects of H 1-receptor antagonists, it is necessary to appreciate the pathophysiology of allergic inflammation, which begins with a sensitization phase followed by a clinical phase (Fig. 1). Individuals with a genetic predisposition to allergic disease develop IgE antibodies to allergens after exposure, called ‘‘sensitization.’’ Allergens are processed by antigen-presenting cells (macrophages, dendritic cells) and presented to T101

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Figure 1 Simplified schematic representation of the development of allergic rhinitis. During phase 1, persons become sensitized to an allergen, and during phase 2 clinical disease develops. The majority of patients have an early response on exposure to allergen. The early response is dominated by activation of the mast cells and release of mediators. After the early response, most patients have cellular infiltration of the nasal mucosa that causes late inflammatory events. These include the spontaneous recurrence of release of mediators (late-phase reaction), hyperresponsiveness to irritants, and increased responsiveness to allergen (priming). The circles indicate the heterogeneity of these late inflammatory events. The inflammation can resolve spontaneously, cause a complication, or potentially lead to an irreversible form of chronic rhinitis. (From Naclerio RM. N Engl J Med 1991; 325: 860–869.)

helper cells (Th: CD4⫹) and, in turn, B cells. Interleukins (IL), especially IL-4 and IL-13 from Th2 lymphocytes, favor IgE synthesis by B cells. Allergen-specific IgE binds to high-affinity receptors on mast cells and basophils and to lowaffinity receptors on other cells, including monocytes, eosinophils, and platelets (2–5). The early-phase response (EPR) begins when subsequent exposure to an allergen leads to cross-linking of adjacent IgE molecules, and mast cells degranulate, releasing multiple inflammatory mediators such as histamine, leukotriene C4 (LTC4 ), and prostaglandin D2 (PGD2 ) (6). In allergic rhinitis, the mediators stimulate the nasal end organs (nerves, glands, and blood vessels) to produce itching, sneezing, rhinorrhea, and congestion. These symptoms usually resolve spontaneously, but may return 3–10 h after allergen challenge. Spontaneous recurrence of symptoms occurs in approximately 50% of persons with seasonal allergic rhinitis (7). The dominant symptom in this late-phase response (LPR) is nasal congestion. On histological examination, the LPR is

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characterized by cellular influx of eosinophils, neutrophils, basophils, mononuclear cells, and T cells. The principal cells entering nasal secretions are eosinophils, whereas Th lymphocytes predominate in the submucosa, suggesting that secretions and the nasal mucosa are distinct compartments with different cellular arrays and cytokine profiles (8). Eosinophils can contribute mediators, neurotoxins, and peroxidases to the inflammatory milieu of the LPR. Activated basophils rather than mast cells cause histamine release during the LPR (9). Recruited basophils can also serve as targets during subsequent allergen exposure. In addition to the mediators secreted by these inflammatory cells, cytokines such as IL-4 produced by mast cells (10), IL-3, IL-4, IL-5, granulocyte macrophage-colony stimulating factor (GM-CSF) by Th2 lymphocytes, and IL-6 by epithelial cells (11) are released to orchestrate and regulate the inflammatory response. Neuronal reflexes also play a role in the allergic response, by mediating local responses to mediators and possibly by playing a part in the activation of T lymphocytes (12). Recruitment of cells such as eosinophils and activated T lymphocytes is mediated, in part, by interactions between adhesion molecules both on the cells themselves and on vascular endothelial cells, with cytokines playing a variety of regulating roles in these interactions. A series of events occurs during the migration of circulating leukocytes in response to inflammatory stimuli: leukocyte activation, vascular endothelial cell expression of adhesion molecules, adhesion of leukocytes to vascular endothelium, rolling of leukocytes along the vessel wall, transendothelial migration into the mucosa, and migration across the epithelium into nasal secretions. Important adhesion molecules expressed on endothelial cells include intercellular adhesion molecule-1 (ICAM-1), E-selectin, and vascular cell adhesion molecule-1 (VCAM-1). Their ligands on eosinophils include lymphocyte function-associated antigen-1 (LFA-1) and macrophage antigen-1 (Mac-1) for ICAM-1, very late antigen-4 (VLA-4) for VCAM-1, and sialyl-Lewis X for E-selectin. These adhesion molecules and their coreceptors participate in the migratory process. Once inflammatory cells have left the vascular compartment, they make their way through the extracellular matrix to the site of inflammatory reaction, and finally, to the mucosal surfaces. It has recently been found that epithelial cells contribute to the pathophysiology of the allergic inflammation at the mucosal level, besides providing a natural barrier against particulates, bacteria, and allergen. For example, epithelial cells can synthesize and release a wide range of mediators, including IL-1, IL-1β, IL6, IL-8, GM-CSF, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, and regulated on activation, normal T-cell expressed and secreted (RANTES) (13). A number of studies have suggested an increase in levels of adhesion molecule expression on the nasal epithelium during allergic inflammation. Nasal epithelial cells of patients with allergic rhinitis express increased ICAM-1 after ei-

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ther seasonal exposure (14) or allergen challenge (15). Asymptomatic patients sensitive to house dust mites express ICAM-1 on nasal and conjunctival epithelial cells (16). Moreover, a number of inflammatory cytokines, such as interferon (IFN)-γ, TNF-α, IL-1β, IL-4 (17, 18), and eosinophil cationic protein (ECP) and major basic protein (MBP) (19), can induce upregulation of epithelial ICAM-1 expression in vitro. The increased epithelial ICAM-1 by ECP and MBP might indicate a feedback mechanism responsible for epithelial damage and shedding via eosinophil products (13). An increase in the epithelial expression of ICAM-1 is an early signal of the development of inflammation and can be monitored as such. Allergic inflammation not only involves an EPR and LPR but also leads to increased sensitivity to allergen, known as the priming effect. The increased responsiveness after allergen provocation reverses spontaneously when allergen exposure ceases. Priming mechanisms probably involve cellular infiltration, increased mediator production, and increased end-organ responsiveness. Influx of inflammatory cells is hypothesized to alter the mucosal penetration of allergen, to provide additional targets for allergen stimulation, to increase the generation of inflammatory mediators, and to increase end-organ responsiveness. Patients with allergic rhinitis also show hyperresponsiveness to nonantigenic stimuli such as histamine, cold, dry air, and methacholine (12, 20, 21). Several studies show a dissociation between nasal hyperresponsiveness to methacholine after allergen challenge and the influx of eosinophils into nasal secretions (21–23). These studies suggest that the allergen-induced increase in nonspecific responsiveness is a complex phenomenon. It probably reflects interactions among inflammatory cellular influx, epithelial injury, and increased end-organ responsiveness and is not dependent solely on eosinophil influx into the nasal mucosa. In summary, allergic inflammation can be characterized as an initial sensitization phase, in which allergen presentation results in antibody (IgE) formation, and a clinical disease phase, in which symptoms develop during exposure to allergen. The clinical condition involves an early- and late-phase inflammatory reaction. The former involves mast cell degranulation, and the latter is associated with cellular infiltration and release of cytokines into the nasal mucosa. The production of cytokines and the interactions of mediators result in an extremely complex network, directing adhesion molecule expression, production of chemoattractants, and subsequent recruitment of inflammatory cells that affect the response to additional allergenic and nonallergenic stimuli.

III. HUMAN MODELS FOR THE STUDY OF ANTIALLERGIC EFFECTS OF ANTIHISTAMINES Nasal challenge with allergen has helped us to understand the pathophysiology of allergic inflammation and the action of H 1-antihistamines and other medica-

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tions, and facilitates quantitative assessments of the release of inflammatory mediators during the early and late nasal allergic response (24). Nasal provocation involves direct application of allergen to the nasal mucosa and observation of the response both objectively and subjectively. It can be performed easily and frequently and has several advantages over other types of provocation challenge. First, the human nasal mucosa is the organ in which allergic rhinitis occurs. Second, the technique examines the organ in its entirety, not isolating any single element. Third, the human condition is not necessarily mimicked in animal models. Fourth, nasal challenge is a simple, safe, reliable, and reproducible tool for evaluating the effectiveness and possible mode of action of medications used in the treatment of allergic rhinitis. A. General Considerations Several methods for the provocation and measurement of the nasal response have been used in recent years. Each technique or model has its own advantages and disadvantages. For experimental research, quantitative measurements with high reproducibility are essential (25). The interpretation of the results demands basic knowledge of the techniques employed, as well as of the study design. All provocation studies require careful selection of participants, including an assessment of the disease state by using subjective and objective parameters. The participants should be free of other underlying diseases and should not be taking any medications that may confound the interpretation of results. We prefer to challenge patients with seasonal allergic rhinitis out of season, because pollen exposure can prime their mucosa and affect the laboratory responses in vivo during the season and for weeks afterward. They should be studied during the asymptomatic stage several weeks after termination of the pollen season, and at least 2 weeks should pass between challenges, to avoid the priming effect. Nasal challenges with histamine or methacholine have been used to assess the nonspecific hyperreactivity of the nasal mucosa after allergen challenge. Both histamine and methacholine induce a dose-dependent increase in secretion weights on the challenged (ipsilateral) side, whereas only histamine induces a contralateral reflex rhinorrhea (26). The use of a control group is essential for assessment of the ‘‘placebo effect’’ or other potential confounding environmental factors (27). B. Allergen Precise quantification of the amount of allergen to be used for challenge is essential. The purity and stability of the allergen must be known. Allergens are usually given as aqueous solutions, powder, or pollen grains mixed with lactose in capsules. We prefer to use standardized and lyophilized extracts. Aqueous extracts

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must be stored appropriately as their potency may decrease rapidly. Optimal allergen concentrations, which vary for seasonal and perennial allergens, should be selected. In general, the amount of administered allergen that causes asymptomatic individuals to respond is far greater than that required during several days of natural pollen exposure, mostly because of the priming effect that occurs during natural exposure. C.

Delivery System

Delivery systems for liquid extracts commonly include nebulizers, atomizers, metered-dose inhalers, direct instillation, and placement of extract-soaked paper discs in the nose. The choice of a delivery system depends on the question being addressed by the experiment. It must be reproducible, and its effect on the parameters being measured must be known. The diluent used for the allergen extract and preservatives such as glycerol, benzalkonium chloride, or phenol may induce nonspecific nasal reactions. The diluent is often administered before the allergen exposure so that its effect can be studied. In addition, with all delivery systems, an attempt should be made to minimize the exposure of the lower airways to allergen, because allergen deposited in the lower airway can cause bronchoconstriction. D.

Assessment of the Response

1. Subjective The subjective assessment of symptoms by either participants or the observer can be recorded using different techniques, such as symptom scores or a visual analog scale. Congestion, rhinorrhea, and itching are easy to self-assess and yield valuable information. Sneezes counted by the investigator provide an objective symptom index. At least one additional objective measurement of the nasal response should be used to strengthen the validity of any observations. 2. Outcomes Evaluated Nasal Airway Resistance. Nasal congestion is one of the cardinal symptoms of allergic inflammation and the major symptom of the LPR following allergen challenge. Rhinomanometry measures nasal airway resistance (NAR) by quantitatively measuring nasal airflow and pressure. Active anterior rhinomanometry is used most frequently as it is well tolerated by patients. Posterior rhinomanometry is preferable because it does not distort the nasal valve, but only about 85% of volunteers can successfully perform this maneuver (28). The physiological fluctuation in nasal resistance, termed the nasal cycle, may interfere with nasal

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monitoring in the nasal provocation test (29). A large number of subjects and/ or a large change in resistance are needed to overcome the variations in this measurement. Inspiratory Nasal Peak Flow. This is the simplest technique for detecting changes in nasal patency for repeated measurements before and after nasal challenge. It can also be performed at home for monitoring nasal congestion as a response to treatment. Peak flow measurements are less reproducible than rhinomanometry measurements (30). Nasal Volume. The geometric cross-sectional area and nasal volume can be measured using acoustic rhinometry. This rapidly performed test, which does not assess flow, complements NAR measurement and provides information about the site of obstruction. It is also affected by nasal cycle. Measurement of Mucosal Swelling. Rhinostereometry is an optical method that exclusively measures changes in nasal swelling using stereotactic measurement of one defined point through an eyepiece of a microscope to evaluate changes in mucosal edema. Although it is highly accurate, correlation with the subjective symptom of nasal obstruction is poor (31). Nasal Secretions. Several methods have been used for collecting and quantifying nasal secretions: suction, blowing, dripping, washing, lavage, and absorption. Blown secretions can be quantified by weighing of paper tissues. The amount of nasal secretions can also be obtained by the placement of discs or other substances on the nasal mucosa to determine the weight of secretions generated during a fixed period of time. Nasal lavage samples epithelial lining fluid (ELF) from a large mucosal area, whereas discs sample a localized area. The volume of ELF in the lavage fluid can be estimated by using urea as a marker (32). Nasal secretions can be processed for assessment of both their cellular and their biochemical contents. Biological Markers. Biological markers can be measured in collected secretions to monitor changes in the underlying pathophysiology. These markers include inflammatory mediators, cytokines, plasma proteins and glandular secretory products. It is important to know the stability of each marker after recovery, the sensitivity and specificity of each assay, and the potential cellular sources of the markers when interpreting the results. The changes in markers reflect their levels on the mucosal surface, but may not reflect levels in the underlying tissue. Cells. Cells can be obtained from the nasal cavity using various techniques. The epithelial layer can be scraped or brushed for evaluation of specific areas of the nasal cavity. Obtaining blown secretions is simple and painless; however, the specimen only reflects secretions and usually yields few cells. Nasal

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lavage samples secretions from the entire nasal cavity. It provides a technique for simultaneous measurement of cells and biological markers. Nasal biopsy samples provide information about structural elements and cellular contents of the epithelial layer and the deeper submucosa. A wide range of histochemical or immunohistochemical techniques can be employed for light microscopy to provide a more detailed evaluation of the cellular content. As an alternative, samples may be processed specifically for either transmission or scanning electron microscopy.

IV. ANTIALLERGIC EFFECTS OF H 1-ANTIHISTAMINES Human in vivo models provide an excellent opportunity to evaluate both the H 1receptor antagonism and the other anti-inflammatory effects of antihistamines. In this section, we describe studies of the antiallergic activities of antihistamines. A.

Acrivastine

Acrivastine, which is related to triprolidine, is a short-acting H 1-antagonist with a rapid onset of action. Lau and colleagues studied the effect of acrivastine on histamine release from rat peritoneal mast cells and found it to be ineffective in inhibiting anti-IgE- or calcium ionophore A 23187-induced histamine release at concentrations from 10⫺9 M to 10⫺4 M (33). Acrivastine was, however, demonstrated to inhibit PAF-induced airway hyperreactivity in guinea pigs (34). The mechanism responsible for this finding is unclear, but is not related to H 1-antagonism. Antiallergic activities of acrivastine have not been studied in humans. B.

Astemizole

Astemizole, a benzimidazole–aminopiperidine compound, is a long-acting, highly selective H 1-antagonist with no central nervous system (CNS) or anticholinergic effects. Because of its rare but potentially serious cardiac side effects, it has been removed from the market. It significantly decreased IL-1 levels in nasal lavage fluid and also decreased IL-8 and LTB4 levels (35, 36). C.

Azatadine

Azatadine, a tricyclic antihistamine of the piperidine class, is an effective H 1receptor antagonist for relieving the histamine-mediated symptoms of seasonal allergic rhinitis (37). In vitro experimentation with azatadine base showed that it inhibited histamine and LTC4 release from human lung mast cells by 45 and

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85%, respectively, when used at a concentration of 10⫺3 M (38). Concentrations less than 10⫺4 M had no significant effect. Because these concentrations would be difficult to obtain from oral administration of the drug, Togias and colleagues investigated topical intranasal delivery of azatadine 0.5 mg in a double-blind, placebo-controlled, crossover study in eight allergic individuals (39). Azatadine significantly inhibited allergen-induced sneezes, and increases in histamine, Nalpha-tosyl-L-arginine methyl ester (TAME)-esterase activity, and kinins in nasal lavage fluids collected after allergen challenge. These observations were consistent with the notion that azatadine, given in sufficient concentration, was capable of inhibiting mast cell histamine release in vitro and in vivo. D. Azelastine Azelastine, a phthalazinone compound, can be administered orally or as an intranasal spray. In addition to histamine H 1-receptor blockade, it has inhibitory effects on cells and chemical mediators of the inflammatory response in vitro (40– 45). For example, it inhibits histamine release from human basophils (41) and from animal (43, 44) and human lung mast cells (45) in vitro. Anti-inflammatory effects of azelastine have also been shown in vivo. Shin and colleagues performed a double-blind, placebo-controlled, crossover study comparing the effect of treatment with oral azelastine or placebo on the EPR to nasal challenge with allergen in 13 asymptomatic allergic subjects (46). Pretreatment with a single oral 2 mg dose of azelastine resulted in a dramatic reduction in the number of sneezes as well as in the levels of TAME-esterase activity, LTC4 , and kinins without a significant reduction of histamine and PGD2 compared to placebo. These results suggest that azelastine blocked the effects of histamine on nerves and blood vessels. An interesting finding in this study was the inhibition of leukotriene production by azelastine. This finding probably reflects the fact that the concentration of azelastine in vivo was sufficient to inhibit only LTC4 , but not histamine release, because in vitro studies showed that azelastine inhibited LTC4 release at a dose lower than that required to inhibit histamine release (39, 47). Alternatively, since mast cell activation was not inhibited, eosinophils, macrophages, and endothelial cells may have contributed to the production of LTC4. Another possible explanation is that azelastine may have some 5-lipoxygenase inhibitory activity that leads to a preferential reduction of leukotriene generation in nasal mast cells (48, 49). Because histamine itself does not affect LTC4 production (50), this is not an H 1-receptor blockade effect. These results emphasize the importance of correlating in vivo and in vitro results, and the greater complexity of in vivo systems. IL-4 from CD4⫹ lymphocytes and CD23 antigen from B lymphocytes are important triggering mechanisms in cells producing IgE antibodies (51, 52). Ito

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and colleagues studied the effect of azelastine on IL-4 and soluble CD23 (s-CD23), the soluble component of membrane-type CD-23, in subjects with allergic rhinitis. They performed a randomized, placebo-controlled, parallel trial in allergic subjects who were treated with either azelastine (orally 2 mg daily) or placebo for 4 weeks during the allergy season (53). Compared to placebo, azelastine significantly decreased symptoms and the levels of IL-4 and s-CD23 from baseline. Ciprandi and colleagues studied the effect of azelastine nasal spray on the EPR and LPR to nasal challenge with allergen in 20 subjects with pollen allergy in a randomized, double-blind, placebo-controlled, parallel study (54). Azelastine significantly decreased the total symptom score, as well as eosinophil and neutrophil infiltration and ICAM-1 expression during both EPR and LPR (Table 1). Furthermore, ECP levels in nasal lavage fluid decreased significantly during the LPR. The antiallergic effect of intranasal azelastine was more prominent and effective when treatment was used continuously, rather than as needed (55). Using a conjunctival provocation model, Ciprandi and colleagues also demonstrated the antiallergic activity of azelastine eye drops on the EPR and LPR to conjunctival challenge with allergen (56). In contrast, Pelucchi and colleagues failed to show an inhibitory effect of intranasal azelastine on the number of eosinophils recovered in nasal lavage in allergic subjects during the pollen season (57). A possible explanation for its antiallergic effect in the LPR is that azelastine may downregulate ICAM-1 expression by acting on epithelial cells directly, or by acting on mast cells or other cells that are able to release factors that upregulate ICAM-1 expression (58). Jacobi and colleagues studied the effect of a 1-week pretreatment with intranasal azelastine or systemic cetirizine on allergen-induced release of mast cell mediators from the human nasal mucosa (59). They performed a randomized, double-blind, placebo-controlled, three-way crossover study on 11 allergic subjects and 5 nonallergic subjects. Each subject was treated with azelastine nasal spray, 0.14 mg per nostril twice daily, cetirizine 10 mg once daily, or placebo for 1 week. There were significant increases in the number of sneezes and the levels of histamine and tryptase in lavage fluid after allergen challenge. Both azelastine and cetirizine significantly reduced allergen-induced sneezing and the associated increases in histamine and tryptase levels (Fig. 2). Reduced levels of mast cell mediators in nasal lavage fluid may result from a reduced release of mediators from mast cells and/or a reduced transfer of released mediators from the nasal mucosa to lavage fluid. The fact that antihistamines reduce histamineinduced plasma exudation and secretion from nasal glands supports the latter concept (26). The discrepancies between this study and that of Shin and colleagues may be related to the differences in study population and methods (e.g., allergen concentrations, or route of administration).

T0 T7 T0 T7 T0 T7 T0 T7 T0 T7

Total symptom score 10 (7–12) 7 (3–10) 45 (28–80) 28 (10–49) 13.5 (9–22) 8.5 (4–15) 4 (2–4) 2 (1–2) 33 (20–43) 29 (19–35)

Azelastine 10 (8–11) 10 (8–12) 39 (22–70) 37 (24–63) 12 (5–21) 14 (6–19) 3.5 (3–4) 3 (3–4) 30 (19–42) 30 (20–41)

Placebo NS 0.01 NS 0.01 NS 0.03 NS 0.001 NS NS

p value 3 (1–3) 1 (1–2) 39 (18–63) 20 (10–79) 17 (10–26) 11 (8–20) 2 (1–3) 1 (0–3) 40 (27–50) 25 (11–37)

Azelastine

3 (2–3) 3 (2–3) 28 (19–63) 26 (18–60) 16 (10–26) 17 (12–25) 2 (1–3) 2 (1–3) 40 (25–52) 41 (30–56)

Placebo

Late-phase response

NS 0.01 NS 0.01 NS 0.01 NS 0.05 NS 0.01

p value

Twenty asymptomatic subjects with allergic rhinitis were studied in a randomized, double-blind, placebo-controlled, parallel trial. Numbers represent the median values (range) after allergen challenge. T0, allergen challenge performed at baseline; T7, allergen challenge, which was done 1 week after T0, performed 30 min after subjects received either azelastine (0.137 mg intranasally) or placebo; ICAM-1, intercellular adhesion molecule-1; ECP, eosinophil cationic protein; NS, not significant. Source: Ref. 54.

ECP (µg/L)

ICAM-1 positivity

Eosinophils

Neutrophils

Time

Early-phase response

Results of Parameters Measured During Early- and Late-Phase Response After Nasal Challenge with Allergen

Parameter

Table 1

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Figure 2 Effect of 1 week pretreatment with intranasal azelastine, oral cetirizine, and placebo on the early allergic response. Eleven asymptomatic subjects with allergic rhinitis were treated with azelastine nasal spray (0.14 mg per nostril twice daily), cetirizine tablets (10 mg daily), or placebo 1 week prior to allergen challenge in a randomized, doubleblind, placebo-controlled, three-way crossover trial. The challenge protocol is shown on the abscissa. The nasal challenge was begun with 0.9% NaCl solution as a control challenge, followed by three incremental dosages of allergen. The median values of number of sneezes and the levels of histamine and tryptase in nasal lavage fluid are shown. Pretreatment with azelastine or cetirizine significantly inhibited the allergen-induced sneezes and the increase in the levels of tryptase and histamine compared with placebo. SQU, standardized quality units. (From Ref. 59.)

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Cetirizine

Cetirizine, a piperazine derivative and the carboxylated metabolite of hydroxyzine, is a specific H 1-receptor antagonist. To evaluate the effects of cetirizine on mediator release during the early allergic response, Naclerio and colleagues performed a double-blind, placebo-controlled, crossover study in 10 asymptomatic patients with seasonal allergic rhinitis, comparing pretreatment with cetirizine 20 mg daily for three doses, or placebo, on the response to nasal challenge with allergen (60). After pretreatment with placebo, the volunteers sneezed in response to antigen stimulation, and there was a dose-dependent increase in the levels of histamine, TAME-esterase activity, albumin, LTC4 , and PGD2 in the recovered nasal lavage fluid. After cetirizine pretreatment, there was a significant reduction in the number of sneezes, TAME-esterase activity, LTC4 , and albumin, whereas the histamine and PGD2 levels were not reduced. These findings support the notion that cetirizine competes with histamine for H 1-receptors on nerves (reduced sneezing) and blood vessels (decreased vascular permeability). The inhibition of leukotriene production by cetirizine could be explained in the same way as discussed above for azelastine. In another study, the effect of cetirizine on histamine-induced changes in lavage protein concentration was studied in 10 healthy volunteers in a randomized, double-blind, placebo-controlled manner (61). The increase in lavage total protein and albumin concentration after histamine challenge was almost completely abolished by cetirizine compared to placebo. This finding supports the concept that the increase in albumin after allergen challenge is mediated by histamine acting through H 1-receptors on blood vessels, resulting in plasma leakage, which is inhibited by cetirizine. The effect of cetirizine on accumulation of inflammatory cells has also been studied in the skin and upper airways. Double-blind, placebo-controlled, crossover studies evaluating its effect on the cutaneous allergic response have shown that it reduces eosinophilic infiltration at the site of allergen challenge in a skin chamber challenge model (62), and also in a similar study in which it decreased eosinophil infiltration by approximately 80% in ragweed-sensitive subjects (63). Furthermore, cetirizine has been shown to inhibit cellular recruitment, particularly eosinophils, into bronchial washings from asthmatic subjects with an early and late response (64). Klementsson and colleagues evaluated the effect of cetirizine (10 mg daily), terfenadine (60 mg twice daily), and placebo on eosinophil infiltration into nasal secretions and on allergen-induced nonspecific nasal hyperreactivity after nasal allergen challenge (65). The allergen challenge increased surface eosinophils, which were unaffected by both active drugs. Why cetirizine prevents the selective recruitment of eosinophils to the skin, but not to the nasal mucosa, is unknown. A surprising finding was that both antihistamines inhibited the increased nonspecific nasal reactivity induced by methacholine 24

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Table 2 Effect of Terfenadine and Cetirizine on Nasal Symptoms After Allergen Challenge and on Allergen-Induced Nonspecific Nasal Hyperreactivity to Methacholine Parameter

Placebo

Total nasal symptom score Volume of nasal secretion (mL) after methacholine challenge (before allergen challenge) Volume of nasal secretion (mL) after methacholine challenge (24 h after allergen challenge)

4.8 ⫾ 0.63 0.3 ⫾ 0.06

0.36 ⫾ 0.07

Terfenadine 2.2 ⫾ 0.49** 0.2 ⫾ 0.05

0.25 ⫾ 0.08*

Cetirizine 2.13 ⫾ 0.51** 0.27 ⫾ 0.06

0.27 ⫾ 0.05*

Fifteen asymptomatic subjects with allergic rhinitis were treated with terfenadine (60 mg twice daily), cetirizine (10 mg daily), or placebo for 5 days before allergen challenge in a randomized, doubleblind, placebo-controlled trial. Methacholine challenge was performed before and 24 h after allergen challenge for assessment of nasal hyperresponsiveness. The data are mean ⫾ SEM of 15 subjects. *p ⬍ 0.05; **p ⬍ 0.01 compared to placebo. Source: Ref. 65.

h after allergen challenge (Table 2). This study suggests that the allergen-induced increase in nonspecific responsiveness is a complex phenomenon not dependent solely on eosinophil influx into the nasal mucosa. In addition, histamine stimulation of the nasal mucosa does not increase the reactivity to methacholine 24 h later (50), suggesting that histamine released from mast cells after allergen challenge is not responsible for increased methacholine responsiveness. Thus, the mechanism by which these two antihistamines reduce nasal hyperresponsiveness is unrelated to H 1-antagonist activity. Ciprandi and colleagues investigated the antiallergic activity of cetirizine in 20 allergic children with allergic rhinoconjunctivitis during the pollen season (66). Cetirizine significantly reduced clinical symptoms, inflammatory cell infiltrates, ICAM-1 expression on nasal epithelial cells, and soluble ICAM-1 (sICAM-1) and ECP in nasal lavages (Fig. 3). In another study comparing loratadine and cetirizine during natural allergen exposure, similar findings were obtained (67). These data suggest that cetirizine has inhibitory effects on expression of adhesion molecules, and on cellular influx, as well as on eosinophil mediators. Even when asymptomatic, individuals who suffer from house dust mite allergy have both conjunctival and nasal mucosal inflammation, characterized by infiltration of inflammatory cells (eosinophils and neutrophils) and by ICAM-1 expression on epithelial cells (16). In one randomized, double-blind, placebocontrolled, parallel study, Fasci et al. investigated the effect of 2-weeks treatment with cetirizine on chronic, naturally occurring inflammation in 20 children, all of whom had allergic asthma associated with mite sensitivity and had been symptom-

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Figure 3 Effect of cetirizine on nasal allergic inflammation during natural pollen exposure. In a double-blind, placebo-controlled, parallel design, 20 allergic children were treated with either cetirizine (0.15 mg/kg daily) or placebo for 4 weeks during the pollen season. Nasal lavages were performed before and after treatment. Cell counts and mediator levels (ECP and soluble ICAM-1) were measured in nasal lavage. Expression of ICAM1 on nasal epithelial cells was also evaluated by a five-point rating scale. Individual data for each parameter are shown. Compared with placebo, cetirizine significantly decreased eosinophil counts (a), ICAM-1 positivity on nasal epithelium (b), and levels of sICAM1 (c) and ECP (d) in nasal lavage fluid. The solid horizontal bars represent median values. Pre, pretreatment; post, after 4 weeks of treatment. The intragroup comparisons are shown in the upper part of the each graph (p value, NS). NS, not significant. (From Ref. 66.)

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free for at least 2 months (68). In contrast to patients treated with placebo, cetirizinetreated children showed a significant reduction in ICAM-1 on epithelial cells in nasal scrapings. There was also a trend to a reduction in eosinophil and neutrophil numbers, consistent with the above finding. It can be speculated that longer treatment might have diminished the inflammatory cell infiltration even further. A soluble form of ICAM-1 (sICAM-1), thought to consist of extracellular parts of membrane ICAM-1, has been identified in nasal lavage fluid samples of patients with allergic rhinitis (69, 70). It is assumed to be generated by local production in the nasal mucosa, followed by release into nasal secretions. The cells of origin and the mechanisms for releasing the soluble components of these adhesion molecules are unknown, but either shedding or enzymatic cleavage from nasal epithelial cell surface could be involved (71). There is a significant correlation between cell membrane expression of ICAM-1 and of sICAM-1, suggesting that the measurement of sICAM-1 in secretions reflects the expression of ICAM1 at the cell-surface level (66, 72). In a 2-week study, the effects of cetirizine (10 mg daily) and loratadine (10 mg daily) on the release of sICAM-1 in nasal secretions were compared in patients with allergic rhinitis during the grass pollen season (73). Cetirizine and loratadine significantly reduced the sICAM-1 released in nasal secretions, whereas the levels in the control group of untreated patients were unchanged. In vitro evidence of inhibitory effects of cetirizine on eosinophil adhesion on human endothelial cells (74) and on eosinophil chemotaxis (75, 76) supports these findings. F.

Ebastine

Ebastine, a piperidine derivative, and its metabolite, carebastine, are selective H 1-receptor antagonists devoid of any other known receptor binding (77). Campbell and colleagues studied the antiallergic effect of ebastine in both in vitro and in vivo models (78). They used nasal polyp cells to examine the effects of ebastine on the release of LTC4 , LTD4 , and PGD2 in vitro after stimulation by anti-IgE, and on the spontaneous release of cytokines (GM-CSF, TNF-α, and IL-8). Ebastine at concentrations ranging from 0.1 to 10 µmol/L significantly inhibited the release of PGD2 , LTC4 , and LTD4 in a dose-dependent manner. In addition, ebastine at 10 µmol/L significantly inhibited the release of GM-CSF, TNF-α, and IL-8. The same investigators performed a randomized, double-blind, placebocontrolled, crossover study comparing the antiallergic effects of ebastine (10 and 20 mg daily) and placebo on the release of inflammatory mediators after allergen challenge in 12 asymptomatic patients with seasonal allergic rhinitis (78). They found that ebastine dosages of 10 and 20 mg induced a significant increase in the mean threshold number of pollen grains required to induce a positive response compared with placebo. Ebastine significantly reduced the release of GM-CSF in a dose-dependent manner; however, levels of LTC4 , LTD4 , PGD2 , TNF-α,

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and IL-8 were not significantly affected. These data suggest that ebastine exerts its anti-inflammatory effect by inhibiting the release of PGD2 , LTC4 , LTD4 , and cytokines from nasal polyp cells in vitro and by decreasing the release of GMCSF in vivo. G.

Fexofenadine

Fexofenadine, the carboxylic acid metabolite of terfenadine, is a new secondgeneration antihistamine that is nonsedating and does not cause QT prolongation. Paolieri and colleagues evaluated the effect of fexofenadine on ICAM-1 expression of a human continuously cultured conjunctival epithelial cell line (WK) and a fibroblast cell line (HEL) (79). They found that fexofenadine in a concentration of 50 µ/mL significantly decreased ICAM-1 basal expression on WK cells, sICAM-1 levels in IFN-γ-stimulated WK cells, and IFN-γ-induced ICAM-1 upregulation on HEL. A dose-dependent decrease of spontaneous IL-6 release was also observed. This study shows that fexofenadine exerts an anti-inflammatory effect directly on epithelial cells and fibroblasts, reducing ICAM-1 expression and sICAM-1. Abdelaziz and colleagues cultured epithelial cells from nasal biopsy specimens from patients with seasonal allergic rhinitis outside the pollen season and studied the effect of fexofenadine on eosinophil-induced release of proinflammatory mediators, on eosinophil chemotaxis, and on adherence to endothelial cells in response to conditioned medium from human nasal epithelial cell (HNEC) cultures (80). Incubation of HNECs in the presence of eosinophils significantly increased the release of RANTES, IL-8, GM-CSF, and sICAM-1 from HNECs. Fexofenadine treatment (10⫺9 –10⫺3 mol/L) significantly attenuated the eosinophil-induced release of IL-8, GM-CSF, and sICAM-1 from the HNECs. Moreover, conditioned medium from HNECs significantly altered the activity of eosinophils, as indicated by increased release of ECP, and increased both eosinophil chemotaxis and adherence to endothelial cells. Addition of 10⫺6 –10⫺3 mol/L fexofenadine to the conditioned medium significantly decreased eosinophil chemotaxis and adherence to endothelial cells. In vivo, fexofenadine also modulates the release of inflammatory mediators, cytokines, and adhesion molecules. H. Ketotifen In addition to being a competitive (81) and noncompetitive H 1-receptor antagonist (82), ketotifen inhibits the release of histamine from rat peritoneal mast cells (83). It also inhibits both histamine and leukotriene release from human basophil leukocytes stimulated by both anti-IgE and low concentrations of calcium ionophore A23187 (84–86). Majchel and colleagues evaluated the effect of pretreatment with ketotifen (1 and 2 mg twice daily) on the early response to nasal

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challenge with allergen in a double-blind, crossover trial (87). Six weekly nasal challenges followed by lavage were performed in 10 allergic subjects after 1 h and 1, 2, 3, and 4 weeks of ketotifen administration. The number of sneezes decreased significantly after a single dose of drug with both the 1 and 2 mg doses. Increasing the duration of drug administration did not improve the results. Neither dosage significantly reduced levels of histamine and TAME-esterase activity in recovered nasal lavages. Despite the efficacy of ketotifen in inhibiting sneezing, it did not block the release of histamine or TAME-esterase activity during the EPR to allergen challenge. The authors concluded that ketotifen reduces allergic symptoms by its antihistaminic activities rather than by inhibiting histamine release from mast cells. They could not exclude the possibility that ketotifen may selectively inhibit release of other mast cell mediators, since they did not measure other mediators. Kato and colleagues investigated the effect of prophylactic treatment with ketotifen on nasal symptoms, blood eosinophil counts, and serum ECP in subjects with allergic rhinitis before and after the pollen season (88). Ten subjects who received ketotifen (orally 2 mg daily) for 4 weeks before the start of the pollen season (prophylactic treatment group) and 12 subjects who began their medication 12 days after the start of the season (post-symptomatic treatment group) were enrolled in this study. Treatment with ketotifen was maintained until the end of the season. Total subjective symptom scores, blood eosinophil count, and serum ECP values were significantly higher during the season than during preseason. There were significant decreases in these three parameters in the prophylactic treatment group compared to the post-symptomatic treatment group. The same group of authors demonstrated that prophylactic treatment with topical ketotifen decreased the total symptom score, blood eosinophil counts, and serum MBP during the season compared to post-symptomatic treatment (89). These data suggest that blood eosinophils and levels of ECP and MBP in serum of allergic individuals were upregulated during the season, and that ketotifen’s antiallergic properties include inhibiting eosinophil recruitment and its activation in the blood. It is of interest that topical administration of ketotifen could reduce blood eosinophils and serum MBP, as plasma concentrations of ketotifen are undetectable when it is applied intranasally. The decrease in mediator release from mast cells in the nose by ketotifen might reduce local allergic inflammation, which subsequently suppressed the systemic allergic response (89). I.

Levocabastine

Levocabastine, a cyclohexyl piperidine derivative, is a selective H 1-receptor antagonist developed for nasal and ocular administration. It is effective and well tolerated in the treatment of allergic rhinitis (90). It has been shown to reduce the severity of the immediate nasal response to allergen significantly when admin-

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istered 5 min before the challenge, and its protective effect persists for 24 h after administration (91). To study the anti-inflammatory effect of levocabastine on the EPR and LPR to nasal challenge with allergen in vivo, de Graaf and colleagues evaluated 21 house dust mite-allergic rhinitis patients in a double-blind, placebo-controlled, two-way crossover study (92). Subjects who had EPR but no LPR on nasal challenge received either topical intranasal levocabastine (400 µg daily) or placebo for 1 week. Levocabastine significantly reduced the symptom score, but did not reduce albumin or tryptase levels in nasal lavage fluid or hyperresponsiveness to methacholine. In agreement with these data, another study failed to show the inhibition of an allergen-induced increase in albumin levels by levocabastine (400 µg daily) during the early response to nasal challenge with birch allergen extract (93). Bachert and colleagues also demonstrated no significant differences in allergen-challenge-induced increments of albumin levels in nasal secretions after levocabastine (400 µg daily) treatment, compared to placebo (94). These findings suggest that after allergen challenge the principal effect of levocabastine is its H 1-antagonist effect. In a contrasting single-blind, placebo-controlled study, the effect of 8 days pretreatment with levocabastine (intranasally 800 µg daily) was investigated in 12 asymptomatic subjects with allergic rhinitis (95). There were significant increases in albumin levels and inflammatory cells in lavage fluid after allergen challenge in the placebo group, but not in the levocabastine-treated group (Fig. 4). Levocabastine significantly decreased nasal symptoms, albumin, and inflammatory cell influx (neutrophils, eosinophils, metachromatic cells) after allergen challenge compared to placebo (Fig. 4). The differences in study population, methods and levocabastine dosages may explain the apparent discrepancies between this study and earlier ones. J. Loratadine Loratadine is a tricyclic, selective H 1-receptor antagonist without anticholinergic or sedative properties. In vitro it decreases antigen- and calcium ionophoreinduced histamine and LTC4 release from mast cell lines (96). The antiallergic activity of loratadine may be mediated by blockade of calcium influx into the cells (96). To study its antiallergic properties in vivo, Bousquet and colleagues performed a three-way crossover study comparing the effect of 1-week treatment with loratadine (10 mg daily), terfenadine (60 mg twice daily), or placebo on mediator release during the immediate response to nasal challenge with allergen in 14 individuals allergic to pollen (97). Both active drugs suppressed symptoms and the release of histamine and PGD2 , suggesting that they affected mast cell activation. Using a similar model, Andersson showed a significant reduction in the release of histamine and TAME-esterase activity during the early allergic

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Figure 4 Effect of intranasal levocabastine on nasal challenge with allergen. Twelve asymptomatic subjects with allergic rhinitis were treated with placebo or intranasal levocabastine (800 µg daily) for 8 days before nasal allergen challenge in a randomized, singleblind, placebo-controlled, crossover study. Nasal lavages were performed 20 h before and 2 h after allergen provocation. Levels of albumin and inflammatory cells in nasal lavage fluid were evaluated. The albumin levels (a) and the number of inflammatory cells (total cells, eosinophils, and neutrophils) (b) in nasal lavage fluid before and 2 h after allergen challenge are shown. The data are shown as mean ⫾ SEM. Pretreatment with levocabastine significantly decreased albumin levels, total cells, eosinophils, and neutrophils compared to placebo. Filled bars, levocabastine; open bars, placebo; AC, allergen challenge; Ag, allergen; *p ⬍ 0.05 vs. placebo; †p ⬍ 0.05 vs. before AC. (From Ref. 95.)

reaction after loratadine treatment (98). These studies show that loratadine is able to block the release of mediators during the immediate nasal allergic reaction; however, loratadine did not significantly inhibit the histamine concentration after allergen administration to the skin (99, 100). In a double-blind, placebo-controlled, crossover study in 14 patients allergic to ragweed or grass, loratadine (10 mg daily for 1 week before allergen challenge) markedly inhibited the sneezing response (101). Release of histamine or PGD2 was not decreased significantly. Loratadine had some inhibitory effects on the release of LTC4 , albumin, and kinin, but these were not statistically significant. Baroody and colleagues performed another double-blind, placebo-controlled, three-way crossover study comparing the effects of 1 week pretreatment

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with loratadine, 10 mg once daily, terfenadine, 60 mg twice daily, or placebo on the early response to nasal challenge with allergen, the subsequent cellular influx, and the increased responsiveness to methacholine 24 h later (23). Both loratadine and terfenadine treatment resulted in significant reductions in allergen-induced sneezing and in the levels of histamine, kinins, albumin, and TAME-esterase activity in recovered nasal lavage, with no significant differences between the treatments (Fig. 5). Neither treatment decreased the levels of tryptase, PGD2 , or LTC4. There was a significant increase in total eosinophils 24 h after allergen challenge in the placebo group, and this was not affected by loratadine or terfenadine treatment. A significant increase in reactivity to methacholine, as assessed by weights of secretions, was found 24 h after allergen challenge compared to screening challenge, and both antihistamines prevented this. These results suggest that loratadine may not only antagonize the effects of histamine following its release from mast cells after the early response to nasal challenge with allergen, but also inhibit subsequent cellular influx and allergen-induced hyperresponsiveness of the nasal mucosa. Raptopoulou-Gigi and colleagues treated patients with allergic rhinitis with either loratadine, 10 mg daily, or placebo for 1 month during a high-pollen-count period (102). Loratadine-treated patients had significantly lower symptom scores and, at the end of treatment, the numbers of cells expressing IL-2R, HLA-DR, and proliferating cell nuclear antigen (PCNA) in the nasal biopsies were significantly decreased in the loratadine-treated group. How loratadine exerted its inhibitory effect on the activation of T cells is unknown. Furthermore, Greiff and colleagues (103) have investigated the effect of treatment with loratadine 20 mg daily for 5 days on allergen-induced changes in the level of tryptase and α2-macroglobulin in 12 subjects with allergic rhinitis in a randomized, double-blind, placebo-controlled, crossover trial. Loratadine significantly decreased nasal symptoms as well as the release of tryptase and α2-macroglobulin during the EPR, but did not affect the number of eosinophils during the LPR. The reduction in both mediators suggests that loratadine inhibits mast cell activation and modulates the permeability of the microvasculature in the nasal mucosa. Ciprandi and colleagues (67) conducted a randomized, double-blind, parallel study in 20 seasonal allergic rhinitis subjects examining the effect of 2 weeks treatment with loratadine 10 mg daily and cetirizine 10 mg daily on cellular infiltration and expression of adhesion molecules after natural allergen exposure. Loratadine and cetirizine significantly reduced symptoms, eosinophil and metachromatic cell infiltration, levels of ECP and histamine in nasal lavage fluid, and ICAM-1 expression on nasal epithelial cells compared to the pretreatment baseline (Table 3). The reduction of ICAM-1 expression on the conjunctival epithelium by loratadine was also shown in a study of allergen-specific conjunctival challenge (104). Loratadine and its metabolite desloratadine decrease histamineinduced expression of ICAM-1 on nasal epithelial cells in vitro significantly

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Figure 5 Effects of loratadine and terfenadine on nasal challenge with allergen. In a double-blind, placebo-controlled, three-way crossover study, 14 asymptomatic allergic individuals were treated with loratadine 10 mg daily, terfenadine 60 mg twice daily, or placebo for 1 week. Nasal challenge and lavage were then performed. Twenty-four hours later, the lavage was repeated, and methacholine challenge was performed to assess allergen-induced increased nasal hyperresponsiveness. Mediator levels were measured in nasal lavage fluid. The net changes from the diluent challenge for each parameter are shown as mean ⫾ SEM. Compared with placebo, both loratadine and terfenadine significantly decreased allergen-induced sneezing and the levels of histamine, kinins, TAME-esterase activity, and albumin in recovered nasal lavage, with no significant differences between the two treatments. *p ⬍ 0.05 vs. placebo; TAME, N-α-tosyl L-arginine methyl ester. (From Ref. 23.)

2 (0–7) 0 (0–1) 3 (1–4) 2.5 (1–5) 1 (1–2) 26 (15–31) 41 (19–58) 96 (52–238) 0.1 (0–0.7)

After 0.002 0.02 NS 0.016 0.01 0.002 0.006 NS 0.01

p value 14 (11–18) 2 (1–2) 4 (1–5) 3 (1–4) 3 (1–4) 28 (19–45) 45 (31–61) 88 (53–137) 0.1 (0.1–2.8)

Before

2 (0–8) 0.5 (0–1) 3 (1–4) 2 (1–4) 1 (1–3) 21 (16–32) 33 (19–55) 93 (32–144) 0.1 (0–0.7)

After

Cetirizine

0.002 0.01 0.015 0.03 0.001 0.01 0.002 NS 0.02

p value

In a randomized, double-blind, parallel design, 20 subjects with allergic rhinoconjunctivitis were treated with either loratadine 10 mg daily or cetirizine 10 mg daily for 2 weeks during natural allergen exposure. The parameters were compared before and after treatment. The data are presented as median (range). Cells and mediators were measured in nasal lavage fluid. ICAM-1, intercellular adhesion molecule-1; ECP, eosinophil cationic protein; EPO, eosinophil peroxidase; MPO, myeloperoxidase; NS, not significant. Source: Ref. 67.

13 (11–16) 2 (1–3) 4 (2–5) 3 (2–6) 2 (1–4) 38.5 (30–51) 50 (29–63) 81 (50–133) 0.2 (0.1–3.7)

Before

Loratadine

Effect of Loratadine and Cetirizine on Chronic Naturally Occurring Allergic Inflammation

Clinical score ICAM-1 positivity Neutrophils Eosinophils Metachromatic cells ECP (µg/L) EPO (µg/L) MPO (µg/L) Histamine (µg/L)

Parameters

Table 3

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(105). These studies demonstrate that loratadine provides an antiallergic effect by modulating ICAM-1 expression on epithelial cells. The different results, compared with earlier studies, could be related to differences in the design, techniques, and outcome measures used. Miadonna and colleagues studied 10 subjects with allergic rhinitis due to dust mites, who were treated with loratadine (10 mg daily) and with placebo for 1 week, in a double-blind, crossover trial (106). Subjects treated with placebo had nasal symptoms after allergen challenge, followed by a significant increase in histamine concentration in nasal lavage fluid collected 5 min after stimulation. Loratadine significantly reduced allergen-induced nasal symptoms and histamine release in the 5 min, 10 min, and 20 min postchallenge lavages (Table 4). The results of this study are consistent with those of earlier studies (23, 97, 98). Furthermore, ex vivo basophil histamine release induced by anti-IgE (10 µg/mL), formyl methionyl leucyl phenylalanine (fMLP) (1 µm), and Ca 2⫹ ionophore A23187 (1 µ) was reduced significantly after treatment with loratadine. The most interesting feature is that loratadine also inhibited histamine release from basophils activated by different agents. Although anti-IgE, fMLP, and Ca 2⫹ ionophore A23187 have different mechanisms of action, they all cause an increase in intracellular Ca 2⫹ concentration. A previous study has shown that one possible mecha-

Table 4 Effect of Loratadine on Histamine Levels in Early Allergic Inflammation Nasal lavage Prechallenge 1st 5th Postchallenge 5 min 10 min 20 min 30 min 60 min

Placebo

Loratadine

p value

6.5 (2–25) 0.5 (0–1)

6.5 (2–40) 0.5 (0–2)

NS NS

4 (1–28) 0.5 (0–5) 0 (0–2) 0 (0–1) 0 (0–0)

0.5 (0–3) 0 (0–1) 0 (0–0) 0 (0–0) 0 (0–0)

⬍0.01 ⬍0.001 ⬍0.01 NS NS

Ten asymptomatic subjects with allergic rhinitis were treated with loratadine 10 mg daily and with placebo for 1 week before allergen challenge. Nasal lavages were done before and after challenge with the relevant allergen after each treatment period. Five nasal lavages were performed at 4-min intervals before allergen challenge in order to obtain low and uniform prechallenge histamine levels (1st: first prechallenge lavage; 5th: fifth prechallenge lavage). Nasal lavages were repeated 5, 10, 20, 30, and 60 min after allergen challenge. Results are histamine levels in nasal lavage fluids (ng/mL) before and after allergen challenge. The data are median (range) for 10 subjects. NS, not significant. Source: Ref. 106.

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nism by which an antiallergic drug can inhibit histamine release is through induction of membrane stabilization (107). It is reasonable to speculate that the inhibitory effect of loratadine on basophil histamine release is related to its effect on membrane stabilization, transmembrane Ca 2⫹ influx, and intracellular Ca 2⫹ increase. K. Mizolastine Mizolastine, a novel benzimidazole derivative, is highly selective for histamine H 1-receptors and has no anticholinergic, antiadrenergic, or antiserotoninergic activity. At a dosage of 10 mg daily it reduces the symptoms associated with seasonal and perennial allergic rhinitis (108, 109). Anti-inflammatory properties of mizolastine were demonstrated in animal experiments (110, 111). Levrier and colleagues studied the antiallergic activities of mizolastine in actively sensitized guinea pigs and passively sensitized rats (110). Mizolastine significantly reduced allergeninduced release of histamine from mast cells in bronchoalveolar lavage fluid of guinea pigs and in the peritoneal fluid of sensitized rats. This study suggests a potential mast cell inhibitory role for this agent in allergen-induced reactions. Pichat and colleagues studied the effects of mizolastine, loratadine, terfenadine, and pyrilamine on arachidonic acid (AA)-induced edema in the rat paw (111). Mizolastine significantly inhibited AA-induced paw inflammation in a dose-dependent manner, whereas other antihistamines failed to inhibit the inflammatory action of AA. These data suggest inhibitory effects of mizolastine on AA-induced inflammation. Mizolastine is one of the newest antihistamines and there are few published data on its antiallergic effects in humans. L.

Oxatomide

Oxatomide is an H 1-receptor antagonist chemically related to cinnarizine, with potent antihistaminic activity and inhibitor effects on mast cell degranulation (112). In addition, oxatomide exerts some antiserotonin, anticholinergic activity, and anti-slow-reacting substance of anaphylaxis (SRSA) in in vitro and in vivo models (113). Preincubation of basophils with oxatomide (10⫺7 –10⫺5 mol/L) concentration dependently inhibited the immunological release of histamine and LTC4 before anti-IgE challenge (114). Oxatomide (10⫺7 –10⫺5 mol/L) also reduced histamine, tryptase, and LTC4 release from human lung mast cells (HLMC) activated by anti-IgE. The efficacy of oxatomide (30 mg daily) in the treatment of seasonal allergic rhinitis and/or conjunctivitis has been demonstrated in a double-blind, placebo-controlled study (115). To study the effect of 4 weeks of treatment with azelastine (orally 1 mg twice a day) and oxatomide (orally 30 mg twice a day) on substance P (SP)

Ciprandi et al. (66) NAE

Ciprandi et al. (68) NAE

Klementsson et al. (65) NCA

Jacobi et al. (59) NCA Cetirizine Naclerio et al. (60) NCA

Azelastine (Intranasal) Pelucchi et al. (57) NAE Ciprandi et al. (54) NCA

Azatadine Togias et al. (39) NCA

Drug

↓ ICAM-1 expression on nasal epithelial cells ↓ Neutrophils, eosinophils, ICAM1 expression on nasal epithelial cells, sICAM-1, ECP

↓ TAME-esterase, LTC 4 , albumin No effect: histamine, PGD 2 NE

No effect: eosinophils ↓ Neutrophils, eosinophils, ICAM1 expression on nasal epithelial cells ↓ Histamine, tryptase

↓ Histamine, TAME-esterase, kinin

Early phase

—

—

No effect: eosinophils

NE

↓ ECP in nasal lavage, neutrophils, eosinophils, ICAM-1 expression on nasal epithelial cells NE

NE

Late phase

—

↓ increased nonspecific hyperreactivity to methacholine —

NE

NE

— NE

NE

Hyperresponsiveness in vivo

Table 5 In Vivo Studies of the Effect of H 1-Antihistamines on Nasal Allergic Inflammation Either After Nasal Challenge with Allergen or During Natural Allergen Exposure

126 Assanasen and Naclerio

Raptopoulou et al. (102) NAE

Bachert et al. (94) NCA de Graaf et al. (92) NCA Svensson et al. (93) NCA Loratadine Bousquet et al. (97) NCA Andersson et al. (98) NCA Naclerio et al. (101) NCA

Levocabastine (Intranasal) Padgrak et al. (95) NCA

Kato et al. (89) NAE

Kato et al. (88) NAE

Ketotifen Majchel et al. (87) NCA

Jacobi et al. (59) NCA Ebastine Campbell et al. 1996 (78) NCA

Campbell et al. (73) NAE Ciprandi et al. (67) NAE

↓ Histamine, PGD 2 ↓ Histamine, TAME-esterase No effect: histamine, PGD 2 , LTC 4 , albumin, kinin ↓ IL-2R, HLA-DR, PCNA positive cells

No effect: albumin No effect: albumin, tryptase No effect: albumin

NE

—

NE NE NE

↓ albumin, neutrophils, eosinophils, metachromatic cells NE NE NE

—

—

NE

—

NE No effect NE

NE No effect NE

NE

—

—

NE

NE

↓ GM-CSF -No effect: LTC 4 , LTD 4 , PGD 2 , TNF-α, IL-8

No effect: LTC 4 , LTD 4 , PGD 2 , GM-CSF, TNF-α, IL-8 No effect: TAME-esterase, histamine ↓ Blood eosinophil count, serum ECP ↓ Blood eosinophil count, serum MBP

NE

— —

NE

— —

↓ sICAM-1 ↓ Eosinophils, neutrophils, metachromatic cells, ICAM-1 expression on nasal epithelial cells, ECP, EPO, histamine ↓ Histamine, tryptase

Antiallergic Anti-Inflammatory Effects 127

Late phase

— NE —

↓ SP

—

No effect: eosinophils No effect: eosinophils

No effect: tryptase, PGD 2 , LTC 4 ↓ Eosinophils, metachromatic cells, ICAM-1 expression on nasal epithelial cells, ECP, EPO, histamine ↓ sICAM-1 ↓ Histamine

↓ Tryptase, α2-macroglobulin ↓ Histamine, kinin, albumin, TAME-esterase

Early phase

—

— NE

—

NE ↓ increased nonspecific hyperreactivity to methacholine

Hyperresponsiveness in vivo

NCA, nasal challenge with allergen; NAE, natural allergen exposure; NE, not evaluated; IL, interleukin; LT, leukotriene; TAME, N-alpha-tosyl-L-arginine methyl ester; GM-CSF, granulocyte macrophage colony-stimulating factor; ECP, eosinophil cationic protein; ICAM-1, intercellular adhesion molecule-1; SP, substance P; sICAM-1, soluble intercellular adhesion molecule-1; EPO, eosinophil peroxidase; TNF, tumor necrosis factor; PG, prostaglandin; MBP, major basic protein; HLA-DR, human leukocyte antigen-DR.

Campbell et al. (73) NAE Miadonna et al. (106) NCA Oxatomide Shinoda et al. (121) NAE

Ciprandi et al. (67) NAE

Greiff et al. (103) NCA Baroody et al. (23) NCA

Drug

Table 5 (Continued)

128 Assanasen and Naclerio

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and vasoactive intestinal peptide (VIP) levels in nasal secretions, Shinoda and colleagues performed a randomized, double-blind, parallel study in 40 subjects with house dust allergy and 210 healthy subjects (116). Mean values of SP, but not VIP, were significantly higher in the nasal allergy group than in the control group. Patients with severe symptoms had significantly higher levels of SP and VIP in nasal secretions than those in the control group. Oxatomide and azelastine significantly reduced SP levels in nasal secretions, and VIP levels were suppressed by 70%, although this did not achieve statistical significance. The mechanism by which oxatomide decreases neuropeptides in nasal secretions is unknown. Eosinophils from human peripheral blood were demonstrated to contain significantly higher levels of SP and VIP than did neutrophils, mononuclear leukocytes, and platelets (117). One possible mechanism for the decrease of the neuropeptides in nasal secretions after oxatomide administration might be the reduction of eosinophil infiltration into nasal secretions. This hypothesis is supported by the study of Ciprandi and colleagues (118). Using allergen-specific conjunctival challenge, they demonstrated that oxatomide significantly decreased total numbers of inflammatory cells as well as the number of single cell types (neutrophils, eosinophils, and lymphocytes) during the earlyand late-phase reactions. M. Terfenadine From an historical point of view, terfenadine was one of the first H 1-antagonists to be investigated for antiallergic properties, and was one of the most comprehensively studied. Rarely, it caused cardiac toxicity, and regulatory approval was withdrawn for it in most countries. In addition to its H 1-receptor antagonist effects it also inhibits the anti-IgE-induced release of histamine, LTC4 , and PGD2 from human lung mast cells in vitro (119). After allergen challenge in subjects with allergic rhinitis, pretreated with terfenadine, the following have been reported: reduced symptoms, decreased histamine, kinins, albumin and TAMEesterase activity, decreased inflammatory cell infiltrates and ICAM-1 expression on nasal epithelial cells, and ECP in lavage fluid (120–125).

V.

SUMMARY

Data from in vitro, in vivo, and ex vivo studies suggest that second-generation antihistamines have a number of antiallergic, anti-inflammatory properties that appear to be independent of their H 1-blockade activity. First-generation antihistamines also have antiallergic, anti-inflammatory properties, as suggested by the studies with azatadine, chlorpheniramine, mepyramine, and promethazine; most other first-generation antihistamines have not been studied for these properties.

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In vitro studies have shown that H 1-antihistamines reduce the release of proinflammatory mediators from mast cells and basophils, the chemotaxis and activation of inflammatory cells (especially eosinophils), and the expression of adhesion molecules induced by immunological and nonimmunological stimuli in epithelial cell lines. Nasal allergen challenge models have similarly demonstrated that H 1-antihistamines inhibit mediator release from mast cells and basophils, and that they decrease inflammatory cell infiltration and the expression of adhesion molecules on epithelial cells. The results of published studies of the effects of H 1-antihistamines on nasal allergic inflammation in humans have been summarized in this chapter. Recent investigations indicate that H 1-antihistamines may modulate airway inflammation by downregulating the activity of airway epithelial cells, which have an important role in allergic airway inflammation. The modulation of adhesion molecules and of inflammatory cell infiltration by H 1-antihistamines may be beneficial during long-term treatment in patients with allergic rhinitis. The rationale for this hypothesis is the persistence of inflammation on the nasal epithelial cells even when patients are symptom-free (16). All of the events affected by H 1-antihistamines are important in the allergic inflammation cascade. The underlying mechanisms for such effects remain unclear, but are unrelated to H 1-antagonist activity. Several studies have demonstrated that H 1-antihistamines can form an ionic association with cell membranes and inhibit calcium ion influx into the mast cell or basophil plasma membrane, or inhibit Ca 2⫹ release within the cells, and may therefore influence the signal transduction pathways. However, these effects appear to occur at concentrations higher than those achieved in therapeutic practice (126–128). It has recently been hypothesized that the anti-inflammatory activity of H 1-antihistamines may be a consequence of their ability to influence the activation of genes responsible for the expression and synthesis of proinflammatory mediators (129). The contribution of the antiallergic effects of H 1-receptor antagonists to their clinical efficacy is not fully understood. There have been no data suggesting that H 1-antihistamines with well-documented antiallergic properties are superior to the others for which such properties have not been as extensively investigated. Additional studies are needed to elucidate the mechanisms(s) by which H 1-antihistamines exert anti-inflammatory effects. This knowledge might lead to the development of novel therapies with more potent and specific anti-inflammatory effects.

ACKNOWLEDGMENTS This work was supported in part by NIH grant DC 02714 and Anandamahidol King Scholarship.

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5 Clinical Pharmacology of H1-Antihistamines F. Estelle R. Simons and Keith J. Simons University of Manitoba, Winnipeg, Manitoba, Canada

I.

INTRODUCTION

H1-antagonists have similar efficacy in the treatment of patients with allergic rhinitis or urticaria; however, they are diverse with regard to their chemical structure (Fig. 1), clinical pharmacology, and potential for toxicity (1). The scientific foundation for using these medications with optimal effectiveness in all patient populations, including the very young, the elderly, and those with hepatic or renal dysfunction, or those taking other medications concurrently, is provided by results of pharmacokinetic and pharmacodynamic studies (2). The pharmacokinetics and pharmacodynamics of some of the old H1-antagonists (brompheniramine, chlorpheniramine, diphenhydramine, hydroxyzine, and triprolidine) have been reviewed previously (3–11) (Fig. 2). Many of these medications have a surprisingly long terminal elimination half-life (t1/2 β); for example, chlorpheniramine, brompheniramine, and hydroxyzine have mean t1/2 β values of 24, 25, and 21 h, respectively. In contrast, diphenhydramine has a mean t1/2 β of 9.5 h, and the value for triprolidine is 1.7 ⫾ 0.5 h. The pharmacokinetics and pharmacodynamics of other first-generation H1-antagonists have never been adequately studied. The pharmacokinetics and pharmacodynamics of two of the nonsedating H1-antagonists, astemizole and terfenadine, while extensively studied, are mainly of historical interest. These medications have been removed from the pharmaceutical register by governmental regulatory agencies because of their susceptibility to interactions with other medications eliminated by the cytochrome P-450 system, and their potential cardiac toxicity (12, 13). These 141

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Figure 1 Chemical structures of selected H1-antihistamines. All are administered by mouth except for levocabastine, which is applied topically to the nasal mucosa or conjunctiva; and azelastine, which is commonly administered intranasally, although available in an oral formulation in a few countries. Azelastine, ebastine, loratadine, and mizolastine are extensively metabolized; in contrast, acrivastine, cetirizine, desloratadine, fexofenadine, and levocabastine are not extensively metabolized.

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Figure 2 Temporal relationships between the pharmacokinetics and pharmacodynamics of four H1-antihistamines. Information was obtained in prospective, randomized, doubleblind, single-dose studies in children. After oral dosing, plasma concentrations of (a) diphenhydramine, (b) brompheniramine, (c) carebastine (the active metabolite of ebastine) and (d) cetirizine were monitored for at least 24 h, along with suppression of the histamineinduced wheal and flare. Following ingestion of cetirizine and ebastine, wheal-and-flare suppression was maintained even after H1-antihistamine concentrations became negligible. These temporal relationships are characteristic of most H1-antihistamines studied to date using this model. (From Refs. 9, 11, 46, 77.)

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Figure 2 Continued

medications, and the first-generation H1-antagonists, will not be discussed further here. In this chapter, we focus on the new second-generation H1-antagonists, highlighting comparative studies (14–18) and reviewing the following medications in detail: acrivastine (19–25), azelastine (26–39), cetirizine (40–62), deslor-

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atadine (63–72), ebastine (73–86), fexofenadine (87–102), levocabastine (103– 107), loratadine (108–133), and mizolastine (134–147). Information about these medications was obtained by searching the Medline database, by reviewing Current Contents on Diskette, and, for the newest H1-antagonists, by hand-searching for relevant recent abstracts and accessing manufacturers’ data on file. Considerable pharmacokinetic and pharmacodynamic information about some of the new H1-antagonists remains unpublished in peer-reviewed journals, despite the fact that these medications were introduced more than a decade ago.

II. OVERVIEW OF PHARMACOKINETICS AND PHARMACODYNAMICS A. Measurement of H1-Antihistamines in Body Fluids H1-antagonists are generally present in low concentrations in plasma (20, 28, 41, 42, 109, 110, 136) and are not routinely measured. During the past few years, new assays, including gas–liquid chromatography (GLC) and high-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) have been developed. This has facilitated detection of minute concentrations of H1antagonists in plasma and tissues, identification of parent compounds and their metabolites (Table 1), pharmacokinetic studies (Figs. 2, 3), and medication interaction studies. The comparative pharmacokinetics of new H1-antagonists in healthy young adults are shown in Table 2. After oral administration, H1-antagonists are generally well absorbed, with peak plasma concentrations being reached within a few hours after administration to fasting individuals. Many new H1-antagonists appear to be extensively distributed into body tissues and bound to plasma proteins. Volumes of distribution (Vd) measured pharmacokinetically are seldom corrected for absolute bioavailability, because few of the new H1-antagonists can be administered to humans in intravenous formulations for comparison with oral formulations. Pharmacokinetic disposition is characterized by open two-compartment models and H1-antagonist kinetics are generally linear over the dosage ranges studied (Fig. 2). The t1/2 β values range from 2 to 24 h. The basic information obtained on H1-antagonists in traditional pharmacokinetic studies, performed in healthy young adults without concomitant disease and taking no other medications, can be usefully compared with the population pharmacokinetic data obtained during phase II and III clinical trials. These trials involve hundreds or even thousands of volunteers with allergic disorders who differ in age, sex, race, and body weight, in whom blood samples obtained at intervals for chemistry tests can also be used for measurement of

RIAa (HPLC-FL) a HPLC

HPLC-FL HPLC-MS RIA specific

RIA GLC-MSa RIA HPLC-FL HPLC-UV GLC GLC-NP HPLC/MS/MS (HPLC-UV) (GLC-MS)

— 1 µg/L 0.1 mg/L (plasma) 0.5 µg/L (urine) 0.3 µg/L (0.6 µg/L) 0.5 µg/L

(3x baseline, 20 µg/L)

0.025 µg/L

0.1–0.25 µg/Lb 2 µg/L — 0.3 µg/L (0.5 µg/L) 3 µg/L

Limit of quantitation

linear 0.1–20 µg/L (linear 0.6–24 µg/L) solid-phase extraction; 15–300 µg/L, CV ⬃6%

(linear 50–700 µg/L) CV: (3.8% at 500 µg/L; 7.6% at 75 µg/L) or (5.3% at 250 µg/L; 12.5% at 25 µg/L) Precision 5.9–9.7% linear 1–500 µg/L —

5–200 µg/L, CV ⬍ 6%

— CV: 15% at 4 µg/L; 35% at 2 µg/L —

Comments

CV, coefficient of variation; FL, fluorimetric; GLC, gas–liquid chromatography; HPLC, high-performance liquid chromatography; MS, mass spectrometry; RIA, radioimmunoassay; UV, ultraviolet; NP, nitrogen phosphorous detector. a Can differentiate between parent compound and metabolites. b Cannot differentiate between parent compound and metabolites. c Not available in the United States at time of publication.

Mizolastinec

Loratadine (descarboethoxyloratadine)

Levocabastine

Fexofenadine

Ebastine c (carebastine)

Desloratadine (3-hydroxydesloratadine)

Cetirizine

Azelastine (desmethylazelastine)

Acrivastine

Assay

Assays for New H1-Antihistamines in Plasma

Drug (active metabolite)

Table 1

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Figure 3 Population pharmacokinetic analyses. The marginal discrete distribution of the oral clearance of mizolastine, estimated by the nonparametric maximum likelihood method in the learning sample (population), and its smoothed representation, is shown. A two-compartment open model with zero-order absorption was used to describe the pharmacokinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed. The eight covariates introduced were sex, pharmaceutical dosage form, age, body weight, serum creatinine concentration, renal creatinine clearance, aspartate transaminase, and alanine transaminase. The pharmacokinetic parameters of mizolastine in patients with allergic disorders were similar to those obtained in young healthy volunteers, and no particular high-risk group of patients was identified. (From Ref. 142.)

H1-antagonist concentrations. This facilitates assessment of the possible influences of clinical and biological covariates (including dosage form, age, sex, race, body weight, and, theoretically, hepatic and renal function, and medication interactions) on kinetic parameters (142) (Fig. 3). The studies may contribute to identification of subgroups of individuals who require special dosage regimens. Several validation techniques have been proposed, and standards are available from the FDA. It is important to recognize, however, that patients with systemic disorders other than allergic disorders, including those with impaired hepatic or renal function, and those who regularly use medications in addition to the H1-

257/10 580/20 3/7.5 (90–120)/10

5.3 ⫾ 1.6 (20.5) 1.0 ⫾ 0.5

24.3–30.5/40 (6.7–30.5)/40 276/10

1.2 ⫾ 0.3 (1.5 ⫾ 0.7) 1.5

1–2

290–500/120,80 286/60–180 1.4–2.2 po 0.26–0.29 n, o

1.5–12.5 µg-eq/L/4

1.4 ⫾ 0.4

— (2.6–5.7) (3.6 ⫾ 1.1) 1–3

73/4

tmax (h) a

12.9

35–40 (po, iv) 33 (n, o) 7.8 ⫾ 4.2 (24 ⫾ 9.8)

21–31 (10.3– 19.3) 14.4

6.5–10

22–27.6 (54 ⫾ 15)

1.4–3.1

t1/2β (h)

— (98) 60–70 55

— (90–143 L) 5.8 ⫾ 0.7 1.14

— n/a 1.10 ⫾ 0.144

98 (73–76) 98

119

1.4

8.52 ⫾ 3.36 (n/a) 0.69

1.8 L/h

93

0.56

78–88

50

0.06 ⫾ 0.012

0.26 ⫾ 0.036 14.5

0.64

Cl/F (L/h/kg) b

Protein binding (%)

0.54 ⫾ 0.19

Vd b (L/kg)

—

0.04–0.14/40 (0.14–0.39)/40

1.9–3.1/ 120,180 —

2.9/10 5.8/20 104/7.5 (1.75–2.94)/10

47.3–405.9 µg-eq/4 (oral)

0.64/4

AUC (µg/L/h)/ dose (mg)

0.5/0

trace

65–70/20

12/80

— (75–95)/0

60/0

2(3)/0

59/0

Ae24 in urine/ feces (%)

Results are given as mean ⫾ standard deviation. a Time from oral intake to peak plasma concentration. b Clearance and volume of distribution measured pharmacokinetically, seldom corrected for bioavailability because few of the new H1-antagonists are available in intravenous formulations for comparison with oral formulations. c Acrivastine has a propionic acid derivative metabolite that has not been studied in humans. d Not available in the United States at time of publication. Ae24, amount of parent compound excreted unchanged in 24 h; AUC, area under the concentration-time curve; Cmax , peak plasma drug concentration after single dose administration; Cl/F, apparent oral clearance; n, nasal; n/a, minimal published data available; o, ocular; po, oral; tmax , time from oral intake to peak plasma drug concentration; t1/2β, terminal elimination half-life; Vd, volume of distribution.

Loratadine (descarboethoxyloratadine) Mizolastined (none)

Desloratadine Ebastined (carebastine) Fexofenadine (none) Levocabastine (none)

Acrivastine (none)c Azelastine (desmethylazelastine) Cetirizine (none)

Cmax (µg/L)/ dose (mg)

Single-Dose Pharmacokinetics of Representative H1-Anthistamines in Healthy Nonallergic Young Adults

Drug (active metabolite)

Table 2

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antagonists being studied, are generally excluded from phase II and III clinical trials.

B. Pharmacokinetics 1. Extensively Metabolized H1-Antihistamines Some new H1-antagonists such as azelastine, ebastine, loratadine, and mizolastine undergo extensive metabolism in the cytochrome P-450 (CYP-450) system in the liver and/or gastrointestinal tract, which can affect rate and/or extent of absorption due to gut metabolism, active transport, and first-pass hepatic extraction. After ordinary single oral doses, the plasma concentration of the parent compound is low, in contrast with a high concentration of the metabolite(s). Compared with the values found in healthy young adults, t1/2 β values for these H1-antagonists may differ in children (10, 11, 77, 115, 116), the elderly (32, 78, 117, 139), in patients with hepatic dysfunction (34, 80), or renal insufficiency (34, 79, 118), or those concomitantly receiving macrolide antibiotics, imidazole antifungals, cimetidine, or other medications eliminated by the CYP-450 system (33, 83, 107, 123–126, 140). A reduction of the dose or an increased interval between doses may be required (Table 3). For research purposes, patients who are extensive metabolizers or poor metabolizers can be identified by phenotyping hepatic enzymes, such as CYP3A4 or CYP2D6 in vitro or in vivo. H1-antagonist metabolism and medication interactions can also be studied in vitro using human liver tissue slices, hepatocytes, hepatoma cells, microsomal preparations, or purified recombinant fusion proteins containing CYP-450, with some accuracy in prediction of the in vivo response (82, 121, 122). 2. H1-Antihistamines Excreted Largely Unchanged Other new H1-antagonists, such as acrivastine, cetirizine, desloratadine, fexofenadine, and levocabastine, are not metabolized as extensively in the CYP-450 system; indeed, fexofenadine is excreted largely unchanged. These medications are unlikely to compete for elimination with other medications metabolized in this system and are also less likely to be implicated in causing adverse medication interactions (Table 3). Fexofenadine is primarily eliminated unchanged in the feces after biliary excretion. More than 50% of a dose of acrivastine, cetirizine, and levocabastine is eliminated unchanged in the urine. Although the elimination of acrivastine, fexofenadine, and levocabastine may be reduced in patients with impaired renal function (95, 106), and the elimination of cetirizine may be reduced in those with either impaired renal or hepatic function (51–54), the magnitude of the increases in maximum plasma drug concentrations (Cmax) and area

n/a — t1/2β ↑, not clinically significant t1/2β ↑ ↓ Cmax

n/a — t1/2β ↑, not clinically significant ↓ Cmax , ↑ tmax

↑ Cmax t1/2β ↑, minimal

↑ Cmax 68% t1/2β ↑ 10.4%

n/a (t1/2β ↑ to 95 h) no significant ↑ in t1/2β; AUC doubles t1/2β ↑ 47%

↑ Cmax t1/2β ↑ to 19–24 h

t1/2β ↑, 23–26 vs 17–19

t1/2β ↑ 27.2 vs 18.7

—

t1/2β ↑ to 20 h

t1/2β ↑ to 14 h n/a

— —

—

— (t1/2β ↑, minimal)

—

n/a

dependent on renal function n/a

— (t1/2β ↑)

↑ (35%) AUC doubled

Renal dysfunction

none

(renal dysfunction) hepatic/renal dysfunction

hepatic dysfunction, no change in Cmax or AUC none (UK) renal dysfunction (US): lower initial dose

hepatic or renal dysfunction/geriatric n/a

none (elderly)

none

Population in which dosage adjustment is requireda

possible, no effect identified in population pharmacokinetics

unlikely; loratadine is also eliminated via CYP2D6

unlikely

systemic bioavailability ↑ by 107% (erythromycin) and 164% (ketoconazole); bioavailability ↓ by antacid

unlikely; however, systemic bioavailability is increased possible (ketoconazole, erythromycin)

unlikely possible (cimetidine, ketoconazole) unlikely

unlikely

Interactions with other medications eliminated via CYP system

Dosage adjustment required only in patients with moderate/severe hepatic or renal dysfunction: Child’s class III hepatic disease or renal insufficiency with glomerular filtration rate ⬍30 mL/min. b Not available in the United States at time of publication. AUC, area under the concentration–time curve; Cmax , peak plasma drug concentration after single-dose administration; CYP, cytochrome P-450; tmax , time to reach peak concentration following drug administration; t1/2β, elimination half-life; ↑, increase; ↓, decrease.

a

Mizolastineb

Levocabastine nasal b (oral) Loratadine

Fexofenadine

Ebastine b

Desloratadine

Cetirizine

Azelastine nasal (oral) b

Elderly t1/2β

Hepatic dysfunction

Pharmacokinetics of H1-Antihistamines: Potential Increase in Elimination Half-Life in Special Populations

Acrivastine

Drug

Table 3

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under the concentration–time curve (AUC) is such that dosage adjustments usually are not necessary (34, 51–54, 95, 96, 106). Fixed-dose H1-antagonist/pseudoephedrine combination medications are widely used, and medication interaction studies with H1-antagonists and pseudoephedrine are, therefore, of interest. This is especially true of the H1-antagonists that are eliminated largely unchanged in the urine, since this is also the primary route of elimination for pseudoephedrine (23, 113, 120).

C. Pharmacodynamics 1. Wheal-and-Flare Model Understanding the relationship between plasma H1-antagonist concentration and the intensity of the H1-antagonist effect is facilitated by objective assessments of the suppression of the histamine-induced wheal-and-flare response in the skin (14, 15, 18, 24, 25, 35, 36, 38, 46, 49, 55–59, 77, 85, 93, 98–100, 127–132, 143– 145, 147), or the antigen-induced wheal-and-flare response, to which histamine is the major contributor. H1-antagonists decrease the size of the wheal directly by decreasing postcapillary venule permeability and leakage of plasma protein, and they decrease the size of the flare indirectly by blocking the histamine-induced axon reflex. Using a standardized wheal-and-flare bioassay, dose–response curves can be identified for an H1-antagonist. Significant differences in onset, potency, and duration of activity among H1-antagonists can be identified during the first 24 h after administration (14, 15) (Figs. 2, 4).

2. Allergic Rhinitis Model In contrast to the differences detected by using the wheal-and-flare model, clinical evaluations over several weeks using subjective symptom scores in patients with allergic rhinoconjunctivitis tend to demonstrate similarities in dose–response to the same H1-antagonists, and in efficacy and effectiveness among H1-antagonists. Although the unique ability of H1-antagonists to suppress the wheal-andflare response is used as the end point in most pharmacodynamic studies, in other studies their ability to suppress the histamine- or allergen-induced response in the nose, eye, or lower airways has been used (16, 17, 37–39, 62, 86, 101, 132, 133). In patients with allergic rhinitis, after intranasal histamine or allergen challenge, pretreatment with an H1-antagonist prevents symptoms. In these studies, direct evidence of histamine blockade on postcapillary venules and prevention of vascular leak can be obtained by measuring α2-macroglobulin in nasal secretions (16) (Fig. 5).

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Figure 4 Cutaneous antihistaminic effects of cetirizine, ebastine, epinastine, fexofenadine, terfenadine, and loratadine. In a randomized, double-blind, crossover study, cetirizine 10 mg, ebastine 10 mg, epinastine 20 mg, fexofenadine 60 mg, terfenadine 60 mg, loratadine 10 mg, or placebo was given to 14 healthy men. Wheal-and-flare inhibition was assessed using epicutaneous tests with histamine phosphate 100 mg/mL and measurement of the least-squares mean surface area of the resulting wheal and flare, before and up to 24 h after a single dose. Epinastine had the fastest onset of action, inhibiting the wheal (shown) and flare (not shown) significantly compared to placebo and to all other active treatments at 0.5 and 1 h. (From Ref. 15.)

3. Onset of Action and Peak Action The pharmacodynamics of H1-antagonists are medication- and dose-dependent. The Cmax of the H1-antagonists in target organs such as the skin is achieved rapidly after oral administration (Fig. 6). It correlates well with onset of H1-antagonist activity, and amount of H1-antagonist activity, as evidenced by suppression of the histamine-induced wheals and flares (14, 15) (Table 4; Figs. 2, 4, 6). Peak suppression of the histamine-induced wheals and flares by H1-antagonists generally occurs 5–8 h after oral administration of a single dose, later than the Cmax (14, 15). Maximum H1-blockade usually persists for hours even after plasma concentrations have declined to the lowest limits of analytical detection. For some medications, such as cetirizine and fexofenadine, this persistent effect is associated with high tissue/plasma concentration ratios (56, 99) (Fig. 6). For other medications, such as ebastine and loratadine, the presence of active metabo-

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Figure 5 H1-activity on the nasal mucosa produced by intranasal and oral H1-antihistamines. In a double-blind, single-dose, crossover study, healthy individuals received either azelastine nasal spray 0.254 mg/nasal cavity, or oral cetirizine 10 mg, or placebo. Histamine challenges (40 and 400 µg/L) were given 1 h before, and 1, 6, 9, 12, and 24 h after, treatment. α2-Macroglobulin in the nasal lavage fluid was measured as a marker of increased vascular permeability and exudation of bulk plasma onto the nasal mucosa. From 1 to 12 h after administration, azelastine or cetirizine, but not placebo, decreased the histamine-induced mucosal exudation of plasma, as shown by a significant decrease in the α2macroglobulin marker (1 h results shown). (From Ref. 16.)

lites in tissue is probably important, although they have not been directly measured there. 4. Duration of Action and Residual Action The duration of action of a single dose of an H1-antagonist, assessed objectively from suppression of the histamine- or allergen-induced wheals and flares in the skin, or subjectively by suppression of nasal symptoms after allergen challenge, is more prolonged than might be expected from consideration of plasma H1-antagonist concentrations and t1/2 β values. For many H1-antagonists, the duration of action is at least 24 h (Figs. 2, 4, 6), facilitating once-daily administration (Tables

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Figure 6 Correlation of skin and plasma H1-antihistamine concentrations during multiple-dose administration. In a randomized, double-blind, multiple-dose, crossover study, fexofenadine 120 mg/day was administered for 1 week, during which skin and plasma fexofenadine concentrations were monitored, and wheal-and-flare areas were measured after epicutaneous tests with histamine phosphate 1 mg/mL. The tests were performed at baseline and 1, 3, 6, 9, and 24 h after the initial dose of fexofenadine 120 mg. On each of 6 subsequent consecutive days, participants took fexofenadine 120 mg at 2100 h, and all the tests were repeated at 168 h (steady state), exactly 12 h after the seventh and last dose. Values are means ⫾ standard error of the mean; * indicates significantly different from predose values (p ⬍ 0.05). Fexofenadine achieves excellent concentrations in the skin and excellent wheal-and-flare suppression, in contrast to the comparator H 1-antihistamine diphenhydramine 50 mg/day (not shown). (From Ref. 99.)

4, 5). For some H1-antagonists, the duration of action may be even longer in the elderly and in patients with hepatic or renal dysfunction, and may necessitate a reduced dosage or dose frequency of some H1-antagonists in these populations (Table 3). The residual action of an H1-antagonist is defined as the pharmacological effects that last for days or weeks after the medication has been discontinued. This is clinically relevant information because it defines the time during which an H1antagonist must be discontinued before allergen skin tests or inhalation challenge tests with allergen or histamine can be performed with acceptable clinical accuracy. Most H1-antagonists need to be discontinued 2–7 days before these tests. 5. Peripheral H1-Activity Does Not Diminish During Regular Administration Loss of effectiveness of the peripheral H1-receptor blocking activity of H1-antagonists during regular daily administration has not been found in rigorously con-

Acrivastine 8 mg Azelastine: nasala (oral)c 4 mg Cetirizine 10 mg Desloratadine Ebastinec 10 mg Fexofenadine 60 mg Levocabastine (nasal,c eye) a Loratadine 10 mg Mizolastinec 10 mg

Nose, eyes, lower airways Nose (lower airways) Nose, lower airways n/a Nose, eyes, lower airways Nose Nose, eyes Nose, lower airways — no no (no) nob n/a no no no nob nob

n/a — (7) 3 n/a 3 2 — 7 n/a

8 — (12) ⱖ24 n/a ⱖ24 24 — 24 24

b

Wheal-and-flare suppression does not occur after application to the nasal mucosa or eye, due to minimal systemic absorption. Excellent published wheal-and-flare data. c Not available in the United States at time of publication. n/a, minimal published information available.

a

0.5 — (4) 0.7 n/a 1 2 — 3 1

Drug and dose

Other organs in which pharmacodynamic studies have been performed

Tachyphylaxis during regular administration

Residual effect after stopping (days)

Regular administration

Duration of action (h)

Single dose

Suppression of skin wheal and flare

Pharmacodynamics of Representative H1-Antihistamines

Onset (h)

Table 4

Clinical Pharmacology 155

Tablets 60 mg, 120 mg, 180 mg Intranasal microsuspension 50 µg/spray c Ophthalmic suspension 0.05% (0.5 mg/mL) Tablets 10 mg Rapidly disintegrating tablets (Reditabs) 10 mg Syrup 5 mg/5 mL Tablets 10 mg

Tablets 8 mg Nasal solution 0.1% (0.137 µg/spray) Tablets 2 mg c Tablets 10 mg Syrup 5 mg/5 mL Tablets 5 mg Tablets 10 mg

Pediatric (2–9 yrs): 5 mg od Adult: 10 mg od

Adult 8 mg tid Adult intranasal: 2 sprays per nostril bid; oral: 2–4 mg bid Adult: 5–10 mg od Pediatric (6–11 yrs): 5–10 mg od Adult: 5 mg od Adult: 10–20 mg od Pediatric (6–12 yrs): 5 mg od Pediatric (2–5 yrs): 2.5 mg od Adult: 60 mg bid or 120 or 180 mg od Adult nasal: 2 sprays/nostril bid-qid Ophthalmic: 1 drop in each eye bid-qid Adult: 10 mg od Pediatric (6–10 yrs): 10 mg od

Recommended dosage

b

Only the most commonly used proprietary names are listed. Available with pseudoephedrine; acrivastine is only available in fixed-dose combination with pseudoephedrine hydrochloride, 120 mg. c Not available in the U.S. at time of publication. od, once daily; bid, twice daily; tid, three times daily; qid, four times daily.

a

Mizolastine (Mizollen) c

Loratadine (Claritin)b

Fexofenadine (Allegra, Telfast) b Levocabastine (Livostin)

Desloratadine Ebastine (Ebastel) c

Cetirizine (Zyrtec, Reactine) b

Acrivastine (Semprex) b Azelastine (Astelin)

Formulation

Formulations and Dosages of Representative H1-Antihistamines

Generic/proprietary namea

Table 5

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trolled, double-blind studies of up to 12 weeks duration in which H1-activity has been monitored objectively using the suppression of skin wheals and flares (46, 131, 147) (Fig. 7). Nor has loss of H1-activity been found in clinical studies of up to 6 weeks duration during which suppression of urticaria lesions or perennial allergic rhinitis symptoms has been monitored subjectively (1). The apparent tachyphylaxis to some H1-antagonists demonstrated in a few lower-airway studies or central nervous system (CNS) studies may be due to study design and to the variable effects of the specific H1-antagonist being tested in these organs, since H1-receptors do not differ in skin, upper airways, lower airways, and CNS.

Figure 7 H1-activity does not diminish during regular daily administration of an H1antihistamine. In a double-blind, placebo-controlled, parallel study in 60 patients with atopy, mizolastine 10 mg/day was given for 8 weeks. Epicutaneous (puncture) tests with histamine chlorhydrate 10 mg/mL, codeine phosphate 9%, or allergen (five incremental concentrations of orchard grass pollen or house dust mite) were performed 2 h after the mizolastine or placebo dose on 6 test days at least 1 week apart (7 days before the first dose, immediately before the first dose, and on the 7th, 28th, 42nd, and 56th day of administration). Suppression of the wheals and flares induced by all three agents was maintained throughout the study. The figure shows the changes from baseline in patients with allergeninduced skin reactions during placebo and mizolastine treatment, all concentrations of both types of treatment being considered together (intergroup comparisons by MANOVA, p ⫽ 0.0001). The model incorporates treatment, allergen, and interaction. (From Ref. 147.)

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III. NEW H1-ANTIHISTAMINES: DIVERSE PHARMACOKINETICS AND PHARMACODYNAMICS A detailed review of the pharmacokinetics and pharmacodynamics of selected new H1-antagonists follows. The medications are discussed in alphabetical order. A.

Acrivastine

1. Pharmacokinetics Absorption of acrivastine (19–25) is rapid after oral administration. In healthy individuals, the mean Cmax is 73 µg/L, achieved at a mean time of 1.4 ⫾ 0.4 h after administration of acrivastine 4 mg (Table 2). Absorption is not significantly decreased by the concomitant ingestion of food. During administration of acrivastine three times daily for 7 days, accumulation does not occur (19–23). The mean apparent Vd is 0.64 and 0.75 L/kg after single and multiple doses, respectively. Acrivastine is approximately 50% protein-bound. The principal acrivastine metabolite, a propionic acid analog formed by reduction of the acrylic acid side chain, accounts for about 10% of the total plasma concentration and for between 15 and 17% of the dose recovered in the urine. It is more active than the parent compound in vitro. Unchanged acrivastine accounts for 59% of the administered dose recovered in the urine. After a single 8 mg dose of [14C]acrivastine, 88% of the ingested radioactivity is recovered in the urine within 48 h; the remainder is excreted in the feces within 5 days. After single or repeated doses, the apparent total body clearance is 0.26 L/ h/kg and t1/2 β ranges between 1.4 and 3.1 h. The mean t1/2 β of the metabolite is 2.3 h (19, 21, 22). In 36 elderly volunteers (aged 65–75 years) receiving acrivastine 8 mg or 16 mg three times daily for 22 doses, a 25% decrease in clearance, a 35% increase in t1/2 β and time to Cmax (tmax), and a doubling of the AUC have been reported (Table 3). There is minimal information about the pharmacokinetics of acrivastine in children or in patients with impaired renal or hepatic function. Acrivastine is generally formulated in a fixed-dose combination with pseudoephedrine; there are no pharmacokinetic interactions between the H1-antagonist and the decongestant. There is also minimal information on interactions between acrivastine and other coadministered medications (19, 23). 2. Pharmacodynamics After administration of acrivastine, suppression of the histamine-induced wheal and flare begins within 30 min (Table 4), and peaks at between 1.5 and 2 h (19, 24, 25). The duration of action is shorter than that of any other new H1-antagonist. Acrivastine 4 mg, but not 2 mg, reduces the response to histamine in nasal chal-

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lenge studies. Acrivastine 8 mg reduces the conjunctival response to histamine. In patients with asthma, acrivastine protects against histamine-induced bronchoconstriction. No studies on the potential development of tachyphylaxis to acrivastine have been published.

B. Azelastine 1. Pharmacokinetics It is not possible to perform pharmacokinetic studies after the administration of a single dose of the nasal formulation of azelastine (26–39), as the plasma concentrations of the parent compound and its pharmacologically active major metabolite, desmethylazelastine, are below 0.25 µg/L, the lowest limit of detection using the HPLC assay available (Table 1). Using the older radioimmunoassay, at steady-state, after intranasal administration of 0.56 mg (4 puffs) daily for 29 days, the Cmax is 0.306 µg/L, the tmax is 2.5 h, and the steady-state plasma concentration is 0.26 µg/L in healthy individuals and 0.65 µg/L in those with allergic rhinitis. These plasma concentrations are considerably lower than the Cmax of 1.5–12.5 µg/L achieved 4–5 h after azelastine 4 mg by mouth (Table 2). Systemic bioavailability is 40%; after intranasal administration, systemic exposure is estimated as six to eight times lower than after oral administration of azelastine 4 mg. Using the new HPLC assay and measuring only the parent compound azelastine, the Cmax is 5.9 µg/L, and tmax is 5.3 h. The Vd of azelastine at steady-state is 14.5 ⫾ 4.0 L/kg and it is 78–88% bound to plasma proteins. Azelastine is almost completely metabolized by hepatic oxidation. After intranasal administration to steady-state, plasma concentrations of desmethylazelastine account for 20–50% of total measurable concentrations of azelastine and its metabolites. Additional metabolites include the 2- and 7-acid derivatives formed by oxidation and subsequent azepinyl ring opening. Following administration of a single oral dose of [14C]azelastine, 75% of the radioactivity is recovered within 120 h: 50% in the feces and 25% in the urine. HPLC analysis of urine reveals that 2% of an azelastine dose is eliminated as parent compound and 3% as desmethylazelastine. The pharmacokinetics of azelastine are similar when determined after oral or intravenous administration. In single-dose studies, the t1/2β is 22 ⫾ 4 h for azelastine and 54 ⫾ 15 h for desmethylazelastine. At steady-state after multiple oral doses of 4 mg twice daily, the t1/2β is reported as 35.5 h (27, 29–31). There is minimal information on the pharmacokinetics of the nasal or ophthalmic formulations of azelastine in children, in patients with hepatic or renal dysfunction, or in those concomitantly taking other medications. The pharmaco-

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kinetics of orally administered azelastine have been studied in the elderly (mean age, 70 years) in whom elimination is decreased, leading to a doubling of plasma concentrations during multiple doses; a 50% reduction of the oral dose is required in this population (32) (Table 3). In patients with mild or moderate hepatic or renal dysfunction, azelastine elimination is not greatly affected and dose reductions are not considered necessary (34). 2. Pharmacodynamics Azelastine administered intranasally before challenge with histamine or allergen decreases sneezing and other symptoms (16, 26, 27, 35–39) and also decreases α2-macroglobulin concentrations in nasal lavage fluid, providing direct evidence of histamine blockade on postcapillary venules and prevention of vascular leak (16) (Fig. 5). Azelastine nasal spray administration, 0.14 mg/nostril twice daily for 1 week, has no suppressive effect on histamine-induced wheals and flares in the skin, suggesting that there is little systemic absorption. Orally administered azelastine has a dose-related suppressive effect on histamine-induced wheals and flares (Table 4), on histamine-induced nasal obstruction as measured by posterior rhinomanometry, and on histamine-induced bronchoconstriction in patients with asthma in whom it also has a dose-related bronchodilator effect. Tachyphylaxis to azelastine has not been reported. C.

Cetirizine

1. Pharmacokinetics After oral administration of a 10 or 20 mg dose, cetirizine (40–62) is rapidly absorbed from the gastrointestinal tract, with a mean Cmax of 257 and 580 µg/L, respectively, achieved in 1 h (Table 2). Concurrent ingestion of food may decrease the rate but not the extent of absorption. The Vd of cetirizine, 0.56 L/kg, is low compared with that of the other H1-antagonists. At 24 h after a single dose and at steady-state, skin cetirizine concentrations are similar to, or exceed, serum concentrations (56). Plasma protein binding is reported to be 93% at plasma concentrations of 25–1000 µg/L. Approximately 60% of the administered dose is recovered unchanged in the urine within 24 h. Renal excretion involves an active transport mechanism. Steady-state concentrations are achieved within 3 days. During long-term administration, no accumulation occurs and the rate of elimination does not change (40, 43–45). After administration of [ 14C]cetirizine, more than 90% of plasma radioactivity is attributed to unchanged cetirizine at 2 h, 80% at 10 h, and 70% at 24 h. Small amounts of a metabolite produced by oxidative O-dealkylation appear in the plasma at 10 h and in the feces from 24 to 48 h. About 50% of the adminis-

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tered radioactivity is excreted in the urine during the first 24 h after administration, and a further 10% is excreted in the next 4 days. The major source of urinary radioactivity is unchanged cetirizine, accounting for 93% of the radioactivity during the first 2 h after administration and 83% from 12 to 24 h postdose. The remaining radioactivity is attributable to small amounts of unidentified metabolites (43). Mean t1/2β values for cetirizine are 6.5–10 h after a single 10 mg dose in healthy adults. In children with a mean age of 8 years, the t1/2β is approximately 7 h (Fig. 2); in those with a mean age of 2–4 years, it is 4.9 h; and in infants with a mean age of 12 months, it is 3.1 h. In infants and children, only 40% of cetirizine is eliminated unchanged in the urine (46–49). In the elderly (mean age, 75 ⫾ 11 years), the mean t1/2β of cetirizine is 11.8 h (Table 3); this slight prolongation is associated with significant reduction in total body renal clearance and apparent nonrenal clearance, and is dependent on renal function rather than age (50, 51). In patients of any age with moderate renal dysfunction, the tmax is increased to 2 h, and the t1/2β is increased to 20–20.9 h. Less than 10% of a dose of cetirizine is removed by hemodialysis. In patients with impaired hepatic function, the clearance rate is 0.018 L/h/kg (0.3 mL/min/kg), the fraction of the dose excreted unchanged in the urine (32% after 96 h) is significantly reduced compared with values obtained in healthy individuals, and the t1/2β is between 13.8 and 14.3 h. These alterations in the pharmacokinetics are clinically relevant and dose reduction is suggested in these patients (51–54). Cetirizine elimination is not inhibited by concomitant administration of other medications such as cimetidine (55). 2. Pharmacodynamics Cetirizine 10 mg suppresses the histamine- or allergen-induced wheal and flare response rapidly with a significant effect in 30 to 40 min, and a peak effect 4 to 8 h after administration (14–18, 40, 46, 49, 55–62) (Table 4). Significant suppression lasts for at least 24 h in adults and children; in infants, it only lasts for 12 h. The comparative suppressive effects of cetirizine and other H1-antagonists have been extensively studied (14, 15) (Fig. 4). Cetirizine is more effective than other antihistamines in suppressing the wheals and flares induced by epicutaneous histamine phosphate 1, 10, or even 100 mg/mL, the concentrations generally used in this pharmacodynamic model. Cetirizine also has favorable pharmacodynamics in the upper airway (16, 17) and lower airways (18, 62). It provides dose-dependent protection against histamine-induced bronchospasm in patients with mild asthma (62). Patients taking cetirizine regularly should discontinue it 3–4 days before having skin tests with histamine or allergen. Tachyphylaxis to cetirizine has not been reported.

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Desloratadine

1. Pharmacokinetics Plasma concentrations of desloratadine (63–72) and its active metabolite 3-hydroxy-desloratadine are determined by liquid chromatography/mass spectrometry with a lower limit of quantitation of 0.025 µg/L (Table 1). Desloratadine has excellent bioavailability in fasted and in fed subjects (64). It exhibits linear pharmacokinetics over the dose range 5–20 mg. After a single dose of 7.5 mg and after multiple dosing with 7.5 mg daily for 14 days, the Cmax is approximately 5.5–10.2 µg/L and the t1/2β is 21–31 h (Table 2). No dosage adjustment is needed for race or sex (67). Although some increases in the AUC and in Cmax are observed when desloratadine is administered concomitantly with either erythromycin or ketoconazole, no clinically important pharmacokinetic changes and no electrocardiographic changes are observed (68, 69) (Table 3). 2. Pharmacodynamics No wheal-and-flare studies with desloratadine have been published to date. E.

Ebastine

1. Pharmacokinetics After oral administration, ebastine (73–86) undergoes extensive first-pass metabolism to its active carboxylic acid metabolite, carebastine. The parent compound is present in extremely low concentrations in plasma, and pharmacokinetic studies are based on the measurement of carebastine (Table 1, Fig. 2). After ingestion of ebastine 10 mg, the carebastine Cmax of 90–120 µg/L was obtained at 2.6– 5.7 h (Table 2), with some variations according to race. The values for the AUC range from 1.75 to 2.94 mg/L/h. Extrapolating from plasma carebastine concentrations, ebastine seems to be readily absorbed and food ingestion increases bioavailability. Carebastine has a Vd of 90–143 L, and is 98% bound to plasma proteins. In human studies, 40% of the radioactivity from labeled ebastine is recovered in urine and 6% in feces over 24 h, increasing to 71% and 28%, respectively, over 312 h. The t1/2 β of carebastine is 10.3–19.3 h in single-dose studies and in multiple-dose studies over 7 days. The pharmacokinetics of carebastine appear to be linear following ebastine doses of 10–90 mg. During once-daily multiple-dose administration of ebastine, the Cmax of carebastine increases 1.6–1.7-fold, but the AUC24 does not change at steady state, reached by days 3–5 (73–76). In a multiple-dose study in which ebastine 10 mg was given daily for 9 days to elderly adults age 65–75 years, no significant differences in mean steadystate pharmacokinetic parameters were found, compared to young adults (Table

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3). In children, the pharmacokinetics and pharmacodynamics of ebastine have been well studied (77) (Fig. 2). Patients with hepatic or renal dysfunction may have a significant increase in the t1/2 β of carebastine; however, they have no significant increase in the Cmax or in the AUC of carebastine, and dosage adjustments may not be necessary. Ebastine does not appear to interact with ethanol, diazepam, or cimetidine. A significant increase in plasma carebastine concentrations may occur when ketoconazole 400 mg/day or erythromycin 500 mg every 6 h are concomitantly administered with ebastine (83, 84). 2. Pharmacodynamics Ebastine has a dose-related suppressive effect (15, 86) on the histamine-induced wheals and flares over the range of 3–30 mg (61, 73, 77, 85). After a single dose, the maximum suppressive effect occurs at 6–8 h, and significant suppression is still present at 24 h (Table 4). The comparative suppressive effects of ebastine and other new H1-antagonists are shown in Figure 4 (15). A single oral dose of ebastine 10 mg or 30 mg, administered before bronchial challenge with histamine, shifts the dose–response curve 3- to 27-fold. There is a good correlation between plasma carebastine concentrations and suppression of the histamine-induced wheals and flares, or suppression of histamineinduced bronchoconstriction. After a short course of ebastine, the residual effect lasts for 3–4 days. Tachyphylaxis to ebastine has not been reported.

F.

Fexofenadine

1. Pharmacokinetics Fexofenadine (87–102) is readily absorbed when administered orally, with Cmax reached between 1 and 2.6 h after administration (Table 2). Absorption is not markedly affected by food (89). Bioavailability is reported as being at least 33% (90). In equilibrium dialysis studies, 60–70% of plasma fexofenadine is proteinbound, predominantly to albumin and α1-acid glycoprotein. During the 24 h after a single dose of fexofenadine 120 mg, and at steadystate, skin fexofenadine concentrations exceed plasma concentrations (99) (Fig. 6). The primary pathways of elimination of fexofenadine are biliary and renal excretion, and there is no evidence of significant biotransformation. In a study in which healthy volunteers were given fexofenadine 60 mg twice daily for 4 days to achieve steady-state and then received a single 60 mg oral dose of [ 14C]fexofenadine, 80% of the dose was recovered in an unchanged form in the feces and 12% in the urine. The only other substances recovered in urine and feces are azacyclonol, an inactive degradation product, and fexofenadine methyl

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ester, which may be a true metabolite, a product of intestinal microflora activity, or a minor synthetic impurity. The t1/2 β of fexofenadine in healthy adults is 11–15 h and is similar in children (91–94) (Table 2). In participants older than 65 years of age given a single 80 mg dose, the mean Cmax is 68% higher and t1/2β 10.4% longer than in younger adult males; however, the resulting plasma concentrations are considerably below those observed in clinical trials in which fexofenadine dosages of up to 800 mg daily have been administered (94) (Table 3). In patients with renal disease, higher peak plasma fexofenadine concentrations and slower elimination are observed in proportion to the severity of impairment of renal function. Although renal clearance of fexofenadine decreases as the severity of renal disease increases, there is little correlation between plasma clearance and the severity of renal disease, and it is possible that decreased renal elimination may be compensated to some extent by higher biliary clearance. Hemodialysis removes only 1.7% of the fexofenadine in blood. Hepatic impairment does not affect the absorption or elimination of fexofenadine to any extent, with mean plasma clearance, Cmax , t1/2β, and renal clearance all within 25% of that in healthy individuals (95, 96). When fexofenadine is coadministered with erythromycin or ketoconazole, its systemic bioavailability increases by 107% and 164%, respectively. This has been attributed to increased gastrointestinal absorption (seen with both erythromycin and ketoconazole), decreased biliary excretion (erythromycin), or decreased gastrointestinal secretion (ketoconazole). The resulting increased plasma concentrations are within the range of concentrations that are well tolerated in clinical trials (87, 88, 102). Ingestion of fexofenadine within 15 min of ingestion of an aluminum- and magnesium-containing antacid decreases bioavailability by 40% (87, 88). 2. Pharmacodynamics The effectiveness of a single oral dose of fexofenadine (15, 87, 88, 93, 97, 101) in inhibiting the histamine-induced skin wheal and flare response has been studied over a dose range of 20–800 mg. Doses of ⱖ40 mg produce significant suppression of wheals and flares 2 h after administration (Table 4). An 80 mg dose of fexofenadine is said to be equivalent to a 60 mg dose of the parent compound, terfenadine. Peak suppression occurs from 3 to 12 h, and suppression is still significant at 24 h. The comparative suppressive effects of fexofenadine and other new H1-antagonists are shown in Figure 4 (15). In the skin wheal-and-flare model and in the nasal challenge model, fexofenadine has a prompt onset of action (98– 101). When fexofenadine is given for a week and then discontinued, the residual effect lasts for only 2 days. Tachyphylaxis to fexofenadine has not been reported.

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Levocabastine

1. Pharmacokinetics In healthy individuals, absorption of levocabastine (103–107) from nasal or ophthalmic formulations occurs within 1 to 2 h (Table 2) and bioavailability is between 60 and 80%, and between 30 and 60%, respectively. Swallowed levocabastine may contribute to the overall systemic availability of the nasal spray. Steady-state plasma concentrations, achieved in 7–10 days, are approximately 10.4 µg/L after two nasal sprays (50 µg/spray) per nostril three times daily, and 1.6 µg/L after application of a 0.05% ophthalmic suspension, 1 drop (15 µg) per eye three times daily. Steady-state plasma concentrations with the nasal spray are lower in patients with allergic rhinitis (3.5 to 5.2 µg/L) than in healthy individuals; this is in contrast to azelastine, which is absorbed to a greater extent by those with allergic rhinitis. After application to the nasal mucosa or the eyes in nursing mothers, minute amounts of levocabastine have been detected in breast milk. The pharmacokinetics of levocabastine have also been studied after oral and intravenous administration; these formulations are not used clinically because of sedative effects. After oral administration, Cmax is attained within 2 h and systemic bioavailability is 100–120%, indicative of a negligible first-pass effect. At steady-state, intravenously administered levocabastine has a mean Vd of 82 L (1.14 L/kg). The plasma protein binding is approximately 55%. Levocabastine undergoes little hepatic metabolism; 65–70% of absorbed levocabastine is excreted in the urine as unchanged drug and 10–20% appears unchanged in the feces, probably because of biliary excretion. The remainder is recovered in the urine as the acylglucuronide metabolite. After single or repeated doses, the t1/2β of levocabastine is between 35 and 40 h, regardless of the route of administration. In patients with renal impairment, orally administered levocabastine has an increased t1/2 β of 95 h and a 56% increase in the AUC; urinary excretion of unchanged levocabastine is reduced (Table 3). Although hemodialysis removes 10% of a dose of levocabastine, it does not alter the effect of impaired renal clearance on pharmacokinetics. There is minimal information on topically administered levocabastine in patients with renal impairment and on levocabastine administered by any route in children, the elderly, or in patients with hepatic impairment (106). No medication interactions have been reported (107).

2. Pharmacodynamics Topically applied levocabastine (103, 104) prevents histamine- or allergen-induced nasal or conjunctival symptoms. Levocabastine nasal spray or levocabastine eye drops administered regularly have no significant suppressive effects on

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histamine-induced wheals and flares, suggesting that little systemic absorption occurs when these formulations are applied topically (Table 4). H.

Loratadine

1. Pharmacokinetics Loratadine is well absorbed following oral administration (108–126), with peak plasma concentrations of 24.3–30.5 µg/L occurring 1–1.5 h after ingestion of a 40 mg dose (111–114) (Table 2). Concurrent ingestion of food decreases the rate but not the extent of absorption. Steady-state is achieved by the fifth day of multiple dosing. Loratadine has a large Vd of 119 L/kg and is 97–99% plasma proteinbound. It is extensively metabolized by hydroxylation by the CYP3A4 family to descarboethoxyloratadine (DCL). After administration of single doses of 20–40 mg, its mean distribution and terminal elimination (t1/2 β) half-life values are 0.9– 1.0 h and 7.8–11 h, respectively. At steady-state, after administration of 40 mg daily for 10 days, the distribution half-life does not change, and the t1/2 β is 14.4 h; little accumulation occurs. The major metabolite, DCL, has a mean t1/2 β of 17.3–24 h (14.4–18.7 h at steady-state). It is 73–76% protein-bound. It is further converted to an inactive metabolite excreted primarily in the urine. Like its parent compound, DCL has dose-proportional pharmacokinetics and does not accumulate to any extent during multiple-dose administration. In children, the t1/2 β of DCL arising from loratadine in vivo is 13.8 h. In healthy elderly individuals, the mean t1/2 β of loratadine and DCL are 18.2 and 17.5 h, respectively. In patients with impairment of renal or hepatic function, although there may be increases in Cmax and AUC for loratadine and DCL, the rate of elimination is not significantly decreased (115–118). Loratadine is one of the few H1antagonists for which elimination in breast milk has been optimally investigated: a 4 kg infant is estimated to receive 0.46% of a 10 mg maternal dose (119). Potential pharmacokinetic interactions of loratadine and other medications have been extensively studied (120–126). In the presence of CYP3A4 inhibitors, loratadine is also metabolized by CYP2D6. Coadministration of ketoconazole 200 mg twice daily for 5 days in 12 healthy volunteers inhibited the metabolism of a single 20 mg oral dose of loratadine, as did coadministration of erythromycin or cimetidine; however, these findings are of minimal clinical relevance. The pharmacokinetics of loratadine are not influenced by concomitant administration of pseudoephedrine. 2. Pharmacodynamics Loratadine 10 mg suppresses histamine-induced wheals and flares significantly within a few hours, and the suppression lasts for 12–24 h (14, 15, 127–130) (Table 4). The comparative suppressive effects of loratadine and other new H1-

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antagonists are shown in Figure 4 (15). In the wheal-and-flare model, and in the nasal challenge model (17), significant suppression begins a few hours later after loratadine than after some other H1-antagonists; however, the data obtained in studies with a duration of only 24 h are not necessarily reflected in allergic rhinitis studies lasting several weeks. Loratadine also prevents the bronchoconstrictor response to histamine or allergen (132, 133). After a short course of loratadine, the residual effect lasts for less than 1 week. Tachyphylaxis to loratadine has not been reported (131).

I.

Mizolastine

1. Pharmacokinetics Mizolastine is rapidly absorbed with a mean Cmax of 276 µg/L and a median tmax of 1.5 h (134–142) (Table 2). Bioavailability is 65.5% and is not affected by age or concomitant ingestion of food or alcohol. Linear dose–response curves are observed for Cmax and AUC over the dose range 5–20 mg. The Vd of mizolastine after intravenous administration is 1.4 L/kg, reflecting its low lipophilicity (log P ⫽ 2.9 at pH ⫽ 7.4). It is 98.4% protein-bound in plasma. Mizolastine is extensively metabolized, with less than 0.5% of the administered dose excreted unchanged in the urine. After administration of [ 14C]mizolastine to humans, 84–95% of the radioactivity is excreted in the feces. The main metabolic pathway is glucuronidation of the parent compound (66% of the administered dose). In vitro studies with specific metabolic inhibitors have shown CYP3A4 and CYP2A6 to be responsible for the oxidation pathways. No active metabolites have been identified (134, 135). The distribution half-life is 1.9 h and the t1/2 β is 12.9 h. Systemic plasma clearance is 0.69 L/h/kg and does not change with repeated once-daily oral administration of mizolastine for 5 or 14 days. Steady-state is reached on the third day of administration and accumulation does not occur (137, 138). In the elderly (aged 66–77 years), Cmax is lower and apparent t1/2 β slightly longer than in young healthy individuals (Table 3). In patients with renal disease, the t1/2 β of mizolastine is prolonged by 47%, but values remain within the range found in healthy young volunteers, and no dose adjustments are necessary (139). Mizolastine is not cleared by hemodialysis. In patients with hepatic cirrhosis, tmax is delayed and Cmax is 35% lower than in healthy volunteers, but the t1/2 β is similar. Mizolastine has no effect on the pharmacokinetics of theophylline, digoxin, R⫺(⫹)⫺ and S⫺(⫺)⫺ warfarin or diltiazem. In the in vitro human hepatocyte model, there are minimal interactions between mizolastine and ketoconazole, and none between mizolastine and erythromycin; however, incubation of mizolastine

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and ketoconazole with human microsomes results in inhibition of the biotransformation pathway (140, 141). Population kinetics in 696 individuals in whom 960 plasma samples were obtained have not identified any particular age, sex, or body weight group to be at risk for mizolastine accumulation (142) (Fig. 3). 2. Pharmacodynamics Mizolastine 10 mg suppresses histamine-induced wheals and flares significantly within 1 h of administration (Table 4). Peak effect occurs from 3 to 12 h, and suppression is still significant at 24 h (134, 135, 137, 143–147). Mizolastine has been measured in skin blister fluid (143). It also produces dose-related bronchodilation and protection against histamine-induced bronchoconstriction. There is minimal information about the residual effects of mizolastine. Tachyphylaxis to mizolastine has not been reported. The suppressive effect of mizolastine on wheals and flares induced by histamine, codeine, or allergen remains highly significant after 3 months of regular administration (147) (Fig. 7).

IV. SUMMARY AND FUTURE DIRECTIONS We have reviewed pharmacokinetic and pharmacodynamic studies of the H1antagonists acrivastine, azelastine, cetirizine, desloratadine, ebastine, fexofenadine, levocabastine, loratadine, and mizolastine. The differences in the pharmacokinetics and pharmacodynamics among these medications directly influence recommendations for dosage and administration interval in patients with allergic disorders, and facilitate their use in the very young, the elderly, and other unique populations. The importance of these clinical pharmacology studies should not be underestimated, since they provide the scientific rationale for administration of H1-antagonists with optimal benefit and minimal risk. The ideal H1-antagonist does not yet exist. New medications in this class continue to be introduced at intervals. Pharmacokinetic and pharmacodynamic studies of emedastine (148), epinastine (15), levocetirizine (149), tecastemizole (150), rupatadine, and other new H1-antagonists will provide the scientific basis for their use in clinical trials, as these types of studies have done for new H1-antagonists currently in use worldwide.

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6 Antihistamines in Rhinoconjunctivitis Peter Howarth University of Southampton, Southampton, England

I.

INTRODUCTION

H1-receptor antagonists have been the mainstay of therapy for allergic rhinitis since they were first introduced for clinical use, following the demonstration by Staub and Bovet in 1937 that this class of compounds, newly developed at that time, protected against allergen-induced anaphylaxis (1). The experimental use of antihistamines in allergic disease was a natural sequel to the suggestion by Dale that histamine was central to immediate anaphylaxis (2) and the demonstrated release of histamine following allergen exposure in vitro (3, 4). The relationship between rhinitis and conjunctivitis symptoms and allergen (grass pollen) exposure in ‘‘hay fever’’ sufferers was established at the end of the 19th century (5). Although observational studies reported symptom relief in allergic rhinoconjunctivitis with use of the earliest antihistamines, the widespread acceptance of these medications was limited by their adverse pharmacological effects such as sedation, dry mouth, and blurred vision. In addition, there was concern that asthma, a condition often associated with rhinitis, might be worsened by antihistaminic therapy (6, 7). This concern was compounded by the reports from in vitro studies that antihistamines might potentiate mast cell degranulation (8). Careful subsequent studies, however, did not confirm the bronchoconstrictor effects of H1-antihistamines. Indeed they suggested that bronchodilatation (9, 10) and the in vitro effects identified only at high (suprapharmacological) con179

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centrations were found to be unrelated to the H1-receptor-inhibitory effects (11, 12). In general, an ethylamine chain is common to all H1-receptor antagonists. However, it was realized that many of the additional properties of this class of compounds, with the exception of sedation, were related to side chain radical structure. Thus with structural engineering it was possible to synthesize H1-antihistamines without the anticholinergic (13), antiserotoninergic (14), alpha-adrenergic receptor antagonistic (15), or local anesthetic (16) activity evident in early compounds. Although these approaches resulted in the synthesis of improved compounds, the major breakthrough in the development of H1-antihistamines for clinical use came with the serendipitous synthesis of the H1-antihistamine terfenadine. This agent, while retaining peripheral H1-receptor antagonistic activity, was devoid of central nervous system (CNS) antihistaminic effects and thus did not induce sedation or impair psychomotor function (17). Furthermore, it had no H2receptor antagonism, no alpha- or beta-adrenergic activity, no antiserotonin effect, and no antimuscarinic effect (18). Thus, in 1981 it was introduced as the first oral nonsedating antihistamine for the treatment of rhinoconjunctivitis and represented a major advance in the use of H1-antihistamines in the treatment of this condition. Astemizole (1983), cetirizine (1988), and loratadine (1989) followed subsequently as orally administered nonsedating H1-antihistamines. During the 1990s, additional nonsedating antihistamines were launched including fexofenadine, mizolastine, and ebastine. Others such as desloratadine, levocetirizine, and tecastemizole are under advanced development for the treatment of rhinoconjunctivitis and are licensed for use in some countries. Topical H1-antihistamines such as levocabastine, azelastine, and ketotifen have also been developed. Current guidelines for the management of rhinitis, such as the World Health Organization ARIA Guidelines, advocate H1-antihistamines as first-line therapy for intermittent (seasonal) disease and also as an initial treatment option in mild/ moderate persistent (perennial) disease in which nasal obstruction is not a prominent symptom (19). In this review of H1-antagonists and rhinoconjunctivitis, we discuss the current understanding of mucosal inflammation and histamine release in rhinoconjunctivitis, the role of histamine in disease generation and its receptor specificity, the influence of H1-receptor blockade on experimental and clinical rhinoconjunctivitis, the clinical use and comparative effects of different H1-receptor antagonists, the adverse effects of antihistamines, and the newer developments in this field. Although much information was gathered in relationship to the early second-generation H1-antihistamines terfenadine and astemizole, since these are no longer used clinically because of their potential adverse cardiac effects, this chapter will focus largely on the later second-generation antihistamines.

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II. MUCOSAL INFLAMMATION AND HISTAMINE RELEASE A. Rhinitis Allergic rhinitis is characterized by mucosal inflammation associated with epithelial accumulation of mast cells, basophils, and eosinophils along with endothelial and epithelial cell activation, expansion of dendritic antigen-presenting cells and, in persistent disease, T-lymphocyte accumulation and activation (20). The endorgan effects of nasal itch, sneeze, rhinorrhea, and nasal obstruction arise due to mediator release from activated effector cells, primarily mast cells, basophils, and eosinophils. Histamine is a major granule constituent of both tissue mast cells and circulating basophils (23). Immunological activation of mast cells and basophils induces histamine release amounting to 3–5 ng/106 cells and 1 ng/106 cells, respectively. This far exceeds the reported ability of both mast cells and basophils to generate leukotriene C4 (LTC4) on immunological activation (each 60 ng/106 cells) and the ability of mast cells to generate prostaglandin2 (PGD2) or plateletactivating factor (PAF; 60 ng/106 cells and 2 pmol/106 cells, respectively). Thus, histamine is quantitatively the major mediator generated on immunological activation by both mast cells and basophils. Within the nose, mast cells represent the primary source of histamine (21). Recent studies on nasal polyps and turbinate tissue reveal a tissue histamine content of 6.4 µg/g wet weight and 3.9 µg/g wet weight, respectively, with histamine release induced by anti-IgE and calcium ionophore but not formyl-methionylleucyl-phenylalanine (FMLP). Because FMLP is a potent histamine secretagogue from human basophils, this suggests that basophils, unlike mast cells, are not a constitutive component in nasal tissue. In allergic rhinitis, basophils are only identified in nasal secretions (20) and thus represent a lesser component of the histamine release in this condition. Nasal lavage has been used to recover tissue lining fluid from the nose and to enable mediator measurements to be made. Although increments in histamine concentrations in nasal lavage fluid can be identified when repeated lavage is undertaken prior to allergen challenge, in order to obtain a low prechallenge baseline (22), single lavage measurements in naturally occurring allergic rhinitis have surprisingly not identified a disease-related difference (23). This lack of increase in allergic rhinitis may occur on account of both histamine generation in the normal nose by alternative sources such as bacteria (24) and the rapid degradation of histamine in active rhinitis by histaminase in the nasal cavity. The latter may be derived either from the circulation in association with plasma protein leakage or possibly released in association with eosinophil activation (25). Alternative methods have therefore been used to document mast cell degranulation in allergic rhinitis. Ultrastructural changes of degranulation are re-

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ported following nasal allergen challenge by use of transmission electron microscopic (EM) examination of nasal biopsies (26). Using this same technique, and quantifying all granules present in each mast cell as intact or degranulating, we have identified ultrastructural evidence of mast cell degranulation in naturally occurring seasonal allergic rhinitis. These results are confirmed by measurement of alternative markers of mast cell degranulation to histamine in nasal lavage, such as tryptase, which is less susceptible to metabolism and allows seasonal increments to be identified in naturally occurring allergic rhinitis. B.

Conjunctivitis

The cellular changes in allergic conjunctivitis are similar to those identified in allergic rhinitis, involving mast cells, eosinophils, and T lymphocytes. In the healthy conjunctiva, although eosinophils are rarely evident, mast cells are a normal constituent with an estimated 5000–6000 mast cells/mm3, usually found below the basement membrane in the substantia propria (27). Mast cells are not usually found in the normal epithelium of the bulbar or tarsal conjunctiva (28, 29). In allergic conjunctivitis mast cells increase in number and infiltrate into the epithelium (29, 30). Eosinophils are also recruited into the conjunctival tissue and can be identified both in the substantia propria and the epithelium (29). T lymphocytes are found in the epithelium and substantia propria of normal conjunctiva (28), consistent with their ‘‘immunological policing role.’’ As in rhinitis, their levels are only increased in severe chronic disease, such as keratoconjunctivitis (31). T cells, cloned from conjunctival biopsies of patients with vernal keratoconjunctivitis, have been shown to have a cytokine profile compatible with a T helper (Th2) subset (32). Histamine is present in normal tears (5 ng/mL) and levels are elevated in vernal keratoconjunctivitis (16 ng/mL), in which there is severe conjunctival inflammation (33). As in rhinitis, it has been more difficult to detect histamine increments in milder forms of conjunctivitis or indeed after conjunctival allergen challenge; however, it has been demonstrated that histaminase is present in human tears. With inactivation of this enzyme, it has been possible to demonstrate acute increments in tear levels of histamine following conjunctival allergen challenge in sensitized individuals (33).

III. ROLE OF HISTAMINE AND RECEPTOR SPECIFICITY IN RHINOCONJUNCTIVITIS A.

Rhinitis

Nasal challenge with histamine has been used to investigate the role of histamine in the nose. Nasal insufflation of histamine mimics acute allergic rhinitis in induc-

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ing immediate nasal itching, sneezing, and rhinorrhea as well as causing nasal obstruction (34). Following single-nostril application of histamine, the rhinorrhea is bilateral, indicative of reflex neuronal stimulation. The nasal itching and sneezing are also neuronally mediated, due to stimulation of histamine-sensitive afferent receptors, while nasal obstruction is vascular in origin. Histamine exerts several different effects on the nasal vasculature. It increases mucosal blood flow (35), enhances vascular permeability (36), inducing plasma protein exudation from fenestrated superficial capillaries, and produces nasal venous engorgement through its regulatory effects on the nasal capacitance vessels. By increasing turbinate volume, this latter effect reduces nasal airflow and increases nasal airways resistance. The neuronal effects of histamine are H1-receptor-mediated: specific H1receptor antagonism prevents histamine-induced nasal itch, sneeze, and rhinorrhea (37). The receptor regulation of the nasal vascular effects is less precise. H1receptor blockade can prevent histamine-induced nasal vascular plasma protein leakage (Fig. 1), suggesting a specific H1-receptor effect in this regard (36). Hista-

Figure 1 The influence of topical azelastine (0.254 mg per nasal cavity), topical placebo, and oral cetirizine (10 mg) on histamine- (40 µg/ml and 400 µg/ml delivered in nasal pool device) induced increments in α2-macroglobulin as an index of induced plasma protein exudation in 12 healthy subjects. ■, azelastine; , cetirizine; 䊐, placebo. *p ⬍ 0.05, **p ⬍ 0.01. Challenge was undertaken 1 h after drug pretreatment. (From Ref. 36.)

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mine H2-receptor antagonism can also partially reduce plasma protein exudation (38). This effect may be indirect due to a regulatory effect on mucosal blood flow, however, since within the skin, H2-receptor stimulation causes vasodilatation and within the nose H2-receptor antagonism reduces the increase in mucosal blood flow in response to allergen (39). An H2-receptor antagonist, by reducing mucosal blood flow, would indirectly limit the potential plasma protein exudation from the superficial mucosal capillaries. Both H1- and H2-receptor antagonists also modify histamine-induced nasal obstruction (38). Their combined effects have been reported to be greater than with either administered alone, although, in general, there is little additional benefit, particularly in reducing histamine-induced nasal blockage (38, 40). This limited effect in inhibiting histamine-induced nasal blockage could relate to the histamine-induced kinin generation shown to occur within the nose (41); however, since kinins also induce nasal blockage (42) as well as promoting plasma protein leakage (43), this is unlikely as H1-receptor blockade completely inhibits plasma protein extravasation (38). More probable is an effect of histamine on H3-receptors. In rodents, H3-receptors have been identified on presynaptic perivascular nerve terminals, where they regulate sympathetic tone (44). Since the nasal vasculature is under sympathetic tone, with stimulation inducing constriction, inhibition of this effect by H3-receptor activation would lead to vasodilatation and nasal venous engorgement. Thus, the nasal obstruction that is not H1- or H2-receptor-mediated following nasal histamine insufflation is likely to be H3-receptor-mediated. Histamine may also contribute to the recruitment of cells that characterize allergic mucosal inflammation. In cultured human umbilical vein endothelial cells, histamine upregulates the expression of the cell adhesion molecule P-selectin (45). It has been proposed that P-selectin, which induces a rolling margination of leukocytes when upregulated on the vascular endothelium, is critical to tissue eosinophil recruitment (46). In vivo studies in rodents have demonstrated that histamine-induced rolling margination is inhibited by a P-selectin antibody and that the mobilization of P-selectin onto the vascular endothelium by histamine is mediated by H1- rather than H2-receptors (47). Histamine H1-receptors also appear to be relevant to the epithelial expression of the adhesion molecule, intercellular adhesion molecule-1 (ICAM-1), since terfenadine has been shown to reduce epithelial ICAM-1 expression in pollen-sensitive patients during seasonal pollen exposure (48). In addition to promoting eosinophil–endothelial adherence, histamine will contribute to eosinophil activation (49). This action is H3-receptormediated: the H3-receptor antagonist thioperamide, but not the H1- or H2- receptor antagonists pyrilamine or cimetidine, respectively, prevents histamine-induced eosinophil activation (49). It is thus apparent that histamine can contribute to many of the features of allergic rhinitis.

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B. Conjunctivitis Instillation of histamine into the conjunctival sac reproduces many of the features of allergic conjunctivitis. Itching, lacrimation, hyperemia, and conjunctival edema occur rapidly after histamine instillation. Investigation of the effects of the topical H1-receptor antagonist levocabastine identified that itching, tearing, redness, and conjunctival edema are all H1-receptor-mediated (50). In guinea pigs, the inhibition of histamine-induced conjunctival edema by levocabastine has been shown to be dose-related (51). Within the conjunctiva there is also an H2-receptormediated effect of histamine on blood flow (52). As such, the hyperemia and conjunctival edema are in part H2-receptor-determined. No details exist concerning H3-receptors and the conjunctiva. The pertinence of histamine to tissue cell recruitment and activation in allergic conjunctivitis is as described previously for rhinitis. IV. ANTIHISTAMINES AND EXPERIMENTAL ALLERGIC RHINOCONJUNCTIVITIS Allergen challenge in sensitized individuals has been used to investigate the effects of oral and topical antihistamine preparations in both the nose and the eye. Nasal allergen challenge, either with an aqueous extract or with pollen grains, induces an immediate response characterized by nasal itch, sneeze, rhinorrhea, and nasal obstruction. The nasal blockage is often long-lasting but the biphasic obstructive response that typifies the immediate and late responses in the lower airways is not as readily discernible in the upper airways. A symptomatic latephase response is not a characteristic finding following ocular allergen challenge. There are, however, biochemical and cellular measures indicative of events extending beyond the immediate response. During the immediate nasal response to allergen, an increase in histamine, tryptase, prostaglandin D2, and kinins is evident, consistent with mast cell degranulation, while further increments in histamine and kinins but not prostaglandin D2 or tryptase are apparent 6–10 h postchallenge (22). The late changes in histamine, but not the other mast cell markers, is indicative of basophil activation. Consistent with this, an accumulation of basophils is evident within nasal lavage during the late response (53), although the most marked cellular change 24 h post-allergen challenge relates to eosinophil influx (54, 55), which is associated with concomitant allergen-induced nasal hyperresponsiveness. A. Onset of Action Treatment with H1-receptor antagonists modifies the response to allergen challenge in both the nose and the eye (39, 56). The onset of relief of symptoms

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after a single dose is more rapid with topical than oral medication. Topical levocabastine is reported to afford protection within 5 min of application (56). Oral H1antagonists have to be absorbed into the circulation before distribution to the target organ, in this case the nose and eye, and thus have a slower onset of action. In pollen chamber challenge studies, in which individuals or groups of individuals are exposed to a regulated amount of pollen for a prolonged duration, sometimes with repeated daily priming exposures prior to the actual study, relief of symptoms has been reported to be significant within an hour of ingestion for fexofenadine (57) and cetirizine (58) but to take longer (3 h) for loratadine (58). A recent study with one of the active metabolites of loratadine, desloratadine, reveals pharmacological heterogeneity in the effects of H1-receptor antagonism on the nasal response to allergen. By implication, this would point to heterogeneity in the involvement of histamine in the nasal obstructive response to allergen. Fourteen of 28 subjects (50%) were found to have a major improvement in allergen-induced nasal obstruction (mean 50% reduction at 2 h) with desloratadine in a pollen chamber challenge study (59); thus allergen-induced nasal obstruction may only be histamine-dependent in a proportion of rhinitics. When assessed 3 h after ingestion, cetirizine has been shown to afford greater protection than terfenadine, loratadine, or astemizole (60). A more rapid onset of effect of cetirizine compared to loratadine has also been reported from nasal histamine challenge studies (61). The use of a pollen chamber for group allergen nasal challenge may be a more sensitive method of evaluation than individual nasal allergen challenge. For example, one study investigating the protective effect of loratadine and cetirizine on nasal allergen challenge (62) found these H1-antihistamines to be comparable, in a placebo-controlled evaluation, in the magnitude of their displacement of the threshold pollen grain challenge required to induce a positive nasal challenge. By contrast, a pollen chamber challenge study in which symptoms were induced and relief evaluated (58), identified a significantly greater effect of cetirizine (36.7% mean reduction in total symptom scores) than either loratadine (15.4% reduction) or placebo (12.0% reduction). This study addressed relief after singledose therapy, whereas the allergen challenge study referred to above (62) investigated the protective effect after 7 days of treatment. This study, in which loratadine and cetirizine were reported to afford comparable protection against allergen-induced rhinitis, also tested these drugs’ effects on skin wheal responses to histamine and allergen. Cetirizine had a significantly greater effect on the histamine-induced skin wheal response than loratadine, whereas they had an equal effect in inhibiting the allergen-induced skin wheal responses. An interpretation of these findings is that an effect of loratadine on allergen-induced mediator release makes up for its relative lack of potency as an end-organ H1-receptor antagonist. Such an ‘‘antiallergic’’ effect may only be achieved at steady state and may not be evident in single-dose studies.

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B. Extent and Duration of Effect In general, allergen-challenge studies reveal that it is predominantly the H1-receptor-mediated events (e.g., nasal itch, sneeze, and rhinorrhea) that are reduced by H1-antihistamine therapy (39), with less effect on the nasal obstructive response. Some studies report some reduction in allergen-induced nasal obstruction in comparison to placebo (56). Many others have failed to find any effect of either H1receptor or H2-receptor blockade (63–65). Studies in which objective monitoring of nasal obstruction has been undertaken, by either rhinomanometry or nasal inspiratory peak flow, have failed to identify clear effects of H1-receptor antagonism on allergen-induced increases in nasal airways resistance or reduction in nasal airflow (63–65), despite clear effects of such treatment on sneezing and rhinorrhea. These nasal obstructive effects relate to the indirect and direct actions of mediators on the state of engorgement of the venous sinusoids, and indicate that histamine is not prominently involved in this vascular response to allergenic challenge, at least through H1-receptor-mediated mechanisms. Histamine may, however, contribute to the microcirculatory response to allergen within the nose.

Figure 2 Duration of action of intranasal levocabastine in reducing allergen-induced increments in total nasal symptom score (NSS). Results presented as mean (⫾ SD) total NSS after levocabastine (LEV) administration and allergen challenge. *Symptom scores were significantly lower than placebo (p ⬍ 0.05). (From Ref. 65.)

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Objective recording of nasal mucosal microcirculatory blood flow by laser Doppler flowmetry has shown that allergen challenge reduces this superficial capillary blood flow within the nose and that this effect is inhibited by H1- but not H2receptor antagonism (66). No evidence of an additive effect of H1- and H2-receptor antagonism was evident in this study. Although laboratory allergen challenge studies could be used as a model to investigate the duration of effect, few studies have assessed duration of antihistaminic effect at the organ site. Usually they have investigated the H1-receptor inhibitory effect at a single time point, the choice of time point being derived from time course studies performed on skin wheal and flare responses. Topical levocabastine therapy (0.05% solution) has, however, been shown to reduce allergen-induced conjunctival itch, hyperemia, tearing, and chemosis 10 min and 4 h after initial application (67), and also to be effective in the nose, within 5 min of administration (56, 65) (Fig. 2). In separate studies it was found to remain protective at 12 h and 24 h after single-dose administration (65) (Fig. 2).

V.

ANTIALLERGIC ACTIVITIES OF H1-ANTIHISTAMINES IN RHINOCONJUNCTIVITIS

Nasal allergen challenge has also been used to investigate the antiallergic properties of H1-antihistamines in vivo. These investigations are based on the in vitro findings that H1-antihistamines inhibit anti-IgE-induced histamine release from human lung fragments at low concentrations, although at high concentrations they enhance histamine liberation (11). Comparative in vitro studies suggest that this effect does not relate to H1-receptor antagonist potency but more to the lipophilicity of the compound. H1-antihistamines with low lipophilicity have a lesser effect on histamine liberation than those with greater lipophilicity. This ‘‘antiallergic’’ potential of antihistamines has been extended by other in vitro studies reporting inhibition of LTC4 and leukotriene D4 (LTD4) release from dispersed human lung cells and from eosinophils, modification of macrophage function, inhibition of both neutrophil and basophil activation, and alteration in platelet cytotoxicity (68). When administered orally at standard clinical doses, the piperidine antihistamines azatadine, terfenadine, and loratadine have all been shown to reduce the allergen-induced increment in nasal lavage concentrations of histamine and kinins (69–71). Where measured, this protective effect is also associated with a reduction in induced increments in albumin. Cetirizine is without effect on histamine release (63), although it does decrease allergen-induced changes in LTC4 and LTD4 (80). The interpretation of these findings is complicated: kinins are likely to be generated in association with plasma protein extravasation (41). Thus the inhibitory action of antihistamines may reflect purely an H1-mediated action on

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vascular permeability, with the inhibitory action on the histamine increase reflecting reduced tissue availability of histamine on account of the reduced tissue fluid exudation. Against such an explanation, however, is the reported lack of inhibitory effect of cetirizine on the histamine rise in the presence of an inhibition of the allergen-induced albumin changes (72). Evidence in support of an additional action for loratadine over and above end-organ H1-receptor antagonism has been derived indirectly from comparisons of loratadine with cetirizine in nasal and skin challenge studies (62). In these studies, cetirizine had greater activity against histamine-induced skin wheal formation than loratadine, but equal activity against allergen-induced skin wheal and nasal responses. This difference was interpreted as being indicative of a dual activity of loratadine, involving both end-organ H1-receptor antagonism and inhibition of tissue histamine release. Such an interpretation would be consistent with the nasal lavage studies (70–71) but is in contrast to a careful skin study using a microdialysis technique to sample venous blood draining the skin wheal site directly (73). This placebo-controlled study failed to detect any effect of loratadine on induced histamine release. There may be several explanations for these discrepant skin and nasal findings. First, there may be target organ differences in the mast cell sensitivity to the effects of loratadine, although there is no evidence for this. Target site discrepancies may also relate to the inducing stimulus being stronger in the skin and thus less amenable to inhibition. A third consideration is that the increase in histamine within the nasal lumen following allergen challenge is, in part, a reflection of basophil activation and that this component, rather than a mast cell component, is inhibited by loratadine. Consistent with such a possibility is the failure to detect any significant effect of loratadine on allergen-induced increments within the nose of tryptase and PGD2 (70), two mast cell–derived mediators, and the ex vivo identification that loratadine inhibits IgEmediated basophil activation (71). In addition to the assessment of the impact of antihistamine therapy on cell activation, in vivo studies have investigated the ability of H1-receptor antagonists to modify plasma protein leakage, eosinophil recruitment and activation, and epithelial activation. Clemastine pretreatment does not modify allergen-induced nasal vascular responses (74). No effect on either eosinophil recruitment or eosinophil activation has been found with loratadine (70) or cetirizine, either alone or in combination with the H2-receptor antagonist cimetidine (63), in the allergen nasal challenge model. A number of H1-antihistamines have, however, been found to modify epithelial activation. Nasal allergen challenge is associated with increased epithelial expression of the adhesion molecule ICAM-1 and the appearance in the lavage of the shed form of this, soluble ICAM-1 (sICAM-1). In the nose, topical azelastine pretreatment has been found to inhibit this response (75) as has topical levocabastine (76), as well as oral therapy with cetirizine (77), oxatomide (78), and loratadine (79) in the conjunctiva with topical allergen chal-

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lenge to the eye. These findings have been extended into naturally occurring disease, with topical azelastine (80) and oral cetirizine (81–83) and loratadine (81–82). All of these are reported either to downregulate epithelial ICAM-1 expression or to reduce the recovery of sICAM-1. The relevance of this to the modification of allergic rhinitis or conjunctivitis is undefined, but increasingly the epithelium is considered to play an important role in cell recruitment through the release of chemokines. In vitro, fexofenadine has been found to modify epithelial–eosinophil interactions and the release of the chemokines regulated on activation, normal T-cell expressed and secreted (RANTES) and interleukin 8 (IL-8), as well as the cytokine granulocyte macrophage colony-stimulating factor (GM-CSF) and the adhesion molecule ICAM-1 from epithelial cells (84). These findings have been extended by reports from some workers that cetirizine and loratadine can inhibit both eosinophil recruitment and activation in the nose in naturally occurring disease (82, 83). One of these studies is uncontrolled (82) and therefore difficult to evaluate. The other, with cetirizine is a placebocontrolled evaluation in seasonal allergic disease demonstrating a clear effect of active therapy (83). These findings are compatible with studies in the skin, using a skin blister model in which cetirizine inhibits allergen-induced eosinophil recruitment (85). Other nasal and skin studies have not identified an effect of cetirizine on either acute allergen-induced eosinophil recruitment or mucosal eosinophil accumulation in naturally occurring disease (54, 85, 86). An inability to identify additional benefit with ‘‘antiallergic’’ antihistamines brings into question the relevance of these findings to cell recruitment and activation, a difficulty that is also reflected in naturally occurring disease in which most modern H1antihistamines appear equally efficacious when used at standard clinical doses (see below). Subtle differences between therapies may need very large numbers of patients to be clinically discernible, due to the variability of the disease expression. Also, as in some H1-antihistamines, the effect may appear primarily related to inhibition of histamine release, rather than a broader effect on cell activation, and consequently no real additional biological benefit is accrued over the H1receptor antagonism alone.

VI. ORAL H1-ANTIHISTAMINES AND NATURALLY OCCURRING RHINOCONJUNCTIVITIS A.

Seasonal (Intermittent) Allergic Disease

Minor differences exist among clinical trials, attributable to the number of patients enrolled, local environmental factors, patient selection, and individual patient variability; however, in general, H1-antihistamines modify nasal itch, sneeze, and rhinorrhea in seasonal allergic rhinitis with little or no effect on nasal obstruction (87–90). The effect on the H1-responsive symptoms is only partial (40%–

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60% reduction) since histamine is not the sole contributor to the generation of these symptoms (91). Oral H1-antihistamines also modify the conjunctival symptoms of itch, watering, and redness (92, 93). The effect on conjunctival symptoms may be less marked than on rhinitis symptoms, possibly on account of a higher local allergen load in the eye. Topical H1-antihistamines have a similar profile (94) and while theoretically they may achieve a higher local concentration (thereby creating a greater effect), comparative trials of topical H1-antihistamine therapy with oral H1-antihistamine therapy report a similar overall effect in reducing ocular symptoms (95). Due to the potential for first-generation H1-antihistamines to cause subclinical central nervous system (CNS) adverse effects, interfering with performance at work and school, and in some individuals, frank somnolence, these H1-receptor antagonists are no longer recommended for use, with the second-generation nonsedating H1-antihistamines being preferred. Few details will be given regarding terfenadine and astemizole, since these second-generation H1-antihistamines are no longer approved for use in many countries because of their potential to cause serious cardiac arrhythmias. 1. Placebo-Controlled Studies Cetirizine. Cetirizine, a piperazine derivative and carboxylated metabolite of hydroxyzine, is a potent H1-receptor antagonist. Placebo-controlled comparative studies of cetirizine 5 mg daily (96), 10 mg daily (96, 97), and 10 mg twice daily (98) have been conducted and all dosages are found to be effective in seasonal allergic rhinitis. A subsequent study compared 5 mg, 10 mg, and 20 mg cetirizine dosages with placebo in seasonal allergic rhinitis and found all active treatments to be effective (Fig. 3), with no significant dose–response relationship (89). A study using a syrup preparation in children aged 6–11 years found 5 mg no different from placebo, while the 10 mg dosage was significantly more effective (99). Cetirizine is marketed at a dosage of 10 mg daily for the treatment of seasonal allergic rhinoconjunctivitis. In the placebo-controlled trials, cetirizine, like other H1-antihistamines, is effective for relief of nasal pruritus, runny nose, and sneezing but less effective for nasal obstruction or lacrimation, although effects are evident in studies with sufficient power (100). Cetirizine affords better relief when taken on a daily basis rather than on an as-needed basis (101). Desloratadine. Desloratadine is an active metabolite of loratadine that has been developed for clinical use in its own right. It has a high affinity for H1receptor binding. Details in a review article suggest a relative selectivity for the H1-receptor, with 15–50 times the dosage being required to demonstrate antagonism of the H2-receptor or muscarinic receptors (102). A recent abstract does, however, indicate that the selectivity ratio for H1- to muscarinic M2-receptors is

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Figure 3 The influence of three separate dosages of cetirizine on mean daily symptom scores, in comparison to placebo, in a double-blind, randomized, parallel-group study design involving 419 patients with seasonal allergic rhinitis. Treatment was given once daily for 1 week. Cetirizine was significantly (p ⱕ 0.05) more effective than placebo on all days, but no dose–response relationship was evident. (From Ref. 89.)

only 5 in comparison to 11 for loratadine and 600 for fexofenadine (103). This indicates a broader receptor antagonistic profile for desloratadine than either its parent compound or a comparable H1-receptor antagonist. At the time of writing, no peer-reviewed original articles relating to desloratadine in allergic rhinitis were available, although data are available in abstracts from presentations at meetings, a supplement publication, and a review article (104). The supplement referred to focused on the effects of desloratadine in relieving nasal congestion (59). Clinical trials in patients with seasonal allergic rhinitis identified, in comparison to placebo, that desloratadine not only relieved nasal itch, sneeze, and rhinorrhea but also improved nasal obstruction. This was reported by the Desloratadine Study Group (105) in a double-blind, randomized study design involving 346 patients and a 2-week treatment period with desloratadine 5 mg once daily or placebo. Desloratadine treatment led to a 25% reduction in the nasal congestion score in comparison to placebo ( p ⫽ 0.04). A separate abstract from the same group reported that this reduction was statistically significant, compared to baseline, within 12 h of initial administration (106). A third abstract from the Desloratadine Study Group reported the influence of treatment

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on quality of life (QOL) using the rhinitis health-related quality-of-life questionnaire (RQLQ). After 14 days treatment with desloratadine 5 mg or 7.5 mg once daily, the abstract indicates that five of the RQLQ domains improved (practical problems, nasal symptoms, eye symptoms, activities, overall) in the group treated with 5 mg (107). No level of statistical significance in comparison to placebo and no details of the effect of the 7.5 mg dose are provided, so it is not possible to evaluate this information in comparison with other published studies on QOL. Loratadine. Loratadine is a piperidine derivative. Placebo-controlled, double-blind, randomized trials of loratadine in seasonal allergic rhinitis have confirmed the efficacy of this H1-antihistamine at a dosage of 10 mg daily (40, 108–100) (Fig. 4). Loratadine is less effective in relieving nasal obstruction than the other nasal symptoms of rhinitis (111). The choice of 10 mg daily is supported by the findings of a study that investigated the effect of 40 mg daily loratadine in seasonal allergic rhinitis and suggested that this dosage was no more effective and carried the potential risk of sedation (112). Loratadine is also effective in the relief of conjunctival symptoms in seasonal allergic rhinitis.

Figure 4 Mean change from baseline in 24-h reflective symptom scores for sneezing, itchy nose/palate, rhinorrhea, itchy red eyes, and nasal congestion following treatment with fexofenadine 120 mg once daily (n ⫽ 232, ■), loratadine 10 mg once daily (n ⫽ 228, ), and placebo (n ⫽ 225, 䊐) over a 2-week treatment period in seasonal allergic rhinitis. *p ⬍ 0.05, **p ⬍ 0.01, ***p ⬍ 0.005, ****p ⬍ 0.001, *****p ⬍ 0.0001 in comparison to placebo; p ⬍ 0.05 for comparison between fexofenadine and loratadine: itchy red eyes and nasal congenstion. No details of baseline starting score for individual symptoms are provided in the publication. NS, not significant. (From Ref. 139.)

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Fexofenadine. Fexofenadine is the pharmacologically active metabolite of terfenadine. It does not undergo hepatic metabolism and is thus free of the hepatic drug interactions associated with terfenadine. In addition, fexofenadine has no intrinsic cardiac activity in vivo. A number of large multicenter, doubleblind, randomized, placebo-controlled studies have evaluated the effect of fexofenadine in grass pollen– and ragweed pollen–induced seasonal allergic rhinitis (100, 113–115). These identify its significant benefit in relieving nasal itch, sneeze, and rhinorrhea as well as conjunctival itch and watering. There is a clear, although smaller, effect in relieving nasal obstruction (Fig. 4). Dose-ranging studies have investigated both twice-daily and once-daily treatment regimens. Initial studies focused on twice-daily therapy in fall seasonal allergic rhinitis with placebo-controlled comparisons against 40 mg, 60 mg, and 120 mg twice daily (113) and 60 mg, 120 mg, and 240 mg twice daily (114). All dosages of fexofenadine were found to be significantly better than placebo in improving nasal and conjunctival symptoms over a 2-week treatment period. There was no clear dose–response effect at dosages above 60 mg twice daily (114); thus fexofenadine was initially launched in the United States at a recommended dosage of 60 mg twice daily although once-daily studies were underway. Such studies in the United States in ragweed-sensitive rhinitics (115) and in Europe in grass pollen–sensitive rhinitics (100) compared once-daily treatment with fexofenadine 120 mg and 180 mg to placebo. The emphasis was not only on the overall effect over 24 hours but also on the level of protection afforded at trough drug levels, immediately prior to the daily dosing, to ensure that once-daily treatment did truly provide 24 hours symptom relief. These evaluations found that once-daily fexofenadine was indeed protective throughout the 24 hours and that both 120 mg daily and 180 mg daily were significantly better than placebo in improving both rhinitis and conjunctivitis. There was no statistical difference between the 120 mg and the 180 mg dosages. Fexofenadine was licensed for use, following recommendations from the appropriate licensing authorities, as a oncedaily treatment for seasonal allergic rhinitis at 120 mg in Europe and 180 mg in the United States. Both the 120 mg daily and the 180 mg daily dosages have been shown to improve quality of life in patients with seasonal allergic rhinitis, ameliorating both work and activity impairment (116). Mizolastine. Mizolastine has also been developed as a once-daily medication. An early placebo-controlled study in 494 patients with seasonal allergic rhinitis compared the efficacy of 5, 10, and 15 mg once-daily dosages. The two higher dosages had a significant effect in relieving total nasal and ocular symptoms after 7 days of treatment (117). Further evaluations focusing on the 10 mg daily dose have confirmed the benefit of mizolastine in reducing nasal itch, sneeze, and rhinorrhea in seasonal disease (118–120). Onset of symptom relief began as early as 2 hours after dosing (118) in established disease (Fig. 5).

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Figure 5 The onset of symptom relief following oral administration of mizolastine 10 mg (n ⫽ 122, 䊉), cetirizine 10 mg (n ⫽ 125, 䊐), and placebo (n ⫽ 128, 䉱) in seasonal allergic rhinitis. p ⬍ 0.05 and p ⬍ 0.01 vs. placebo, respectively. Starting baseline total symptom scores were 13.4 ⫾ 4.2, 13.2 ⫾ 4.4, and 13.1 ⫾ 4.3 for mizolastine, cetirizine, and placebo, respectively. Results represented a mean group decrease from pretreatment baseline. (From Ref. 118.)

Prophylactic therapy, initiated before symptom development, delayed the onset of seasonal disease in comparison to placebo (120). An open-label effectiveness study, involving 5408 patients with seasonal allergic rhinitis, reported that symptoms improved in 93% of patients receiving mizolastine 10 mg once a day over a 14-day treatment period, and that symptoms decreased by at least 50% in 86% of patients (121). Ebastine. Ebastine is a piperidine derivative in the same class of H1-antihistamines as azelastine, terfenadine, and loratadine. It, too, has been developed as a once-daily medication at a dosage of 10 mg. Placebo-controlled studies have confirmed its clinical effect in significantly reducing nasal itch, sneeze, and rhinorrhea, but no effect on nasal obstruction (122). Several studies have compared ebastine at the 10 and 20 mg dosage in the treatment of seasonal allergic rhinitis (123, 124) and have suggested that 10 mg may not afford 24 hour symptom relief. A 10 mg dose taken at night was found to be no more effective than placebo, while 10 mg taken in the morning (123). Ebastine in a dosage of 20 mg,

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whether taken in the morning or in the evening, was superior to placebo. There was no statistical significance between the 10 and 20 mg treatment groups, but it has been proposed that 10 mg ebastine be used for mild rhinitis and the higher dosage for more severe disease (123, 124). Others. Acrivastine is related to the H1-antihistamine triprolidine. It does not have advantages over the once-daily nonsedating H1-antihistamines since it has a short half-life, needing to be taken three times a day (8 mg three times daily), and has CNS effects (125), especially in association with alcohol (126). It is effective in the treatment of seasonal allergic rhinitis (127, 128). Emedastine has been developed for ocular application (129, 130) and tested in a conjunctival challenge model (131). No placebo-controlled clinical trials have been published with either this H1-antihistamine or another H1-antihistamine under development, epinastine (132). Levocetirizine is being developed for clinical use (40), based on the findings that cetirizine is a racemic mixture of two enantiomers: levocetirizine (R-enantiomer) and dextrocetirizine (S-enantiomer), and that histamine nasal challenge studies indicate that the H1-receptor antagonistic activity resides with the R-enantiomer. No trial reports are published as yet relating to its efficacy in seasonal allergic rhinitis (SAR). A further novel H1-receptor antagonist, rupatadine, has been found to be clinically effective in SAR when given at a dosage of 10 mg once daily (133). 2. Comparative Studies Comparisons have been made between nonsedating H1-antihistamines and sedative H1-antihistamines such as chlorpheniramine and pheniramine, other nonsedating H1-receptor antagonists, and other classes of medication used for allergic rhinitis. While sedating and nonsedating H1-antihistamines often have similar clinical efficacy, the two generations of H1-receptor antagonists are clearly distinguishable by their sedative adverse effect profile. The nonsedating H1-antihistamines have a much more favorable risk/benefit profile. A recent study compared a sustained-release formulation of brompheniramine with loratadine and found that brompheniramine 12 mg twice daily was clinically more effective in relieving nasal and ocular symptoms than loratadine 10 mg once daily (134). This dosage of brompheniramine was, however, clearly sedative (134). A comparative evaluation of cetirizine and chlorpheniramine similarly found that while both treatments were effective in the clinical control of allergic rhinitis, the first-generation H1-antihistamine chlorpheniramine caused sedation in 40.5% of patients but only 11.6% of cetirizine-treated patients reported sedation (135). Comparisons of second-generation H1-antihistamines have, in general, not found any major clinical differences over 1–2 week study periods (100, 110, 118, 124, 136–139).

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Fexofenadine, when administered in a dose of 120 mg once daily, is comparable to cetirizine 10 mg daily in relieving both nasal and ocular symptoms (100). A recent comparative study of fexofenadine 120 mg once daily and loratadine 10 mg once daily with placebo in 688 patients with SAR revealed, however, that while these H1-antihistamines were both effective in reducing symptoms in comparison to placebo, there were differences in their profile of effect (139). The two active treatments both improved nasal itch, sneeze, and rhinorrhea comparably but only fexofenadine improved nasal obstruction (Fig. 4). This improvement was statistically greater than that with either placebo or loratadine. Fexofenadine also significantly improved the RQLQ index more than either placebo or loratadine. This suggests a potential for fexofenadine to modify disease in addition to its H1-receptor antagonism. An analysis of the quality-of-life data using the number of patients needed to treat (NNT) as an endpoint revealed that 8.4 patients needed to be treated with fexofenadine for one patient to have a clinically important improvement in quality of life as compared with loratadine, and 7.2 patients in relationship to placebo therapy. The equivalent calculation for loratadine was that 57.2 patients needed to be treated with loratadine to see an improvement in QOL over placebo (139). The use of such NNT analysis with a standardized QOL score from other studies would facilitate an evaluation of comparable efficacy of differing treatments. These findings of an improvement in QOL with fexofenadine confirm other findings (116, 140). A range of studies have found that topical intranasal corticosteroid therapy is more effective than systemic antihistamine therapy in allergic rhinitis (141– 144) (Fig. 6). This has been confirmed by a meta-analysis of a range of comparative studies between H1-antihistamines and nasal steroids which showed that regular use of intranasal corticosteroids is more efficacious in reducing symptoms then regular H1-antihistamine therapy (145). While this would be anticipated for nasal obstruction, the meta-analysis identified that this was also the case for nasal itch, rhinorrhea, and sneezing. Although it might be anticipated, on account of their systemic bioavailability, that oral H1-antihistamines would have additional activity in reducing ocular as well as nasal symptoms over topical treatment to the nose, the meta-analysis revealed that topical nasal steroids and oral H1-antihistamines have comparable effects in reducing eye symptoms in seasonal allergic rhinitis. This may relate to systemic bioavailability of steroids from the nose, or possibly to improved nasolacrimal drainage with improvement in nasal obstructive responses. The former is more likely since, even with a standard dose, evidence for systemic effects has been found with nasal steroid therapy (146), although this appears drugrather than class-specific (147). As expected, a decongestant has a greater effect on nasal obstruction than an H1-antihistamine (148), although the profile of effect is limited to nasal blockage. Comparative studies between oral H1-antihistamines

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Figure 6 Influence of intranasal fluticasone 200 µg/day (n ⫽ 121) and oral loratadine 10 mg daily (n ⫽ 119) on symptoms in seasonal allergic rhinitis. Results are presented as median percentage of symptom-free days for each of the nasal and conjunctival symptoms scored over the 4-week treatment period. (From Ref. 144.)

and topical cromoglycate identify that both therapeutic approaches have comparable clinical benefit, although the frequency of treatment regimens differs and would favor H1-antihistamines on the basis of compliance with regular medication. B.

Perennial (Persistent) Allergic Rhinitis

As for seasonal allergic rhinitis, H1-antihistamines are effective in the treatment of this condition. With chronic persistent disease, however, nasal obstruction is often a more prominent symptom while nasal itch is less common. The benefit from H1-antihistamines may therefore be less marked than that reported in seasonal allergic disease and time to treatment improvement may be more prolonged. Indeed an early study in perennial disease found no treatment benefit (149). Due to these differences from seasonal disease, patient selection is often more rigorous, with exclusion of patients in whom nasal obstruction is the most troublesome symptom, or the results are biased by the exclusion of this symptom from an overall rhinitis evaluation score.

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1. Placebo-Controlled Studies Significant clinical benefit over placebo has been reported with cetirizine 10 mg daily (150–152), loratadine 10 mg daily (153), and mizolastine 10 mg daily (154). Symptom improvement can progressively increase during 28 days of treatment (153) and these trials report the most marked benefit for nasal pruritus, sneezing, and rhinorrhea, with a lesser effect on nasal obstruction. The lack of benefit on nasal obstruction was highlighted in one study in which the nasal corticosteroid beclomethasone dipropionate was administered after the use of regular antihistamine treatment. This identified a further reduction in symptoms, in particular, blocked nose (155). Both cetirizine (152) and mizolastine (154) have, however, been found to significantly improve nasal obstruction and this symptomatic benefit has also been matched by a significant improvement in rhinoscopic appearance with mizolastine (154). The improvement in perennial rhinitic symptoms with cetirizine is associated with an improvement in quality of life (152). In a 26week treatment period, a higher dosage of cetirizine (20 mg daily) was found not only to improve rhinitis, including nasal obstruction, but also to improve lower airway symptoms, increase peak flow, and reduce the requirement for asneeded beta-agonist therapy in subjects with coexisting asthma (156). To date, there are no published placebo-controlled trials of desloratadine, fexofenadine, or levocetirizine in perennial allergic rhinitis.

2. Comparative Studies with H1-Antihistamines As for seasonal allergic disease, comparative studies among the nonsedating H1antihistamines indicate that at standard dosages they have similar clinical efficacy. A comparative evaluation reported cetirizine to be more effective over the first week of treatment than ebastine (157), although this difference was not evident after 4 weeks of treatment. No difference is evident between mizolastine or loratadine in reducing nasal or ocular symptoms in perennial allergic rhinitis over 4 weeks of treatment (158). With respect to comparisons with older H1-antihistamines, a 6-month trial of loratadine, 10 mg once daily, and clemastine, 1 mg twice daily, reported comparable effects. Good or excellent responses were considered to have occurred in 63% of patients treated with loratadine and 64% of those receiving clemastine (159). The clemastine-treated patients did, however, experience more sedation (28%) than those receiving loratadine (4%). A similar difference in sedative profile was reported in a separate study of loratadine and clemastine (160). The persistence of benefit with both loratadine and clemastine over the 6-month treatment period indicates that there is no tachyphylaxis to the effects of these H1antihistamines.

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3. Comparative Studies with Other Agents Fewer studies have been undertaken in perennial disease than in seasonal disease. Topical nasal corticosteroid therapy is more effective than H1-antihistaminic therapy (161–163). Studies have been undertaken with a combination of an H1-antihistamine and an oral decongestant in comparison to an H1-antihistamine alone (see combination therapy section). No good comparisons exist with respect to cromoglycate preparations.

VII. TOPICAL H1-ANTIHISTAMINES AND NATURALLY OCCURRING RHINOCONJUNCTIVITIS Two H1-antihistamines have been developed primarily for topical application: levocabastine for nasal and ocular administration and azelastine for nasal administration (51, 164). Dimethindene has been tested in an allergen challenge model but not as yet in clinical disease (165). Clinical data are available for olopatadine (166) and ketotifen (166). Antihistamines such as azelastine, ketotifen, and levocabastine may be sedating when administered orally but are free from this adverse effect when administered topically due to the smaller dose required to achieve clinical benefit. The nasal dosage for levocabastine and azelastine is 0.1 mg and 0.14 mg to each nostril twice daily, respectively. The conjunctival dosage of levocabastine is 0.03 mg administered to each eye twice daily. The nasal efficacy of these topical H1-antihistamines has been demonstrated under challenge conditions (39, 56, 67). They have a rapid onset of action (10–15 min) and are effective for up to 12 h. These findings have been confirmed in the eye using conjunctival challenge (56, 65). Concern that the effect of topical therapy might be limited by rhinorrhea has not been substantiated. Experimentally induced rhinorrhea with methacholine and nasal washing 30 seconds after nasal levocabastine therapy has not been found to reduce its efficacy in inhibiting histamine-induced sneezing and rhinorrhea (167). A.

Rhinitis

Both levocabastine and azelastine administered topically are most effective against nasal itch, sneeze, and rhinorrhea. In some studies nasal obstruction is also reduced by azelastine (168–171). There are a number of published placebocontrolled trials in seasonal allergic rhinitis (172–174), but the majority of studies report comparison with active medications such as H1-antihistamines (169, 170, 175–177), cromoglycate (172, 178), or nasal corticosteroids (176, 179). One placebo-controlled study reported no effect of levocabastine on nasal obstruction in Mountain Cedar-sensitive patients with seasonal allergic rhinitis, when used at

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a dosage of 0.2 mg twice daily (1 spray into each nostril twice daily), despite clear effects on the neurally medicated symptoms of itch, sneeze, and rhinorrhea (173). In patients with seasonal allergic rhinitis, regular therapy with topical nasal azelastine is more effective than on-demand use, with effects on nasal inflammation (ICAM-1 expression on epithelial cells) as well as clinical parameters (80). Half the standard daily dosage (0.28 mg/day) was also found in this study to be as effective as the standard dosage (0.56 mg/day), although there was significantly greater use of rescue medication in the lower-dosage treatment group. Azelastine, administered as a nasal spray (180), is more effective than either oral azelastine or terfenadine in relieving nasal obstruction, while producing comparable relief of other nasal symptoms. Levocabastine is reported to be more effective than a topical antihistamine/decongestant (antazoline/naphazoline) preparation (176) or topical cromoglycate (172, 178) in the treatment of seasonal allergic rhinitis. The two comparative studies of levocabastine (0.5 mg/mL, two sprays each nostril four times daily) and cromoglycate (20 mg/mL, two sprays each nostril four times daily) involving 114 patients over 2 weeks found significantly fewer symptoms with levocabastine therapy (76% of patients improving vs. 46% on cromoglycate) (181), which was paralleled by more symptom-free days in the levocabastine-treated patients (172). An open comparison of the onset of action of topical levocabastine and nedocromil to both the nose and eye reported that more than 80% of patients with seasonal allergic rhinitis reported symptom relief with both medications within 1 h. This amounted to approximately a 50% reduction in symptom severity (182). While both levocabastine (176) and azelastine (179) nasal sprays are reported to be as efficacious as topical nasal steroid administration, the comparative studies are limited and further studies are required before valid comparison can be made. One study of patients with seasonal allergic rhinitis taking nasal steroids or oral antihistamines who remained symptomatic after a 1- to 2-week washout period compared double-dose azelastine (1.1 mg/day) with the combination of loratadine 10 mg daily and nasal beclomethasone dipropionate 200 µg twice daily. After 1 week of treatment there was no statistical difference between the treatments, and azelastine was concluded to be as effective as the combination therapy (179). Such studies are likely to be misleading: in essence, this represents predominantly a comparison of azelastine and loratadine, since the effects of the nasal steroid will not be fully expressed within the timeframe of such a study. Another study that assessed nasal nitric oxide measurements as a marker of nasal inflammation, found a significant effect with nasal steroid therapy but not with topical levocabastine (183). Studies in perennial rhinitis are limited. One preliminary 2-week study reported improvement in sneezing and rhinorrhea with topical levocabastine, in comparison with placebo, which could not be improved further by the addition

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of topical nasal beclomethasone dipropionate. Nasal blockage did respond to the additional therapy (184). Another 6-week study of azelastine nasal spray therapy (0.14 mg per nostril twice daily; total dosage 0.56 mg) reported a significant effect, in comparison to placebo, on all nasal symptoms, including nasal obstruction in children with perennial allergic rhinitis (174). B.

Conjunctivitis

Levocabastine (0.5 mg/mL, one drop in each eye twice daily) has been shown to be superior to placebo for the treatment of itchy eyes, runny eyes, and red eyes associated with seasonal allergic conjunctivitis (185). Relief of symptoms is rapid, occurring within 15 min of application (168). Topical levocabastine (0.5 mg/mL) appears to be more efficacious than topical cromoglycate (20 mg/mL) when both preparations are administered four times daily for seasonal allergic conjunctivitis over a 4-week period (186, 187). Patient diary card recordings identified fewer symptoms in the levocabastine-treated patients (181). In one of the studies, the proportion of patients virtually symptom-free on high pollen count days was greater in the levocabastine (33%)- than in the cromoglycate (6%)treated patients (187).

VIII. ADVERSE EFFECTS The use of medication for treatment of a condition is based both on its beneficial effects and on its adverse effects potential. The major advantage of the secondgeneration oral H1-antihistamines, which considerably improved their risk/benefit profile, was their absence of CNS sedative effects when used at standard clinical dosages. With loratadine, fexofenadine, mizolastine, and ebastine, the reported side effects of tiredness and drowsiness are no different from placebo at the recommended dosage level (188–190). This clinical reporting is substantiated by laboratory assessment incorporating reaction time analysis, the performance of complex sensorimotor tasks such as simulated car driving, sleep latency studies, and electroencephalographic (EEG) monitoring (191–198). The topical H1-antagonist levocabastine has also been shown to be devoid of adverse CNS effects by using such methods (199). When the dosage of loratadine and mizolastine is increased above the standard 10 mg once daily, there are reports of cognitive or psychomotor performance test impairment (190). Cetirizine is labeled as a nonsedating H1-antihistamine in Europe and as a sedating antihistamine in the United States. Many studies with cetirizine show no difference from placebo in the reporting of drowsiness or sleepiness, although some do at the standard dosage (reviewed in 190) and there are reported EEG abnormalities (200).

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Cetirizine is only 40% metabolized in adults and is thus relatively uninfluenced by impaired hepatic function. Loratadine, while sharing the same cytochrome P-450 isoenzyme (CYP3A) as astemizole and terfenadine (201), is also metabolized by an alternative isoenzyme (CYP2D) (202) and no adverse cardiac effects are recorded with this H1-antihistamine (203). Of the newer H1-antihistamines, ebastine is metabolized by cytochrome P-450 isoenzymes. At higher dosages or in interaction with agents such as ketoconazole, there is the potential for QTc prolongation (204), although there are no adverse effects at standard dosage. Mizolastine is also metabolized in part by liver cytochrome P-450 isoenzymes and care has to be taken in relationship to drug interactions and hepatic impairment; however, the tendency for QTc prolongation is considerably less with this H1-antihistamine than with terfenadine, and no adverse cardiac effects are seen at standard dosage (205). Fexofenadine is not metabolized hepatically and appears very safe from the cardiac perspective based on in vitro and in vivo studies. No effect of fexofenadine on QTc intervals has been found when administered either at 480 mg/day for 2 weeks to patients or at either 800 mg/day for 6 days or 240 mg/day for a year to healthy volunteers (206). Topical H1-antihistamines are associated with very low plasma levels and, in standard doses, they generally do not induce systemic effects. The main adverse effect of topical therapy is either nasal or ocular irritation (168, 172, 186). This affects approximately 5% of patients receiving the nasal spray and 16% of those receiving eye drops (168). This profile of adverse reaction reporting is equally associated with placebo application (6% and 16%, respectively) and does not appear related to the drug per se. Detailed ophthalmological studies have not revealed any structural or functional adverse effect with regular use (177).

IX. NEW DEVELOPMENTS AND SPECIAL CONSIDERATIONS A. H1-Antihistamine/Decongestant Combination Therapy The lack of effect of H1-antihistamines on nasal obstruction, whether orally or topically administered, has led to the development of combination products containing both H1-antihistamines and decongestants. For decades, two oral alphaadrenergic agonists, pseudoephedrine and phenylpropanolamine, have been commonly used as decongestants. Recently, a review of adverse effects related to the intake of ephedra alkaloids instigated by the U.S. Food and Drug Administration (FDA) revealed deaths due to cardiovascular and CNS events (207), and the FDA has requested that pharmaceutical companies stop marketing products that contain phenylpropanolamine (208). There is also concern over the use of pseudoephedrine due to the potential

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for serious cardiac adverse effects (209); however, modified-release formulations for the combination preparations provide a sustained release and appear safe from the cardiovascular viewpoint. Clinical trials in perennial allergic rhinitis have been undertaken with combinations of pseudoephedrine and the newer nonsedating H1-antihistamines. The advantage of a combination approach over an H1-antihistamine alone in improving nasal obstruction has been shown in large studies involving administration of pseudoephedrine (120 mg) with fexofenadine (5 mg), loratadine (5 mg), or cetirizine (5 mg) used in twice-daily dosing regimens (210–212). Studies in children with the loratadine and pseudoephedrine combination given on a dose/kg basis (213) and nasal allergen challenge studies involving a cetirizine/pseudoephedrine combination (214) have also shown the benefit of the combination in relieving nasal symptoms, in particular, nasal obstruction in comparison to the H1-antihistamine alone. It has also been possible with the combination product to demonstrate an objective improvement in nasal obstruction by measuring nasal peak inspiratory flow (215). Acrivastine-D, a combination of 8 mg acrivastine and 60 mg pseudoephedrine, taken three times daily, has also been found to improve nasal symptoms and nasal airflow in comparison to placebo (216). The improved ability to demonstrate clinical benefit of the combination product over the individual components in more recent studies can be attributed to improved study design and to larger sample size. Multicenter studies of loratadine-D, involving over 800 patients (146, 217), and fexofenadine-D, involving 651 patients (210), have shown that it is possible to separate the effect of the component medications and demonstrate a significant effect of the combination product (Fig. 7). Such studies also have demonstrated a significant effect of the combination over and above the additive effects of the two products (212). The formulation may also be critical to the acceptance of these preparations. Loratadine-D, which is a combination of 5 mg loratadine and 120 mg pseudoephedrine in a Retab tablet formulation, such that there is an immediate-release coating of 5 mg loratadine and 60 mg pseudoephedrine, has a low adverse effect profile. Nervousness after loratadine-D administration (4–7%) is more common than with placebo (1–2%). The comparable figure for fexofenadine-D is 1.7%. The combination product is, however, associated with a higher prevalence of insomnia (12.8% for fexofenadine-D vs. 1.8% for fexofenadine alone) (210). B.

Other Combinations

The addition of regular therapy with a nedocromil sodium nasal spray to oral therapy with astemizole has been found to provide improved control in ragweed seasonal allergic rhinitis, despite greater use of rescue medication in the astemizole-treated group (218). In patients with perennial rhinitis (both allergic and

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Figure 7 Comparative study of the effects of fexofenadine 60 mg twice daily, pseudoephedrine sustained-release 120 mg twice daily, or a combination of the two over a 2-week treatment period. This randomized, double-blind, parallel-group study design involved 651 patients allergic to ragweed. The combination product was more effective than fexofenadine alone in reducing the 7.0 pm reflective nasal congestion score (NCS). Baseline NCS scores were between 2.32 and 2.36 for the 3 treatment groups. (From Ref. 210.)

nonallergic) in whom rhinorrhea is a prominent symptom, the addition of regular therapy three times a day with an ipratropium bromide nasal spray has been found to decrease both the severity and duration of rhinorrhea when used in combination with terfenadine compared to terfenadine treatment alone (219).

C. Common Cold Nasal lavage studies in the common cold have failed to demonstrate histamine release and nonsedating H1-antihistamines have not been found to be effective (220, 221). One study of loratadine-D vs. placebo has, however, reported that loratadine-D, administered twice daily, is more effective than placebo in relieving symptoms, with improvement not only in nasal obstruction, as might be anticipated with pseudoephedrine, but also in sneezing and rhinorrhea (222). In view of the previous lack of effect of H1-receptor antagonism alone, assessment of pseudoephedrine alone administered by the same method is now required to assess whether modification of nasal obstruction itself may modify other sequelae, or whether such a combination is essential for benefit.

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Nonallergic Rhinitis

Some patients with rhinitis who are skin-test negative have nasal eosinophilia (NARES) and may benefit from H1-antihistamine therapy. So may individuals who experience cold air–induced rhinorrhea, as in these individuals there is evidence of mast cell degranulation (223, 224). Clinical trials have thus reported some benefit with H1-antihistamines in nonallergic rhinitis patients. Subanalysis reveals that patients in whom sneezing is the most prominent symptom respond best to this mode of therapy (155, 225).

X.

SUMMARY

In allergic rhinoconjunctivitis, histamine is known to contribute predominantly to nasal itch, sneeze, rhinorrhea, conjunctival itch, and lacrimation and these symptoms benefit most from H1-antihistamine therapy. The discovery in the early 1980s of nonsedating H1-receptor antagonists contributed dramatically to the more widespread acceptance of this mode of therapy. This also led to the undertaking of well-designed clinical trials that have added significantly to our understanding of allergic rhinitis. Oral treatment modifies both nasal and ocular symptoms and provides effective control throughout a 24-h period with once- or twice-daily medication. The advent of topical H1-receptor antagonists offers a wider choice of treatments and provides equal or greater efficacy with lower systemic bioavailability. While having a major impact on rhinoconjunctivitis symptoms, H1-antihistamines do not fully modify disease since histamine is not the only contributor to symptom generation in allergic rhinoconjunctivitis. While the search for oral H1-antihistamines with more widespread ‘‘antiallergic’’ activity continues, the currently available medications modify predominantly histamine-regulated events despite in vitro evidence of greater potential. The development of these new medications may be the next significant advance in this mode of treatment.

REFERENCES 1. Staub AM, Bovet D. Action de la thymoxyethyldiethylamine (929F) et des ethers phenoliques sur le choc anaphylactique. CR Soc Biol 1937; 125:818–821. 2. Dale HH. Some chemical factors in the control of the circulation. Croonian lectures. Lancet 1929; 1233–1237, 1285–1290. 3. Bartosch R, Feldberg W, Nagel E. Das Freiwerden eines histaminin-ahnlichen Stoffes bei der anaphylaxic des Mierschweinchens. Pflugers Arch Ges Physiol 1932; 230:129–153.

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7 H 1-Antihistamines in Asthma James L. Lordan and Stephen T. Holgate University of Southampton, Southampton, England

I.

INTRODUCTION

Epidemiological studies have documented an increase in the prevalence of asthma and allergic diseases over the last 20 years, associated with an increase in morbidity and mortality, as reflected by increased hospitalizations and increased use of medications for asthma (1). Although treatment with inhaled corticosteroids and as-needed short-acting β 2-adrenergic agonists maintains disease control in the majority of asthmatics, some patients remain symptomatic and require additional treatment with long-acting β 2-adrenergic agonists, theophylline, leukotriene receptor antagonists, or oral corticosteroids for control of symptoms (2). There are a number of studies to support the involvement of histamine in the pathogenesis of lower airway inflammation in asthma; however, the results of clinical trials with first-generation H 1-antagonists showed limited efficacy. In most countries H 1-antagonists have not traditionally been prescribed for the management of asthma. Indeed, it was believed that the first-generation antihistamines could potentially exacerbate asthma by drying airway secretions as a result of anticholinergic side effects. In this chapter, we will discuss the evidence for histamine release by mast cells and basophils in the airway, review the involvement of histamine in airway bronchoconstriction in response to known spasmogens, and detail the involvement of histamine in the pathogenesis of asthma. We will also describe the bronchodilator and bronchoprotective properties of currently available H 1-antagonists, and examine the ability of H 1-antagonists to delay the development of asthma in 221

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high-risk atopic infants and the potential role of H 1-antagonists in the continuing management of patients with chronic asthma.

II. MAST CELLS, BASOPHILS, HISTAMINE RELEASE, AND THE INVOLVEMENT OF OTHER MEDIATORS IN ASTHMA Before discussing the involvement of histamine in the pathogenesis of asthma, it is necessary to review the contribution of mast cells and basophils to the inflammatory process through the release of histamine and other mediators. A.

Mast Cells

In 1953, Riley and West identified the mast cell as a major source of histamine (3). Stimuli that increased the numbers of mast cells in tissues were also noted to result in increased release of histamine. The identification of circulating IgE and the discovery of high-affinity IgE (FcεRI) receptors on mast cells supported the hypothesis that allergen cross-linkage of IgE receptors on mast cells resulted in mast cell degranulation, histamine release, and the characteristic bronchoconstriction of asthma (4). In healthy and asthmatic subjects, the airways have been shown to contain numerous mast cells, which originate from CD34 ⫹ precursor cells, and are predominantly of the tryptase only phenotype (MC T ), as distinct from chymasepositive, tryptase-positive mast cells (MC CT ) found in other tissues (5). The polarization of airway mast cells to the MC T type is promoted by the presence of mast cell growth factors derived from infiltrating Th2-type lymphocytes (interleukin [IL]-3, IL-4, and IL-9), and stem cell factor released by the bronchial epithelium and adjacent fibroblast/myofibroblast layer (6). Although some investigators have not noted any difference in mast cell numbers in endobronchial biopsies (5, 7) or bronchoalveolar lavage (BAL) fluid (8) between asthmatics and healthy subjects, others have confirmed increased numbers in BAL fluid of stable asthmatics (9), and endobronchial evidence of a further rise in mast cell numbers in parallel with the extent of the late allergic response to allergen challenge (10, 11). In patients with asthma, some mast cells show ultrastructural evidence of degranulation, which is not found in healthy subjects, and become localized to the bronchial epithelium after allergen challenge, where they are more likely to encounter inhaled allergens or be activated by other noxious stimuli (12). Consistent with the hypothesis of increased activation of mast cells in asthma is the observation that mast cell mediator levels such as histamine, tryptase, and leukotrienes are increased in BAL fluid in asthmatics after allergen challenge (13). Flint et al.

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showed increased numbers of mast cells containing histamine in BAL fluid of asthmatics compared to healthy subjects, with an inverse relationship among forced expiratory volume in 1 second (FEV 1), numbers of mast cells, and the levels of histamine (12). Increased levels of histamine have been found in the BAL fluid of subjects with active asthma, accompanied by increased levels of other mast cell–derived products including prostaglandin (PG)D 2 , leukotriene (LT) C4, and the protease, tryptase. Increased numbers of airway MC T cells have been particularly associated with more severe forms of asthma. In the airway inflammation of asthma, the mast cell has been confirmed as an important source of cytokine release (IL-3, IL-4, IL-5, IL-6, IL-8, IL-13, IL-16 and tumor necrosis factor [TNF-α]), both stored preformed in secretory granules and newly generated by transcriptional mechanisms in response to cross-linkage of Fc⑀RI receptors and other stimuli (14–17). B. Basophils Until recently, it has been difficult to differentiate between mast cells and basophils in tissues, since both cells contain metachromatic granules and stain positively for FcεRI receptors. Similar to mast cells, airway and circulating basophils are derived from CD34 ⫹ cells. Upon activation by IgE-dependent or IgE-independent mechanisms, basophils release a number of potent mediators, including histamine, leukotrienes, proteoglycans, and cytokines such as IL-4 and IL-13 (18– 22). Earlier studies have applied morphological criteria including cell surface expression of FcεRI receptors, the presence of metachromatic granules staining negatively for trypsin, and multilobular nuclei to identify basophils in tissues. Using these indirect criteria, increased numbers of basophils have been described in the sputum of asthmatics during exacerbations. After subsegmental allergen challenge with ragweed antigen in sensitized allergic asthmatics, Guo et al. reported a 20- to 200-fold increase in the numbers of IgE-bearing, histamine-containing cells in BAL fluid, 95% of which were considered to be basophils (23). McFarlane and colleagues have recently developed a monoclonal antibody (BB1) that stains antigens specific to basophils (24) and have used this antibody to assess the role of basophils in the allergic airway responses of asthma. They have confirmed increased numbers of basophils in bronchial biopsies of atopic asthmatics compared to healthy controls, atopic nonasthmatics, or even nonatopic asthmatics. They noted a further increase in the numbers of BB1-positive basophils at 24 hours after allergen challenge, coincident with the late allergic response, with a proportion of these cells showing evidence of degranulation. The influx of basophils into the airways was significantly lower than the numbers of eosinophils recruited, suggesting that although basophils contribute to the development of the late allergic response (LAR), eosinophils play a more important role.

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III. INVOLVEMENT OF HISTAMINE IN BRONCHOCONSTRICTOR RESPONSES IN ASTHMA The initial isolation of histamine in 1907 by Windaus and Vogt (25), and the recognition that anaphylactic challenge of lung tissue resulted in histamine release, stimulated the search for mediators involved in airflow dysfunction in patients with asthma (26). Early studies by Weiss et al. observed that the administration of intravenous or intramuscular histamine to patients with bronchial asthma precipitated attacks of breathlessness associated with bronchial obstruction as measured by decreased vital capacity (27). It was recognized that the bronchoconstriction induced by histamine was unique to asthmatic subjects, was not observed in healthy subjects, and could be abrogated by pretreatment of asthmatic subjects with an early histamine receptor antagonist, β-dimethylaminoethyl-benzhydrylether hydrochloride, which had shown effectiveness in animal studies and in allergic rhinitis (28, 29). It has been well documented that histamine is released in airway inflammation in asthma and it is possible to detect histamine or its metabolites in airway fluids, peripheral blood, or urine of asthmatic subjects. In the circulation, histamine release was initially localized to the granulocyte fraction of blood (30), and it was later confirmed by Ishizaka et al. that basophils were responsible for histamine release from blood stimulated in vitro with an anti-IgE antibody (31). Barnes et al. showed that plasma histamine levels were increased in asthmatics compared to healthy controls, atopic nonasthmatics, or chronic bronchitic subjects (32). Plasma histamine release is noted to increase in atopic asthmatics after allergen challenge, and in asthmatic subjects experiencing an exacerbation, compared to stable asthmatics. The levels of histamine found correlate with the severity of underlying disease (23). Patients receiving effective treatment for asthma have also been shown to release lower levels of histamine than asthmatic subjects with poorly controlled disease (33).

IV. BRONCHOCONSTRICTOR RESPONSES IN ASTHMA: EFFECTS OF H 1-ANTIHISTAMINES A number of studies have assessed the ability of H 1-antihistamine compounds to prevent the bronchoconstriction induced by inhalation of known spasmogens [histamine, methacholine, adenosine, and platelet-activating factor (PAF)]. The bronchoconstrictor response to histamine inhalation in asthmatic subjects has been widely applied as a measure of airway hyperresponsiveness, in which the histamine inhalation challenge determines the concentration of histamine required to cause a 20% reduction in the forced expiratory volume in 1 second (histamine PC 20 FEV 1). Wood-Baker and Holgate compared the effect of some

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H 1-antihistamines (including brompheniramine, cetirizine, chlorpheniramine, clemastine, and cyproheptadine) on inhibition of bronchospasm induced by histamine or methacholine inhalation in asthmatic subjects (34) (Fig. 1). Cetirizine was most effective at inhibiting histamine-induced bronchospasm. None of the H 1-antagonists protected against methacholine-induced bronchospasm (34). Other investigators confirmed that cetirizine at three doses (5, 10, or 20 mg) and hydroxyzine (25 mg) had a protective effect against the bronchoconstrictor response to histamine, and also confirmed the significant bronchodilator effect of both compounds (35). The inhalation of adenosine or its 5′-nucleotides [adenosine monophosphate (AMP), adenosine diphosphate (ADP)] has been used to study the involvement of histamine in asthma. The bronchoconstrictor response induced by inhalation of adenosine results from the selective activation of A 2b receptors on mast cells, resulting in mast cell degranulation, and the release of preformed mediators including histamine (36–40). Histamine release in the airway fluids and blood of atopic and asthmatic subjects is increased after inhalation of AMP or local

Figure 1 The protective effects of H 1-antihistamines against histamine-induced bronchoconstriction. All antihistamines provided significant protection against histamine-induced bronchoconstriction (black bars) and none provided protection against methacholine-induced bronchoconstriction (white bars). (From Ref. 34.)

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endobronchial challenge with AMP, and the bronchoconstrictor responses can be inhibited by prior treatment with a selective H 1-antagonist (41–43). Inhalation of PAF has been shown to induce acute reversible bronchoconstriction of a degree greater than histamine or leukotriene inhalation. A doubleblind, placebo-controlled trial has assessed the effects of cetirizine on PAF-induced bronchoconstriction (measured by specific airway conductance, sGaw) in 10 subjects with mild asthma (44). Patients inhaled a dose of PAF titrated to cause a 35% fall in sGaw, but cetirizine did not significantly inhibit the bronchoconstriction induced by PAF inhalation.

V.

INVOLVEMENT OF HISTAMINE IN THE BRONCHOCONSTRICTOR RESPONSE TO ALLERGEN

Histamine contributes to the development of airway hyperresponsiveness after allergen challenge in asthma. Following inhalation allergen challenge, an increase in the plasma histamine level is seen within minutes (41, 45, 46), associated with a later increase in the level of the histamine metabolite, N-methyl histamine in the urine (47), suggesting that histamine is involved in the development of the early bronchoconstrictor response. Although pretreatment with an H 1-receptor antagonist attenuates the first phase (0–7 min) of the early allergic response (EAR) (48–50), it does not completely abolish it, implying that other mediators such as leukotrienes or PGE 2 are also involved (51, 52). The involvement of histamine in the LAR is even less certain. An increase in the plasma histamine level coincident with the LAR has been reported (53), but temporal relationships were not found among the airway changes, the rise in plasma histamine, or the urinary excretion of the histamine metabolite, N-methyl histamine (54). The influx of basophils described by McFarlane and others coincident with the late allergic response supports the involvement of basophils in this process; however, H 1-antihistamines have had limited effectiveness at suppressing the LAR, and do not reduce nonspecific airway hyperresponsiveness (55–57). Asthmatics have an enhanced baseline release of histamine in the peripheral circulation and lungs compared to healthy or atopic nonasthmatic subjects, presumably as a result of basophil and mast cell degranulation. Increased histamine levels are also noted following an exercise- or allergen-induced asthmatic attack (58). Segmental allergen challenge has been shown to result in increased local histamine release and bronchoconstriction in healthy and asthmatic subjects (59), and there is a correlation between the increased levels of histamine in BAL fluid and the increased bronchial hyperresponsiveness as assessed using methacholine challenge (60). A recent study suggests that leukotrienes play a more prominent role than histamine in the development of the EAR and LAR after allergen challenge

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Figure 2 The allergen-induced reduction in FEV 1 during the early and late allergic response to inhaled allergen in 12 asthmatic subjects after 1 week of treatment with placebo (open circles), zafirlukast 80 mg twice daily (closed circles), loratadine 10 mg twice daily (open squares), or a combination of zafirlukast and loratadine (solid squares). The pulmonary function is expressed as a percentage of the postdiluent FEV 1. (From Ref. 61.)

(Fig. 2). Roquet and colleagues noted that pretreatment of asthmatic subjects with the selective cysteinyl leukotriene LT 1 receptor antagonist zafirlukast (80 mg twice daily) reduced the extent of the EAR by 62% and the LAR by 55% (61) (Fig. 2). The H 1-antagonist loratadine (10 mg twice daily) had a lower efficacy and reduced the EAR and LAR by 25 and 40%, respectively. The combination of the two agents was most effective, suppressing the EAR and LAR by 75 and 74%; however, a recent study by Dahlen et al. showed that high-dose loratadine alone offered less protection against exercise-induced bronchoconstriction (⫺9%) than high-dose zafirlukast alone (57%), or the combination of loratadine and zafirlukast (65%) (62). Although it does appear that leukotrienes play a more important role than histamine in the development of allergen- or exercise-induced bronchoconstriction, these studies support the view that a combination of an antihistamine and an antileukotriene in high doses may represent a novel strategy for the treatment of asthma.

VI. HISTAMINE AND H 1-ANTIHISTAMINES: PROPOSED MECHANISMS OF ACTION AND INVOLVEMENT IN INFLAMMATORY PROCESSES IN ASTHMA Histamine is an important mediator of inflammation in asthma and has a number of actions mediated through H 1-receptors, including vasodilation of postcapillary

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venules and increased microvascular permeability leading to mucosal edema; smooth muscle contraction and stimulation of parasympathetic reflexes leading to bronchoconstriction; cough mediated by the stimulation of H 1-receptors on afferent airway sensory nerve endings; and mucus hypersecretion as a result of H 2-receptor activation on mucus glands (58). A.

Mechanism of Action of H 1-Antihistamines

Although H 1-antihistamines have been shown to have anti-inflammatory properties (Table 1), the precise mechanisms involved are unclear. Although many actions involve the activation of selective H 1-receptors on target cells, antihistamines may also effect responses by other mechanisms. Studies have suggested that they may inhibit the influx of calcium into cells and interfere with signal transduction pathways that are dependent on cytosolic calcium. Studies performed by Arnold et al. on pulmonary epithelial cells (A549) and endothelial cells suggest that many of the actions of cetirizine could be linked to the modulating effect of this H 1-antihistamine on the expression of the transcription factor nuclear factor kappaB (NF-κB) (63, 64). Yoneda et al. also showed that azelastine can block the activation of NF-κB and the expression of messenger (m)RNA transcripts for IL-1β, IL-6, granulocyte macrophage colony-stimulating factor (GM-CSF), and TNF-α in human peripheral blood leukocytes, lending support Table 1

Anti-Inflammatory Actions of H 1-Antihistamines Relevant to Asthma

Cell Mast cells and basophils Eosinophils

Neutrophils Vascular endothelium

Bronchial epithelium

Antigen-presenting cells

Anti-inflammatory actions Inhibition of mediator release (histamine, leukotrienes, and PGD 2) Suppression of influx to airways after allergen challenge Reduced chemotaxis Reduced mediator release (superoxide radicals) Reduced chemotaxis Reduced release of mediators Reduced expression of leukocyte adhesion molecules (ICAM-1, VCAM-1) on vascular endothelium Reduced NF-κB expression Reduced expression of activation markers, HLA-DR, and ICAM-1 Reduced release of RANTES, IL-16, and soluble ICAM-1 Reduced expression of NF-κB Possible reduction of antigen-presenting/antigen-processing activity by APCs

ICAM-1, intercellular adhesion molecule-1; RANTES, regulated upon activation, normal T expressed and secreted; HLA-DR, human leukocyte antigen-DR; NF-κB, nuclear factor kappa B; APC, antigen presenting cell; VCAM-1, vascular cell adhesion molecule-1.

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to the hypothesis that H 1-antihistamines may inhibit the activation of genes responsible for the synthesis of proinflammatory mediators (64). B. Mediator Release The potential of various antihistamines to inhibit the generation of proinflammatory mediators has been widely studied. Church et al. observed an inhibition of anti-IgE-induced histamine release from human lung fragments by antihistamine compounds at low concentrations, but a paradoxical increased release at higher concentrations independent of the challenge used (65), suggesting inhibitory effects by mechanisms independent of the H 1-histamine receptor. Ketotifen has shown poor inhibitory actions on histamine release by human lung mast cells, but was noted to antagonize effectively the release of slow-reacting substance of anaphylaxis (SRSA) (66). Azelastine has also been shown to inhibit histamine and leukotriene release from human lung mast cells at concentrations of 3 µM (67–69) while loratadine reduces leukotriene but not histamine release (70). Ketotifen also inhibits the release of superoxide radicals by human neutrophils. In addition, inhibition of oxygen free radical production has been described for ketotifen in human alveolar macrophages, and for azelastine, oxatomide, loratadine, and cetirizine in human eosinophils. Of interest, the actions of cetirizine were more pronounced in cells obtained from atopic subjects, with effective inhibition of mediator release at lower concentrations in eosinophils obtained from atopic donors than from nonatopic controls (71). The airway epithelium is an important source of autacoid mediators, cytokines, and chemokines, and plays an important role in regulating the inflammation, repair, and remodeling process in asthma (72). In vitro studies involving the culture of bronchial epithelial cells transformed by virus 12-SV40 cells (BEAS-2B) have confirmed that histamine is capable of activating the airway epithelium with increased accumulation of intracellular calcium, an effect that can be abrogated by the antihistamine diphenhydramine (73). Vignola et al. also showed that histamine exposure increases the expression of the activation markers HLA-DR and ICAM-1 and the production of fibronectin by airway epithelial cells, which can be inhibited by either the H 1-receptor antagonist pyrilamine or the H 2-receptor antagonist ranitidine (74). More recently, it has been shown that histamine augments the release of IL-16 (a potent chemokine for CD4 ⫹ lymphocytes and eosinophils) from airway epithelial cells in culture, particularly after priming by IL-1β and TNF-α (75). These effects were inhibited by the protein synthesis inhibitor cyclohexamide, and by dexamethasone, suggesting de novo synthesis of IL-16 by mechanisms involving the activation of transcription factors, such as NF-κB (75). Bayram and colleagues observed an increased release of IL-8, RANTES, and soluble ICAM-1 by primary bronchial epithelial cell cultures after exposure to the air pollutant nitrogen dioxide (NO 2, 400 ppb), and inhibition by loratadine or its metabolite SCH34117 (desloratadine) (76, 77)

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(Fig. 3). Arnold et al. also confirmed that the release of IL-8 from bronchial epithelial cells (A549) in response to TNF-α or phorbol 12-myristate 13-acetate (PMA) exposure was inhibited by pretreatment with cetirizine, and was associated with a decreased amount of accessible DNA-binding sites of NF-κB as determined by flow cytometry automated cell sorting (FACS) analysis, providing further evidence for the anti-inflammatory effects of H 1-antagonists (78). C.

Effects of H 1-Antihistamines on Inflammatory Cell Recruitment

The accumulation and activation of inflammatory cells in the airways of asthmatics contribute significantly to the chronic inflammation and airway remodeling of asthma. Histamine has been shown to promote the recruitment of inflammatory cells to the airway by the upregulation of adhesion molecules on pulmonary vascular endothelial cells. It is a potent stimulus for the transport of P-selectin from the Weibel palisade bodies to the cell surface in the microvascular endothelium (79). The interaction of P-selectin with its carbohydrate ligand expressed on circulating T lymphocytes, eosinophils, and neutrophils promotes the initial rolling and margination of leukocytes. In addition, cytokines released by mast cells promote the subsequent migration of inflammatory cells into the airways by augmenting the tight adherence and transendothelial migration of leukocytes, resulting from increased expression of E-selectin and ICAM-1 (TNF-α, IL-1β, and interferon-γ), and vascular cell adhesion molecule 1 (VCAM-1) (TNF-α, IL-4, and IL-13). In 1987, Fadel and colleagues showed that cetirizine inhibited the accumulation of eosinophils at sites of allergen challenge in the skin of pollen-sensitive subjects (80). Redier et al. also showed that the influx of eosinophils to the airways, synchronous with the LAR after allergen challenge in allergic asthmatics, is inhibited by prior treatment with cetirizine (55). Subsequent in vitro work has shown that cetirizine effectively inhibits PAF-induced adherence of human eosinophils to human umbilical vein endothelial cells (HUVEC) at extremely low concentrations (81). Similar responses have also been noted in allergic diseases of the eyes and skin. Cetirizine inhibits the increase in ICAM-1 expression on epithelial conjunctival cells after conjunctival allergen challenge (82), suppresses the allergen-induced expression of VCAM-1 in the skin of subjects with atopic dermatitis (83), and decreases the expression of ICAM-1 on nasal epithelial cells in children with mite-sensitive asthma (84). There is also evidence from in vitro studies that antihistamines may have a suppressive effect on the chemotaxis of inflammatory cells to sites of inflammation. In vitro studies by Gonzales et al. have shown that ketotifen inhibits the chemotaxis of neutrophils at concentrations as low as 10 µg/mL (85). Results with azelastine on neutrophil chemotaxis were equivocal, while the concentration

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Figure 3 The release of (a) RANTES and (b) sICAM-1 by primary bronchial epithelial cell cultures after 24 h in vitro exposure to 400 ppb NO 2 in the presence or absence of loratadine (0.25–25 µM). Expressed as median and range, n ⫽ 6 in each group. RANTES, regulated upon activation, normal T expressed and secreted; sICAM-1, soluble intercellular adhesion molecule. (From Refs. 76, 77, and 122.)

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of cetirizine required to inhibit neutrophil chemotaxis, above 35 µg/mL, was too high to be of clinical relevance (86). Cetirizine effectively inhibits eosinophil chemotaxis induced by PAF, LTB 4, IL-8, and C5a, even at concentrations within the therapeutic range (87). Ketotifen is reported to inhibit PAF-induced eosinophil chemotaxis at concentrations lower than that required for inhibition of LTC 4 production. Other antihistamines have been shown to be less effective or ineffective at concentrations likely to be achieved in vivo by doses used in clinical practice. The accumulation of inflammatory cells at the site of inflammation is also dependent on the rate at which the cells die or are removed from the tissue by programmed cell death, or apoptosis. The apoptosis of eosinophils and mast cells is delayed and survival increased by the cytokine IL-5 and stem cell factor (SCF), respectively. The survival of eosinophils in the presence of IL-5 is reduced by ketotifen, although relatively high concentrations are required (10 ⫺3 or 10 ⫺4 M) to elicit the response (88). It has been suggested that antihistamines may have some suppressive effects on the initial processing or presentation of antigen by antigen-presenting cells. Ketotifen enhanced lymphocyte proliferation at concentrations up to 50 µM, but had inhibitory effects at higher concentrations (71). Todoroki and colleagues also reported a weak suppressive effect of azelastine on the induction of IL-2 responsiveness by Dermatophagoides farinae antigen in peripheral blood mononuclear cell cultures from patients with asthma (89).

VII. EFFECTS OF H 1-ANTIHISTAMINES IN CLINICAL ASTHMA As early as 1949, Herxheimer reported clinical improvement in an open study of 26 patients with mild to moderate asthma following treatment with mepyramine, diphenhydramine, and promethazine (90). It was believed, however, that antihistamines would thicken airway mucus, and concerns were expressed about the frequent side effects of the first-generation H 1-antihistamines, in particular sedation and dry mouth. Schuller et al. (91) reported that antihistamines could cause bronchoconstriction and have a deleterious effect on lung function in children with asthma. This led to a warning that they should not be used in the management of asthma; however, in contrast to the extremely limited evidence that antihistamines cause bronchoconstriction, there are now considerable supportive data for an H 1-antagonist bronchodilator effect (92). In a position statement, the American Academy of Allergy, Asthma and Immunology advised removal of the warning, and recommended that antihistamines should be prescribed if required for patients with asthma, unless a previous adverse reaction had been documented in a specific patient (93).

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In reviews of the role of H 1-antagonists in the management of asthma (94), concerns have been expressed over the design of many of the studies performed before 1996 including the absence of a double-blind, placebo-controlled (DBPC) design, inadequate washout period for other medications, insufficient patient numbers to detect a significant effect, and inadequate characterization of asthma severity prior to inclusion in the study. Van Ganse and colleagues performed a meta-analysis of clinical trials of antihistamines in the management of mild, moderate, and severe asthma (95), in which 71 DBPC trials were reviewed, and 19 studies submitted for quality assessment (Fig. 4). The overall quality of studies was low, with a mean score of 59%. Asthma was generally uncontrolled at inclusion. The antihistamines assessed included azelastine, cetirizine, ketotifen, loratadine, oxatomide, pemirolast, picumast, and terfenadine. H 1-antihistamines had

Figure 4 Meta-analysis of the efficacy of H 1-antihistamines in adults with asthma. The antihistamines selected were azelastine (study number 7 in meta-analysis), cetirizine (15), ketotifen (1, 2, 3, 5, 8,), loratadine (13), oxatomide (4), pemirolast (12), picumast (9), and terfenadine (6, 10, 14). H 1-antihistamines and placebo had a similar effect on morning and evening PEF and FEV 1. Sedation was reported more frequently than for placebo (p ⬍ 0.001). (From Ref. 95.)

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little effect on morning peak expiratory flow (PEF), evening PEF, or FEV 1. Sedation was noted more frequently in the active treatment group compared to those receiving placebo, and additional side effects of weight gain, altered taste, headache, and dry mouth were recorded. The second-generation H 1-antihistamines have many advantages over the first-generation H 1-antihistamines in terms of specificity, safety, and side effect profile. Similar to H 1-receptor effects in the upper airways and skin, there is no evidence of tachyphylaxis to bronchodilator effect in the lower airway (96–105), and no increase in asthma symptoms has been documented with continued use of antihistamines (106, 107). Some authors have suggested that antihistamines may have a corticosteroid-sparing effect in asthma (102) (Fig. 5a), but this has not been consistently shown (103) (Fig. 5b). A.

Cetirizine

Cetirizine, a carboxylated metabolite of hydroxyzine, is a potent antihistamine with documented bronchodilator and anti-inflammatory properties (108) and no effect on calcium channels, serotoninergic, muscarinic, or dopaminergic receptors (109). In a study of symptomatic grass pollen–sensitive asthmatics, treatment with cetirizine 15 mg daily for 2 weeks led to a reduction in asthma symptoms, and allowed a reduction in the concomitant use of β 2-agonists and inhaled cortico-

Figure 5 (a) Glucocorticosteroid-sparing effect of H 1-antihistamines in adults with asthma. Azelastine reduced the requirement for inhaled corticosteroids (ICS) in adults with chronic asthma. In a study of 193 subjects receiving azelastine (6 mg twice daily) or placebo in combination with beclomethasone dipropionate (BDP; 6–16 inhalations/ day), BDP was reduced until maximum reduction or cessation was achieved. Subjects were then evaluated for a maintenance period of 12 weeks at the reduced dosage of BDP. A significantly greater reduction in BDP was achieved in the azelastine group (4.9 puffs/ day) than in patients receiving placebo (3.1 puffs/day; p ⬍ 0.01). (From Ref. 102.) (b) Lack of a steroid-sparing effect by the H 1-antagonist, ketotifen, in children with asthma. In a study of 52 children aged 6–13 years receiving maintenance treatment with ICS at dosages less than 1000 µg/day, ketotifen (2 mg/day) or placebo was administered for 32 weeks, following a 4-week run-in period. From weeks 13 to 20, the dose of ICS was reduced by 25% on alternate weeks to the minimum dose tolerated, and continued during weeks 21–32 if tolerated. At baseline the mean ICS dosages were 432 µg/day and 408 µg/day in the ketotifen and placebo groups, respectively. Although the ketotifen-treated children reported fewer symptoms compared to the placebo-treated group, there was no significant difference in ICS doses (vertical axis) during weeks 21–32 in the ketotifentreated group (18% of baseline) compared to the placebo group (35% of baseline) (no., number). (From Ref. 103.)

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steroids (ICS) compared to placebo (110). Bousquet and colleagues reported that cetirizine (10 or 15 mg twice daily) was more effective than terfenadine (60 mg twice daily) in the control of asthma in 97 grass pollen–allergic subjects with mild seasonal symptoms of recent onset. Spector et al. also confirmed a significant bronchodilator effect of cetirizine in a DBPC trial of 13 patients with mild-tomoderate asthma. After three different doses of cetirizine (5, 10, or 20 mg), they noted a bronchodilator effect that was additive to, and lasted longer than that of, salbutamol (101).

B.

Azelastine

Azelastine has been shown to inhibit the release of both histamine and leukotrienes from human lung mast cells (71), and may also have some suppressive effects on antigen processing or presentation (89). The efficacy of azelastine in the management of persistent asthma has been assessed in a number of studies (97, 102). In a DBPC trial of 24 asthmatic subjects by Gould et al. (97), treatment with azelastine for 7 weeks resulted in a reduction in symptoms of cough and wheeze, associated with improvements in peak flow readings, and a reduction in the use of rescue bronchodilator therapy. Busse et al. also noted that azelastine reduced the requirements for inhaled corticosteroids in adults with chronic asthma (102). In this study of 193 adults with asthma, subjects received either azelastine 6 mg twice daily or placebo in combination with beclomethasone dipropionate 6–16 inhalations per day. The inhaled corticosteroid was then reduced until maximum reduction or discontinuation was achieved and maintained for a 12-week period. The authors noted a significantly greater overall median reduction in corticosteroid dose in the azelastine group compared with placebo (4.9 puffs per day for azelastine compared to 3.1 puffs per day for placebo, p ⬍ 0.01), indicating a mild glucocorticoid-sparing effect of azelastine in asthma (Fig. 5a).

C.

Ketotifen

Studies assessing the role of ketotifen in asthma have shown variable efficacy, but excessive drowsiness has been consistently reported. In a 1-month randomized placebo-controlled study of ketotifen (1 mg and 2 mg) involving 50 atopic asthmatics, Dyson and colleagues showed no improvement in PEF; also, there was a significant reduction in reliever β 2-agonist use in the subgroup of patients not maintained on ICS, but no improvement in patients requiring ICS therapy (111). Fourteen percent of subjects either withdrew from the study or reduced the dose of ketotifen due to excessive sedation. A 7-month DBPC study of ketotifen was performed in 138 children aged 5–17 years with chronic asthma (112). After 10

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weeks of treatment, 60% of ketotifen-treated children were able to discontinue theophylline therapy compared to 34% in the placebo group. Ketotifen-treated children also reported a significant improvement in quality of life. Lane et al. performed a multicenter DBPC study in 86 steroid-dependent asthmatics to assess the steroid-sparing effects of ketotifen use (113). Subjects had documented airflow obstruction and had been taking oral corticosteroids for 1 month prior to inclusion. After a run-in period of 2 weeks, oral corticosteroids were reduced by 1 mg per week until subjects became symptomatic or were off corticosteroids for 1 week. Ten patients (24%) were weaned from corticosteroids in the ketotifen group compared to three subjects in the placebo group. The daily requirement for oral prednisolone was reduced from 8.4 mg to 4.4 mg in the active group. Drowsiness was the major adverse event, being reported in 5% of patients taking ketotifen. D. Loratadine Loratadine has been variably successful in asthma treatment. Kroll et al. performed an uncontrolled study of 25 patients with asthma and showed an improvement in lung function, associated with a reduction in asthma symptoms and bronchodilator use after 6 weeks treatment with loratadine 10 mg daily (114); however, the same dose of loratadine failed to show any effect on peak flow or symptoms in a DBPC crossover trial involving 17 subjects with moderate asthma (115).

VIII. ROLE OF H1-ANTIHISTAMINES IN PATIENTS WITH ALLERGIC RHINITIS AND MILD SEASONAL ASTHMA Allergic rhinitis and asthma are both relatively common disorders and the two conditions commonly coexist. The upper and lower airways share a number of epidemiological, physiological, immunopathological, and pharmacological similarities, yet also exhibit distinct features as summarized by Simons (Table 2). Poorly controlled allergic rhinitis has been shown to sustain asthma-like symptoms (116), and has been associated with a worsening of asthma control. Nasal allergen challenge in subjects with allergic rhinitis and mild asthma results in increased bronchial hyperreactivity to methacholine, which is reduced by prior treatment with cetirizine (10 mg daily) (117). An improvement in symptoms of allergic rhinitis and asthma has been documented for patients with coexistent rhinitis and pollen-sensitive asthma after treatment with cetirizine at dosages as low as 10 mg daily, in comparison with terfenadine (60 mg twice daily) which only improved allergic rhinitis symptoms (118). Grant et al. performed a 6-week randomized DBPC clinical trial of 186 patients with seasonal allergic rhinitis and

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Table 2 Links Between the Upper and Lower Airways in Allergic Rhinitis and Atopic Asthma Epidemiology

30–50% of allergic rhinitis patients have clinical asthma. 80% of asthmatics have undiagnosed or clinical allergic rhinitis.

Anatomy

Nasal mucosa and bronchial mucosa are lined by ciliated columnar epithelium. Increased vascularity is characteristic of allergic rhinitis. Subepithelial fibrosis and smooth muscle hypertrophy are characteristic features of asthma.

Physiology

Increased bronchial hyperresponsiveness is found in patients with isolated allergic rhinitis. Increased bronchial hyperresponsiveness is typical of asthma.

Immunopathology

Inflammation of upper and lower airways, and infiltration by Th2 lymphocytes, activated eosinophils, degranulated mast cells, and basophils. Elevated IgE levels. Increased expression of Th2-type cytokines (IL-4, IL-5, GMCSF), and chemokines (RANTES); and release of mediators (histamine, leukotrienes).

Pharmacology

Anti-inflammatory therapy with topical corticosteroids is the key to management of both conditions. Control of allergic rhinitis symptoms (topical corticosteroids, antiallergics, H1-antagonists) improves asthma symptoms. Asthma may remain poorly controlled despite optimal treatment in the presence of symptomatic allergic rhinitis. α-Adrenergic agonists have a role as vasoconstrictors in allergic rhinitis. β2-Adrenergic agonists are important bronchodilator agents in asthma.

IL-4, interleukin 4; GM-CSF, granulocyte macrophage colony stimulating factor; RANTES, regulated upon activation, normal T expressed and secreted. Source: Adapted from Ref. 94.

asthma (105) (Fig. 6). They reported a worsening of symptoms in the placebo group during the study, whereas the patients treated with cetirizine (10 mg daily) showed improvements in rhinitis and asthma symptoms. Although the use of reliever bronchodilators was reduced, there was no significant improvement in lung function in the cetirizine-treated group. More patients in the cetirizinetreated group completed the trial, suggesting that cetirizine was safe, well tolerated, and effectively relieved symptoms in upper and lower airways disease, at doses commonly used for the treatment of allergic rhinitis (105). These effects

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Figure 6 Effects of H 1-antihistamines in seasonal allergic rhinitis and mild asthma. (a) There was a significant reduction in rhinitis symptoms from week 1 and during the pollen season in cetirizine-treated patients. (b) Cetirizine significantly reduced asthma symptoms during weeks 1, 2, 4, 5, and 6 of the study, but no significant improvements in PEF or FEV 1 were noted. (From Ref. 105.)

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of H 1-antagonists on upper and lower airways disease have also been confirmed by Corren and colleagues in a DBPC trial in which they gave a combined preparation of loratadine 5 mg and pseudoephedrine sulfate 120 mg twice daily (104). Compared to placebo, the combination was shown to improve pulmonary function and symptoms of allergic rhinitis and asthma in 193 patients with seasonal allergic rhinitis and asthma.

IX. DO H 1-ANTIHISTAMINES HAVE A PREVENTATIVE EFFECT ON THE DEVELOPMENT OF ASTHMA IN HIGH-RISK ATOPIC INFANTS? There has been considerable recent interest in the early-life origins of asthma. Management strategies have been devised to prevent the later onset of asthma in infants considered at high risk of asthma due to atopic status or positive history of asthma in one or both parents. Allergen avoidance in early life has been advocated as a possible strategy but is difficult to achieve and may not be effective. Of particular interest are the results of studies suggesting that antihistamine therapy may delay the subsequent development of asthma. Placebo-controlled studies by Iikura et al. and Bustos et al. of 1 and 3 years’ duration, respectively, in infants with atopic dermatitis, positive family history of asthma, and/or elevated IgE levels suggest that ketotifen may delay the onset of asthma (119, 120). The Early Treatment of the Atopic Child (ETAC) study reported similar effects with cetirizine, which was shown to prevent the onset of asthma when administered to grass- or house dust mite–sensitized infants (121). Although the precise mechanisms involved in this process are not yet clear, it has been suggested that inflammatory mediators released from a primary site of atopy (e.g., the skin in atopic dermatitis) may have distant actions on a secondary organ to upregulate the expression of adhesion molecules on the pulmonary vascular endothelium, priming the airways for the recruitment of inflammatory cells to the lungs, and the later development of bronchial asthma. It is possible that cetirizine may act to downregulate the activation state of the pulmonary vascular endothelium by downregulating adhesion molecules through mechanisms involving NF-kB expression, and may prevent the airway inflammation from the outset (63).

X.

SUMMARY

Histamine released from mast cells and basophils is an important mediator of airway inflammation in asthma, particularly in the development of the early allergic response. Although histamine has been shown to contribute significantly to the bronchoconstrictor response to allergen or exercise, leukotrienes are likely

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to play a more prominent role in these responses in asthma. The improved specificity, tolerability, and safety profile of the second-generation H 1-antagonists associated with anti-inflammatory activities and bronchodilator activities, may contribute to relieve the symptoms of the upper and lower airways in patients with coexistent mild seasonal asthma and allergic rhinitis. Considering the global rise in the prevalence of allergy and asthma, the suggestion that H 1-antagonists may delay the onset of asthma in infants is of considerable interest and merits further assessment. Although it is unlikely that monotherapy with most currently available H 1-antagonists will provide significant clinical benefit in asthma, the potential of combined antihistamine and antileukotriene therapy may prove useful, particularly in subjects with poor compliance to inhaled corticosteroid therapy.

ACKNOWLEDGMENTS Dr. Lordan is a clinical research fellow funded by a program grant from the Medical Research Council, UK. Professor Holgate is MRC Clinical Professor of Immunopharmacology. The authors thank Evelyn Lordan for her assistance and support in preparation of the manuscript.

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8 Antihistamines in Urticaria and Angioedema Anne Kobza Black Guy’s, King’s, and St. Thomas’ School of Medicine, London, England

Malcolm W. Greaves National University of Malaysia, Kuala Lumpur, Malaysia

I.

INTRODUCTION

The urticarias and angioedemas form a group of disorders characterized by transient cutaneous swellings that are frequently itchy. Urticarial lesions (wheals, hives) are superficial dermal swellings. In angioedema, the transient swellings are deeper in the dermis, subcutaneous, and submucosal tissue. In most types of urticaria, the wheals are pink or red with a pale center, and are often itchy, especially in the evenings and at night. They occur in varying shapes and sizes on any part of the skin and generally last less than 24 hours, resolving through a flat erythematous stage to normal-appearing skin. Angioedema frequently affects the lips and eyelids, and sometimes the hands, feet, and tongue. Occasionally it involves the submucosal tissue of the oropharynx, larynx, and gastrointestinal tract. Lesions of angioedema may be red or skin-colored, are sometimes itchy, and generally resolve within 48 hours. They are distressing and worrying for patients, who fear the possibility of choking and impending death. In 40% of patients, both urticaria and angioedema occur at some stage of their disease (1) and are generally considered to be part of the same process. Angioedema without urticaria occurs in 10% of patients, and is frequently intermittent. Urticaria and angioedema, if severe, may be accompanied by systemic symptoms including malaise, headache, nausea, vomiting, abdominal pain, and arthralgia (2). 249

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Urticaria/angioedema occur as ordinary urticaria (which affects 75% of patients with urticaria seen in dermatology clinics), physical urticarias (15–20%) (1), urticarial vasculitis (approximately 5%), and contact urticaria, which is underdiagnosed. One uncommon form of angioedema without urticaria is C1 esterase inhibitor deficiency angioedema. In ordinary urticaria, the onset of wheals and the skin areas affected are unpredictable. Wheals last from several to 24 hours. In physical urticarias, a physical stimulus such as minor friction, sustained pressure, heat, cold, exercise, sunlight, and even water induces reproducible whealing. Wheals usually resolve within 1 hour, except for those of delayed pressure urticaria. The clinical types and identifying characteristics of the urticarias and angioedemas are listed in Table 1. Different types of urticaria often occur together, for example, ordinary chronic urticaria and delayed pressure urticaria, and different combinations of physical urticarias. Urticarial vasculitis is an important condition to identify (3). Its wheals have the histological characteristics of vasculitis (venulitis). The individual wheals may be difficult to differentiate clinically from ordinary urticaria, but they often persist for more than 24 hours, may be burning and tender as well as itchy, and infrequently bruise. Arthralgia, lethargy, and abdominal pain are more prominent systemic features than in chronic ordinary urticaria. A suspected diagnosis of urticarial vasculitis must be confirmed by histopathological examination of a wheal. Table 1 Classification of Urticarias with or Without Angioedema Ordinary urticarias Acute Chronic idiopathic Physical urticarias Dermographism Cholinergic urticaria Cold urticaria Solar urticaria Delayed pressure urticaria Aquagenic urticaria Urticarial vasculitis Contact urticaria Angioedema: predominantly or alone Idiopathic Drug-induced (NSAIDs, angiotensin-converting enzyme inhibitor) C1 esterase inhibitor deficiency Inherited Acquired NSAIDs, nonsteroidal anti-inflammatory drugs.

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Contact urticaria is frequently unrecognized. Contact of the skin with a provoking substance induces whealing at that site within minutes. It may be a nonimmunological reaction occurring on first contact, or an immunological IgEmediated reaction. Immunological contact urticaria is more common in atopic persons and may be severe. The urticarias can also be classified into acute, in which the whole episode persists for less than 6 weeks, and chronic, in which wheals are present on most days for longer than 6 weeks. The classification is arbitrary and often urticaria is present intermittently; however, a cause is more likely to be found in acute ordinary urticaria. It is not generally appreciated that, due to appearance of the swellings, associated itching and sometimes pain, and the unpredictability of onset, urticaria can severely interfere in the patient’s quality of life. The Nottingham Profile questionnaire of general health used in patients with ordinary chronic urticaria attending an urticaria clinic revealed that disability evidenced by lack of energy, social isolation, emotional reactions, and sleep disruption was as severe as that experienced by patients awaiting triple coronary bypass surgery (4). A skin-disease-specific questionnaire revealed that patients with chronic ordinary urticaria and pressure urticaria were comparably disabled to outpatients with eczema and those with ordinary urticaria alone were comparably disabled to outpatients with psoriasis (5).

II. PATHOPHYSIOLOGY The physiological processes leading to urticaria and angioedema are thought to be similar, with the exception of C1 esterase inhibitor deficiency and angiotensinconverting enzyme (ACE)–induced angioedema (6). In the latter conditions bradykinin is thought to be an important mediator; however, since ordinary angioedema, which is usually intermittent, has not been extensively investigated, additional or different factors may be present in some of these patients compared to those who also exhibit urticaria. For practical purposes, the term urticaria will be used to describe patients with and without angioedema. Urticaria is due to vasodilation of the microvasculature (venules) with plasma extravasation, associated with a variable dermal inflammatory infiltrate of eosinophils, neutrophils, and mononuclear cells, depending on the type of urticaria and the stage of evolution of the wheal (7). A central role has been ascribed to activation of the cutaneous mast cells, with release of mediators, predominantly histamine but also other inflammatory substances including prostaglandin D 2 , proteolytic enzymes, and cytokines such as IL-4, IL-6, IL-8, and tumor necrosis factor α (TNF-α). Increased levels of histamine in lesional compared to nonlesional skin have been detected in all forms of urticaria using various techniques, including venous blood sampling, skin per-

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fusion, skin chamber, and suction blister techniques. In the skin, histamine reacts with H 1- and H 2-receptors to induce erythema and whealing, but H 1-receptors are predominantly responsible for the flare and itching (8). So far no H 3-receptors have been identified in human skin (9). Because there is subsensitivity to the effects of histamine in the skin after 30 min (10) and wheals persist for many hours, other mediators are also involved in the urticarial process. Upregulation of the vascular adhesion molecules E selectin and VCAM occurs in chronic urticarial wheals and in delayed pressure urticaria (11), enabling leukocytes to traverse the blood vessel walls in response to mast cell-derived chemoattractants such as IL-6 and IL-8. The ensuing dermal inflammatory cells can release their own repertoire of proinflammatory mediators, thus prolonging and amplifying the whealing process. In physical urticarias (except delayed pressure urticaria), wheals are shortlived, often for less than 1 hour, and the reaction appears to be predominantly mediated by histamine although other inflammatory mediators are also involved. Urticarial vasculitis is usually considered to be due to immune complex deposition in the skin and other organs (3).

III. PROGNOSIS The prognosis of urticaria in any individual is unpredictable, with a general tendency toward improvement. There is no evidence that antihistamine therapy alters the long-term prognosis of urticaria; however, it suppresses the symptoms until the urticarial process resolves spontaneously.

IV. GENERAL MANAGEMENT A detailed history is vital (12) for categorizing the type of urticaria, and for elucidating a cause, if one can be found, and aggravating factors, if any. It is helpful to identify patients with physical urticarias, urticarial vasculitis, and contact urticaria since their management will differ from that of the larger group of patients with ordinary ‘‘idiopathic’’ chronic urticaria. In patients with physical urticarias it is important to reduce the exposure to precipitating factors. H 1-antihistamine therapy is generally helpful, except in delayed pressure urticaria, which can be very resistant to this and other treatments. The suspicion of urticarial vasculitis must be confirmed by examination of a biopsy specimen of a wheal, which shows a perivascular dermal inflammatory cell infiltrate rich in neutrophils, with leukocytoclastic (fragmentation of the nucleus of neutrophils), red cell extravasation, and fibrinoid necrosis of mi-

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crovessel walls. Investigation of urticarial vasculitis includes the search for a cause and for any organ involvement, and should include full blood counts, complement C3 and C4 levels, urinalysis, renal and liver function tests, and chest radiograph. The treatment of ordinary urticarias is to eliminate a cause, which is more likely to be found for acute urticaria than for chronic urticaria. Nonspecific aggravating factors such as heat, alcohol, and stress should be minimized. Aspirin and nonsteroidal anti-inflammatory drugs and codeine should be avoided in patients with ordinary urticaria. Acetaminophen is usually a satisfactory substitute. ACE inhibitors should be avoided in patients with ordinary and hereditary angioedema, since these agents can aggravate these conditions severely. If a particular dietary substance has been shown to cause or aggravate ordinary urticaria in a reproducible placebo-controlled trial, it should be omitted from the diet. Patients with severe oropharyngeal or laryngeal angioedema that causes difficulty breathing should be prescribed epinephrine and instructed how to selfadminister it in an emergency. In the management of urticarias it is very important to explain the condition

Table 2

Management of Urticaria

General measures Avoid cause, if known Avoid aggravating factors: NSAIDs, tight clothes Reduce heat, stress, alcohol Provide explanation and reassurance Drug therapy Second-generation low-sedation H 1-antihistamines: treatment of choice Sedating antihistamine at night (on an empirical basis) H 2-antihistamine for trial period Mast cell stabilizers: terbutaline, nifedipine (usually disappointing) Oral corticosteroids Acute exacerbations of chronic ordinary urticaria Exacerbations of delayed pressure urticaria Urticarial vasculitis Avoid long-term administration for chronic urticaria, if possible Anabolic steroids for prophylaxis of hereditary C1 esterase deficiency Immunomodulation: For severe cases not responding to conventional therapy, administered in specialized units Oral cyclosporin Intravenous high-dose immunoglobulin Plasmapheresis NSAID, nonsteroidal anti-inflammatory drug; C1, complement 1.

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to an anxious patient. Patients will expect that their urticaria is due to a food allergy, but in chronic urticaria this is seldom the case. In many patients with acute urticaria and the vast majority of those with chronic ordinary urticarias, no external cause can be found. Although urticaria is distressing and unsightly, usually it does not harm general health. Because the main mediator is histamine, H 1-antihistamines have been and remain the symptomatic treatment of choice for urticaria and angioedema until there is spontaneous remission. Patients are worried about the long-term use of antihistamines; therefore, the benefits, possible side effects, and the relatively good long-term safety record of the second-generation drugs must be explained. The place of antihistamine therapy is set in context of the overall management of urticaria in Table 2.

V.

TREATMENT TRIALS

A.

Design

First, the pharmacodynamics of histamine-induced wheal-and-flare suppression are studied. This is useful for ascertaining onset, potency, and duration of action; however, in one study, an H 1-antagonist administered at a dosage that totally suppressed histamine-induced whealing only caused 60% improvement in spontaneous urticarial wheals (13). The objective assessment of H 1-receptor antagonist treatment of urticarias has been difficult. Because urticaria is a heterogeneous group of conditions, which may vary in response to therapy, the treated group should be defined precisely as to whether they have chronic ordinary or physical urticaria. This has not been done in all studies. Urticaria occurs in patients of all ages, but most studies have been performed in adults. The course of chronic urticaria is notoriously unpredictable, with a tendency to improvement. This makes crossover studies unreliable. As there is a marked placebo effect, a placebo should always be incorporated into the design. Trials should clearly identify the response of individual symptoms and signs of urticaria (itching, erythema, whealing) in addition to a global response. There is no direct objective method to assess itching, one of the most distressing aspects of urticaria, but it can be evaluated subjectively using a point scale of severity or a visual analog scale. Indirect objective assessments based on scratching are rarely included. Whealing is evaluated by various methods including reduction in the numbers of wheals (grouped on a point scale), percentage of patients in whom urticaria cleared or was greatly improved, or a point scale of global improvement scored by subject/and or investigator. Assessments of the effect of treatment on systemic symptoms and quality of life should be included. The challenges involved in designing clinical trials of antihistamine treat-

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ment in urticaria that lead to outcomes that can be analyzed statistically in a satisfactory manner have been reviewed (14). Even if a trial is well designed and conducted, there is difficulty in comparing the results of different trials because the population studied, dose and total time of administration of an individual antihistamine, and methods of assessing improvement vary. B. Studies of Antihistamine Therapy In this chapter we review the controlled studies of H 1-antihistamine therapy in patients with acute urticaria, chronic ordinary urticaria, and physical urticarias alone and in combination with H 2-receptor antagonists. We include a short section on the use of H 1-antihistamine therapy in urticarial vasculitis.

VI. ACUTE URTICARIA Acute urticaria may follow a viral upper respiratory tract infection, may be due to an IgE-mediated reaction to food or drugs such as penicillin, or may be an anaphylactoid (pseudoallergic) reaction to a nonsteroidal anti-inflammatory medication. These aspirin-like drugs divert prostaglandin production by the cyclooxygenase pathway into leukotriene production via the lipoxygenase pathway. In a hospital setting, a cause is found in fewer than 50% of patients with acute urticaria (15). The optimal treatment of acute urticaria is with second-generation lowsedation antihistamines, but there are no controlled trials comparing these medications. Epinephrine treatment of severe angioedema with localized difficulty breathing or swallowing or widespread urticaria is described in Chapter 9 on anaphylaxis. One study compared the treatment of acute urticaria with either loratadine 10 mg/day or prednisolone 40 mg/day for 3 days in 109 patients (15). All patients were evaluated until remission. Complete remission occurred in 94% of patients after prednisolone therapy compared to 66% after loratadine treatment. As a practical step, however, low-sedation antihistamines are begun at the same time as a short course of oral steroids, and continued as long as acute urticaria persists.

VII. CHRONIC ‘‘IDIOPATHIC’’ URTICARIA Chronic idiopathic urticaria (CIU) can be conventionally defined as daily or almost daily wheals for 6 weeks or more. Individual wheals last for more than 1 hour, (differenting them from the wheals of all physical urticarias except delayed

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pressure urticarias), and less than 24 hours (differentiating them from the wheals of urticarial vasculitis, which last individually longer than 24 hours according to generally accepted criteria). Normally the wheals of CIU leave no marks on the skin except for those caused by rubbing. Delayed pressure urticaria occurs concurrently with CIU in about 40% of patients (16). The well-recognized treatmentresistant character of delayed pressure urticaria may at least partly explain the seemingly poor response of some patients with CIU to antihistamine therapy. The wheals of delayed pressure urticaria, in addition to persisting for 36–48 hours, are often painful, occur at pressure sites such as the palms, soles and waistbands, and may be indurated on palpation, which may lead to the erroneous diagnosis of urticarial vasculitis. Histological examination of a skin biopsy of a wheal can facilitate the correct diagnosis. Other physical urticarias, such as symptomatic dermographism and cholinergic urticaria, may coexist with CIU. About 40% of patients with CIU have associated angioedema, which affects skin and mucus membranes (1). Pruritus is an invariable feature of CIU, although it may be a lesser or greater cause of disability in different patients. Itching may occur at any time but is most prevalent in the evening and at night (2). Systemic symptoms are not very common in CIU and, when they occur, should raise the possibility that the correct diagnosis is urticarial vasculitis. Joint pains are common in patients with CIU in whom delayed pressure urticaria is a feature. The natural history of CIU is poorly documented. The best data, available on 554 hospital patients, suggest that 50% of patients with urticaria alone will have achieved remission within 6 months to 1 year and 50% of those with associated angioedema within 2–5 years. In some patients urticaria can be persistent and up to 20% can still be affected in 20 years (1). A.

Pathophysiological Mechanisms

The underlying pathophysiology of CIU is noncontroversial. The numbers of dermal mast cells are not increased. Promiscuous activation of these cells leads to the release of histamine and other mediators, which cause vasodilation and perivascular accumulation of eosinophils, neutrophils, and mononuclear cells, aided by increased adhesion molecule expression in the postcapillary venules. The cause of the unwanted dermal mast cell activation is less clear. Most patients with CIU, their relatives, and very often their physicians as well, believe that dietary factors are causative. In contrast to acute urticaria, however, food items can rarely be implicated as culprits of CIU (17) and exclusion diets rarely lead to remission of hives (18). Chronic infections and infestations including candidiasis (19), bacterial sinusitis (20), and most recently Helicobacter pylori infection (21) have been proposed to be causative. The weight of evidence, recently comprehensively reviewed, is against a direct role for these agents (22); however, the possibility that H. pylori could play an indirect role in genetically

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predisposed individuals with autoimmune urticaria (see below) cannot be excluded. It is now generally acknowledged that the whealing in some, but not all, patients with CIU has an autoimmune basis. It has been recognized that there is a positive association with thyroid disease (23). In 1989 Grattan reported the recovery of a mediator in the serum of some patients with CIU but not in those with physical urticarias or in healthy individuals (24). Subsequent analysis of this factor showed it to be composed of IgG autoantibodies against the highaffinity IgE receptor (FcεRI) expressed on human basophils and mast cells, or less commonly against IgE itself (25, 26). That these autoantibodies are functional and are therefore involved in the pathogenesis of the disease is indicated by their ability to evoke histamine release from mast cells and basophils, to cause whealing in the skin, by the positive correlation between serum autoantibody titer and disease activity, and by the beneficial clinical effect of suppression or removal of autoantibodies (27, 28). The importance of the anti-FcεRI autoantibodies in CIU has been confirmed independently by several groups (29, 30–32). It turns out that, depending on the patient population, between 30 and 50% of CIU patients have functional autoantibodies. B. Diagnosis A careful history is important. If the diagnosis of a physical urticaria has been made, further investigation should focus only on the physical urticaria and need not involve tests for circulating autoantibodies or food additive reactivity. In some patients without physical urticaria, it may be worthwhile carrying out a placebocontrolled food additive challenge, which is the gold standard for diagnosis of food additive reactivity (33, 34). An autologous serum skin test can be carried out to screen patients for autoimmune urticaria (antiFcεRI or anti-IgE), but it is time-consuming and needs to be interpreted by someone experienced in performing the test (35). Positive results need to be confirmed by demonstrating in vitro histamine release from basophils of low- and high-IgE occupancy donors, with inhibition by human recombinant FcεRIα or monoclonal IgE (26). Some laboratories use Western blotting or enzyme-linked immunosorbent assays (ELISAs) (29, 32), but since these methods also detect immunoreactive but nonfunctional anti-FCεRI autoantibodies, false-positive results may occur in autoimmune connective tissue and immunobullous disease (32). The cause of CIU remains elusive in at least 40% of all patients despite investigations along the lines recommended here. As discussed previously, searching for infections, infestations, and food allergies is usually not helpful; however, it is worthwhile to identify histamine-releasing autoantibodies in severely affected patients in whom plasmapheresis or intravenous immunoglobulin therapy may be indicated.

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VIII. TREATMENT OF CHRONIC IDIOPATHIC URTICARIA General measures provide significant symptomatic relief in some patients. Overtiredness, stress of traveling, overindulgence in alcohol, and wearing tightly fitting garments (especially woollen fabric) all cause exacerbations and/or enhancement of itching. Patients also need to be reassured that CIU is not an outward manifestation of cancer, human immunodeficiency virus (HIV), or other infection, that the disease is usually self-limiting, running an average course of 2–3 years, and that it is not inherited from an affected parent. Drugs that may exacerbate CIU and therefore need to be avoided include aspirin, morphine, morphinelike drugs, and dextran. Pruritus is especially troublesome at night (2). A tepid shower taken before retiring to bed may be timely and the bedroom should be cool. Many patients find application of 1% menthol in aqueous cream to be soothing, although its beneficial effects are short-lived (about 30 min). A.

General Principles of CIU Antihistamine Treatment

The redness and whealing of CIU are probably caused by a number of mast cell– or basophil-derived mediators, but histamine clearly plays a major role, especially in itching, due to the action of histamine on H 1-receptors (36). Histamine-evoked redness and whealing involve both H 1- and H 2-receptors (37,38). Combined treatment with H 1- and H 2-antihistamines has been proposed and found to be effective (39), but it is doubtful if the advantage gained is clinically useful. Some combinations, for example, hydroxyzine and cimetidine, in which a pharmacokinetic interaction as well as a synergistic end-organ response occur, appear to work better than other combinations, for example, cetirizine and cimetidine (40). H 1-antihistamine treatment is the cornerstone of drug therapy of CIU and ameliorates the symptoms, especially itching, by blocking the actions of dermal or mast cell–derived histamine. The newer low-sedation antihistamines enable this purpose to be fulfilled with few or no side effects. One of the earliest studies of the use of antihistamines in CIU was reported in the Proceedings of the Staff Meetings of the Mayo Clinic in 1946. Thirty-five patients with chronic urticaria were treated with diphenhydramine 50–100 mg three or four times daily. The skin lesions disappeared in 25 of these and were greatly improved in 7 others. In all but one patient the wheals recurred when a placebo tablet was substituted for diphenhydramine (40a). Arrays of side effects such as drowsiness and atropine-like symptoms, including dry mouth and blurred vision, were noted. Subsequently, H 1-antihistamines became the treatment of choice in CIU. As detailed in Chapter 3 antihistamines are currently classified as first-generation (chlorpheniramine, hydroxyzine, diphenhydramine, promethazine) and second-

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generation (cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, mizolastine) (41). First-generation antihistamines are invariably accompanied by sedative and atropine-like side effects due to penetration of the blood–brain barrier. Secondgeneration antihistamines are at least as potent as their predecessors, but cause minimal or no sedation. It is widely and correctly believed that the clinical efficacy of antihistamines in CIU is attributable to antagonism of histamine at the H 1-receptor; however, additional so-called antiallergic activity may play a part, especially at higher dosages (42, 43). This activity, which is independent of H 1-receptors, is probably due to the stabilizing effect on plasma membranes of mast cells and basophils. The importance of regular antihistamine dosing in the treatment of CIU needs to be emphasized (44). Apparent failures of antihistamine treatment can often be attributed to intermittent, instead of continuous, usage: indeed, studies in allergic rhinitis support the value of uninterrupted administration (45). Whether this increased efficacy involves the above-mentioned H 1-receptor-independent antiallergic action is unclear. H 1-antihistamines are more effective in alleviating pruritus than in reducing the frequency and severity of whealing. It is important to determine from the CIU patient’s history the period(s) of the day and night when the itching is most troublesome so that the timing of the antihistamine dose is appropriate. Most patients find pruritus is most intense in the evening and at night (2), although whealing may be most troublesome first thing in the morning and throughout the day. Some physicians recommend a low-sedation antihistamine early in the morning with a sedative antihistamine in the evening; however, this approach needs to be tested in a randomized, double-blind, placebo-controlled trial and the patient needs to be warned that cognitive function and reflexes may be impaired the following morning, although the sedative effect of the firstgeneration H 1-antihistamine is no longer evident. Tolerance is frequently claimed by patients and physicians to develop after a few days of continuous administration of H 1-antihistamines, but the most likely cause of dwindling efficacy is poor compliance (44). More than 20 H 1-antihistamines are currently available. Since it is difficult to predict the response of a given patient, and since the efficacy of individual members of the first- and second-generation H 1-groups is not greatly different, a self-assessment method has proved useful (46). B. First-Generation H 1-Antihistamines There is no precise definition of first-generation antihistamines, but members of the group were generally licensed before 1981 and characteristically cause marked drowsiness and atropine-like (anticholinergic) side effects, leading to

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impaired psychomotor function and perhaps to poor compliance. The sedative actions of the group may be useful in some circumstances. Some of the firstgeneration H 1-antihistamines widely used in the context of CIU are discussed below. 1. Hydroxyzine Like other members of its class, hydroxyzine penetrates the endothelial lining of the capillaries of the central nervous system (CNS) and causes marked sedation. It also has marked atropine-like (anticholinergic) activity. Nevertheless it remains one of the most widely used H 1-antihistamines in the treatment of CIU, since it is potent, inexpensive, and its soporific effect can be put to good use. It has an elimination half-life of 14 to 20 hours in adults. Hydroxyzine is best given in the evening to allay nocturnal pruritus. The dosage is 25–75 mg (one to three 25 mg tablets). The sedative action assists in providing patients with a full night’s sleep and also allays anxiety associated with severe protracted urticaria and angioedema. The patient must be warned that computer skills and car driving may be impaired in the morning from the evening dose of hydroxyzine, and that consumption of alcohol must be avoided. Hydroxyzine plasma levels and whealsuppressive activity increase significantly when it is coadministered with cimetidine. 2. Chlorpheniramine Chlorpheniramine has, like hydroxyzine, marked sedative and anticholinergic side effects, low cost, and rapidity of action. It is prescribed orally for adults at a dosage of 4 mg (one tablet every 6 hours). By injection it can be prescribed at a dose of 10–20 mg. The cautions with its use are the same as for hydroxyzine. 3. Doxepin Tricyclic antidepressants, including doxepin, were introduced as antihistamines although they were rapidly ‘‘adopted’’ for psychiatric use owing to their moodelevating properties. Doxepin is a potent H 1-antihistamine with a high affinity for H 1-receptors. It also possesses significant H 2-antihistaminic activity (47). In a double-blind, crossover study of 50 patients with CIU, doxepin 10 mg three times a day conferred a more favorable response than diphenhydramine 25 mg three times a day (48). The dosage can be gradually increased up to 75 mg a day in divided doses; however, because it has a half-life of 19 hours, doxepin is best used as a single evening dose of 10–75 mg in adults. On an empirical basis, it is sometimes combined with a morning dose of a low-sedation antihistamine such as loratadine, fexofenadine, or mizolastine (see below). It is very useful in patients with severe CIU that is unresponsive to low-sedation antihistamines alone.

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Such patients frequently become anxious and depressed, and respond to doxepin’s anxiolytic and mood-elevating actions. Doxepin is also available in a topical cream formulation in a concentration of 5%, but its topical use in CIU presents no real advantages over systemic antihistamines, since drowsiness due to percutaneous absorption is common. Doxepin needs to be used cautiously. It has sedative and anticholinergic side effects. Concurrent alcohol consumption should be avoided. Doxepin should not be coadministered with any other medication that potentially prolongs the QT interval (e.g., cimetidine), as this may lead to cardiac arrhythmias. Doxepin enhances the hypertensive actions of epinephrine and other sympathomimetics and should not be used with monoamine oxidase–inhibiting drugs. It should not be used during breast feeding. Doxepin is not recommended in children. 4. Ketotifen Pharmacologically this compound has a range of interesting actions. In addition to its ability to produce H 1-blockade, it inhibits release of histamine and other mediators from mast cells and basophils in vitro (49). Its mast cell and basophil stabilizing-action may be at least partly due, at the molecular level, to inhibition of transmembrane calcium transport. Ketotifen causes a number of side effects, including sedation and atropine-like effects (dry mouth, blurred vision, constipation). Whether its mast cell–stabilizing properties are clinically significant is unclear. We were unable to demonstrate any reduction of urinary excretion of histamine or its metabolites in patients with cutaneous mastocytosis treated with ketotifen (50); however, plasma histamine levels have been demonstrated to be reduced in patients with physical urticarias (51). There have been a number of studies of its usefulness in chronic urticaria. A Japanese study compared ketotifen 1 mg daily, clemastine (a first-generation H 1-antihistamine) 2 mg, and placebo in 305 patients with chronic idiopathic urticaria in a double-blind trial (52). Significantly greater relief of pruritus and whealing was observed in patients receiving ketotifen than clemastine or placebo. The frequency of side effects (20–21% of patients) was the same in the ketotifenand clemastine-treated patients. A number of other reports, mainly anecdotal, also support its use in the treatment of chronic idiopathic urticaria (53).

C. Second-Generation Low-Sedation H 1-Antihistamines These agents impair CNS function significantly less than the ‘‘first-generation’’ compounds due to their low blood–brain barrier penetration. Some members of this group, including cetirizine, retain some sedative activity. Low-sedation antihistamines can therefore be administered safely with alcohol and other CNS de-

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pressants. They also possess little or no atropine-like (anticholinergic) side effects. They have no H 2-receptor antagonistic activity. Currently the most widely used are cetirizine, loratadine, mizolastine, and fexofenadine, which are reviewed individually below. Results of studies are summarized in Table 3. 1. Cetirizine Cetirizine is the carboxylated metabolite of the first-generation H 1-antihistamine hydroxyzine (see above). It is long-acting (up to 24 hours) with a rapid onset and potent activity at the H 1-receptor. It possesses significant antiallergic activity, especially in inhibiting eosinophil chemotaxis (54), although the clinical relevance of this action of cetirizine in patients with CIU is unclear. It has no cardiac toxicity. In adults, the licensed dosage is 10 mg daily or 5 mg twice daily. There is an oral solution (5 mg/mL) for children 2 years and older. Several studies of the efficacy of cetirizine in CIU have been published. An early multicenter double-blind study in 219 patients compared cetirizine 5– 20 mg daily with hydroxyzine 25–75 mg daily and placebo (55). The results showed equivalence with hydroxyzine in terms of clinical efficacy and superiority with regard to severity of side effects, which with cetirizine were no greater than placebo. It is a criticism of this and most other clinical studies of antihistamines in CIU that the criteria for diagnosis of CIU are not clearly set out, and the question arises as to how many patients recruited actually had predominantly physical urticaria. A subsequent smaller placebo-controlled study in which 30 patients with CIU received 10–20 mg cetirizine daily also showed a significant benefit (56). Cetirizine is as effective as another low-sedation antihistamine, loratadine, as suggested by a double-blind placebo-controlled study of 116 patients with chronic urticaria (57). These results are summarized in Table 3. 2. Loratadine Loratadine is a long-acting minimal-sedation H 1-antihistamine with little or no affinity for cholinergic or alpha-adrenergic receptors and no cardiotoxicity. It is widely used in the treatment of CIU because of its efficacy and low frequency of adverse reactions, leading to a high degree of patient compliance. In addition to its H 1-antagonist activity, it has antiallergic action independent of the H 1-receptors. This action includes ‘‘stabilization’’ of the mast cell membrane, leading to reduced secretion of mast cell–derived mediators including eicosanoids, suppression of adhesion molecule expression, and inhibition of vasopermeability (58). There is convincing evidence that loratadine in therapeutic dosages suppresses mediator release into nasal secretions in patients with seasonal allergic rhinitis (59). To what extent these actions form a part of the therapeutic response to loratadine in the skin of patients with CIU, at least at a therapeutic dosage of 10 mg daily, is uncertain.

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Several well-controlled clinical trials attest to the value of loratadine in CIU. In one of the first studies (60), in 187 patients with CIU, loratadine 10 mg daily was as effective as terfenadine 60 mg and both active medications were significantly more effective than placebo. Adverse side effects were few and similar among the treatments. In other studies, loratadine has been compared to hydroxyzine (61–63). In one of these, 172 patients were assigned to receive loratadine 10 mg daily, hydroxyzine 25 mg three times daily, or placebo. The study was stated to be double-blind but, given the pronounced soporific effects of hydroxyzine, some patients were likely able to discriminate among the three treatments. Nevertheless, two-thirds of patients in each of the active drug groups showed marked or complete relief of symptoms. There was no clear difference between the two active treatments with regard to response, although those receiving hydroxyzine noted greater sedation. Loratadine has been compared with other so-called second-generation H 1-antihistamines, as described previously (57) (Table 3). 3. Mizolastine Mizolastine, a relative newcomer to the ranks of the so-called second-generation low-sedation H 1-antihistamines, has no anticholinergic and minimal sedative effects. It is also claimed to have anti-inflammatory action independent of its affinity for the H 1-receptor. In the rat, it inhibits transformation of arachidonic acid to its lipoxygenase transformation products, the pro-inflammatory leukotrienes and related fatty acids (64). To what extent this is relevant to the actions of the drug in humans is uncertain. A recently published report (65) in 247 patients with CIU compared mizolastine 10 mg daily with loratadine 10 mg daily and placebo. Mizolastine was more effective in suppressing symptoms and signs of CIU than placebo and equivalent to loratadine. Angioedema, when present, was similarly ameliorated. Adverse effects were no different from those occurring with placebo for either active drug. A smaller study involving 56 patients with CIU compared mizolastine with placebo (66). The results showed that mizolastine produced a greater decrease in itching, whealing, and erythema than placebo. Drowsiness and anticholinergic side effects were not significantly different between mizolastine and placebo. Further details of these studies are summarized in Table 3. Overall, mizolastine appears to be equally, but not more, effective than loratadine and cetirizine in the management of CIU. 4. Fexofenadine Fexofenadine is an effective low-sedation antihistamine. It has no cardiotoxic side effects, causes no drowsiness or impairment of cognitive function, and can be safely administered with cytochrome P-450-inhibiting drugs. Its pharmacolog-

30

Cetirizine 10 mg daily, placebo Cetirizine 10 mg, loratadine 10 mg, placebo; all daily

Fexofenadine 60, 120, 180, 240 mg daily; placebo daily

219

Cetirizine 10 mg daily, hydroxyzine 25–75 mg daily, placebo

222

116

Nos

Randomized, doubleblind, parallel, 6 wks

Double-blind, crossover, 4 wks Randomized, doubleblind, parallel, 4 wks

Randomized, doubleblind, parallel, 4 wks

Study design and length

P, W, ordinal: overall

P, E, W, size of W, ordinal

P, E, W, ordinal

P, E, W, ordinal scale, symptoms, VAS

Assessment Severe somnolence: Placebo 3% Cetirizine 6% Hydroxyzine 15%

Cetirizine ⬃ hydroxyzine ⬎ placebo Cetirizine more effective on itch than wheal size Cetirizine more effective than placebo Cetirizine and loratadine ⬎P1 At 4 wks free of symptoms: Loratadine 63% Cetirizine 45% Placebo 13% Fe 180, 240 mg ⬎P1 in total symptom score All doses ⬎ decrease pruritus Drowsiness and other side effects: fexofenadine ⬃ placebo

Dizziness, drowsiness: Cetirizine 20% Loratadine 16% Placebo 8%

Side effects

Result

Treatment of Chronic Ordinary Urticaria with Low-Sedation H1-Antihistamines

Treatments

Table 3

Loratadine significantly more rapid in action than cetirizine

Small numbers

Was double-blinding compromised?

Comments

68

57

56

55

Reference

264 Kobza Black and Greaves

56

Mizolastine 10 mg daily, placebo

Randomized, multicenter, double-blind, parallel, 4 wks Randomized, twocenter, doubleblind, parallel, 4 wks

Randomized, doubleblind, parallel, 4 weeks

Randomized, multicenter, double-blind, parallel, 4 wks Randomized, doubleblind, parallel, 4 weeks

P, E, W, ordinal

P, number and size of W, ordinal

P, W, ordinal, overall efficacy

P, E, W, ordinal, overall improvement

P, W, ordinal All doses of fexofenadine ⬎ placebo for P and mean total symptom score Loratadine ⬎ terfenadine ⬎ placebo Marked relief: Loratadine 64% Terfenadine 52% Placebo 25% Loratadine ⬃ hydroxyzine ⬎ P1 At 4 wks patients with marked relief: Loratadine 65% Hydroxyzine 66% Placebo 41% Mizolastine ⬃ loratadine; sig more effective than placebo Mizolastine sig more effective than placebo Drowsiness more frequent with mizolastine than loratadine or placebo Slightly more drowsiness with mizolastine

Sedation: Loratadine 7% Hydroxyzine 49% Placebo 3%

Active drugs had minimal side effects, no greater than placebo

Frequency of sedation not stated

Hydroxyzine caused marked drowsiness and dry mouth; loratadine caused ⬃ sedation to placebo. Was double-blinding compromised?

Quality-of-life indices also showed improvement on fexofenadine

66

65

63

60

69

Terfenadine has been withdrawn in most countries. VAS, visual analog scores; Pl, placebo; ⬎ significantly better; ⬃ essentially equivalent; P, pruritus, E, erythema, W, wheal; sig, significantly; Nos, number of participants; Fe, fexofenadine.

247

Mizolastine 10 mg, loratadine 10 mg, placebo; all daily

a

172

187

439

Loratadine 10 mg daily, hydroxyzine 25 mg three times daily, or placebo

Fexofenadine 20, 60, 120, 240 mg twice daily or placebo twice daily Loratadine 10 mg daily, terfenadine a, 60 mg twice daily, placebo

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ical and pharmacokinetic properties have recently been reviewed (67). In the treatment of CIU, fexofenadine is administered at a dosage of 180 mg (one tablet) daily. It is licensed in some countries for children under the age of 12 years. In a dose-ranging study, daily fexofenadine doses of 60 mg, 120 mg, 180 mg, and 240 mg were compared to placebo (68). Two hundred and twenty-two patients with CIU were randomly allocated to one or another of these daily dose regimens on a double-blind basis. The 180 mg and 240 mg doses produced significant improvement in total symptom score. Lower doses caused an improvement in scores for itching. As a result of this study, the authors recommended the 180 mg daily dose for the patients with CIU. Adverse side effects were trivial and no greater than with placebo at any of the dosages used. In another randomized, double-blind, placebo-controlled, dose-ranging multicenter study, the fexofenadine doses given were 20, 60, 120, or 240 mg twice daily (69). All four doses were more effective than placebo with regard to amelioration of pruritus, whealing, and total symptom score (Fig. 1). It is interesting that patients receiving fexofenadine experienced less drowsiness than those receiving placebo. The authors concluded that dosages of fexofenadine of 60 mg twice daily or more were most effective. Quality-of-life indices were measured and showed an overall improvement in fexofenadine-treated patients in whom urticaria interfered significantly less with daily activities and with sleep than it did in placebo-treated patients. Overall, fexofenadine appears to be an effective H 1-antihistamine with a very low frequency of unwanted side effects and no sedation or cardiotoxicity. D.

H 2-Antihistamines

Studies on the responses of human skin blood vessels led to the conclusion that H 2- as well as H 1-receptors were present on these vessels (8, 36, 37). Activation of H 1- and H 2-receptors induced erythema and whealing, but H 2-activation had little effect on flare and itching. Cimetidine, an H 2-receptor antagonist, in combination with chlorpheniramine, caused a significantly greater inhibition of histamine-induced erythema than either drug alone (38). This raised the possibility that the combination of H 1- and H 2-antihistamines might be more effective than either drug alone in the treatment of urticaria. The earliest study of H 1- and H 2-antihistamines in urticaria by Commens and Greaves included 19 patients with chronic idiopathic urticaria who were allocated on a randomized, double-blind basis to three consecutive treatments for 2 weeks consisting of a combination of chlorpheniramine 4 mg and cimetidine 400 mg each four times a day, chlorpheniramine 4 mg four times a day, and placebo four times a day (39) (Table 4). There was a significant reduction in whealing and itching with chlorpheniramine treatment, alone and when combined

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Figure 1 Fexofenadine in the treatment of chronic idiopathic urticaria. In a randomized, double-blind, placebo-controlled, parallel-group study, 439 patients with moderate to severe itching and hives received either fexofenadine 20 mg, 60 mg, 120 mg, or 240 mg, or placebo twice daily. The severity of itching, number of wheals, and interference with sleep/normal daily activities because of hives were assessed reflectively over the previous 12 hours. All four doses of fexofenadine were statistically superior to placebo for reducing mean pruritus score, mean new wheal score, and mean total symptom score (sum of itch and wheal scores). The decrease in the average mean total symptom score from baseline over the 4 weeks, compared to placebo, is shown. All doses of fexofenadine were statistically superior to placebo (p ⱕ 0.0010). A dose–response is seen, with the results being better in the 60, 120, and 240 mg groups than in the 20 mg group. (From Ref. 69.)

with cimetidine, compared to placebo; however, there was no statistically significant difference between the two active treatment regimens. The effect of combining an H1- and H2-antagonist was studied in 18 subjects with chronic idiopathic urticaria whose disease was inadequately controlled by traditional therapy. In a double-blind crossover study consisting of two treatment periods of 2 weeks duration, a combination of hydroxyzine 20 mg and cimetidine 300 mg each given four times daily, was compared with hydroxyzine 20 mg four times daily and placebo. The severity of itching, and wheal numbers, frequency, and size were significantly reduced by the combination of hydroxyzine and cimetidine, compared to hydroxyzine alone (70). Nineteen patients with refractory chronic urticaria were sequentially treated in a double-blind, randomized, serial fashion with hydroxyzine 25 mg four times

P, W, ordinal scale

P, W, ordinal

P, W, ordinal

Randomized, double-blind, serial, 7–10 days

Randomized, double-blind, 14 days

19

18

Assessments

Randomized, double-blind, crossover, 2 wks

Study design and length

19

Nos

Treatment of Chronic Ordinary Urticaria with H 1- and H 2-Antihistamines

Chlorpheniramine 4 mg qid alone or in combination with cimetidine 200 mg qid versus placebo Hydroxyzine 25 mg qid alone and with one of the following: terbutaline 2.5 mg qid, cyproheptadine 4 mg qid, chlorpheniramine 4 mg qid, cimetidine 300 mg qid Hydroxyzine 20 mg qid, cimetidine 300 mg qid, combination

Treatments

Table 4

70

Hy ⫹ Ci ⬎ Hy, Ci

39

71

Sedation: chlorpheniramine with or without cimetidine, 12 patients; placebo, 2 patients

Ch ⫹ Ci ⬃ Ch ⫹ P1

Reference

Hy ⫹ Ci ⬎ Hy ⬃ Hy ⫹ Terbut ⬃ Hy ⫹ Ch ⬃ Hy ⫹ Cy (symptom scores)

Side effects

Results

268 Kobza Black and Greaves

74

75

Ch ⫹ Ra ⬎ Ch

Ch ⫹ Ra ⬎ Ch

P, E, W, ordinal

P, W, ordinal

Randomized, double-blind, parallel, 8 wks

Randomized, double-blind, parallel, 9 days

45

a Terfenadine has been withdrawn in most countries. P, pruritus; E, erythema; W, wheal; Ch, chlorpheniramine; Ci, cimetidine; Hy, hydroxyzine; Ra, ranitidine; Terbut, terbutaline; Pl, placebo; ⬃, essentially equal; Cy, cyproheptadine; ⬎, significantly better; nos, number of participants; bid, twice daily; qid, four times daily.

40: those not responding to Ch

P, W, ordinal

73

Randomized, double-blind, serial: 2 wks

20

Chlorpheniramine 4 mg qid, cimetidine 400 mg qid, combination Chlorpheniramine 4 mg qid: increase to max effect; with placebo or cimetidine 400 mg qid Terfenadine a 60 mg bid, ranitidine 150 mg bid, combination

72

4 patients: Ch ⫹ Ci ⬎ Ch, Ci 4 patients: Ch ⬎ Ch ⫹ Ci or Ci 5 patients: no difference Ch ⬃ Ch ⫹ Ci

P, W, persistence of W, ordinal

Double-blind, crossover, 4 wks, washout 1 wk

15

Chlorpheniramine 4 mg qid, cimetidine 200 mg qid, combination

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daily for 7–10 days, in sequential combination with placebo, terbutaline 2.5 mg four times daily, cyproheptadine 4 mg four times daily, chlorpheniramine 4 mg four times daily, or cimetidine 300 mg four times daily. The hydroxyzine– cimetidine combination significantly improved itching and number of wheals compared to all other combinations (71). Combination treatment with H 1- and H 2-antagonists was studied in 15 selected patients with chronic urticaria in a randomized, crossover, double-blind study. Chlorpheniramine 4 mg four times daily, chlorpheniramine 4 mg and cimetidine 400 mg four times daily in combination, and placebo were administered for 4 weeks with a 1 week washout period. The number and persistence of wheals and the presence of itching were scored daily on an ordinal scale. The group as a whole showed no difference in number and persistence of wheals between the antihistamine- and placebo-treated groups; however, four patients fared significantly better on combined antihistamine therapy, so the authors suggested that the combined H 1- and H 2-antihistamine treatment might show modest benefit in some patients (72). A study by Cook and Shuster assessed the severity of 20 patients with chronic idiopathic urticaria without therapy (73). They were then allocated in a double-blind randomized manner to three blocks of 2 weeks’ treatment with cimetidine and placebo, chlorpheniramine and placebo, and cimetidine and chlorpheniramine. Both H 1-receptor blockade alone and in combination with H 2receptor blockade produced a significant reduction in whealing and itching, but there was no significant difference among the treatments. In a multicenter study, 120 patients with chronic idiopathic urticaria were treated with chlorpheniramine for 6 weeks, commencing at 4 mg four times daily. The dosage was increased until symptoms were controlled, or to the maximum tolerated. Forty-three patients did not respond, but chlorpheniramine was continued in all. Forty were randomly allocated to receive in addition either cimetidine 400 mg four times a day or placebo four times a day, and assessed for 8 weeks. The most important change was reduction in total symptom score compared to baseline. Chlorpheniramine and cimetidine in combination were significantly more effective than chlorpheniramine alone at both 4 and 8 weeks (74). These studies do not demonstrate any consistent efficacy of a combination of an H 1- and H 2-antihistamine over an H 1-antihistamine alone. It has been suggested that any modest improvement with the combination may not only have been due to the blockade of H 2-receptors on blood vessels, but also to increased levels of chlorpheniramine or hydroxyzine, which could have occurred because cimetidine inhibits the enzyme complex cytochrome P-450, which metabolizes chlorpheniramine and hydroxyzine and elevates the H 1-antihistamine plasma and tissue concentrations (40). In another study, however, 25 patients with chronic urticaria were treated with the low-sedation antihistamine terfenadine (subsequently withdrawn) in

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combination with a newer H 2-blocker, ranitidine, which is less inhibitory of cytochrome P-450 and less antiandrogenic (75). Forty-five patients with CIU, after 2–5 days of placebo washout, were randomized into three double-blind parallel groups to receive 9 days of treatment with terfenadine 60 mg twice daily, ranitidine 150 mg twice a day, or a combination of both. The reduction in itching was significantly greater with the H 1- and H 2-combination (maximum by 2 days) than with terfenadine alone, while ranitidine alone had no effect. There was a similar trend regarding whealing. Overall, there may be modest, unpredictable improvement in an small subgroup of patients with CIU treated with a combination of H 1- and H 2-antihistamines, compared to H 1-antihistamines alone. It is worth trying this combination in patients not responding to adequate H 1-antihistamine therapy alone, for a limited period of time (4–6 weeks). E.

Antihistamine Therapy in the Context of Alternative Systemic Treatment for CIU

Systemic corticosteroids are best reserved for the treatment of patients with severe and disabling CIU, with or without angioedema, in which H 1-antihistamine treatment has failed to bring about control. They are best used as short, tapering courses: for example, prednisolone 40 mg daily reduced by 5 mg daily every 5 days to zero. Such regimens are rapidly effective in the short term and are useful for tiding a patient over a critical personal or occupational event such as an examination, a wedding, or an overseas assignment. In the longer term, however, systemic corticosteroids are usually unsatisfactory since they ultimately achieve poor control, lead to rebound urticaria upon withdrawal, and cause troublesome toxicity. These undesirable effects can be mitigated by use of a regimen advocated by Kaplan (76). It consists of prednisolone 40 mg daily for 3 days, and then a decrease in the dosage by 5 mg per day to 25 mg daily. Subsequently the dosage is reduced by 5 mg on alternate days only, until eventually the patient is maintained on 25 mg on alternate days. After that, the maintenance dose is reduced by 5 mg every 2 weeks so that about 3 months would be required for total withdrawal of the steroid. Systemic corticosteriods are best given as a single morning dose, and H 1-antihistamines must be continued during corticosteroid treatment. Patients with autoimmune CIU (see above) who are severely disabled and poorly responsive to antihistamines can be offered intravenous immunoglobulin infusions (28) or even plasmapheresis (9) in addition to their H 1-antihistamine treatment. Cyclosporin can also be used as an alternative to systemic corticosteroids (77); again, H 1-antihistamine treatment should be administered concurrently. In the authors’ experience, the majority of patients with CIU can be managed successfully without recourse to corticosteroids or other immunosuppressive modalities.

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IX. PHYSICAL URTICARIAS In this group of urticarias, reproducible whealing occurs in response to a physical stimulus. Except in delayed-pressure urticaria, wheals usually occur within minutes and resolve within 1 hour. Physical urticarias often occur in young adults. If suspected from the history, appropriate challenge tests will confirm the diagnosis. Blood tests are rarely necessary, and allergy testing is inappropriate. If an individual is markedly affected and/or the stimulus is severe, angioedema and systemic symptoms of flushing, headache and syncope may occur. A.

Dermographism

Symptomatic dermographism is the most common physical urticaria (Table 5). It is an abnormal itching, whealing response to moderate friction of the skin (78). A reproducible stimulus can be quantified by using a calibrated spring-loaded stylus (dermographometer), stroked firmly along the skin of the back, and measuring the width of the wheal produced. In symptomatic dermographism, itching and whealing occur within minutes below a 36 g/mm 2 setting of the stylus. Patients generally have very itchy uncomfortable skin, and show wheals, often linear, within minutes of scratching. Dermographism is usually idiopathic and not associated with systemic disease. In symptomatic dermographism, the reproducible whealing response can be assessed objectively, so this has been used to test whether a combination of H 1- and H 2-antihistamines was superior to H 1-antihistamines alone; however, the results obtained may not be applicable to ordinary chronic urticaria. A double-blind trial in 33 patients with symptomatic dermographism showed that hydroxyzine 75 mg daily decreased whealing to a significantly greater degree than chlorpheniramine 12 mg daily, and was preferred by patients (79). A double-blind, randomized trial of antihistamine therapy using chlorpheniramine 4 mg, cimetidine 400 mg, and their combination four times daily in successive 2-week periods was carried out in 10 patients with dermographism (80). The mean diameters induced by the stylus at 49.0 and 73.5 g/mm 2 after 10 min were measured after each treatment period. There was significant overall improvement with the combination treatment, but chlorpheniramine given alone produced no benefit. A similar study showed that only the combination of cimetidine and chlorpheniramine significantly reduced dermographometer-induced wheal and flare compared to either H 1- or H 2-antihistamine alone or to placebo (81). In another study, a single low dose of chlorpheniramine (4 mg) successfully reduced dermographometer-induced wheals (82); therefore, the combination of H 1- and H 2-antihistamine was not necessarily superior to the H 1-antihistamine chlorpheniramine.

Double-blind, 2 wks

Randomized, doubleblind, sequential, 2 weeks Randomized, doubleblind, crossover, 5 days treatment, 2 days washout

Randomized, doubleblind, crossover; each combination, 48 h, 5 days free Randomized, doubleblind, sequential

16

12

19

20

Study design and length

33

Nos

81

82

Hydroxyzine: the most effective

Ch ⫹ Ci ⬎ Pl ( p ⬍ 0.01)

Ch ⫹ Ci ⬎ Ci

Dermographometer wheal widths

Whealing response to dermographometer

78

80

Ch ⫹ Ci ⬎ Ch ( p ⬍.025) Ci worsened

Reference 79

Trimeprazine and cyproheptadine most sedating

Side effects

Hy ⬎ Ch

Results

Dermographometer wheals

Dermographometer wheal widths

Dermographometer wheal widths

Assessments

H 1- and H 2-Antihistamine Treatment of Physical Urticarias

Dermographism Hydroxyzine 75 mg daily, chlorpheniramine 12 mg daily Chlorpheniramine 4 mg qid, cimetidine 400 mg qid, combination Chlorpheniramine 4 mg qid, mepyramine 50 mg tid, promethazine 50 mg nocte, ketotifen 1 mg bid, cyproheptadine 4 mg qid, trimeprazine 10 mg tid, pretreatment Chlorpheniramine 4 mg qid, cimetidine 400 mg qid, combination, placebo Chlorpheniramine 4 mg, cimetidine 400 mg, or combination 2 h before assessment

Treatments

Table 5

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19

19

Cetirizine 10 mg: placebo daily

Cetirizine 10 mg at night, combined with ranitidine 150 mg bid

Cetirizine 10 mg, 20 mg, placebo daily 24

10

10

Cetirizine 10 mg: one dose

Cholinergic urticaria Acrivastine 8 mg, hydroxyzine 20 mg, placebo each tid

Nos

Randomized, doubleblind, crossover, 5 days, 2 days washout Randomized, doubleblind, crossover, 3 weeks each, placebo between Ce treatments

Randomized, doubleblind, crossover, 7 days, 3 days washout

Randomized, doubleblind, crossover, 7 days

Open study

Study design and length

P, E, W, diary card, ordinal days improved

Exercise-induced itch, VAS, wheal numbers

Dermographometer whealing threshold

Dermographometer wheals

4 h after Ce, dermographometer wheals

Assessments

H 1- and H 2-Antihistamine Treatment of Physical Urticarias

Treatments

Table 5

Ce improved P and W ⬎ Pl ( p ⬍ 0.01) Ce 20 mg ⬎ 10 mg for whealing only

Ac ⬃ Hy ⬎ Pl

8 patients whealing absent; 2 patients reduced Significant reduction in itch and wheal by Ce compared to Pl Ce ⫹ Ra ⬎ Ce Small reduction in wheal but no symptomatic relief

Results

2 patients: tiredness on Ce 20 mg daily

Side effects

88

87

85

84

83

Reference

274 Kobza Black and Greaves

11

6

12

18

Double-blind, crossover, 1 week, 2 weeks washout

Randomized, doubleblind, sequential for 2 days

Open, one dose

Randomized, crossover study, 4 wks, 2 wks washout Randomized, doubleblind, crossover

6 child

12

Both studies doubleblind, crossover, 2 weeks, 1 week washout, 1 week, 1 week washout

10(9)

Pressure-induced wheals, area

Phototest for minimum whealing dose

Ce ⬎ Pl on wheal areas (p ⬍ 0.01)

4 patients: Ce ⬃ Te in raising wheal threshold, 2 patients: no effect

5 patients no wheal, decreased in others

Ice cube test, 4 h later: subjective, ordinal

Ice cube test, wheal areas

Ice cube test response

8/9 preferred doxepin Suppression Cy 53% Do 61% Hy 56% Pl 3% Improvement: Cy 85 ⬃ Ke ⫽ 88% Ac ⬎ Cy

Subjective preference, wheal response to ice cube, ordinal

93

Cy ⬎ sedating Ac

100

95

83

91

Ketotifen ⬍ Cy

92

a Terfenadine has been withdrawn in most countries. P, pruritus; E, erythema; W, wheal; Ch, chlorpheniramine; Ci, cimetidine; Ra, ranitidine; Ac, acrivastine (not available in US); Ce, cetirizine; Do, doxepin; Cy, cyproheptadine; Hy, hydroxyzine; Pl, placebo; Te, terfenadine; ke, ketotifen; ⬎, significantly better; ⬃, equivalent response; p, probability; VAS, visual analog score; h, hours; Nos, number of participants; bid, twice daily; tid, three times daily; qid, four times daily; nocte, at night.

Delayed pressure urticaria Cetirizine 10 mg tid, placebo

Solar urticaria Cetirizine 10 mg daily, terfenadine a 60 mg bid

Cold urticaria Cinnarizine 10 mg, doxepin 10 mg, placebo all tid Cyproheptadine 4 mg, doxepin 10 mg, hydroxyzine 10 mg, placebo all tid Cyproheptadine 0.25 mg/kg, ketotifen 1 mg bid Cyproheptadine 4 mg tid, acrivastine 8 mg tid, placebo tid Cetirizine 10 mg

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In a double-blind, randomized, controlled trial, eight different sedating antihistamines (Table 4) were given for 5 days to 12 patients and assessments were made of dermographometer-induced wheal widths. A combination of hydroxyzine and cimetidine was significantly superior to all other treatments, and was associated with the fewest side effects (78). An open study of 10 patients with dermographism showed that 4 hours after administration of cetirizine 10 mg, dermographometer-induced whealing was absent in eight patients and reduced in two (83). A randomized, doubleblind, crossover comparison of cetirizine 10 mg at night and placebo treatment for 1 week given to 19 dermographic patients also showed that cetirizine significantly reduced dermographometer-induced itching and whealing (84). The same investigators used a randomized, double-blind, crossover design in 19 patients with dermographism to compare the effect of a combination of cetirizine 10 mg at night and ranitidine 150 mg twice daily given for 7 days with cetirizine alone and with placebo (85). With the addition of ranitidine, some objective improvement in the increase in threshold whealing response could be demonstrated; however, there was no significant improvement as assessed by patients on linear analog scores for wheal, itch, or sleep. It was concluded that these results did not justify the use of H 2-antagonists in dermographism and, by implication, in chronic urticaria. B.

Cholinergic Urticaria

Cholinergic urticaria (heat bumps, prickly heat) (86) (Table 5), another common type of urticaria grouped with the physical urticarias, occurs in up to 10% of young adults. Within minutes, a rise in core body temperature caused by heating induced by a hot bath, exercise, or stress induces multiple itchy small monomorphic wheals surrounded by a flare. The hives usually last less than 1 hour. Severely affected patients may develop angioedema or a form of exercise-induced anaphylaxis. Challenge tests include exercise or a hot bath to induce the characteristic wheals. The reproducibility of whealing after challenge is not as consistent as dermographometer-induced whealing in dermographism; however, wheal counts in a predefined area have been used as an objective measurement of the severity of cholinergic urticaria. Ten patients with cholinergic urticaria were tested in a randomized, doubleblind, crossover, placebo-controlled trial with hydroxyzine 20 mg three times daily. Each treatment was taken for 5 days with a 3-day washout. There was a significant reduction in the number of exercise-induced wheals with hydroxyzine compared to placebo. One patient in each group reported drowsiness (87). Cetirizine in doses of 10 mg and 20 mg was studied in a double-blind, placebo-controlled, crossover trial involving 3-week treatment periods in 24 pa-

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tients with cholinergic urticaria (88). Evaluation of the patients’ daily symptom scores based on itching, erythema, and whealing showed a high level of improvement with cetirizine, with only whealing showing a greater improvement at the higher dose. Although antihistamines are moderately effective in many patients with cholinergic urticaria, some severely affected patients may not benefit significantly. A controlled trial of danazol 200 mg three times a day significantly controlled whealing in patients with cholinergic urticaria (89). Although this is an unlicensed indication for this drug, it may be an option for short-term treatment of the most severely affected patients. C. Cold Urticaria The most common form is acquired cold urticaria in which contact with cold air, water, or objects induces itching, erythema, and wheals localized to the contact site (90). Wheals develop within minutes and resolve within 1 hour. Exposure of large areas of the body to cold, such as swimming in cold water, can induce massive histamine release with risk of histamine shock and drowning. Patients with cold urticaria must avoid such situations and have epinephrine available. Confirmatory challenge testing is by application of a melting ice cube in a plastic bag against the skin for 20 min, resulting in whealing at the site. The condition usually occurs in children and young adults. It is idiopathic in over 90% of cases. Rarely, it may be secondary to cold-reactive proteins such as cryoglobulins, which should be measured especially if there are unusual associated features such as Raynaud’s disease or purpura. Some patients have cryoglobulinemia secondary to lymphoproliferative malignancy. Treatment of idiopathic cold urticaria is with H 1-antihistamines (Table 5). Early studies showed that cyproheptadine was effective in cold urticaria; however, it is sedative and can cause headaches and inappropriate weight gain. Other H 1-antihistamines with fewer side effects are as, or more, effective. For example, a double-blind, crossover study in six children with cold urticaria showed that ketotifen, a somewhat less sedating antihistamine, was as effective as cyproheptadine (91). A double-blind comparison of cyproheptadine 4 mg, doxepin 10 mg, cinnarizine 10 mg, and hydroxyzine, all administered three times daily, showed similar efficacy of these H 1-antihistamines assessed by suppression of the ice cube test. Doxepin was subjectively the most effective and, although sedating, had the fewest side effects (92). Another second-generation antihistamine, acrivastine, was more effective in treating cold urticaria than cyproheptadine and was less sedating (93). Twelve patients with cold urticaria were tested with an ice cube before and 4 hours after administration of cetirizine 10 mg. The whealing response was abolished in five patients and reduced in the others (83). These studies suggest that second-genera-

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tion low-sedation antihistamines should be the first choice in the treatment of cold urticaria. D.

Solar Urticaria

This is a rare condition in which itching, erythema, and whealing occur within minutes in areas exposed to ultraviolet radiation and/or visible light. The wheals resolve within 1 hour. Confirmation is an immediate whealing response to natural sunlight or a solar simulator, but the monochromator, available in special photobiology units, will demonstrate the specific wavelengths responsible. Treatment is difficult, but some patients respond to low-sedation H 1-antihistamines (94). In a placebo-controlled, double-dummy, crossover study in six patients with solar urticaria, terfenadine 60 mg twice daily (now withdrawn) or cetirizine 10 mg daily was given for 2 days with a washout period of 7 days. Monochromatorinduced whealing was assessed 2 hours after the last dose of medication. At the doses used, cetirizine and terfenadine were equally effective in raising the threshold whealing response in four patients, but two patients failed to respond to either (95) (Table 5). This is in keeping with the variable response to antihistamines in solar urticaria (94). Treatment of patients failing to respond to H 1-antihistamines in combination with sunblocks includes photochemotherapy with ultraviolet A (PUVA) (96) or even plasmapheresis (97) supervised in specialist photobiology centers. E.

Delayed Pressure Urticaria

In this condition there is a whealing response to sustained pressure on the skin occurring 30 minutes to 9 hours after the pressure has been applied. Lesions occur at the waistline, on the soles after walking, and on the palms after using tools. They are often painful and persist for more than 24 hours (98). As mentioned previously, 40% of patients with ordinary urticaria have an element of pressure urticaria but, in some, delayed pressure is the major problem. A positive challenge test consists of the development of an indurated wheal at 6 hours at the site of a 4 kg weight resting on the skin (thigh or back) for 15 min or a 7 kg weight suspended on a broad strap across the shoulders or thighs. The histology of a delayed pressure–induced wheal shows a similar appearance to a wheal in ordinary chronic urticaria, but there may be a more marked eosinophil infiltrate, especially in the deeper dermis. Cetirizine 10 mg three times daily, compared to placebo in a double-blind study in 11 patients with delayed pressure urticaria, led to a significant reduction of the weight-induced wheal area (99); however, since the weight per unit area used for the challenge was not defined, a reliable comparison of the size of the pressure-induced wheals was not possible (Table 5). In practical terms, the use

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of high-dose cetirizine is disappointing, and other antihistamines are also not effective (98). Nonsteroidal anti-inflammatory drugs (NSAIDs) are claimed to be useful (100) but indomethacin had little effect on the size of the induced wheals in a double-blind trial (98). There is a case report of dapsone improving pressure urticaria in five patients, but most patients are resistant to all treatments except oral steroids. Short-term corticosteroid treatment for exacerbations can be used, but often more than 30 mg/day prednisone may be necessary, and long-term treatment should be avoided if possible. F.

Urticarial Vasculitis

Usually a cause cannot be identified for urticarial vasculitis (3). In a few patients it may be due to an infection such as hepatitis B or C, or to a collagen vascular disease such as lupus erythematosus or Sjo¨gren’s disease. Investigation for pulmonary, renal, or other systemic involvement should be undertaken. There are no controlled trials of therapy. Most patients respond poorly to H 1-antihistamine therapy; however, because the lesions are itchy these medications are usually continued and other medications added. The response is unpredictable. Nonsteroidal anti-inflammatory drugs, such as dapsone 50–100 mg daily, colchicine 0.5 mg twice to three times daily, and antimalarials have all been used. Long-term oral corticosteroids may be necessary, but the dosage required for control may exceed prednisone 30 mg daily. Azathioprine can be used for a steroid-sparing effect. G.

Angioedema Without Urticaria

This is the most frequent ordinary idiopathic angioedema, occasionally occurring with physical or contact urticaria (101); however, it is vital to exclude the rare C1 esterase deficiency angioedema with a screening test of serum complement C4. If C4 levels are low, a functional measurement of C1 esterase inhibitor, if also low, will confirm the diagnosis. These swellings do not respond to antihistamines, and life-threatening laryngeal swellings may also respond poorly to epinephrine. Emergency treatment is with fresh frozen plasma or C1 esterase inhibitor concentrate, if available. Prophylactic treatment is with oral anabolic steroids such as danazol or antifibrinolytic agents.

X.

SUMMARY

H 1-antihistamines are the cornerstone of symptomatic treatment in acute and chronic urticaria, in which they not only relieve itching, but also reduce the num-

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ber, size, and duration of urticarial lesions. Relief of whealing, flaring, and erythema may be incomplete as the vascular effects of histamine are mediated to its action at H 2-receptors as well as at H 1-receptors, and other vasoactive substances may also be involved. In randomized, prospective, placebo-controlled, double-blind studies, the new low-sedating H 1-antihistamines have been found to be effective and safe in urticaria. Sedating antihistamines, although effective, place patients at risk for adverse effects, including decreased psychomotor performance. The response to H 1-antihistamines in some types of urticaria, for example, in urticarial vasculitis, is unsatisfactory. An H 2-antihistamine administered concurrently with an H 1-antihistamine may modestly enhance relief of itching and wheal formation in some patients with urticaria refractory to treatment with an H 1-antihistamine alone. The available evidence does not justify the routine addition of H 2-antihistamine treatment to H 1-antihistamine treatment.

REFERENCES 1. Champion RH, Roberts SOB, Carpenter RG, Roger JH. Urticaria and angioedema. A review of 554 patients. Br J Dermatol 1969; 81:588–597. 2. Sabroe RA, Seed PT, Francis DM, Barr RM, Kobza Black A, Greaves MW. Chronic idiopathic urticaria: Comparison of the clinical features of patients with and without anti-FcεRI or anti-IgE autoantibodies. J Am Acad Dermatol 1999; 40: 443–450. 3. Kobza Black A. Urticarial vasculitis. Clin Dermatol 1999; 17:565–569. 4. O’Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The impact of chronic urticaria on the quality of life. Br J Dermatol 1997; 136:197–201. 5. Poon E, Seed PT, Greaves MW, Kobza Black A. The extent and nature of disability in different urticarial conditions. Br J Dermatol 1999; 140:667–671. 6. Sabroe RA, Greaves MW. The pathogenesis of chronic idiopathic urticaria. Arch Dermatol 1997; 133:1003–1008. 7. Sabroe RA, Poon E, Orchard GE, Lane D, Francis DM, Barr RM, Black MM, Kobza Black A, Greaves MW. Cutaneous inflammatory cell infiltrate in chronic idiopathic urticaria: comparison of patients with and without anti-FcεRI or antiIgE autoantibodies. J Allergy Clin Immunol 1999; 103:484–493. 8. Greaves MW, Davies MG. Histamine receptors in human skin: indirect evidence. Br J Dermatol 1982; 107 (suppl 23):101–105. 9. Kavanagh GM, Sabroe RA, Greaves MW, Archer CB. The intradermal effects of the H 3-receptor agonist R α-methyl-histamine in human skin. Br J Dermatol 1998; 138:622–626. 10. Greaves M, Shuster S. Responses of skin blood vessels to bradykinin, histamine and 5-hydroxytryptamine. J Physiol (Lond) 1997; 193:255–267. 11. Barlow RJ, Ross EL, MacDonald D, Kobza Black A, Greaves MW. Adhesion mole-

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61. Monroe EW, Fox RW, Green AW, Izuno GT, Bernstein DI, Pleskow WW, Willis I, Brigante JR. Efficacy and safety of loratadine (10 mg once daily) in the management of idiopathic chronic urticaria. J Am Acad Dermatol 1988; 19:138–139. 62. Monroe EW. Relative efficacy and safety of loratadine, hydroxyzine and placebo in chronic idiopathic urticaria and atopic dermatitis. Clin Ther 1992; 14:17–21. 63. Monroe EW, Bernstein DI, Fox RW, Grabiec SV, Honsinger RW, Kalivas JT, Katz HI, Cuss F, Danzig MR, Garvin PR, Lutsky BN. Relative efficacy and safety of loratadine, hydroxyzine and placebo in chronic idiopathic urticaria. Arzneim Forsch Drug Res 1992; 42:1119–1121. 64. Pichat P, Angel I, Arbilla S. Anti-inflammatory properties of mizolastine after oral administration: arachidonic acid-induced cutaneous reaction in the rat. Arzneim Forsch Drug Res 1998; 48:173–178. 65. Dubertret L, Aguttes MM, Tonet J. Efficacy and safety of mizolastine 10 mg in a placebo-controlled comparison with loratadine in chronic idiopathic urticaria. Results of the MILOR study. J Eur Acad Dermatol Venereol 1999; 12:16–24. 66. Brostoff J, Fitzharris P, Dunmore C, Theron M, Blondin P. Efficacy of mizolastine, a new antihistamine, compared with placebo in the treatment of chronic idiopathic urticaria. Allergy 1996; 51:320–325. 67. Markham A, Wagstaff AJ. Fexofenadine. Drugs. 1998; 55:269–274. 68. Paul E, Berth-Jones J, Ortonne J-P, Stern M. Fexofenadine hydrochloride in the treatment of chronic idiopathic urticaria: a placebo-controlled, parallel-group, doseranging study. J Dermatol Treat 1998; 9:143–149. 69. Finn AF Jr, Kaplan AP, Fretwell R, Qu R, Long J. A double-blind placebocontrolled trial of fexofenadine HCl in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol 1999; 104:1071–1078. 70. Monroe EW, Cohen SH, Kalbfleisch J, Schulz CI. Combined H 1- and H 2-antihistamine therapy in chronic urticaria. Arch Dermatol 1981; 117:404–407. 71. Harvey RP, Wegs J, Schocket AL. A controlled trial of therapy in chronic urticaria. J Allergy Clin Immunol 1981; 68:262–266. 72. Diller G, Orfanos CE. Management of idiopathic urticaria with H 1- ⫹ H 2-antagonists. A crossover double-blind long-term study. Z Hautkr 1983; 58:785–793. 73. Cook LJ, Shuster S. Lack of effect of cimetidine in chronic idiopathic urticaria. Acta Dermato-Venereol (Stockh) 1983; 63:265–267. 74. Bleehen SS, Thomas SE, Greaves MW, Newton J, Kennedy CTC, Hindley F, Marks R, Hazell M, Rowell NR, Fairiss GM, Cartwright PH, Glenny HP, Howland K. Cimetidine and chlorpheniramine in the treatment of chronic idiopathic urticaria: a multi-centre randomized double-blind study. Br J Dermatol 1987; 117:81–88. 75. Paul E, Bodeker RH. Treatment of chronic urticaria with terfenadine and ranitidine. A randomized double-blind study in 45 patients. Eur J Clin Pharmacol 1986; 31: 277–280. 76. Kaplan AP. Chronic urticaria: possible causes, suggested treatment alternatives. Postgrad Med 1983; 74:209–215, 218–222. 77. Grattan CEH, O’Donnell BF, Francis DM, Niimi N, Barlow RJ, Seed PT, Kobza Black A, Greaves MW. Randomized double-blind trial of cyclosporin A in chronic idiopathic urticaria. Br J Dermatol 2000; 143:365–372. 78. Breathnach SM, Allen R, Milford Ward A, Greaves MW. Symptomatic dermo-

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9 Histamine and Antihistamines in Anaphylaxis Stephen L. Winbery Methodist Central Hospital Teaching Practice, Memphis, Tennessee

Philip L. Lieberman University of Tennessee College of Medicine, Memphis, Tennessee

I.

INTRODUCTION

The incidence of severe systemic allergic reactions is increasing. Anaphylaxis and anaphylactoid reactions are provoked by a variety of factors, some of which are iatrogenic. Theoretically, most of these so-called allergic reactions are predictable and preventable; however, in real life, inadvertent exposure occurs. When severe reactions happen, epinephrine injected intramuscularly is the firstresponse medication of choice. H 1-receptor antagonists are secondary and play a minor role in acute treatment. For the prevention of anaphylactoid and anaphylactic reactions, particularly iatrogenic reactions, however, H 1-antagonists play an important role. A brief review of the provoking factors for anaphylaxis and anaphylactoid reactions is shown in Table 1. In its strictest sense, the term anaphylaxis refers to an immediate systemic reaction mediated by antigen–IgE-antibody-induced degranulation of mast cells and basophils. An allergen is a multivalent, physiological cross-link between receptor-bound IgE molecules on the surface of mast cells and basophils. In a medical setting anaphylactoid reactions are more common than true anaphylaxis. The term anaphylactoid reaction refers to an event that is clinically indistinguishable from anaphylaxis, but not due to IgE–antibody–antigen-in287

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Table 1 Provoking Factors for Anaphylaxis and Anaphylactoid Reactions I. Anaphylaxis: IgE-mediated reaction Food peanuts and tree nuts (often concealed in food, bakery goods, Asian cooking, chocolate) (20) seafood (shellfish and fish) eggs milk grains food additives (carmine, tartrazine, aniline) (21) spices (paprika, cumin, anise, mustard) Drugs penicillins cephalosporins sulfonamides Vaccines MMR: bovine gelatin (22) allergen immunotherapy Venoms Hymenoptera fire ants snakes Human proteins insulin, corticotropin, vasopressin serum and seminal proteins Latex Idiopathic Exercise (food or inhalant allergen cotriggers common) II. Anaphylactoid Direct release of mediators from mast cells and basophils Drugs opiates paralytic agents vancomycin fluorescein dextran chlorhexidine (23) Hyperosmolar solutions Idiopathic Exercise (see also anaphylaxis) physical temperature weather conditions (24) Physical factors such as cold, sunlight

Anaphylaxis Table 1

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Continued

Disturbances in arachidonic acid metabolism aspirin other nonsteroidal anti-inflammatory drugs Immune aggregates gamma globulin IgG- anti-IgA antivenoms (25) Cytotoxic Transfusion reactions to cellular elements Miscellaneous Non-antigen–antibody-mediated complement activation radiocontrast material some protamine reactions dialysis membranes Activation of contact system dialysis membranes plasmapheresis radiocontrast material Source: From Refs. 1–24.

duced mast cell and basophil degranulation. The approximate incidence of anaphylaxis and anaphylactoid reactions is provided in Table 2. The same vasoactive and inflammatory mediators, including histamine and tryptase play a role in both types of clinical events. Measurement of serum tryptase levels for mast cell degranulation may differentiate IgE-mediated from nonIgE-mediated reactions but as yet are not widely used (26–28).

II. MEDIATORS OF ANAPHYLAXIS Anaphylaxis and many anaphylactoid reactions are initiated by the release of preformed chemical mediators of inflammation from granules in mast cells and basophils. Histamine is only one of many mediators involved in the pathophysiology of anaphylaxis (Table 3). Besides preformed mediators, activated mast cells also synthesize and release mediators including arachidonic acid metabolites and platelet-activating factor (PAF). Slow-reacting substance of anaphylaxis (SRSA) is a chemotactic mixture of leukotrienes LTB 4, LTC 4, LTD 4, and LTE 4. The reaction is amplified as these chemotactic agents in turn recruit inflammatory cells and their mediators.

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Table 2 Approximate Incidence of Anaphylaxis and Anaphylactoid Reactions to Selected Agents Incidence for specific agents Penicillin 1–5 reactions per 10,000 patient treatments Cephalosporins 3–7% of patients with a history of penicillin allergy and a positive skin test N-acetylcysteine for acetaminophen overdose 50 patients in 17 months at one pediatric hospital Radiocontrast media Estimated 2667 reactions with 500 deaths to hyperosmolar agents Severe reactions in 0.04% of patients receiving lower osmolar agents Plasmapheresis and cryofiltrationa Plasmapheresis: 2 of 21 patients with 497 procedures Cryofiltration: 4 of 28 patients with 680 procedures Drugs used during perioperative period Penicillin, analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) Anesthetics—1: 13,000 Muscle relaxants—1: 6500 Australia: frequency between 1: 5000 and 1: 25,000 with mortality of 3.4% France—1:4500 cases MMR 28 patients reported since 1980 Insect stings 0.4–3% of population is sensitive Estimated 25–50 deaths per year 39 of 138 patients with a previous history upon rechallenge 1: 2000 individuals is severely allergic Aspirin and NSAIDs Anaphylactoid reactions occur in as many as 0.9% of patients taking aspirin 35: 51,797 patients taking NSAIDs experienced shock Most common agent causing anaphylaxis in a series of 267 adult cases Allergen-specific immunotherapy 1: 100,000–1: 1,000,000 doses

References Idsoe et al. (1) Saxon et al. (2)

Bailey and McGuigan (3) Cohan et al. (4) Katayama et al. (5)

Siami et al. (6)

van der Klauw et al. (7) Laxenaire (8) Fisher and More (9) Hatton et al. (10) Kelso et al. (11) Golden (12) Barnard (13) van der Linden et al. (14) Maher et al. (15) Settipane et al. (16) Strom et al. (17) Kemp et al. (18)

Klimet (19)

a All patients who had reactions were taking ACE inhibitors. MMR, measles, mumps, rubella; NSAID, nonsteroidal anti-inflammatory; ACE, angiotensin-converting enzyme.

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Histamine’s principal role in anaphylaxis was established many years ago when it was found to mimic anaphylaxis when infused intravenously. The multiplicity of mediators offers an explanation as to why antihistamines alone do not control anaphylactic episodes. Histamine also has a regulatory role in the subsequent release and production of mediators after stimulation of mast cells by antigen, since antihistamines can block allergen-induced increases in histamine and other mediators. Also, there appears to be an interdependence of PAF and histamine in anaphylactic reactions (30, 31). The role of antihistamines in anaphylactic reactions is largely prophylactic. Once mediators are released, H 1-antagonists are relatively ineffective for treatment of acute symptoms, except as adjunctive treatment to parenteral epinephrine for relief of pruritus and urticaria.

A. The Late Phase of the Anaphylactic Response After resolution of an anaphylactic event, symptoms may reappear within 3– 12 hours. This late response is likely due to recruitment of additional inflammatory cells by chemotactic factors released from mast cells and/or basophils in the initial reaction. Chemotactic factors promote adhesion, diapedesis, migration, and activation of inflammatory cells (32).

B. Amplification of the Anaphylactic Response Amplification of the acute anaphylactic event occurs through activation and recruitment of inflammatory cells, neuropeptides, the contact (kallikrein) system, complement, clotting, and the clot lysis systems. Neuropeptides can be detected in nasal secretions of patients with allergic symptoms. Sensory nerves release substance P and calcitonin gene-related peptide (CGRP), while vasoactive intestinal peptide is released from parasympathetic nerve endings. Both sets of nerves are probably stimulated in a nonspecific manner by inflammation associated with allergic reactions (33). Substance P increases vascular permeability and blood flow, which are mediated in part by histamine acting on H 1-receptors (34). Mast cell kininogenase and basophil kallikrein can activate the contact system (35, 36). Tryptase has kallikrein-like activity and can activate complement and cleave fibrinogen (37). Circumstantial evidence for activation of complement as part of anaphylactic reactions comes from the relationship between levels of C3a and severity of the reaction in eight wasp-allergic patients challenged with wasp stings (14). Several animal studies suggest that pesticides and other environmental pollutants may augment histamine release from mast cells and contribute to both the incidence and severity of allergic reactions (38).

Increase in capillary permeability Positive inotropy Positive chronotropy Exocrine gland secretion Stimulation of sensory nerves Stimulation of release or synthesis of most other mediators Anticoagulation

Heparin

Leukotrienes (B 4, C 4, D 4)

Enhanced basophil mediator release Chemotaxis Contraction of airway smooth muscle Increased vascular permeability Negative inotropic effect Goblet and mucosal cell secretion

Mucus secretion

Smooth muscle relaxation and contraction, peripheral vasodilation

Smooth muscle relaxation and contraction

Histamine

Prostaglandins (D 2 and F2α)

Action

Mediators of Anaphylaxis

Mediator

Table 3

Coagulopathy, could have anti-inflammatory effect, possible complement inhibition Vasodilation, flushing, hypotension, bronchospasm, coronary artery spasm, increased GI motility, diarrhea Rhinorrhea, increased respiratory secretions Potentiation Potentiation Bronchospasm Vasodilation, efflux of inflammatory cells Hypotension, myocardial depression Increased respiratory secretions

Vasodilation, hypotension, bronchospasm, coronary artery spasm, increased gastrointestinal (GI) motility, diarrhea Angioedema, urticaria, flushing Increased contractility Tachycardia Increased respiratory secretions Pruritus Potentiation of reaction, late-phase reaction

Signs and symptoms

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Tumor necrosis factor-α

Neuropeptides, substance P, and vasoactive intestinal peptide (VIP)

Eosinophilic chemotactic factor (ECF-A) Neutrophilic chemotactic factor (NCF) Neutral proteases Tryptase Major basic protein (MBP) Arachidonic acid stimulating factors

Lymphokines (IL-3, IL-5, TNF)

Platelet-activating factor (PAF)

Vasodilation Possible mast cell degranulation Decreases histamine release from mast cells

Neutrophil aggregation Platelet aggregation Adherence, degranulation, and chemotaxis of inflammatory cells Eosinophil chemotaxis Neutrophil chemotaxis Proteolysis May cleave C3 to activate complement Stimulates histamine release Production of lipoxygenase and cyclo-oxygenase products Peripheral nerve stimulation

Contraction of airway smooth muscle Increased vascular permeability

Flushing, hypotension Amplification Inhibition of inflammation (29)

Itching, pain

Amplification, inflammation Amplification, inflammation Inflammation Amplification Amplification Amplification

Bronchospasm Hypotension, flushing, urticaria, angioedema Inflammation Platelet activation Potentiation, inflammation

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Modulation by Histamine

Histamine may play a role in modulating anaphylaxis, as it binds to H 2-receptors on basophils and mast cells, leading to inhibition of further histamine release by the cyclic adenosine 3′,5′–monophosphate (cAMP)-dependent mechanism (39– 41). H 2-receptor agonists cause a dose-dependent inhibition of antigen-induced histamine release from sensitized guinea pig hearts. This suggests histamine feedback inhibition of antigenic histamine release via H 2-receptors (42). In theory, if histamine modulates the anaphylactic response via H 2-receptors, H 2-receptor antagonists could have a detrimental effect on the treatment of anaphylaxis. This has been reported with the use of H 2-antagonists alone in clinical settings (43). As discussed below, the addition of H 2-antagonists may be of benefit in the treatment or prevention of anaphylactic episodes and some authors have suggested the addition of cyclo-oxygenase inhibitors when treating anaphylaxis (44).

III. HISTAMINE AND ANAPHYLAXIS Histamine, an endogenous imidazole compound, is synthesized, stored, and released primarily by mast cells and circulating basophils. In 1949 MacIntosh and Paton (45) showed that basic substances such as diamines, diamides, and diquanides cause histamine release. Histamine is the mediator directly responsible for many of the symptoms early in the course of anaphylaxis and may be indirectly responsible for many of the late responses. Most of the signs and symptoms of anaphylaxis can be produced by histamine infusion, and many can be blocked by H 1- and/or H 2-histamine antagonists (46). Histamine infusion produces increased permeability of the postcapillary venules, vasodilation, decreased total peripheral resistance, and hence decreased blood pressure, myocardial depression, and warm extremities. Emanuel has recently reviewed the historic discovery of histamine and histamine antagonists (47). The considerable species variation in response to histamine has led to confusion in interpretation of experimental results. For instance, guinea pigs and rabbits are extremely sensitive to both the respiratory and cardiovascular effects of histamine and require a much lower lethal dose than the relatively insensitive rat. There is strong species variability in the histamine-releasing ability of the anaphylatoxins, C3a and C5a and compound 48/80. In most animals, histamineinduced increases in microvascular permeability are mediated by H 1-receptors, except in the hamster where these effects are mediated by H 2-receptors (48). The human response tends to be somewhat intermediate, and sensitivity varies from person to person and with different physiological milieux. Modestly increased serum histamine levels (less than 1 ng/mL) are associated with metallic taste, headache, and nasal congestion. Higher levels cause

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generalized skin reactions, gastrointestinal stimulation, flushing, tachycardia, cardiac arrhythmias, and hypotension. Life-threatening hypotension, ventricular fibrillation, bronchospasm, and cardiopulmonary arrest generally result from histamine levels above 12 ng/mL (49). It has been suggested that the clinical manifestations of histamine release during anesthesia are different from those of classic systemic anaphylaxis because of the effects of anesthetic agents and other drugs used perioperatively. Elevated levels of histamine may produce untoward effects in the perioperative patient even though the classic symptoms of anaphylaxis (urticaria, angioedema, bronchospasm, and hypotension) are not necessarily present. In patients undergoing general anesthesia, elevated histamine levels, bradycardia, arrhythmias, hypertension, and myocardial ischemia should be considered as evidence of an anaphylactoid reaction (50, 51). Elevated levels of plasma histamine are associated with arrhythmias, increased thrombosis, stress ulceration, increased intrapulmonary shunt, death from shock, and adult respiratory distress syndrome. Plasma histamine concentrations of 0.2–1.0 ng/mL must be accepted as elevated, and may be clinically relevant despite the absence of classic signs and symptoms of anaphylaxis during anesthesia (52). A. Histamine Receptors Histamine stimulates H 1-, H 2-, and H 3-receptors to produce its characteristic responses (Table 4). Many of the actions of histamine are local and tissue-dependent. H 1-receptor stimulation results in the breakdown of the second-messenger inositol phosphate and calcium mobilization, and H 2-mediated responses are mostly due to activation of adenylate cyclase; however, there is considerable ‘‘cross talk’’ between second messenger systems (54). The mechanisms responsible for many actions of histamine such as vascular smooth muscle dilation are not understood and may involve release of epithelial factors. Histamine can stimulate endothelial cells to produce nitric oxide, a smooth muscle relaxant factor (55, 56). In guinea pig lung tissue, histamine binds to H 1-receptors to produce a phospholipase-C-dependent calcium mobilization that stimulates the conversion of L-arginine to nitric oxide. Nitric oxide activates guanylate cyclase, leading to production of 3′,5′-cyclic guanosine monophosphate (cGMP) (57). The H 3-receptor is identified pharmacologically by its antagonist, thioperamide. These receptors have been located on presynaptic nerve endings both peripherally and in the central nervous system. H 3-receptors control acetylcholine release at the level of the myenteric plexus in the guinea pig intestine (58), modify peripheral neuropeptide release, modulate airway reactivity (59), and control histamine synthesis in brain and lung tissue. H 3-receptors are on presynaptic terminals of sympathetic effector nerves that innervate heart and systemic vasculature. The H 3-receptor modulates norepinephrine release from systemic nerves and, in a

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Table 4

Actions of Histamine Related to Anaphylaxis

H 1-receptor-mediated actions

H 2-receptor-mediated actions

Elevation of cyclic GMP Smooth muscle contraction Increased endothelial permeability Stimulation of nerve endings Pruritus Vagal irritant receptors (cough and bronchospasm) Increased viscosity of mucus Vasodilation Direct Production of endothelium-derived relaxing factors Release of neuropeptides from nerve endings Epinephrine secretion from adrenal medulla Increased rate of depolarization of the sinoatrial node Slowed rate of atrioventricular conduction

Increased intracellular cyclic AMP Increased gastric acid and pepsin secretion Decreased fibrillation threshold of cardiac muscle Positive inotropy Positive chronotropy Increased amount of mucus secretion H 1- and H 2-receptor-mediated actions Vasodilation and flushing Increased vascular permeability Hypotension Eosinophil chemotaxis H 3-receptor-mediated actions Modulation of peripheral and bronchial neurotransmission; possible bronchospasm Presynaptic terminals of sympathetic effector nerves in heart and systemic vasculature (53)

canine model of anaphylaxis, an H 3-receptor antagonist attenuated cardiovascular collapse (53). B.

Anaphylaxis-Related Actions of Histamine

1. Vascular System Histamine exerts a complex action on the vascular system. Its predominant action is a net vasodilation from smooth muscle relaxation in arterioles, precapillary sphincters, and venules, leading to a decrease in total peripheral resistance and a fall in blood pressure. Intravenous histamine infusion produces a marked decrease in diastolic blood pressure and a widening of pulse pressure. Histamine contracts postcapillary venules, which exposes permeable capillary membranes to hydrostatic forces leading to edema. The initial flush from intradermally administered histamine is due to local cutaneous vasodilation, while wheal formation is due to local edema. The vascular effects of histamine are mediated through both H 1- and H 2-receptors, but predominantly through H 1-receptors.

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2. Nerves Histamine directly stimulates nerve endings to produce pruritus. Local inflammation nonspecifically stimulates nerve endings to release neurotransmitters and neuropeptides that can perpetuate and potentiate the actions of histamine and other inflammatory mediators. 3. Heart and Coronary Arteries Mast cells are present in cardiac muscle and coronary arteries. Histamine acts on the heart to increase inotropy and chronotropy, probably through increasing calcium influx in cardiac myocytes. H 2-receptors directly mediate most of the increase in contractile force and in heart rate. H 1-receptors appear to mediate effects on the conducting system and produce coronary artery vasospasm in patients with variant angina. H 1-receptor stimulation results in negative chronotropic effects secondary to atrioventricular conduction delay. In experimental animal models, histamine acting on H 1-receptors slows atrioventricular nodal conduction and decreases fibrillation threshold. Dysrhythmia may result from a combination of effects on conduction and ischemia from coronary artery vasospasm (60). Anaphylactic reactions of isolated perfused guinea pig hearts are characterized by a short initial cardiac stimulation, followed by precipitous constriction of coronary arteries and long-lasting impaired myocardial function. Vasoactive anaphylactic mediators other than histamine are also involved in cardiac malfunction occurring during the later phase of systemic and cardiac anaphylaxis. H 1-receptor antagonist pretreatment generally prevents myocardial depression and cardiac shock in experimental models of anaphylaxis. It has been thought that H 2-receptor-mediated effects are of minor importance in cardiovascular manifestations of anaphylaxis (61); however, histamine acting on H 2-receptors causes pronounced stimulation of spontaneously active cardiac Purkinje fibers in sheep hearts (62). In theory, H 2-antagonists could have detrimental effects by potentiating coronary artery vasoconstriction (63) or by reversing H 2-receptor-mediated inhibition of cardiac histamine release (42). Thus far, investigators have not shown detrimental effects of H 2-antagonists on cardiovascular function (61). A prominent feature of antigen-induced mediator release in isolated rat and guinea pig hearts is coronary artery vasoconstriction and ischemic myocardial damage (63). In other experimental models histamine has a biphasic response on coronary arteries. Vasodilation is produced in part by H 2-receptor-stimulated synthesis of an endothelium-derived relaxing factor that has been postulated to be nitric oxide. An inhibitor of nitric oxide synthesis, N-methyl-L-arginine, causes pronounced coronary constriction in response to histamine. This suggests that dysfunction in the formation of nitric oxide could precipitate histamine-induced coronary artery vasospasm and myocardial infarction (64). Several studies have demonstrated that H 1-receptor stimulation of epicardial coronaries causes con-

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striction, whereas H 2-receptor activation induces dilation. In patients with normal coronary arteries, direct coronary artery infusion of histamine acts via H 1-receptors located in the endothelium to cause coronary artery dilation and decreased coronary artery vascular resistance. H 2-receptors in vascular smooth muscle also mediate coronary vasodilation, whereas H 1-receptors in vascular smooth muscle induce vasoconstriction (65). Thus, the action of histamine on coronary arteries is complex and there is considerable species variation. 4. Respiratory System Histamine acts via H 1-receptors in the lower airways to constrict bronchial smooth muscle, dilate or constrict vascular smooth muscle, cause microvascular leak, and activate sensory nerves. In healthy individuals, histamine does not cause significant bronchoconstriction, but patients with asthma and other lower airway disorders are hypersensitive to its bronchoconstricting effects. H 1-receptors also mediate an increase in airway fluid and electrolyte secretions and increased mucous viscosity. In awake sheep, bronchial vasodilation is mediated primarily by histamine acting on H 1-receptors (66). In experimental models, H 2-receptor stimulation may actually relax constricted bronchial smooth muscle. This is probably not clinically significant, since patients with asthma tolerate H 2-antagonists well (67). Although most reports indicate that cimetidine and ranitidine do not cause or potentiate bronchoconstriction in normal and asthmatic patients, in one study, bronchoconstriction increased in 4 of 24 asthmatic patients treated with cimetidine. In addition, isolated basophils from H 2-antagonist-treated asthmatic patients showed enhanced histamine release (68). H 3-receptors in the lungs modulate cholinergic neurotransmission, neuropeptide release, and bronchoconstriction (59, 69). 5. Gastrointestinal System Histamine plays a physiological role in stimulating gastric acid secretion through H 2-receptors, and H 2-antagonists have been widely used to decrease gastric acid secretion. Histamine also produces gastrointestinal smooth muscle contraction and relaxation. These responses are caused by direct actions on smooth muscle H 1- and H 2-receptors and indirect actions leading to release of several active substances from the gut’s own intrinsic nervous system. 6. Measurement of Histamine Levels in the Diagnosis of Anaphylaxis Anaphylaxis is largely a clinical diagnosis based on clinical signs and symptoms and history of exposure to a potential provoking agent. Atypical presentations may be more common than previously thought and it may not always be possible to identify the offending agent (18). Improved techniques allow histamine levels

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to be measured more accurately and quickly than ever before. Histamine begins to rise in 5–10 min and may remain elevated for up to 60 min. Urine histamine and histamine metabolites may stay elevated longer and are more stable (70). Analysis of the histamine metabolite methylhistamine in urine can be valuable in diagnosing anaphylaxis (71), especially when combined with the measurement of tryptase concentrations (26).

IV. ANTIHISTAMINES H 1-receptor antagonists were introduced into therapeutic use 60 years ago. Binding of the H 1-antagonist to the H 1-receptor does not produce a response but, rather, blocks the actions of endogenous histamine at H 1-receptors. For the most part, H 1-antagonist binding is competitive and reversible, with the exceptions of astemizole, terfenadine, and loratadine. Antihistamines may be ranked on the basis of potency; however, equal efficacy can usually be obtained by giving a relatively larger dose of the less potent drug. Potency may be relevant when considering the limitations of the effects of these agents beyond histamine receptor blockade (72). A. Second-Generation H 1-Antihistamines The newer H 1-antagonists such as cetirizine, fexofenadine, and loratadine are highly selective for the H 1-receptor and are generally well-tolerated at doses that produce high levels of antihistaminergic activity. At the present time, none of the second-generation H 1-antagonists is available for injection, but in one study several of the agents were given intravenously to squirrel monkeys (73). These newer agents have not yet been widely used for the treatment or prevention of anaphylaxis in humans; however, like their predecessors, they prevent anaphylactic death in experimental animal models. The improved selectivity and additional antiallergic properties of these drugs may be of benefit in the treatment of anaphylaxis (73–76). Two of the new H 1-antagonists, terfenadine and astemizole, are no longer used in most countries due to potential cardiac toxicity (72) (see Chap. 12). B. Nonhistamine Receptor Antiallergic Properties of Antihistamines Many of the first-generation antihistamines have antimuscarinic, antidopaminergic, anti-alpha-adrenergic, and antiserotoninergic properties. The contribution of these properties to the treatment of anaphylaxis is unknown and possibly of little consequence. The H 1-antagonists not only block histamine interaction with the

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H 1-receptor but also inhibit cell mediator release (77, 78), basophil migration (79), and eosinophil recruitment (80). In therapeutic concentrations, H 1-antagonists such as chlorpheniramine, mepyramine, ketotifen, promethazine, diphenhydramine, cyclizine, and oxatomide can inhibit IgE-induced histamine release (81). At supratherapeutic concentrations, the H 1-antagonists can release histamine by an antigen-independent direct cytotoxic effect on mast cells. The antiallergic effect to inhibit release of histamine from mast cells and basophils has been shown with the second-generation H 1-antagonists as well, including terfenadine, loratadine, cetirizine, azatadine, azelastine, ketotifen, and oxatomide (82–84). Their antiallergic effects vary depending on the source of the mast cells and the stimulus used (compound 48/80, IgE-antigen, substance P, Con A, or a calcium ionophore). The exact mechanism of inhibiting histamine release is unknown, but may be due in part to the lipophilic and cationic nature of the H 1-antagonists. Many H 1-antagonists are lipophilic, cationic drugs and may dissolve into the cell membrane and produce stabilization to sodium ion and calcium ion flux; however, there is imprecise correlation between lipophilicity and inhibition of histamine release (82). Several other antiallergic effects have been observed with the second-generation antihistamines including inhibition of allergen-induced eosinophil, basophil, and neutrophil migration and inhibition of PAF-induced eosinophil accumulation in the skin. There is a definite need for characterization of the antiallergic properties of H 1-antagonists using double-blind, placebo-controlled human studies with strict criteria for measurement of plasma concentrations, standardization of mediator assays, and reproducibility. The role of antiallergic effects of antihistamines in the treatment of anaphylaxis, if any, has not been established and further clinical investigation is warranted. The effects are reviewed in Chapter 4.

V.

ANTIHISTAMINES IN ANAPHYLAXIS

A.

The Adjunctive Role of Antihistamines in Treatment of Acute Anaphylaxis

It is important to emphasize early diagnosis of anaphylaxis along with prompt treatment with epinephrine and volume expansion, realizing that antihistamines are an adjunctive treatment (85). Histamine is only one of a number of mediators that contribute to the pathophysiology of anaphylaxis, and H 1-antagonists are not effective as single agents for the treatment of anaphylaxis. Before the discovery of the H 1- and H 2-receptors, histamine was thought to be the mediator of anaphylaxis because agents such as diphenhydramine blocked or reversed histamine-induced hypotension and bronchospasm; however, H 1-antihistamines alone were clinically ineffective in reversing all the symptoms

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of anaphylaxis and were of little benefit in severe anaphylaxis. We now know that although histamine mediates anaphylactic signs and symptoms through both H 1- and H 2-receptors, there are many other mediators of the anaphylactic response. Antihistamines are not the major therapy for the anaphylactic event but are helpful when given in addition to epinephrine as adjunctive treatment of pruritus and urticaria. Intravenous or intramuscular diphenhydramine, 1–2 mg/kg, up to 75 mg, should be given early and repeated every 4–6 h as long as anaphylactic symptoms persist (86). Ranitidine, up to 50 mg, or cimetidine 200–300 mg administered intramuscularly or intravenously, has been used adjunctively. Orally administered H 2-antagonists may be of benefit in less serious anaphylactic reactions. An important principle regarding the activity of H 1-antihistamines is that their effect is delayed compared to peak plasma levels and lasts longer than expected from the elimination half-life of these drugs. For example, with hydroxyzine, maximal suppression of wheal and flare does not occur until 7 h after peak serum concentrations have been reached (87). This may indicate that the peak therapeutic effect of these agents is also delayed after a single dose. Another disadvantage of antihistamine therapy in acute anaphylaxis is that H 1-antagonists cannot reverse the consequences of H 1-receptor activation after the fact. They are most effective if they block receptors before histamine binds. This offers a tenable explanation as to why these agents are more effective as prophylactic drugs for anaphylaxis than for treating the acute event. B. Potential Deleterious Effects of H 1- and H 2-Antihistamines in Acute Anaphylaxis When antihistamines are used in the treatment of acute anaphylaxis, H 1-receptor blockade may produce atrioventricular conduction delay, coronary artery vasoconstriction, and initial hypotension (with intravenous administration). H 2-receptor blockade may produce negative feedback inhibition of subsequent histamine release. This emphasizes once again that antihistamines are not primary medications for the treatment of acute anaphylaxis. In general, the benefit of the addition of antihistamines in acute anaphylaxis probably outweighs their potential risks. The relative degree of these deleterious effects with newer antihistamines is not yet known (88). C. Prevention of Anaphylaxis with H 1- and H 2-Antihistamines Pretreatment with antihistamines can prevent or attenuate anaphylaxis in experimental models, whether antigen, exogenous histamine, or compound 48/80 triggers the reaction. Pretreatment with either first- or second-generation antihistamines can prevent anaphylactic death and pulmonary, cardiac, hemodynamic, and cutaneous manifestations of anaphylaxis in experimental animals (89, 90).

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In patients, pretreatment with H 1-antagonists prevents bronchoconstriction to histamine challenge, nonisotonic aerosols, and exercise (91–93), and also reduces microvascular leak in the skin wheal response to histamine. Cetirizine has been reported to protect against late-phase reactions to allergen provocation tests (94). In a crossover trial with six healthy adult volunteers, 8 mg dimethindene and 400 mg cimetidine administered intravenously reversed hypotension and tachycardia caused by intravenous histamine infusion (95). Pretreatment with antihistamines has been used clinically to prevent anaphylaxis and anaphylactoid reactions in patients at risk for reactions to radiocontrast media, volume expanders, plasma exchange, fluorescein, other drugs, and during anesthesia. Antihistamines have failed to prevent reactions to antivenoms for patients with snake bites (25). 1. Reactions to Radiocontrast Materials Radiocontrast materials (RCM) have been used since 1929. Reactions to RCM are heterogeneous and involve nonallergic mast cell degranulation and histamine release as well as complement activation. In pigs, RCM cause release of histamine from cardiac mast cells (96); however, studies with canine mastocytoma cells suggest that direct release of histamine from mast cells does not completely explain the pathogenesis of RCM reactions. Although antihistamines are not the primary drugs of choice for treatment of anaphylaxis, they play an important role in the prevention of anaphylactoid reactions to RCM (97) in patients who have experienced a previous reaction. Zweiman and associates were the first to use an antihistamine for prevention of RCM reactions in patients with a history of previous reactions. Diphenhydramine (50 mg) was given intramuscularly prior to the administration of RCM. There was a significant reduction in recurrence rates, which in the untreated previous reactors, ranged from 16% to a high of 44% (98–100). Since that time, the pretreatment protocol has been refined (Table 5). Patterson and associates showed that the addition of prednisone enhanced the clinical efficacy of the H 1-antagonist (101) Ephedrine (25 mg), added empirically to prevent hypotension with anaphylaxis, produced a further reduction in reaction rates (102). Ephedrine should not be used in patients with ischemic heart disease, moderate-to-severe congestive heart failure, and those being treated with monoamine oxidase inhibitors in whom sympathomimetics are contraindicated. H 2-antagonists have also been studied in this setting. Greenberger and associates found that the addition of cimetidine reduced the efficacy of the pretreatment protocol (102). In another study, patients undergoing intravenous urography were stratified into four treatment groups. Group 1 received intravenous prednisolone alone; group 2 received clemastine; group 3 received clemastine and cimetidine; and group 4 received only saline. There was a significant reduction in ana-

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Table 5 Prophylactic Regimen for Patients with History of Reaction to RCM Prednisone, 50 mg by mouth 13 h, 7 h, and 1 h before Diphenhydramine, 50 mg intramuscularly, 1 h before Ephedrine, 25 mg by mouth, 1 h before a Ranitidine, 150 mg or cimetidine, 300 mg by mouth, 3 h before b a

Omit if patient has contraindication to sympathomimetics, including ischemic heart disease, angina, and cardiac arrhythmias. b Optional (see text). RCM, radiocontrast materials. Source: Ref. 100.

phylactic signs and symptoms for patients in group 3 compared with the other groups: the combination of an H 1- and H 2-antagonist was superior to an H 1antagonist alone. Although not all anaphylactic reactions were suppressed, there were no severe reactions (103). In a third study involving 100 patients with previous reactions to RCM, the addition of an H 2-antagonist did not alter the results of prophylaxis. Combined glucocorticoid–antihistamine treatment prevented the majority of patients from having reactions and none had severe reactions (104). At best, the results are inconclusive as to whether an H 2-antagonist is an effective adjunctive agent to diphenydramine, prednisone, and ephedrine (105), therefore, the use of an H 2-antagonist should be left to the discretion of the physician managing the patient. The protocol for prevention of reactions to RCM in patients at risk should be followed regardless of the route of administration of the RCM or the procedure being performed. Reactions have been reported after hysterosalpingograms, myelograms, and retrograde pyelograms (106). The introduction of nonionic and low-osmolar RCM has decreased the frequency, but not the severity, of adverse events (107). The risk of reactions to RCM in patients with previous reactions decreases to 1% with the use of the prophylactic regimen plus the use of a low-osmolar agent (105). The antihistamine/prednisone prophylactic regimen has been so successful that it has been adopted for prevention of other anaphylactic reactions in patients at risk in the following settings: plasma exchanges (108), general anesthesia (109), fluorescein administration (110). It has also been used in patients with cold urticaria who must undergo bypass surgery (111). Based on studies in ragweed-sensitized dogs, there has been some suggestion that the addition of cyclo-oxygenase inhibitors to the RCM prophylactic regimen may be useful (44). This prophylactic regimen has been demonstrated only to prevent anaphylaxis and anaphylactoid episodes. In two reported instances, it failed to prevent

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recurrence of adult respiratory distress syndrome and noncardiac pulmonary edema associated with RCM (112, 113). 2. Volume Expanders A combination of H 1- and H 2-antagonists with a corticosteroid effectively prevented reactions to urea-linked gelatin solutions used as volume expanders in two studies. In one study, volunteers received intravenous infusions of the plasma expander. Fifteen of 50 had anaphylactic symptoms compared to 0 of 50 in the pretreated group. In the other study, 27 of 150 orthopedic patients had significant reactions when pretreated with only intravenous saline. When pretreated with dimethindene and cimetidine, 4 of 150 patients had reactions; in those pretreated with chlorpheniramine plus cimetidine, 9 of 150 patients had reactions (114). 3. Plasma Exchange Patients undergoing plasma exchange may experience anaphylactic reactions due to multiple causes. Pretreatment using a modification of the program established for the prevention of RCM reactions has been successful in preventing repeat reactions (108). These reactions seem much more likely when patients are treated concurrently with angiotensin-converting enzyme (ACE) inhibitors (6). 4. Fluorescein Fluorescein is commonly employed as an intravenous microvascular contrast agent by ophthalmologists and optometrists. In patients with previous reactions to fluorescein, the incidence of reaction with subsequent exposure can be nearly 50% (115). A modification of the treatment regimen for RCM reactions has been used to prevent recurrent reactions. The modification includes a 3-day regimen of oral prednisone followed by 50 mg diphenhydramine with 400 mg cimetidine 1 h before the test (110). 5. Idiopathic Anaphylaxis Even after exhaustive searches for avoidable provoking factors for anaphylaxis, some triggers remain undetected. Patients with mild episodes of idiopathic anaphylaxis that occur fewer than three or four times per year probably do not need preventive therapy. For moderate or severe episodes occurring more frequently, the combination of an H 1- and H 2-antagonist should be considered on a daily basis. The second-generation, nonsedating H 1-antagonists should be used in preference to potentially sedating drugs. When patients are refractory to antihistamine therapy, glucocorticoids, albuterol, cromolyn, and ephedrine may be empirically added (116). Adult and pediatric patients with idiopathic anaphylaxis have similar clinical profiles and should be treated in a similar way (117).

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6. Anaphylaxis to Latex Exposure to latex is widespread. Sources include condoms, balloons, gloves, bladder catheterization with rubber tubing, intravenous injection ports and tubing, ventilator tubing, electrocardiogram pads, and latex-cuffed enema tubes. In patients with latex allergy, perioperative prophylaxis with corticosteroids, H 1- and H 2-antagonists, and ephedrine has been recommended; however, such a prophylactic regimen, while useful, has not been as successful in preventing reactions to latex as it is in preventing reactions to RCM in at-risk individuals, perhaps due to differences in the inducing or causative mechanisms between RCM and latex (118). 7. Exercise-Induced Anaphylaxis Exercise-induced anaphylaxis was first described by Sheffer and Austen in 1980 (119). The mechanism responsible for anaphylaxis appears to be non-IgE-mediated mast cell activation. Successful prophylaxis with antihistamine therapy is not always achieved (120, 121). Of almost 300 patients, 56% reported improvement with H 1-antagonist prophylaxis compared to 44% who improved by avoiding extreme temperatures and 37% who improved by avoiding certain food co-triggers (24). 8. Drug- and Anesthesia-Related Anaphylaxis Drugs used perioperatively and for anesthesia are frequently implicated as causes of anaphylaxis. Even in asymptomatic patients undergoing surgery and general anesthesia, there is evidence of mediator release from mast cells (122). Histamine is liberated from mast cells in the lung vasculature and the heart during pediatric cardiopulmonary bypass (123). Basophil and mast cell release of histamine appears to be the mechanism underlying adverse reactions to many anesthetic agents. Propanidid, althesin, chemaphor, and opiates are examples of perioperative substances that directly release histamine (41). Muscle relaxants, especially atracurium, can release histamine from human lung and skin mast cells, but the effect varies considerably from patient to patient (124, 125). With the exception of buprenorphine, the majority of these drugs stimulate release of preformed mediators but do not generally stimulate synthesis of late mediators. In a study of 11 patients with previous reactions to anesthesia, patients were premedicated with prednisone and diphenhydramine. In addition, in seven of these patients, substances to which they had positive skin tests were avoided. Only 1 of the 11 patients had any repeat reaction and none had anaphylaxis (109). Other studies have demonstrated the clinical efficacy of antihistamine prophylaxis in perioperative patients (126, 127). In general, H 1-antagonists can decrease the occurrence and severity of anaphylactoid reactions to anesthesia.

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After consideration of the evidence from patients undergoing anesthesia, especially the fact that histamine may be elevated in the majority of asymptomatic patients, it is tempting to recommend universal prophylactic antihistamine therapy (41, 50, 128). Universal prophylaxis with H 1- and H 2-antagonists in the perioperative patient is controversial and many urge restraint. Endorsement of such a policy should come only after large multicenter trials show unequivocal benefit. For now, prophylactic regimens are indicated for those individuals at risk for adverse reactions to procedures that cannot be avoided. Examples of patients at risk may include those with previous reactions, atopy, multiple drug allergies, previous bronchospasm, previous anaphylaxis (any cause), and certain tumors (51). 9. Morphine Morphine is used for preoperative analgesia and induction of anesthesia. Philbin and associates investigated the relationship between plasma histamine levels, systemic vascular resistance, and diastolic blood pressure in patients given 1 mg/ kg intravenous morphine before cardiac bypass surgery. In patients undergoing bypass, intravenous morphine causes significant histamine release. Four groups of 10 patients each were studied. Group 1 received placebo; group 2 received cimetidine; group 3 received diphenhydramine; group 4 received both the H 1and H 2-antagonist. Patients in both groups 3 and 4 had significant decrease in morphine-related reactions, but the combination therapy was more effective than treatment with the H 1-antagonist alone. Thus, pretreatment with antihistamines can attenuate the hemodynamic complications of intravenous morphine administered to patients undergoing cardiac bypass (129). In a postmortem study of heroin-related deaths, 32% of the decedents had elevated mast cell tryptase levels. This suggests that a significant proportion of heroin-related deaths are, at least in part, due to anaphylactoid reactions (130). 10. Vancomycin Intravenous injection with vancomycin or polymixin causes non-immune dosedependent degranulation of mast cells and basophils leading to anaphylactoid reactions. The reaction to vancomycin can be prevented by pretreatment with an antihistamine (131). 11. Protamine Protamine is being used increasingly in cardiac catheterization, cardiothoracic and vascular surgical procedures, dialysis, and leukopheresis. It is also found in some insulin preparations. Reactions to protamine can be IgE-mediated (132). The incidence of reaction to protamine during cardiac bypass can be as high as

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10.7% (133). Patients with known sensitivity to protamine who must undergo procedures in which hexadimethrine bromide cannot be substituted should be pretreated with the prophylactic regimen used for reactions to RCM. 12. Chymopapain Chymopapain, used topically for enzymatic debridement of surface lesions, is known to induce anaphylactoid reactions. Antihistamines have been shown to be effective in the prophylaxis of chymopapain-induced anaphylaxis. In a retrospective review of an uncontrolled trial, the combination of an H 1- and an H 2-antagonist was more effective than an H 1-antagonist alone for prevention of reaction to chymopapain (134). 13. N-Acetylcysteine N-acetylcysteine (NAC) is an antidote for acetaminophen overdose and in much of the world, although not in the United States, is available for intravenous administration. In one study there were 50 cases of anaphylactoid reactions of varying severity to NAC over 17 months in a pediatric hospital. The incidence of anaphylactoid reactions to NAC has prompted clinicians to review the indications for its use. Reactions to NAC can probably be prevented with H 1-antagonists (3). D. The Case for Combination H 1- and H 2-Antihistamine Therapy In 1966 Ash and Schild (135) noticed that the classic antihistamines did not block all of the actions of histamine, especially gastric acid secretion. This was followed by the discovery of the H 2-histamine receptor subtype by Black et al. in 1972 (136). The combination of an H1- and H 2-receptor antagonist is generally needed to reduce histamine-induced peripheral vasodilation, hypotension, and mucus secretion maximally. Combinations of H 1- and H 2-antagonists are more effective in preventing the decrease in diastolic blood pressure and the widening of pulse pressure by histamine. 1. Experimental Evidence In pentobarbitone-anesthetized rats, compound 48/80 produces an anaphylactoid response that includes decreased mean arterial blood pressure, decreased left ventricular pressure, and increased frequency of ventricular tachycardia and fibrillation. Either cimetidine or diphenhydramine reduced the frequency of ventricular tachycardia and fibrillation, but only the combination of the H 1- and H 2-antagonists completely inhibited hypotension and decreased left ventricular pressure and ventricular arrhythmia. (137). Numerous studies have shown that H 1- and

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H 2-receptor antagonists produce a greater inhibition of histamine-induced cardiovascular reactions (129, 138). In a controlled trial using dog and piglet models of anaphylaxis, the combination of the H 1- and H 2-antagonists dimethindene and cimetidine was more effective than dimethindene alone and in combination with famotidine or ranitidine (139, 140). In a crossover study with six human volunteers, dimethindene and cimetidine inhibited histamine-induced decrements in mean arterial pressure and cutaneous reactions (95). After administration of 1 mg/kg morphine intravenously before bypass surgery, there is increased serum histamine, decreased diastolic blood pressure, and decreased vascular resistance. Cimetidine plus diphenhydramine was more effective than either antagonist alone in preventing these hemodynamic effects during reactions to morphine (129). In a dorsal hand vein compliance technique in human subjects, the venodilatory response to histamine is mediated by both H 1- and H 2-receptor subtypes. This study provides compelling evidence that combined H 1- and H 2-antagonist therapy may prevent hypotension during anaphylaxis more effectively than an H 1-antagonist alone (141, 142). The addition of an H 2-antagonist reversed symptoms in several patients who were unresponsive to H 1-antagonists and/or ephedrine (143–145). The combination of H 1- and H 2-antagonists is more effective than either alone for the prevention of anaphylactic reactions to chymopapain, perioperative agents, plasma expanders, and morphine (105). The combination of H 1- and H 2-antagonists for the prophylaxis of anaphylaxis may have additional effects other than blocking the action of histamine at its receptors. The combination may exert a mast cell–stabilizing effect or suppress immune cell function (41, 146). The use of H 2-antagonists alone in patients who experience anaphylactoid reactions may be associated with an increased risk of cardiac arrhythmia (43).

VI. SUMMARY Anaphylaxis and anaphylactoid reactions are potentially fatal. These disorders are sometimes iatrogenic, and increase with increased exposure to drugs, synthetic substances, and medical procedures. Non-IgE-mediated anaphylactoid reactions are common in medical settings and are clinically indistinguishable from anaphylaxis. These reactions may be unrecognized if a rigid classic definition of anaphylaxis is used. Histamine is a primary mediator of anaphylaxis and signs and symptoms of anaphylaxis can be reproduced by histamine infusion. Histamine triggers a cascade of inflammatory mediators and modulates its own release. H 1-antihistamines are adjunctive treatment therapy for acute anaphylaxis and anaphylactoid reactions, in which many mediators of inflammation are in-

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volved. Compared with epinephrine, the first-response medication of choice, antihistamines have a slow onset of action, and they cannot block events that occur subsequent to histamine binding to its receptors. Antihistamines are an important component of regimens for the prevention of anaphylaxis and anaphylactoid reactions in patients at risk, and may eventually have more widespread application in the perioperative setting. In some instances, such as with exercise-induced anaphylaxis and reactions to latex in sensitized individuals, prophylaxis regimens are not always effective. H 2-antagonists are not detrimental in the therapy of anaphylaxis and many studies show a favorable outcome when combining H 1- and H 2-antagonist therapy for prophylaxis. They should be added to therapy at the discretion of the treating physician. Because of decreased antimuscarinic and central nervous system side effects, the newer antihistamines can be given in high doses, allowing more complete blockade of histamine receptors. These agents should lead to a reevaluation of the usefulness of antihistamines in both the treatment of acute anaphylaxis and in prophylactic regimens. The unavailability of parenterally administered second-generation H 1-antagonists limits their usefulness in acute anaphylaxis and perioperative prophylaxis.

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130. Edston E, van Hage-Hamsten M. Anaphylactoid shock—a common cause of death in heroin addicts? Allergy 1997; 52:950–954. 131. Williams PD, Laska DA, Shetler TJ, McGrath JP, White SL, Hoover DM. Vancomycin-induced release of histamine from rat peritoneal mast cells and a rat basophil cell line (RBL-1). Agents Actions 1991; 32:217–223. 132. Weiss ME, Nyhan D, Peng ZK, Horrow JC, Lowenstein E, Hirshman C, Adkinson NF. Association of protamine lgE and lgG antibodies with life-threatening reactions to intravenous protamine. N Eng J Med 1989; 320:886–892. 133. Weiler JM, Gellhaus MA, Carter JG, Meng RL, Benson PM, Hottel RA, Schillig KB, Vegh AB, Clarke WR. A prospective study of the risk of an immediate adverse reaction to protamine sulfate during cardiopulmonary bypass surgery. J Allergy Clin Immunol 1990; 85:713–719. 134. Moss J, Roizen MF, Nordby EJ, Thisted R, Apfelbaum JL, Schreider BD, McDermott DJ. Decreased incidence and mortality of anaphylaxis to chymopapain. Anesth Analog 1985; 64:1197–1201. 135. Ash AS, Schild HO. Receptors mediating some actions of histamine. Br J Pharmacol 1966; 27:427–439. 136. Black JW, Duncan WAM, Durant GJ, Ganellin CR, Parsons EM. Definition and antagonism of histamine H 2-receptors. Nature 1972; 236:385–390. 137. Dai S. Circulatory depression and ventricular arrhythmias induced by compound 48/80 in anaesthetized rats. Agents Actions 1991; 34:316–323. 138. Lorenz W, Ennis M, Doenicke A, Dick W. Perioperative uses of histamine antagonists. J Clin Anesth 1990; 2:345–360. 139. Lorenz W, Kubo K, Stinner B, Sitter H, Hasse C, Dietz W, Schmal A, Krack W. Studies on the effectiveness of H 1- ⫹ H 2-antagonist combinations in preventing life-threatening anaphylactoid reactions in anaesthesia and surgery: problems with selecting the animal model from clinical data and with ‘‘equi-effective’’ dose. Agents Actions 1992; Special Conference Issue C231–237. 140. Lorenz W, Duda D, Dick W, Sitter H, Doenicke A, Black A, Weber D, Menke H, Stinner B, Junginger T, Rothmund M, Ohmann C, Healy MJR, and the Trial Group Mainz Marburg. Incidence and clinical importance of perioperative histamine release: randomized study of volume loading and antihistamines after induction of anaesthesia. Lancet 1994; 343:933–940. 141. Dahl JB. Antihistamine prophylaxis and general anaesthesia. Lancet 1994; 343: 929–930. 142. Dachman WD, Bedarida G, Blaschke TF, Hoffman BB. Histamine-induced venodilation in human beings involves both H 1- and H 2-receptor subtypes. J Allergy Clin Immunol 1994; 93:606–614. 143. Vidovich RR, Heiselman DE, Hudock D. Treatment of urokinase-related anaphylactoid reaction with intravenous famotidine. Ann Pharmacother 1992; 26:782–783. 144. De Soto H, Turk P. Cimetidine in anaphylactic shock refractory to standard therapy. Anesth Analg 1989; 69:264–265. 145. Yarbrough JA, Moffitt JE, Brown DA, Stafford CT. Cimetidine in the treatment of refractory anaphylaxis. Ann Allergy 1989; 63:235–238. 146. Brown AF. Anaphylactic shock: mechanisms and treatment. J Accid Emerg Med 1995; 12:89–100.

10 Cost-Effectiveness of H 1-Antihistamines Michael S. Blaiss University of Tennessee Center for the Health Sciences College of Medicine, Memphis, Tennessee

I.

INTRODUCTION

H 1-antagonists are commonly used in the treatment of seasonal and perennial allergic rhinitis, allergic conjunctivitis, acute and chronic urticaria, atopic dermatitis, asthma, and anaphylaxis. Allergic rhinitis and asthma affect a large percentage of the population. They are associated with high expenditures for medical care and high indirect costs due to work and school absences and decreases in productivity. These disorders lead to impaired quality of life for patients. With the changes occurring in the health care arena and continued decrease in monetary resources, cost and quality-of-life considerations must be assessed in addition to clinical efficacy and safety when evaluating pharmacological treatments. This chapter begins with a general overview of the discipline of pharmacoeconomics. It continues with a review of studies assessing the cost and quality-of-life considerations in prescribing H 1-antagonists for managing allergic rhinoconjunctivitis, urticaria and angioedema, atopic dermatitis, asthma, and anaphylaxis.

II. OVERVIEW OF PHARMACOECONOMICS With the increasing emphasis on economics in health care there has been an incentive to develop new ways to assess the value of health care treatment. This has led to the development of the field of pharmacoeconomics, which can be defined as the identification and measurement of the comparative value of differ319

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ent pharmaceutical therapies in the management of a disease (1). When assessing the value of a drug, one needs to look beyond the purchase price, and take into account the drug’s total economic and health effect on the patient population. This information can lead to improved decisions in caring for the individual patient and in developing public health policy (2). Costs in health care can be organized into two major categories: direct and indirect (3). Direct costs include the monies spent during the course of managing the disease (4, 5). Along with the cost of therapeutic agents, direct costs include medical services, such as outpatient clinic, hospital, and emergency department visits, physician fees, and laboratory procedures. Some direct costs can be nonmedical, including transportation for medical services and monies for research and teaching. Other direct costs are ‘‘hidden.’’ These are monies spent directly for other medical conditions that may have been brought about by the condition being evaluated. Indirect costs encompass all the non-health care costs associated with the illness. These include monies lost due to missing work and decreased productivity due to the illness. Other indirect costs to measure include the monetary value of missing school and unpaid caregivers’ time to look after a sick child. In understanding economic assessments in medicine, it is important to understand the difference between efficacy and effectiveness studies. Efficacy studies measure results in controlled situations with a highly selected population. This type of study is the double-blind, placebo-controlled procedure used to evaluate the effect of the medication and safety. In pharmacoeconomic studies, effectiveness trials are done. This type of evaluation is ‘‘real-world,’’ in which routine conditions in a more generalized population are used to assess outcomes of medication use. Health care economists have developed several different techniques to compare costs among different treatment modalities. The four most commonly used assessments are cost-identification analysis, cost-benefit analysis, cost-effectiveness analysis, and cost-utility analysis (Table 1). A cost-identification anal-

Table 1

Economic Evaluations in Health Care

Cost-Identification Costs are compared Cost-Benefit Costs are compared Cost-Effectiveness Costs are compared Cost-Utility Costs are compared or treatments.

among different programs or treatments. to benefits from a program or treatment as defined by society. to clinical effects produced by different programs or treatments. to quality-adjusted life years attained among different programs

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ysis compares costs when the safety and efficacy of any two or more treatments are assumed to be equal. This technique should not be used if there is any question of differences in outcomes observed with the different treatment modalities. A common use of cost-identification analysis would be comparing a brand-name drug with its generic equivalent. Cost–benefit analysis is a comparison of costs and the accompanying outcomes on a monetary basis (4). This technique requires placing a dollar value on the outcomes produced, which could be very difficult depending on who is setting the value of the benefits obtained. An example of cost–benefit analysis would be a case in which one treatment that costs $500 a year produces outcomes valued by society at $1500, while a second treatment that costs $250 a year produces outcomes valued by society at $1000 per year. The second treatment would have the highest cost–benefit for the outcomes obtained, since for each dollar spent there was a $4 benefit ($1000 outcomes/$250 costs), while the first treatment had a $3 benefit ($1500 outcomes/$500 costs). Difficulties from this type of cost evaluation arise when one tries to put a monetary value on years of life saved or improvements in psychosocial outcomes (2). The cost-effectiveness analysis compares the costs of alternative treatments in monetary units with the clinical results obtained with treatment (6). This analysis uses a natural unit or health outcome such as life-years gained, symptom-free days, or number of cures obtained for assessing outcomes. This method allows for the development of the cost-effectiveness ratio: the cost to achieve a particular outcome. An example would be one treatment that costs $1000 for 5 patients and increases symptom-free days by 50% and a second treatment that costs $1500 for 5 patients and increases symptom-free days by 90%. Treatment A has a costeffectiveness ratio of 20 (1000/50) while treatment B’s ratio is 16.7 (1500/90). Even though the second treatment is more costly, it is more cost-effective due to the higher increase in symptom-free days for each dollar spent. In using costeffective analysis in comparing two treatments, there are four possible outcomes (7) (Fig. 1). Quadrant I shows that treatment A is more effective and costs less than treatment B. In this case treatment A is truly cost-effective. In quadrant III, the scenario illustrates that treatment A is more costly and less effective than treatment B; therefore, treatment B is more cost-effective. The next possibility, quadrant II, shows that treatment A is less costly and less effective than treatment B. In this scenario, treatment A may or may not be the most cost-effective depending upon the particular clinical situation and resources available for treatment. One would need to analyze the cost-effectiveness ratio to determine the optimal therapy. Quadrant IV, the last possibility, shows that treatment A is more costly and more effective. Again it would depend upon the clinical situation, resources available, and assessment of the cost-effectiveness ratio, in determining which treatment produces the best value. The last method of assessing pharmacoeconomics costs is cost-utility anal-

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Figure 1 Possible outcomes of cost-effectiveness analysis (see text for explanation). (Adapted from Ref. 7.)

ysis. This technique compares monies spent to one component of outcomes, health-related quality of life (HRQL) and has led to development of a patientweighted unit of measure: quality-adjusted life years (QALY) (8, 9). A key element in the QALY methodology is that it weighs years of life by the patient’s subjective health quality (10). Usually this form of cost analysis is applied in national or regional health care policy decisions, especially when comparing costs per QALY obtained between different treatments in determining funding for different programs. A difficulty in this type of cost evaluation is measuring the patient’s perception of the disease and its subsequent change with treatment. This has led to the development of psychometric questionnaires to assess the patient’s HRQL to calculate the utility unit, QALY. (8). One evaluates HRQL by using two different types of questionnaires: generic and disease-specific. Generic HRQL questionnaires are broad-based surveys that can be used to assess quality of life over a variety of conditions and populations regardless of disease state. These surveys can compare quality of life among different diseases and populations. Examples of generic quality-of-life questionnaires are the Sickness Impact Profile, the Quality of Well-Being Scale, and the Medical Outcomes Study Short Form 36 (SF-36) and 12 (SF-12). The SF-36 was developed as part of the Medical Outcomes Study and analyzes health status using 36 questions to measure nine different health dimensions (11). Bousquet used the SF-36 to assess the HRQL in patients with perennial allergic rhinitis to

Cost-Effectiveness Table 2

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SF-36 Questionnaire Scores

Health domain Physical functioning Physical limitations Pain Social functioning Energy/fatigue Emotional limitations Mental health General health perception Change in health

Healthy adults (n ⫽ 116)

Allergic rhinitis patients (n ⫽ 111)

95.9 92.0 90.3 91.3 71.9 86.7 73.4 81.7 54.1

88.6* 60.6* 76.9* 73.1* 54.5* 64.2* 64.8 † 62.4* 49.8

* p ⬍ 0.0001. † p ⬍ 0.0005. Source: Adapted from Ref. 2.

pets or dust mites (12) and found that, in all but one health domain, patients with perennial allergic rhinitis had significantly poorer quality of life than the healthy controls (Table 2). Specific instruments used in the evaluation of quality of life are usually focused on one particular interest such as a disease state, a distinct patient population, or certain functions or problems. An example in allergic rhinitis is the Rhinitis Quality-of-Life Questionnaire (RQLQ) (13, 14) (Table 3). It is scored on a six-point scale with a lower score indicating better quality of life. Meltzer et al., using the RQLQ, showed that patients with rhinitis have impaired quality of life compared to the healthy population (15).

Table 3 Domains of the Juniper and Guyatt Rhinoconjunctivitis Quality-ofLife Questionnaire 1. Activities 2. Sleep 3. Nonspecific symptoms: fatigue, thirst, reduced productivity, tiredness, poor concentration, headache, worn out 4. Practical problems: need to rub and blow nose/eyes repeatedly, inconvenience of having to carry handkerchief 5. Nasal symptoms 6. Eye symptoms 7. Emotional problems: frustrated, impatient or restless, irritable, embarrassed by symptoms Source: Adapted from Ref. 13.

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III. ALLERGIC RHINITIS: ECONOMIC IMPACT Up to 40% of the population suffers from allergic rhinitis (16, 17). A majority of patients with allergic rhinitis are children, adolescents, and young adults (18). Because patients are rarely, if ever, hospitalized, rarely require surgery or other sophisticated interventions, and do not have their day-to-day survival threatened by this entity, allergic rhinitis may be seen as a minor nuisance. It is now being recognized as a costly condition in the health care arena. Costs of allergic rhinitis can be classified into two major categories: direct and indirect. Direct costs are monies spent in the care of the patient, while indirect costs are monies lost due to the disease. An important aspect of allergic rhinitis costs is that this disease can lead to or complicate other high-cost disorders such as asthma, sinusitis, otitis media with effusion, and nasal polyposis. These conditions lead to an important cost category: ‘‘hidden’’ direct costs. Table 4 illustrates the direct, ‘‘hidden’’ direct, and indirect costs associated with allergic rhinitis.

Table 4

Direct and Indirect Costs of Allergic Rhinitis

Direct costs Physician/provider consultation Laboratory testing: allergy skin tests, RAST, etc. Costs of specific allergy therapy: environmental control, prescription and OTC medications, and immunotherapy ‘‘Hidden’’ direct costs Costs for antibiotics, radiographs for diagnosis and emergency department visits for sinusitis Surgical costs for nasal polyposis and sinusitis Medical and surgical costs for otitis media with effusion Costs of worsening asthma and frequent upper respiratory infections Orthodontic costs Evaluation and treatment of ocular symptoms Indirect costs Sleep disorders and neuropsychiatric abnormalities Activity limitation due to symptoms and effects of first-generation H 1-antagonists Decreased decision-making capacity Impaired psychomotor function Poor concentration Irritability Fatigue Decreased functioning at work and school Increased motor vehicle accidents and school and workplace injuries Source: Adapted from Ref. 3. RAST, radio allergosorbent test; OTC, over-the-counter.

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Recently several groups of investigators have evaluated the cost of allergic rhinitis in the United States. In each of these studies cost was assessed in different ways, leading to different cost estimates. McMenamin assessed the costs and prevalence of this condition in 1990 by using the National Health Interview Survey (NHIS) to estimate the number of patients with allergic rhinitis and the National Ambulatory Medical Care Survey (NAMCS) to estimate the type of physician treatments provided (19). His results suggested that the prevalence rate of allergic rhinitis was 9.3%, with total costs in 1990 of $1.8 billion. Direct costs totaled $1.16 billion with $881 million from physician costs and $276 million from medication costs. Indirect costs from allergic rhinitis came to $639 million, estimated from a loss of 3.4 million workdays. Ross assessed the indirect cost of allergic rhinitis in the workplace (20). Using the data from the United States Public Health Survey, he calculated that allergic rhinitis affected 12.6 million people in the U.S. workforce in 1989. Next he extrapolated the increase in the workforce through 1993 and calculated the loss of productivity due to allergic rhinitis. For 1993, the loss of productivity in the U.S. labor force was $2.39 billion in men and $1.4 billion in women. Because such a high percentage of the workforce has allergic rhinitis, it is estimated from his data that lost productivity due to this disorder may cost $1000 for each worker in the United States per year. Malone et al. produced another study addressing the burden of allergic rhinitis on the national economy (21). By using data from the 1987 National Medical Expenditure Survey, they calculated estimates of resource utilization, medical expenditures, and lost productivity from allergic rhinitis and extrapolated the data in 1994 dollars. They estimated that 39 million Americans had allergic rhinitis in 1987, but only 12.3% obtained medical care from physicians. Allergic rhinitis accounted for 811,000 missed workdays, 824,000 missed school days, and 4,230,000 reduced activity days in 1987. The total cost of allergic rhinitis in 1994 dollars was $1.23 billion. Storms et al. (22) conducted a nationwide survey in 1993 to evaluate the costs related to the management of allergic rhinitis in the United States. Patients with ocular and/or nasal symptoms for 7 days or more during the previous 12 months were studied with regard to the amount of medical care services, including spending on medication, over that 12-month period. Sixty-three percent of the respondents consulted a physician in the previous 12 months, with an estimated cost of $1.1 billion. The average per-person expenditure for prescription medications was $56/year. The same amount was spent on nonprescription medications yearly, giving an estimated total cost in medications for allergic rhinitis in the range of $2.4 billion. Mackowiak developed an employer cost/benefit economic model for allergic rhinitis (23). In looking at pharmaceutical costs he obtained data on drug sales from various pharmaceutical companies for his model. The preliminary data

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Table 5 Medical Expenditures Attributable to Allergic Rhinitis/Allergic Conjunctivitis in the United States by Age of Patient and Airway Disorder (1996; in millions of dollars) Airway disorder

ⱕ12 years

ⱖ13 years

Total

356.6 1173.5 176.0 253.3 114.3 76.5 41.6 30.3 26.8 2250.9

1506.8 310.0 841.2 751.4 97.6 89.3 46.3 32.0 5.3 3679.9

1863.4 143.5 1017.3 1006.7 211.8 165.7 88.0 62.3 32.0 5930.8

Allergic rhinitis/allergic conjunctivitis Chronic otitis and eustachian tube disorders Sinusitis Asthma Acute upper respiratory tract infection Pharyngitis and tonsillitis Other conjunctivitis Chronic rhinitis Rhinorrhea Total Source: Adapted from Ref. 24.

show direct costs of allergic rhinitis of $4.48 billion and indirect costs of $3.37 billion. Ray et al. assessed direct expenditures for treatment of allergic rhinoconjunctivitis in 1996, along with calculating the ‘‘hidden’’ direct costs of rhinitis, such as sinusitis, asthma, acute upper respiratory tract infection, pharyngitis and tonsillitis, nonatopic conjunctivitis, and chronic otitis media and eustachian tube disorders (24). These investigators found that the primary diagnosis of rhinitis led to direct costs of $1.9 billion (in 1996 dollars). Costs were estimated for rhinitis as a secondary diagnosis and found to be $4.0 billion (Table 5). Although all these studies took distinct approaches and used different methods in determining costs related to allergic rhinitis, it is clear that this disease has a significant economic impact on the health care system.

IV. COST-EFFECTIVE MANAGEMENT OF ALLERGIC RHINITIS In allergic rhinitis, treatment consists of a threefold approach. First, avoidance procedures should be instituted to decrease exposure to harmful allergens. Next, appropriate pharmaceutical agents should be prescribed to help alleviate and prevent chronic symptoms. Last, allergen vaccination may be needed to significantly desensitize or possibly eliminate symptoms due to specific allergens. With the large population of patients with allergic rhinitis and its high total cost, it is important to be able to determine what treatment measures are truly cost-effective in the management of this disorder.

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MEDICAL MANAGEMENT OF ALLERGIC RHINITIS

The mainstays of pharmacological therapy for allergic rhinitis are oral H 1-antagonists and intranasal corticosteroids. Table 6 lists some first- and second-generation H 1-antagonists and their costs per day calculated from their average wholesale price and recommended frequency of daily dosing (25). The average wholesale price is used to keep the data uniform in this analysis. It is important to note that the true cost of the H 1-antagonist for the patient may vary because certain health plans may have arrangements for discounts from pharmaceutical companies and certain pharmacists charge more or less for a particular medication. Also, in many countries most H 1-antagonists, including the new nonsedating ones, are available on a nonprescription basis. First-generation H 1-antagonists have been in use for many years. These drugs are all effective in decreasing the symptoms of allergic rhinitis such as rhinorrhea, sneezing, nasal itching, and ocular symptoms and are the least expensive daily pharmacological therapy in the management of allergic rhinitis (Table 6). They may not be the most costeffective, however, because many patients experience significant side effects that may impair productivity (Chap. 11). These H 1-antagonists cross the blood–brain barrier and may cause significant central nervous system sedation, impairment of psychomotor function, and depression (26, 27). This sedation may be imperceptible. In many states it is illegal to operate heavy machinery or a motor vehicle while using these medications. Internationally, civilian and military aviation authorities prohibit their use. The first-generation sedating H 1-antagonists have been shown to have a detrimental effect on learning in children (28–30). Fireman determined from pharmacy data from a health maintenance organization (HMO) Table 6 Cost per Day from 2001 Drug Topics Red Book Based on Average Wholesale Price of H 1-Antihistamines at the Recommended Daily Dosage Second-generation a Fexofenadine (60 mg) Loratadine (10 mg) Cetirizine (10 mg) First-generation Diphenhydramine (50 mg) Clemastine (2.68 mg) Chlorpheniramine (8 mg) Nasal spray Azelastine a

$2.07 $2.44 $1.92 $0.56 $1.35 $0.21 $1.99

Costs in United States reflect prescription-only status of these H 1-antihistamines. Source: From Ref. 25.

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that first-generation antihistamine usage was associated with significantly more work-related injuries compared to control groups (31). He estimated the annual cost of lost productivity to employers and society as the result of allergic rhinitis and use of over-the-counter sedating H 1-antagonists to be greater than $4 billion. The second-generation H 1-antagonists are relatively nonsedating. These are also listed in Table 6. These agents are as effective in relief of symptoms as the first-generation H 1-antagonists (32, 33). The advantages these H 1-antagonists have over the first-generation agents include rare sedation (no greater than placebo at the indicated dosage, except for cetirizine which is slightly greater than placebo) (34), no anticholinergic effects, lack of tolerance with prolonged use, and decreased dosing frequency (35). These agents have been shown to improve the quality of life in patients with allergic rhinitis (36–38). Comparisons among the different second-generation H 1-antagonists have generally failed to show any clinically significant difference in efficacy in management of allergic rhinitis (39). There are few comparative studies in cost-effectiveness and quality of life among the second-generation agents. Harvey compared cetirizine, terfenadine, and chlorpheniramine in a large managed care setting and found that cetirizine was associated with the greatest improvement in quality of life using the RQLQ (40). Antihistamine nasal sprays (Table 6) are available for treatment of allergic rhinitis. The cost is equivalent to that of oral second-generation H 1-antagonists and their efficacy is similar (41, 42). The major side effects observed with azelastine are somnolence and bitter taste. No cost-effectiveness data have been published to date for ebastine and mizolastine.

VI. COMPARATIVE STUDIES WITH OTHER AGENTS IN ALLERGIC RHINITIS MANAGEMENT Another important modality in the treatment of allergic rhinitis is intranasal corticosteroids. Table 7 summarizes the preparations available along with their daily cost based on average wholesale price. In general, the daily cost of intranasal corticosteroids is less than second-generation H 1-antagonists (see Tables 6 and 7). Several studies have compared the cost-effectiveness and quality of life associated with these two major treatments for allergic rhinitis. Bronsky et al. compared an intranasal corticosteroid, fluticasone, with a second-generation antihistamine, terfenadine, and placebo for treatment of seasonal allergic rhinitis in 348 patients (43). Patient-rated total nasal symptom scores throughout treatment and total nasal airflow, measured by rhinomanometry, were significantly ( p ⬍ 0.05) improved in the fluticasone-treated group compared with the terfenadine-treated

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Table 7 Cost per Day from 2001 Drug Topics Red Book Based on Average Wholesale Price of Intranasal Corticosteroids at the Recommended Daily Dosage Fluticasone propionate Triamcinolone acetonide (aqueous) Budesonide aqueous Flunisolide Mometasone furoate

$1.87 $1.41 $1.66 $1.74 $1.83

Source: From Ref. 25.

group. Other clinical studies have shown that adults and adolescents with seasonal allergic rhinitis had significantly better improvement with fluticasone nasal spray than loratadine tablets (44, 45). Kozma compared cost-efficacy ratios for intranasal fluticasone and terfenadine tablets within a sample of patients with seasonal allergic rhinitis symptoms due to mountain cedar allergy (46). Costs measured were the direct costs of the drugs used for therapy; efficacy was assessed using patient ratings of symptoms and their overall assessment of response to treatment. The cost-efficacy ratios for intranasal fluticasone once daily were more favorable than the ratios for terfenadine 60 mg twice daily. Two cost-effectiveness studies from Canada found fluticasone to be 2.5 times less costly daily than terfenadine and 5.7 times less costly daily than loratadine (47). Other intranasal corticosteroids and second-generation H 1-antagonists have been compared in assessing clinical efficacy. Bernstein et al. conducted a multicenter, double-blind, parallel-group study in 239 patients randomized to receive either triamcinolone nasal spray or astemizole tablets (48). Overall, triamcinolone spray was more effective than astemizole in reducing total nasal symptoms, nasal stuffiness, nasal itching, and sneezing. Schoenwetter et al. compared the safety and efficacy of intranasal triamcinolone with oral loratadine in relieving symptoms of ragweed-induced seasonal allergic rhinitis (49). Improvement in all rhinitis symptoms was significantly greater with triamcinolone than with loratadine. Physicians’ global evaluations indicated that 78% of patients taking triamcinolone had moderate to complete relief, compared with 58% of loratadine-treated patients ( p ⱕ 0.0001). Schulz compared quality of life in patients with allergic rhinitis using triamcinolone nasal spray or loratadine (50). At day 14, the patients using triamcinolone spray were significantly better ( p ⬍ 0.05) in several different components of quality of life and overall quality of life assessment. Ratner assessed use of loratadine tablets alone, fluticasone nasal spray alone, and the combination in the management of seasonal allergic rhinitis. In all aspects, fluticasone alone showed more clinical and quality-of-life improve-

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ment than loratadine tablets. There was no added benefit to the combination of loratadine tablets and fluticasone nasal spray compared to fluticasone nasal spray alone. Weiner performed a meta-analysis of articles comparing intranasal corticosteroids and nonsedating H 1-antagonists in the management of allergic rhinitis (51). The conclusions gained from this study point out the greater improvement in allergic rhinitis symptoms with intranasal corticosteroids, except in eye symptoms, for which both agents were equal. The authors were not truly able to analyze cost-effectiveness from the studies, but did compare the mean daily cost of oral corticosteroids in Australia (by asking pharmacists in four Australian states) with the mean daily cost of intranasal corticosteroids. Their surveillance data found that second-generation H 1-antagonists were 4.5 times more expensive daily than intranasal corticosteroids. Stempel did an evidence-based analysis comparing these agents in allergic rhinitis management and came to the same conclusion (52). A study in South Africa found that intranasal corticosteroids were the least costly in the management of allergic rhinitis (53). In summary, these studies indicate that the intranasal corticosteroids are more cost-effective than the second-generation H 1-antagonists in the management of allergic rhinitis. It is important to remember that convenience and compliance are deciding factors in chronic use of medication. Oral medications have a higher compliance rate than inhaled agents (54). Also, these studies were primarily efficacy-based, involving patients using the medications during short-term clinical trials. In ‘‘real life’’ many patients only use these agents on an as-needed basis. Informing patients of the pros and cons of each type of medication and allowing them to participate in deciding on their pharmacological management may be the best approach for highest compliance. Allergen immunotherapy (vaccinations) is the administration of low, and then sequentially increasing, dosages of allergens by subcutaneous injection in patients with IgE-mediated diseases, such as allergic rhinitis, allergic asthma, and insect sting anaphylaxis (55). It has been shown to be efficacious in the treatment of patients with allergic rhinitis (56, 57). Sullivan reported that the average direct costs for immunotherapy at Emory University were $800 for the first year and $170 for next 2–4 years (58). The estimated costs for immunotherapy based on the Medicare payment schedule are $1640, which includes 24 injections to maintenance dose, followed by monthly injections for 3–5 years and allergen extract preparation for 10 allergens (59). In determining the cost-effectiveness of allergen immunotherapy, Kumar looked at costs of treatment and quality of life in patients with allergic rhinitis prior to allergen immunotherapy and then assessed these variables yearly for 3 years of immunotherapy (60). The cost of care was $1129 ⫾ 321 in the year prior to immunotherapy and $950 ⫾ 352 for the third year of allergen immunotherapy. This study suggests that allergen immunotherapy is no more costly by

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the third year than allergy treatment without immunotherapy, with significant improvement in quality of life. Direct comparisons of cost-effectiveness of immunotherapy and H 1-antagonists are not available.

VII. ATOPIC DERMATITIS Management of patients with atopic dermatitis involves topical emollients, mildmoderate-potency topical corticosteroids, and oral H 1-antagonists. In children in whom a food allergen is implicated in the condition, removal of the offending food can lead to significant improvement in skin manifestations. H 1-antagonists can be beneficial in controlling the chronic pruritus accompanying this disorder. Like allergic rhinitis, the prevalence of atopic dermatitis has been increasing in the pediatric population. The onset in a majority of patients with atopic dermatitis is in infancy, with 90% of patients presenting by 5 years of age. A recent estimate of the annual total national cost for the treatment of childhood eczema in the United States was $364 million (61). Su et al. evaluated the total costs of atopic dermatitis in Australia based on degree of severity. The costs for medication per year ranged from $200 Aus for mild disease to $469 Aus for severe disease. The authors did not differentiate between different categories of medication in their calculations; therefore, the exact contribution of H 1-antagonists’ cost in the total medication’s cost is not known. Studies comparing the cost-effectiveness of different H 1-antagonists in the treatment of atopic dermatitis are lacking. Nunovo reported the use of singlepatient, double-blind controlled studies looking at efficacy of different H 1-antagonists (62). This work found that in both patient and physician preference, chlorpheniramine produced the most noticeable positive therapeutic effect on the patient’s mild but disturbing symptoms (pruritus and eye irritation) compared to the nonsedating H 1-antagonists. Drowsiness was reported with chlorpheniramine. Although it appears as if the sedative effect of the first-generation agents adds to their benefit for nighttime control of pruritus and they bring significant cost savings compared to the newer nonsedating H 1-antagonists, they have the disadvantage of producing adverse effects on patients’ school or work performance and other daytime activities.

VIII. URTICARIA AND ANGIOEDEMA Urticaria and angioedema (Chap. 8) can have a marked effect on the patient’s quality of life. O’Donnell used a generic quality-of-life instrument, the Nottingham health profile, and showed that patients with delayed pressure urticaria had scores showing restriction in the areas of mobility, sleep, and energy, and demon-

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strated high scores in pain, social isolation, and altered emotional reactions (63). H 1-antagonists are the first-line therapy for patients with both acute and chronic urticaria and angioedema. First-generation agents are effective for many forms of urticaria and angioedema, and recent studies have documented the value of the second-generation H 1-antagonists in controlling symptoms (64–66). Research is lacking in comparing the cost-effectiveness of H 1-antagonists in this condition compared to other medications, although it is clear that their safety and efficacy outweigh such treatments as corticosteroids, tricyclic antidepressants, and immunosuppressive therapy, such as cyclosporine. At present there are no studies assessing cost-effectiveness between the first- and second-generation H 1-antagonists in controlling urticaria and angioedema. As with all chronic diseases treated with first-generation H 1-antagonists, one needs to weigh the decreased cost of these agents compared to second-generation agents against the sedative and other adverse effects seen with first-generation agents that can increase indirect costs.

IX. ASTHMA Controversy exists on the role of H 1-antagonists in the management of asthma (Chap. 7). Some studies suggest that H 1-antagonists, especially the second-generation compounds, may be efficacious in some patients (67, 68). A meta-analysis by Van Ganse failed to confirm an advantage of treatment with these medications (69). If further data suggest the efficacy of H 1-antagonists in the treatment of asthma, studies evaluating the cost-effectiveness of these agents would be worth pursuing because of the high direct and indirect costs associated with this disease (70).

X.

ANAPHYLAXIS

H 1-antagonists are considered adjunctive treatment to epinephrine injection in patients with anaphylaxis. Their minimal contribution to the total cost of care in patients with this life-threatening condition does not lend itself to studies assessing cost-effectiveness among different H 1-antagonists in anaphylaxis management.

XI. SUMMARY In the health care arena, assessment of a medication’s clinical efficacy is no longer enough. It is important to confirm the medication’s cost-effectiveness and the improvement in quality of life it provides in relationship to other options in ther-

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apy. H 1-antagonists are widely used in the treatment of many atopic disorders, especially allergic rhinitis. This review has pointed out cost-effectiveness and quality-of-life studies comparing the different H 1-antagonists among themselves, and with other treatments used in allergic rhinitis, such as intranasal corticosteroids and allergen immunotherapy. Cost-effective analyses among H 1-antagonists in other allergic diseases, such as atopic dermatitis, urticaria and angioedema, and asthma, are lacking at this time. REFERENCES 1. Drummond MF, Stoddart GL, Torrance GW. Methods for the Economic Evaluation of Health Care Programmes. New York: Oxford University Press, 1987. 2. Sullivan SD. Cost and cost-effectiveness in asthma. Immunol Allergy Clin North Am 1996; 16:819–839. 3. Blaiss M, Bukstein D, Davis M, Luskin A. Improving allergy and asthma care through outcomes management. In: Davis M, ed. Managed Care Focus Series. Chicago: American Academy of Allergy, Asthma, and Immunology, 1997. 4. Eisenberg JM. Clinical economics: a guide to the economic analysis of clinical practices. JAMA 1989; 262:2879–2886. 5. Luce BR, Manning WG, Siegel JE, Lipscomb J. Estimating costs in cost-effectiveness analysis. In: Gold MR, Siegel JE, Russell LB, Weinstein MC, eds. Cost-Effectiveness in Health and Medicine. New York: Oxford University Press, 1996:176– 213. 6. Gibaldi M, Sullivan SD. A look at cost-effectiveness. Pharmacotherapy 1994; 14: 399–414. 7. Rich MW, Nease RF. Cost-effectiveness analysis in clinical practice: the case of heart failure. Arch Intern Med 1999; 159:1690–1700. 8. Patrick DL, Erickson P. Health Status and Health Policy: Quality of Life in Health Care Evaluation and Resource Allocation. New York: Oxford University Press, 1993. 9. Nord E. The QALY—a measure of social value rather than individual utility? Health Econ 1994; 3:89–93. 10. Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the panel on cost-effectiveness in health and medicine. JAMA 1996; 276:1253– 1258. 11. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I. Conceptual framework and item selection. Med Care 1992; 30:473–483. 12. Bousquet J, Bullinger M, Fayol C, Marquis P, Valentin B, Burtin B. Assessment of quality of life in patients with perennial allergic rhinitis with the French version of the SF-36 Health Status Questionnaire. J Allergy Clin Immunol 1994; 94:182–188. 13. Juniper EF. Measuring health-related quality of life in rhinitis. J Allergy Clin Immunol 1997; 99:S742–749. 14. Juniper EF, Guyatt GH, Griffith LE, Ferrie PJ. Interpretation of rhinoconjunctivitis quality of life questionnaire data. J Allergy Clin Immunol 1996; 98:843–845.

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15. Meltzer EO, Nathan RA, Selner JC, Storms W. Quality of life and rhinitic symptoms: results of a nationwide survey with the SF-36 and RQLQ questionnaires. J Allergy Clin Immunol 1997; 99:S815–819. 16. Sibbald B, Rink E. Epidemiology of seasonal and perennial rhinitis: clinical presentation and medical history. Thorax 1991; 46:895–901. 17. Naclerio RM. Allergic rhinitis. N Engl J Med 1991; 325:860–869. 18. Arrighi HM, Maier WC, Redding GJ, Morray BH, Llewellyn CE. The impact of allergic rhinitis in Seattle school children (abstract). J Allergy Clin Immunol 1995; 95:192. 19. McMenamin P. Costs of hay fever in the United States in 1990. Ann Allergy 1994; 73:35–39. 20. Ross RN. Allergic rhinitis, an expensive disease for American business. Am J Manag Care 1996; 2:285–290. 21. Malone DC, Lawson KA, Smith DH, Arrighi HM, Battista C. A cost of illness study of allergic rhinitis in the United States. J Allergy Clin Immunol 1997; 99:22–27. 22. Storms W, Meltzer EO, Nathan RA, Selner JC. The economic impact of allergic rhinitis. J Allergy Clin Immunol 1997; 99:S820–824. 23. Mackowiak J. The health and economic impact of rhinitis—a roundtable discussion. Am J Managed Care 1997; 3:S8–S18. 24. Ray NF, Baraniuk JN, Thamer M, Rinehart CS, Gergen PJ, Kaliner M, Josephs S, Pung YH. Direct expenditures for the treatment of allergic rhinoconjunctivitis in 1996, including the contributions of related airway illnesses. J Allergy Clin Immunol 1999; 103:401–407. 25. 2001 Drug Topics Red Book. Montvale, NJ: Medical Economic Company, 1999. 26. Nolen TM. Sedative effects of antihistamines: safety, performance, learning, and quality of life. Clin Ther 1997; 19:39–55. 27. Storms WW. Treatment of allergic rhinitis: effects of allergic rhinitis and antihistamines on performance. Allergy Asthma Proc 1997; 18:59–61. 28. Kemp JP. Special considerations in the treatment of seasonal allergic rhinitis in adolescents: the role of antihistamine therapy. Clin Pediatr (Phila) 1996; 35:383– 389. 29. Simons FE. Learning impairment and allergic rhinitis. Allergy Asthma Proc 1996; 17:185–189. 30. Vuurman EF, van Veggel LM, Uiterwijk MM, Leutner D, O’Hanlon JF. Seasonal allergic rhinitis and antihistamine effects on children’s learning. Ann Allergy. 1993; 71:121–126. 31. Fireman P. Treatment of allergic rhinitis: effect on occupation productivity and work force costs. Allergy Asthma Proc 1997;18:63–67. 32. Busse WW. Role of antihistamines in allergic disease. Ann Allergy 1994; 72:371– 375. 33. Du Buske LM. Clinical comparison of histamine H 1-receptor antagonist drugs. J Allergy Clin Immunol 1996; 98:S307–318. 34. Adelsberg BR. Sedation and performance issues in the treatment of allergic conditions. Arch Intern Med 1997; 157:494–500. 35. Pedinoff AJ. Approaches to the treatment of seasonal allergic rhinitis. South Med J 1996; 89:1130–1139. 36. Pariente PD, LePen C, Los F, Bousquet J. Quality-of-life outcomes and the use of

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11 H 1-Antihistamines and the Central Nervous System Michael J. Welch and Eli O. Meltzer Allergy and Asthma Medical Group and Research Center and University of California, San Diego, San Diego, California

F. Estelle R. Simons University of Manitoba, Winnipeg, Manitoba, Canada

I.

INTRODUCTION

First-generation histamine-1-receptor (H 1-receptor) antagonists such as diphenhydramine, triprolidine, hydroxyzine, and chlorpheniramine (chlorphenamine), frequently cause somnolence, performance impairment, and other adverse central nervous system (CNS) effects. Various subjective and objective methods have been utilized to detect these adverse effects. Because the CNS changes induced by H 1-antagonists are complex and cannot be reflected in one measurement, a variety of assessments are required. Dosing strategies have been proposed to circumvent these unwanted effects (pm dosing, relying on tolerance to CNS effects to develop) but their effectiveness is at best uncertain. Second-generation H 1-antagonists such as loratadine, cetirizine, fexofenadine, ebastine, and mizolastine represent a true advance in therapeutics. At manufacturers’ recommended dosages, they result in little or no sedation in contrast to their predecessors, and do not exacerbate the adverse CNS effects of alcohol or other CNS-active chemicals. Differences among various agents within each generation of H 1-antagonists in their effects on the CNS have been noted, and with certain of the secondgeneration H 1-antagonists (e.g., acrivastine and cetirizine), these differences can be clinically relevant. When given in higher than usual dosages by mouth, or even when applied topically, some subjective and/or objective CNS abnormalities have been noted with certain second-generation H 1-antagonists. Given the 337

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availability of the safer second-generation products, the future usefulness of the older first-generation H 1-antagonists used orally in allergic disease is in doubt. The need for a phase-out plan of the sedating first-generation H 1-antagonists will likely become more clear as we collect further experience and information about the advantageous benefit/risk ratio of the second-generation H 1-antagonists.

II. FIRST- VERSUS SECOND-GENERATION H 1-ANTIHISTAMINES Orally administered H 1-antagonists are an integral part of pharmacotherapy for allergic disease. H 1-antagonists applied topically to mucosal surfaces are available as well. Use of the traditional or first-generation H 1-antagonists (Table 1) has been limited by adverse CNS effects. Many allergic individuals choose to suffer with their symptoms and ignore the benefits of H 1-antagonists rather than endure the soporific effects of the old sedating medications in this class. Although new or second-generation H 1-antagonists with less potential for CNS adverse effects have become available (Table 2), the problems of somnolence and impairment with H 1-antagonists continue to exist, and will likely continue for some time. The reason is that the old sedating agents are present in numerous overthe-counter (OTC) allergy and cold formulations, and are inexpensive and widely used by millions of allergy sufferers throughout the world. It is estimated that over 1.4 billion dollars per year is spent on OTC antihistamine-containing products in the United States alone (1). Because second-generation nonsedating H 1antagonists are available by prescription only in some countries, including the United States, and are more costly than their predecessors, first-generation H 1-

Table 1

Selected First-Generation H 1-Antihistaminesa

Alkylamines Brompheniramine (Dimetane) Chlorpheniramine (Chlor-Trimeton) Dexchlorpheniramine (Polaramine) Ethanolamines Carbinoxamine (Clistin) Clemastine (Tavist) Dimenhydrinate (Dramamine) Diphenhydramine (Benadryl) Doxylamine (Unisom) Ethylenediamines Tripelennamine (PBZ) a

U.S. brand names are given in parentheses.

Piperidines Azatadine (Optimine) Cyproheptadine (Periactin) Phenindamine (Nolahist) Piperazines Hydroxyzine hydrochloride (Atarax) Hydroxyzine pamoate (Vistaril) Meclizine (Antivert)

Effects on CNS Table 2

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Second-Generation H 1-Antihistaminesa

Generic name

Brand name

Fexofenadine Loratadine Cetirizine Acrivastine

Allegra Claritin Zyrtec Semprex D

Ebastine Mizolastine Ketotifen Azelastine

NA NA Zaditor Astelin

Levocabastine

Livostin

a

Comments

Available only as a combination antihistamine-decongestant

Available only as ophthalmic drops in USA Available only as nasal spray and ophthalmic drops in USA Available only as ophthalmic drops

U.S. brand names are given.

antagonists are still being selected by consumers and recommended by some physicians. The most common and bothersome adverse effect of H 1-antagonists is CNS depression or sedation, but other adverse nervous system effects may occur. Most first-generation H 1-antagonists possess anticholinergic properties, and can cause blurred vision, dry mouth, urinary retention, impotence, and gastrointestinal effects, mainly due to their peripheral nervous system activity. Central manifestations of their anticholinergic activities include hallucinations and psychosis, even at therapeutic dosages (2). Some, such as promethazine, have alpha-adrenergicblocking ability. Others, such as cyproheptadine, are effective inhibitors of both histamine and serotonin activity, and may cause appetite stimulation and weight gain (3) or aggressive, violent behavior (4), both of which are thought to be related to the drug’s effects on serotonin pathways. Rare adverse effects have also been described either with chronic use or high-dosage acute use of firstgeneration H 1-antagonists and include dyskinesia, muscle spasms, tremor, activation of epileptogenic foci, paresthesias, and various psychiatric disturbances such as anxiety, confusion, hallucinations, and psychosis (5–7). Second-generation H 1-antagonists were developed after a long and costly search for H 1-antagonists that did not have sedative properties. The initial nonsedating compound introduced for clinical use was terfenadine, the earliest of what have been termed ‘‘second-generation’’ H 1-receptor antagonists. A number of additional agents have since become available (e.g., acrivastine, astemizole, loratadine, cetirizine, fexofenadine, ebastine, mizolastine, levocabastine, azelastine). Second-generation, relatively nonsedating H 1-antagonists have been compared with first-generation agents and placebo in an extensive number of controlled subjective and objective studies. Findings from these studies confirm the

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clinical impression held by physicians: these second-generation H 1-antagonists are better tolerated and safer than their predecessors (8–15). Specifically, secondgeneration H 1-antagonists produce significantly less somnolence and other adverse CNS effects than the first-generation H 1-antagonists, and do not exacerbate the adverse CNS effects of alcohol and other CNS-active chemicals. They also appear to have little or no affinity for muscarinic cholinergic receptors and therefore do not cause dry mouth or other anticholinergic effects (16, 17). Most do not have antiserotoninergic activities, and do not cause appetite stimulation or weight gain, although this has been reported in some patients after astemizole and ketotifen administration (18, 19). Over the last several years, two of the original second-generation H 1-antagonists (terfenadine and astemizole) have been removed from the market in most countries. An extensive body of literature pertains to these two very important and widely used H 1-antagonists. Because they are no longer available to patients, they will not be discussed in detail in this chapter. However, they may be mentioned or referred to when needed for historical reasons, or because they were used as comparators in studies of other H 1-antagonists.

III. THE BLOOD–BRAIN BARRIER AND MECHANISMS OF CNS ADVERSE EFFECTS The blood–brain barrier, formed by endothelial cells lining CNS capillaries, has evolved to provide a stable chemical environment for neurons. Endothelial cells in CNS capillaries are characterized by tight junctions, with cell membranes being fastened along the length of their contact. The capillaries are encased by astrocytes. Lipid-soluble molecules travel freely across these endothelial membranes, but other chemicals need the help of pinocytosis, receptors, or specific transport mechanisms (20). Most first-generation H 1-antagonists readily penetrate the blood–brain barrier (21). The variable propensity of these medications to cause somnolence and other CNS effects now limits their use in the treatment of allergic disorders. In other patient populations, some of these CNS effects are considered to be therapeutic; for example, the use of nonprescription dimenhydrinate for the treatment of motion sickness and diphenhydramine or doxylamine as medications for insomnia. The mechanisms by which the first-generation H 1-antagonists cause useful and adverse CNS effects are still being elucidated. The role of histamine as a neurotransmitter is now firmly established. Histamine has important neuromodulatory influences on CNS electrophysiology that determine normal thalamocortical function in the brain (22). The histaminergic system seems to be concerned with mechanisms that favor vigilance during the wakeful state and the balance

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between wakefulness and slow-wave activity during sleep (23). Histamine also functions as a neuroregulator for higher brain functions (e.g., cognition, memory), with deficits of the histaminergic system having been implicated as playing an important role in major diseases such as Alzheimer’s, schizophrenia, and Down syndrome (24–26). Histaminergic pathways are widespread. They originate from the reticular formation and project diffusely to the cerebral cortex. Most firstgeneration H 1-antagonists in therapeutic dosages lead to the occupation of a major fraction of the cerebral H 1-receptors; hence, central effects in humans are thought to be predominantly mediated by a blockade of endogenous histamine (22). Yanai, (27) using positron emission tomography and comparing the histamine H 1-receptor occupancy between chlorpheniramine and terfenadine, demonstrated that first-generation H 1-antagonists in recommended doses occupied almost all H 1-receptors in the brain and that the full occupancy of H 1-receptors was closely related to their unwanted central side effects. Further proof that somnolence and CNS dysfunction arise from H 1-antagonism alone within the CNS is based on studies demonstrating that subjective and objective measurements of drowsiness and performance are limited to H 1-antagonist enantiomers with a high affinity for CNS histamine H 1-receptors. For example, (⫹)-chlorpheniramine (chlorphenamine) and (⫺)-dimethindene enantiomers produce sleepiness, decrease daytime sleep latency, and impair digit–symbol substitution tests, whereas the enantiomers (⫺)-chlorpheniramine and (⫹)-dimethindene, both of which have low affinity for the H 1-receptor, do not differ from placebo in their subjective or objective CNS effects (28). Other mechanisms may play a role in the central effects of some H 1-antagonists, such as their known ability to inhibit the metabolism of histamine by N-methyltransferase, and the additional ability of some to block cholinergic, alpha-adrenergic, and serotonin receptors in the brain. The idea that peripheral and central H 1-receptors differ (29) is no longer accepted; however, H 1-receptor subtypes possibly exist (30). Also, in contrast to earlier views (31), it is now believed the H 1-antagonists probably have similar affinity for peripheral H 1-receptors and for central H 1-receptors (32). The precise structural requirements for receptor selectivity and affinity are still being elucidated (33). Most of the second-generation H 1-antagonists penetrate poorly into the CNS, which accounts for their relative nonsedating properties. The proportional contribution of factors such as large molecular size, electrostatic charge, lipophilicity, binding to serum albumin, and small volume of distribution to this phenomenon is either unknown or is still being elucidated (34, 35). The addition of a chemical group that is ionized at physiological pH will convert a potentially sedating H 1-antagonist into a less sedating one. For example, the oxidation of the terminal alcohol group of hydroxyzine to a carboxylic acid group results in cetirizine, which is less sedating than its parent compound. The second-generation H 1-antagonists also have much less affinity for muscarinic cholinergic and

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serotoninergic receptors than their predecessors do, and this, too, contributes to their relative lack of adverse CNS effects (31, 36–38).

IV. ASSESSMENT OF CNS EFFECTS CNS effects after oral H 1-antagonist administration have been assessed subjectively (self-reported impairment) and objectively (investigator-measured impairment) (12, 39) (Table 3). One common source of subjective assessment is from clinical trials of H 1-antagonists in large numbers of patients with chronic allergic rhinitis or urticaria (15, 40). Adverse CNS effects in these trials are usually unsolicited: patients are asked to simply state if they had any problems while taking the medication being studied. The data obtained in these multiple-dose studies reflect ‘‘real-life’’ conditions (the disorder being treated, as well as the treatment itself ) and are thus helpful. Subjective information is also obtained in a more direct and quantifiable way by having patients self-rate CNS symptoms such as somnolence, impairment of concentration, or fatigue, using a simple scoring system, a standardized score such as Stanford Sleepiness Scale, Leeds sleep evaluation score, Epworth Scale, the Profile-of-Moods Questionnaire, or a linear or visual analog rating scale. In objective studies (Table 3), usually performed in healthy volunteers, performance tests and several electroencephalographic (EEG) tests are used to assess CNS function. Drowsiness can be objectively measured through the use of the EEG, such as with continuous 24-hour EEG monitoring. The multiple sleep latency test measures the time needed to induce EEG signs of stage 1 sleep in individuals given repeated opportunities to fall asleep. The EEG, in particular the P300 (or P3), a positive auditory EEG response, can also be used as an objective and sensitive measure of sustained attention and cerebral processing speed. Its latency depends on the amount of time required for evaluation of the stimulus. Medications that cause cognitive impairment can prolong P300 latency. Objective EEG tests are useful in that they are not influenced by subjects’ motivation, performance strategy, task familiarity, boredom, memory, or amount of practice. Objective assessment of the effects of H 1-antagonists on performance and learned tasks involves sensorimotor coordination, memory, CNS arousal/ information processing, and psychomotor tests. Most investigators use a battery of standardized tests which, although influenced by a number of patient variables that are difficult to control fully, are believed to be representative of real-life functions. The relative sensitivity of the various performance tests in identifying persons susceptible to CNS dysfunction from H 1-antagonists is not well documented. The critical flicker fusion (CFF) test, a task of cognitive capacity, and the choice reaction time (CRT) test, a measure of sensorimotor performance, are both thought to be sensitive indicators of impairment with H 1-antagonists.

Effects on CNS Table 3

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Tests Used to Assess CNS Function After H 1-Antihistamine Treatment

Subjective Adverse event reporting in clinical trials (unsolicited; multiple-dose, real-life conditions) Scoring systems (volunteers asked specifically about somnolence or impairment) Stanford Sleepiness Scale (SSS) Leed’s sleep evaluation score Profile-of-moods status questionnaire Linear analog rating scale (LARS) Visual analog rating scale (VARS) Objective Electroencephalogram (EEG) tests Continuous EEG monitoring Multiple sleep latency (time to stage 1 EEG sleep when subjects are given repeated opportunities to sleep under standardized daytime conditions) P3 or P300 event-related potential (time-locked electrical field potential reflecting active cognitive processing of information) Performance Tests Sensorimotor coordination Critical tracking test (using a control stick to keep an oscillating vertical line in the center of a television screen) Adaptive tracking Pursuit meter or rotor Trials B maze Visuomotor coordination Reaction time Simple Choice Auditory Memory Waking Visual Short-term, long-term Sensory Attention task Auditory vigilance Continuous performance task Spatial perception Dynamic visual acuity (determining the orientation of gaps in rings as the images sweep by) CNS arousal information processing Mental arithmetic Visual screening Digit-symbol substitution (filling in blank spaces with the appropriate symbol indicated by a code)

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Welch et al. Continued

Color test Stroop test Critical flicker fusion (defining the frequency at which a group of flickering lights appears steady) Motor ability Glass bead picking test Dexterity tests Psychomotor Computerized simulated car driving Computerized flight simulator Actual car-driving tests (steering, weaving and gap acceptance; usually computer monitored)

The Digit Symbol Substitution Test, a simple pencil and paper test, believed to measure integration, speed, and accuracy of visual and fine motor skills, is also employed in a large number of studies and appears to be a reliable indicator of sedation (41). Actigraphy, the process in which one continuously measures movement (the motor component of behavior throughout the day) has been used to detect impairments in performance and to overcome the problems associated with testing at fixed time intervals. Tests involving complex sensorimotor activities (e.g., application of learned strategy, car tracking, simulated driving or flying tests, or, where permitted by law, computer-monitored on-the-road driving tests) have also been utilized, and are believed to be more representative than simple tests of reaction time or memory (41). In a few performance studies, a school environment (42, 43) or a work environment (44–46) has been simulated. Most of the objective performance and EEG studies have been conducted following a single H 1-antagonist dose in healthy volunteers, using a double-blind, crossover study design. Multiple-dose studies, studies in patients with allergic disorders such as rhinitis or urticaria, and dose–response studies are less common. In an ideal situation, a new H 1-antagonist is compared not only with placebo but also with an H 1-antagonist known to be sedating, so that the sensitivity of the tests being used to identify CNS dysfunction can be assessed. If an old H 1-antagonist comparator either is not given or is given but does not produce impairment of CNS function, it cannot be ascertained if the tests being used have the required sensitivity. Tests are usually performed at baseline and at one or more additional preselected intervals, almost always including tests 2–3 h postdose, at the time of anticipated peak serum concentrations, and presumably peak CNS effects. In some studies, attempts have been made to relate CNS effects to peripheral H 1blockade and/or to serum H 1-antagonist concentrations (47–58). This is helpful

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in the interpretation of test results and prevents the problem of mistakenly identifying an H 1-antagonist as being nonsedating when, in fact, the dose administered was too low to produce adequate peripheral H 1-blockade and was, therefore, clinically irrelevant. In EEG and performance studies, after H 1-antagonist administration there is generally good correlation among the objective tests (56, 59–65). The relationship between performance and subjective feelings of somnolence, however, seems to be more complex and less well understood. Sleepiness/alertness level provides a basic capacity (or incapacity) for performance. Performance, therefore, should be lowest when alertness is lowest and sleepiness is highest; however, it can be modified by factors such as motivation and task familiarity. In most studies in which subjective and objective measures are used, patients who report somnolence or show EEG evidence of decreased sleep latency also have performance impairment on psychomotor tests or driving tests. Various researchers, however, have reported an inconsistent correlation between the symptoms and measures of drowsiness and H 1-antagonist-induced mental impairment. The most common type of discrepancy between subjective and objective measures of sedation occurs when the patient shows impairment on psychomotor tests but does not report a

Figure 1 Effects of cetirizine 10 mg, hydroxyzine 50 mg, diphenhydramine 50 mg, and placebo on objective testing of CNS function. Percentage difference from baseline in the latency of the P300 event-related potential 2.5 h after drug ingestion. EEG recordings made at the PZ electrode. Double-blind, placebo-controlled, single-dose four-way crossover design in 20 healthy subjects. *p ⬍ 0.05 from pre-dose; **p ⬍ 0.05 from cetirizine; †p ⬍ 0.005 from placebo. (From Ref. 56.)

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subjective feeling of impairment or sleepiness (66–68). In a few studies, the opposite phenomenon has been observed: although patients were able to achieve good results on performance tests, they reported somnolence (69–71). The results obtained in the single- and multiple-dose studies in healthy volunteers generally correlate well with results obtained in studies of patients with allergic disorders. An interesting, unexplained exception is that in many objective EEG and performance studies cetirizine has been documented to be free from objective CNS adverse effects (48, 52–54, 56, 57, 67, 72, 73) (Fig. 1), yet it has been reported to produce more subjective somnolence than placebo in patients with allergic rhinoconjunctivitis being evaluated in clinical trials for efficacy and safety (74–76) (Fig. 2). A number of theories have been proposed for the more than occasional observation of a lack of correlation between subjective and objective findings. One hypothesis is that sleepiness and psychomotor performance may be caused by different mechanisms (77). Another theory is that thresholds for objective and subjective CNS effects of H 1-antagonists differ (i.e., the slope of the plasma concentration vs. time curve may be steeper for impairment of performance than

Figure 2 Reports of somnolence in a clinical trial evaluation of cetirizine in 3 doses compared with placebo in patients with seasonal allergic rhinoconjunctivitis. 10 mg and 20 mg doses of cetirizine were significantly different from placebo (*p ⬍ 0.05). (From Ref. 75.)

Effects on CNS

347

for somnolence) (12, 49). It has also been postulated that the time course and pattern for induction of sleepiness and performance impairment in the day do not coincide, resulting in a potential poor correlation between the two types of CNS effects (41). Finally, it has been suggested that self-assessments of performance and sleepiness are basically unreliable and easily influenced by a multitude of factors, while performance-based and objective measures are superior to subjective ones, although also affected by changing performance strategies and/or motivation levels (41). Whatever the mechanism, both subjective and objective tests should be conducted in order to determine the potential for CNS impairment, because either one alone may underestimate the CNS effects of an H 1-antagonist.

V.

FIRST-GENERATION H 1-ANTIHISTAMINES

The true prevalence of CNS dysfunction after ingestion of first-generation H 1antagonists in recommended dosages is unknown. While some individuals seem more prone than others to develop CNS dysfunction, the problems are surprisingly common. For example, chlorpheniramine is not generally considered to be a very sedating first-generation H 1-antagonist, yet approximately 45% of healthy volunteers ingesting chlorpheniramine (4 mg) will have some objective impairment of CNS function (70, 78, 79). Approximately 50% of healthy volunteers ingesting diphenhydramine (50 mg) and 80% of volunteers ingesting hydroxyzine (50 mg) will have some objective impairment of CNS function (56, 78). Impairment of cognitive function, diminished alertness, and slow reaction times may be documented even in the absence of complaints of somnolence. O’Hanlon devised a specially instrumented automobile to evaluate ‘‘real-world’’ driving performance by measuring lane weaving on the open road and in traffic (80). Triprolidine (10 mg) and two second-generation antihistamines, terfenadine (60 mg) and loratadine (10 mg), were studied. The weaving tendency produced by triprolidine was comparable to that seen in drivers with blood alcohol concentrations of 0.05%; terfenadine and loratadine had no undesirable effect on the weaving index. Although this effect of triprolidine persisted for up to 4 h, most drivers reported sedative effects and impairment performance at 1–2 h but not at 3 and 4 h after drug ingestion. This suggests that the drivers had adapted to the sensation of sedation, but not to the objective adverse effects of sedation on driving. It has been hypothesized that patients with delayed elimination of firstgeneration H 1-receptor antagonists, such as the elderly or those with hepatic dysfunction, may be particularly prone to CNS adverse effects that correlate with peak serum and presumably peak CNS drug concentrations (21, 58, 81–83). First-generation H 1-antagonists vary in their proclivity to cause CNS dysfunction, but significant impairment is well documented to occur after single doses of diphenhydramine (25–50 mg), hydroxyzine (20–50 mg), triprolidine

348

Welch et al.

(1.25–10 mg), chlorpheniramine (4–8 mg), and clemastine (1–3 mg) (42, 44– 50, 52, 53, 55–57, 59, 61, 64, 65, 67, 69–73, 79, 81, 84–118). Impairment has also been documented to occur after ingestion of azatadine, brompheniramine, dimethindene, mequitazine, promethazine, trimeprazine, and tripelennamine (66, 70, 90, 96, 100, 108, 119–130). First-generation H 1-antagonists are still commonly used for treatment of symptoms of allergic disorders in children, since some of the newer nonsedating H 1-antagonists are not available in pediatric formulations in many countries, and because of the former’s low-cost nonprescription availability. Few objective evaluations of their adverse CNS effects have been performed in young subjects (42, 55, 131, 132). When diphenhydramine and hydroxyzine were studied in children ages 6–12 years using objective (P300 latency test) and subjective (visual analog scale) measures, CNS impairment was seen in much the same manner demonstrated in adults with these measures of sedation (132). The elderly population as a special group has also been studied in a limited fashion in terms of sensitivity to H 1-antagonists. Results showed that first-generation H 1-antagonists such as chlorpheniramine and diphenhydramine impair cognitive processing and cause subjective somnolence in a way similar to young adults (58). (See Chapters 14 and 15 for more details regarding effects of H 1-antagonists in the young and elderly). Diphenhydramine and other older H 1-antagonists were used in the past for induction of sleep EEGs, and are still commonly used as a remedy by selfmedicating insomniacs (133–136). Six hours postdose, diphenhydramine (50 mg) has a sedative effect comparable to that of alcohol and triazolam (137). Hydroxyzine continues to be used as a preoperative sedative and anxiolytic (138, 139).

VI. ATTEMPTS TO AVOID SEDATION FROM FIRST-GENERATION H 1-ANTIHISTAMINES Several strategies have been suggested for minimizing the sedative effects of H 1antagonists when used for the treatment of allergic rhinitis, allergic conjunctivitis, or chronic urticaria. One strategy is to use a first-generation H 1-antagonist in a single large dose at bedtime. Since the patient will be sleeping during the night, sedation or impairment of CNS function might not cause any problems. This strategy is based on the assumption that the sedative effects are limited to the hours of sleep and that symptom relief from peripheral H 1-blockade lasts throughout the next day. Goetz (69) studied this idea prospectively and found that patients given hydroxyzine (50 mg) at bedtime maintained peripheral H 1-blockade for up to 24 h, based on suppression of histamine-induced wheals and flares, but subjective drowsiness was also increased significantly the morning after the nighttime dose. In another study using the Multiple Sleep Latency Test and the Stanford Sleepiness Scale, the sedating effects of pm dosing with chlorpheniramine and am

Effects on CNS

349

dosing with terfenadine were investigated. Results demonstrated that the CNSdepressant effects of evening administration of a sedating H 1-antagonist persisted throughout the following day (140) (Fig. 3). Similar findings of daytime sleepiness following evening dosing with chlorpheniramine were obtained using the new technique of functional magnetic resonance imaging as a tool to assess levels of brain activation (141). Carryover effects are most likely a result of the long elimination half-lives of sedating antihistamines, which for hydroxyzine, brompheniramine, and chlorpheniramine are 20–24 h (13) (Chap. 5). Some physicians advise regular daily use of a first-generation H 1-antagonist with the expectation that tolerance to the CNS adverse effects will occur after a few days. It is known that tolerance to the peripheral H 1-blockade effects of H 1-antagonists (e.g., skin test suppression) does not develop (52, 68, 89, 142). Tolerance to H 1-antagonist-induced drowsiness and sedation has been reported by some, but not all, investigators. Volkerts (65) treated volunteers with triprolidine 5 mg twice daily or placebo for 4 consecutive days and conducted testing on the first and fourth treatment day. Triprolidine significantly reduced scores

Figure 3 Carryover sedative effects of PM dosing with a sedating H 1-antihistamine. A. Daytime alertness was objectively measured using the multiple sleep latency test (MSLT) in 29 volunteers on the day after (i.e., day 2) receiving a PM dose of chlorpheniramine (8 mg or 12 mg), or placebo. The MSLT is an objective physiological measure of alertness used to quantify daytime sleepiness; lower values indicate sleepiness. B. Subjective sleepiness was measured using the Stanford Sleepiness Scale. P, placebo; C8, chlorpheniramine 8 mg; C12, chlorpheniramine 12 mg. Note reduced alertness (i.e., decreased sleep latency) and increased subjective sleepiness on the day after PM dosing with chlorpheniramine. (From Ref. 140.)

350

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on the various tests done on the first day, including self-assessment rating, objective sleep latency test, cognitive performance test, and an actual driving test. By the fourth day, the subjective (self-rating) and objective (sleep latency) measures of drowsiness, as well as the speed performance in the driving test, were no longer statistically different between the triprolidine-treated and placebo groups. In contrast to this evidence for the development of tolerance, some of the cognitive studies and the lateral weaving part of the driving test continued to show statistically significant differences between groups, perhaps implying partial tolerance. Schweitzer (114) treated subjects with diphenhydramine (50 mg three times daily) for 3 days and measured multiple sleep latency, a simulated assembly-line task, and sleepiness ratings by visual analog scale on day 1 and day 3. Diphenhydramine produced marked impairment and drowsiness only on the first day of treatment; no difference between diphenhydramine and placebo was noted on the third day, suggesting that tolerance occurred. Manning (142) using diphenhydramine, and Bye (89) using triprolidine, also reported tolerance to the CNS effects of these first-generation H 1-antagonists; however, the development of tolerance is not universal or predictable. Volunteers given hydroxyzine 25 mg twice daily for 5 days did not develop tolerance to the CNS effects, as evidenced by continued drowsiness and prolongation of reaction time (95). Similarly, Brookhuis (143) gave volunteers triprolidine 10 mg/day for 5 days and tolerance to its adverse effects on a car-driving test was not observed. Kay (98) tested various measures of sedation after dosing with diphenhydramine 50 mg on day 1, and then on days 3 and 5 after continual dosing with 25 mg four times daily. Fatigue and sleepiness were reported, and scores were reduced on the measures of divided attention, working memory, and vigilance on day 1. On days 3 and 5, the amount of fatigue had decreased but was still significantly greater than it was for subjects receiving loratadine 10 mg daily or placebo. Furthermore, subjects on day 5 receiving diphenhydramine continued to have significantly greater psychomotor impairment than those receiving placebo or loratadine. Given these conflicting findings, using a first-generation H 1-antagonist and hoping the patient develops tolerance to the adverse CNS effects appears to be unwise, as tolerance is an inconsistent and unpredictable phenomenon. The two aforementioned strategies to avoid the sedating effects of firstgeneration H 1-antagonists are not currently recommended. Physicians should be aware of the recommendations made by the Joint Task Force on Practice Parameters in Allergy, Asthma, and Immunology (1998): Sedation and performance impairment are undesirable and potentially dangerous side effects of first-generation antihistamines. Consequently, secondgeneration antihistamines that are associated with less risk or no risk for these side effects should usually be considered before sedating antihistamines for the treatment of allergic rhinitis, and are even mandated in some segments of the transportation industry. Studies have demonstrated that many patients

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351

may not perceive performance impairment that is associated with first-generation (classical) antihistamines. In the majority of states, patients taking sedating antihistamines are legally considered ‘‘under the influence’’ of drugs (144).

Furthermore, physicians advocating any use of first-generation H 1-antagonists should be aware of the epidemiological data implicating these medications as a cause of traffic fatalities (145–148).

VII. SEDATIVE EFFECTS OF ALLERGIC DISEASE Research on the sedative effects of H 1-antagonists is often conducted in individuals not experiencing allergic disease symptoms. Although this has the advantage that the CNS effects of allergic disorders (of varying severity) do not interfere with the results, findings from these studies may be misleading since the allergic disease itself can cause performance and learning impairment. There has been found to be significant impairment in patients with allergic rhinitis in many of the dimensions of the SF-36, a widely used quality-of-life questionnaire, some of which reflect central nervous system functioning (149). Treatment of allergic rhinitis with the second-generation H 1-antagonist cetirizine 10 mg daily, actually improves overall SF-36 scores, further indicating that allergic disease alone may have an impact on CNS function which can be reversed with treatment (150). Marshall and Colon (151) studied depressed individuals with allergic rhinitis in and out of their ‘‘allergy season’’ and demonstrated effects of the season on mood and cognitive functions. Atopic and control subjects were given tests to assess mood, psychomotor speed, and cognitive functioning. Atopic subjects exhibited declines in verbal learning, slower decision-making, and psychomotor speed on both simple and choice reaction times, and lower positive affect during their ‘‘allergy season’’ compared to out of their ‘‘allergy season.’’ Vuurman (42) found similar adverse effects of seasonal allergic rhinitis alone in children. Children with seasonal allergic rhinitis and healthy matched controls were instructed on a computer assignment and tested 2 weeks later on their knowledge of the material. The atopic children received different treatments just before their instruction: diphenhydramine (first-generation), loratadine (second-generation), or placebo. Both the placebo- and diphenhydramine-treated groups learned significantly less than the nonallergic untreated controls. The loratadine-treated group’s learning performance was superior to either of the other atopic groups but still inferior to that of the healthy children. These findings suggest that allergic rhinitis alone reduces learning ability in children, that this effect is partially counteracted by treatment with loratadine, and can be aggravated by a first-generation H 1antagonist such as diphenhydramine. A similar study in young adults revealed

352

Welch et al.

the same findings (43). Spaeth used a visual analog scale to measure vigilance in patients with untreated symptomatic seasonal allergic rhinitis (152). Their baseline scores were below normal, but improved after treatment with either a second-generation oral or topical H 1-antagonist. The exact mechanisms by which CNS impairment occurs with symptomatic allergic disease are not known. Sleep disturbance may be playing a role (153), as patients with allergic rhinoconjunctivitis often report difficulty initiating or maintaining sleep (154) and sleep disruption/deprivation is known to cause excessive daytime sleepiness, cognitive difficulties, and poor school academic performance (155). Whatever the mechanisms, the above studies point out the importance of controlling for the presence or absence of allergic symptoms when conducting research on the effects of new H 1-antagonists on mental function.

VIII. SECOND-GENERATION H 1-ANTIHISTAMINES Information regarding CNS effects can be obtained from results of clinical trials conducted primarily to evaluate the efficacy and safety of the second-generation H 1-antagonists in patients who have symptomatic allergic disease (e.g., allergic rhinitis, urticaria), or from results of studies specifically performed with objective tools to measure sedation and/or impairment, usually carried out in healthy volunteers. Clinical trials almost always involve multiple dosing over days to weeks, with adverse effects such as somnolence being self-reported and unsolicited by the investigator. Conclusions from these studies may be difficult since some lack a placebo group, the percentage of patients reporting any adverse events is sometimes low, and/or statistical analysis of the difference between groups may not be performed with regards to adverse effects. Nevertheless, results of these clinical trials have shown, in general, that patients taking loratadine and fexofenadine and the now unavailable terfenadine and astemizole, report somnolence at a rate not significantly different than patients treated with placebo (see US package inserts for each agent). However, findings from clinical trials evaluating acrivastine, ketotifen, ebastine, mizolastine, cetirizine, and topical azelastine are more variable, with one or more studies showing self-reported somnolence with use of these agents to be higher than with placebo, even at the usual recommended therapeutic dosage (14, 18, 75, 156–159). In objective, single-dose studies in healthy volunteers, the incidence of somnolence and impairment of CNS function associated with manufacturers’ recommended daily dosages of many of the second-generation H 1-antagonists is similar to that produced by placebo and significantly lower than that produced by first-generation H 1-antagonists such as triprolidine, diphenhydramine, chlorpheniramine, clemastine, or hydroxyzine. The first of the second-generation H 1-

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antagonists, terfenadine, has been studied most extensively (47, 53, 55, 57, 59, 60–62, 65, 69, 71, 85, 90, 94, 95, 99, 101–106, 111, 112, 120, 160, 161). Another early second-generation H 1-antagonist, astemizole, has also been well studied with similar findings to terfenadine (51, 57, 79, 104, 105, 123, 162–165). As noted previously, both terfenadine and astemizole have been removed from the market in many countries throughout the world because of adverse cardiac effects; however, they remain historically important because they were the first H 1antagonist agents to demonstrate an absence of sedation and performance impairment properties. Other well-studied second-generation H 1-antagonists that are widely available include cetirizine (46–48, 50, 52–54, 56, 57, 63, 65, 67, 72, 73, 93, 114, 160, 166, 167) (Table 4), loratadine (42, 44, 45, 54, 57, 63, 64, 86, 93, 98, 106, 111, 120, 168) (Table 5), and fexofenadine (41, 73, 115, 150, 169–171, 178) (Table 6). These second-generation agents produce significantly less somnolence and mental impairment than their first-generation predecessors (Fig. 4). Less well-studied and less widely available oral second-generation H 1-antagonists include ebastine (97, 116, 143, 172, 173) (Table 7) and mizolastine (99, 107, 117, 174, 175) (Table 8). Information from studies so far show that both of these H 1-antagonists, when used at their usual therapeutic dosage, have objective sedative profiles similar to placebo. There are few studies of acrivastine (91, 92, 110) and ketotifen (68, 70, 176–178), both of which have been considered second-generation H 1-antagonists. Unlike the other agents in the second-generation category, acrivastine and ketotifen have been shown to cause more somnolence and impaired performance than placebo (Table 9), although not consistently in all tests.

IX. TOPICAL H 1-ANTIHISTAMINES Local administration of H 1-antagonists is intended to confine the activity of the drug to the site of application while reducing possible adverse effects from systemic exposure. Azelastine can be sedating when administered orally (179), and has therefore been developed for nasal mucosal topical use. Self-reported somnolence, despite intranasal use, can still result from use of azelastine compared with placebo (158, 180, 181) but is less than that seen with ebastine (182) or cetirizine (183) when studied in a comparative fashion. Other studies with intranasal azelastine, especially more long-term ones, have shown no increased incidence of somnolence (184, 185). One trial using a visual analog scale to assess vigilance showed an actual improvement in vigilance during a 2-week treatment period (152). Levocabastine, like azelastine, can cause sedation when given systemically,

12

36

9

14

16

15

Doms et al. (166)

Pechadre et al. (53)

Alford et al. (47)

De Roeck (93)

Gengo et al. (50)

No. of volunteers

db, pc, co

db, pc

db, pc, co

db, pc, co

db, pc, co

db, pc, co

Design

C 5, 10, 20 D 50 P

C 20 L 20 D 50 ⫻ 2 P

C 10, 20 qd T 60 bid Ch 4 tid Tr 5 tid P

C 10, 20 H 25 P C 10 P Alc 0.6g/kg (positive control) C 10 T 60 P

Drug/dose (mg)

Objective CNS Studies of Cetirizine

Gengo et al. (48)

Reference

Table 4

DSS; Trails B maze; driving simulator

DSS; MSLT; SSS

EEG; LARS; PHB

EEG spectrum analysis; VAS; PHB

Psychomotor; learning, memory, attention; concentration; coordination; VAS; anxiety

CFF; Stroop; VAS; PHB

Tests

2, 4, 6, 8, 24

Every 2 hrs ⫻ 5

1.5 (LARS) continuous (EEG)

3, 6

Not stated

0.5, 1, 2, 4, 6, 8, 12, 24, 36

Time postdose (h)

C did not affect EEG; T inhibited EEG at 6h; C, T or P did not cause subjective feelings of impairment; no positive control C 10 & 20, T 60 and P produced ⬍20% total EEG sedation; Ch & Tr produced ⬎40% EEG sedation. Significant subjective sedation seen only with Tr D ↓ sleep latency in 1h and this effect differed significantly from L and P, but not C; similar trends were seen in performance and subjective data D, but not C, ↑ reaction time and produced significant drowsiness

Results for C ⫽ P; Alc impaired all tests except one

H, but not C, ↓ CNS function

Results

354 Welch et al.

12

10

16

27

12

Pechadre et al. (54)

Ramaekers et al. (63)

Volkerts et al. (65)

Walsh et al. (46)

Not stated

Betts et al. (160)

Levander et al. (52)

60

Seidel et al. (67)

db, pc, co

db, pc, co

db, pc, co

db, pc, co

db, pc, co

pc

db, pc, pa

Simulated assembly line task with seven variables; 8 ⫻ 50 min tasks; subjective

Actual driving; computerized memory tasks; sleep latency

C 10 daily ⫻ 4d T 60 bid ⫻ 4d T 120 qd ⫻ 4d Tr 5 bid ⫻ 4d P

C 10 H 25 P

Actual driving; EEG; subjective

Quantified EEG; VAS; PHB

Psychological tests; VAS; PHB

Actual slow driving; EEG visual evoked potential

MSLT; EEG ⫹ eye movements; RT; SSS; POMS

C 10 L 10 P ⫾ Alc

C 10 L 10, 40 P

T 120, 240 C 10, 20 P C 10 ⫻ 7d H 20 ⫻ 7 d P⫻7d

C 5, 10, 20 H 25 P

0.5, 1.5, 2.5, 3.5, 5.5, 6.5, 7.5, 8.5

1, 2, 2.5, 3.5, 6

0.5–5

2, 6

4 (after AM dose on d1 and d7)

Not stated

2, 4, 6, 8, 10 (MSLT, SSS); 2.5, 8.5 (RT); 4.5 (POMS)

H, but not C, ↓ CNS function after single dose; no difference between C and H at steady-state C and P did not affect EEG; L 10 and 40 produced slight EEG changes at 2 h; no positive control C alone and L, C, or P ⫹ Alc affected EEG, driving (weaving, speed), and subjective drowsiness. Alc had a greater effect than C. L had no effect on any of measures C 10 mg, T 120 mg, and P did not affect any tests. Tr ↓ driving and psychometric tests and reduced sleep latency; tolerance to Tr by day 4; T 60mg bid ↓ psychometric performance after subchronic treatment Pretrained to minimum correct response rate; H, but not C, ↓ performance and ↑ sleepiness; H & C did not differ subjectively

H, but not C, affected MSLT, EEG and eye movement tests, but no subjective impairment was reported in any group C 20, but not C 10, T 120, T 240, produced impairment

Effects on CNS 355

12

20

18

Simons et al. (56)

Patat et al. (175)

No. of volunteers

db, pc, co

db, pc, co

db, pc, co

Design

C 10 H 50 D 50 P C 10 qd ⫻ 7d M 10 qd ⫻ 7d P Alc or P, single dose, d 5 or 7, 2h post dose of M, C, or P

C 10 qd ⫻ 3d D 50 tid ⫻ 3d P

Drug/dose (mg)

Objective CNS Studies of Cetirizine—Continued

Schweitzer et al. (114)

Reference

Table 4

1) Driving (actual and simulated) 2) CFF, adaptive tracking, divided attention

P300; VAS; PHB

MSLT; simulated assembly line task; actigraphy; subjective (VAS)

Tests

1) 4, 7.3 (actual); 3.2, 6.5 (simulated) 2) 1.5, 2.6, 4.5, 6, 7.8

3

1, 3, 5, 7, 9 (MSLT); VAS 1.5, 3.5, 5.5, 7.5 (assembly line task) on days 1 and 3

Time postdose (h)

M and C had no effect on driving or CFF; both did cause minimal but significant changes in tracking and divided attention tasks at certain time points post-dose. Alc caused significant detrimental effects in all psychomotor and driving tests

D, not C, adversely affected all objective tests and increased subjective sleepiness by day 1. No effect by D seen at day 3. H and D but not C or P ↑ P300 latency

Results

356 Welch et al.

db, pc, co

db, pc, co

db, pc, co

C 10 C 20 Ch 4 P C 10 L 10 A 10 T 60 K2 D 50 P C5 C 10 C 15 Pr 10 P EEG sleep latency; DSS; tracking task; visual vigilance; subjective

Short-term Retention Test; Backward Digit Span Test; Immediate Retention Test; quantitative EEG P300; subjective somnolence (SSS)

0.5, 1.5, 2.5, 3.5, 5.5, 7.5

2–2.5

1, 2, 3, 4, 6

C at various doses reduced sleep latency, impaired tracking, and increased subjective sleepiness at certain time points but not all. No dose-response relationship seen with these effects. Pr decreased vigilance, impaired tracking and increased subjective sleepiness.

C 20 and Ch affected EEG, but not C 10. No effect on any performance tests by C or Ch. C had no effect on P300 latency, but did ↑ subjective somnolence compared to baseline and P. D affected P300 and ↑ somnolence.

A, astemizole; Alc, alcohol; C, cetirizine; CFF, critical flicker fusion; Ch, chlorpheniramine (chlorphenamine); co, crossover; d, days; D, diphenhydramine; db, double-blind; DSS, digit-symbol substitution; EEG, electroencephalogram; h, hours; H, hydroxyzine; K, ketotifen; L, loratadine; LARS, line analog rating scale (subjective sedation); MSLT, multiple sleep latency test; P, placebo; P300, P300 event-related potential; pa, parallel group; pc, placebo-controlled; PHB, peripheral H 1-blockade; POMS, Profile of Mood States questionnaire; RT, reaction time; SSS, Stanford Sleepiness Scale; T, terfenadine; Tr, triprolidine; VAS, visual analog scale; ↑, enhance/increase; ↓, impair/decrease; m, mizolastine; Pr, promethazine; qd, once daily; bid, twice daily; tid, three times daily.

6

15

Simons et al. (57)

Nicholson and Turner (167)

8

Sannita et al. (72)

Effects on CNS 357

1) 20 2) 16

O’Hanlon (106)

16

Roth et al. (64)

1) 12 2) 16

20

Riedel et al. (111)

Gaillard et al. (120)

6

No. of volunteers

db, pc

db, pc

db, pc, co

db, pc, co

db, pc, co

Design

Objective CNS Studies of Loratadine

Bradley and Nicholson (86)

Reference

Table 5

L 10, 20 T 60 Tr 10 ⫾Alc P L 10 ⫻ 2d L 40 ⫻ 2d D 50 tid ⫻ 2d P 1) L 10 T 60 Cl 1 P 2) ⫹ Diaz 5 1) L 10 T 60 Tr 10 P 2) L 10 qd ⫻ 4d T 60 mg bid ⫻ 4d P ⫾ Alc

L 10, 20, 40 Tr 10 P

Drug/dose (mg)

Car driving (high-speed, open road, 10 km); highway circuit, weaving index

Reaction time; tracking; memory; subjective (VAS)

MSLT; SRT; CRT; auditory vigilance; DSS; symbol copying; SSS

Actual driving (weaving index); self-reported sedation

VMC; DVA; short-term memory; DSS; subjective

Tests

1, 3

MSLT 1, 3, 5, 7, 9; performance (i.e., everything else) 1.5, 5.5 6

4

0.3, 1.5, 3.5, 5.5

Time postdose (h)

1) L & T no effect; Cl ↓ performance on tracking test, ↑ subjective drowsiness 2) Diaz no effect with any drug or with placebo. Tr impaired driving; T and L did not; T and L did not potentiate Alc

D, but not L 10 or L 40, ↓ sleep latency, affected performance tests and ↑ sleepiness

L 40, but not L 20 or L 10, ↓ DSS (5.5h) and DVA, suggesting sedation; Tr ↓ all tests Tr, but not T or L, caused weaving comparable to that seen with blood Alc of 0.05%

Results

358 Welch et al.

15

db, pc, co

16

Simons et al. (57)

db, pc

40

Neves-Pinto et al. (168) Ramaekers et al. (63)

db, pc, co

db, pc, pa

db, pc, co

10

Pechadre et al. (54)

52 (included children with allergy)

db, pc

16

Vuurman et al. (42)

pc, co

69

Adelsberg and D’Amico-Beadon (44) De Roeck (93)

L 10 A 10 C 10 T 60 K2 D 50 P

L 10 P L 10 C 10 P ⫾Alc L 10 D 25 bid ⫻ 2 doses P

L 10, 40 C 10 P

L 20 C 20 D 50 ⫻ 2 P

L, D, P

P300; subjective somnolence

Factual and conceptual knowledge, application of learned strategy (computer simulation)

Actual driving; EEG; subjective

Flight simulation; subjective

Quantified EEG; VAS; PHB

DSS; MSLT; SSS

12 performance tests relating to office skills

2–2.5

?8

0.5–5

2

Allergic rhinitis alone ↓ learning ability in children; this effect was partially counteracted by treatment with L but aggravated by D L had no effect on P300 latency or subjective somnolence; D did

D ↓ sleep latency and this effect differed significantly from L and P but not C; similar trends were seen in performance and subjective data C and P did not affect EEG; L 10 and 40 produced slight EEG changes at 2h; no positive control L did not ↓ performance or subjective somnolence L had no effect on driving, EEG, subjective drowsiness; C and Alc did

Every 2 h ⫻ 5

2, 6

L did not ↓ performance; D significantly impaired 8/12 tests

1.5, 6

Effects on CNS 359

db, pc, co

24

18

Hindmarch et al. (169)

Valk et al. (45) L 10 Tr 5 P

Vig Track; MAT (objective); SSS (subjective); in a hypobaric chamber simulating an altitude of 8,000 ft.

CFF; CRT; subjective (LARS); actigraphy

VAS; SSS; Mood Scale; numerous cognitive and psychomotor performance measures

L 10 qd ⫻ 5d D 50 first dose, then 25 qid ⫻ 5d

L 10 F 80 F 120 F 180 Pr 10

Tests

Drug/dose (mg)

1, 2, 3, 5, 6

1.5, 3, 6, 9, 12, 24

1.5 on days 1, 3, 5

Time postdose (h)

L caused no deficits at anytime; D caused deficits in measures of sleepiness, fatigue, mood, divided attention, speed, working memory, and vigilance on day 1; some deficits with D present at day 3; all deficits with D gone by day 5 L and F at all doses caused no significant impairment on any of the tests while Pr negatively affected CFF, recognition reaction time, and actigraphy No significant difference in alertness and performance results between L and P. Tr caused significant detrimental effects on subjective and objective measures

Results

A, astemizole; bid, twice daily; C, cetirizine; CFF, critical flicker fusion; CRT, choice reaction time; d, days; D, diphenhydramine; db, double-blind; DSS, digit–symbol substitution; DVA, dynamic visual acuity; F, fexofenadine; h, hours; K, ketotifen; L, loratadine; LARS, line analog rating scale; MAT, MultiAttribute Task Battery; MSLT, multiple sleep latency test; P, placebo; P300, P300 event-related potential; pa, parallel group; pc, placebo-controlled; PHB, peripheral H 1-blockade; qd, once daily; SRT, simple reaction time; SSS, Stanford Sleepiness Scale; T, terfenadine; tid, 3 times daily; Tr, triprolidine; VAS, visual analog scale; Vig Track, Vigilance and Tracking test; VMC, visuomotor coordination; ↑, enhance/increase; ↓, impair/decrease; Pr, promethazine; Alc, ethanol; EEG, electroencephalogram; qid, four times daily; co, crossover.

db, pc, co

db, pc, co

Design

98

No. of volunteers

Objective CNS Studies of Loratadine—Continued

Kay et al. (98)

Reference

Table 5

360 Welch et al.

24

6

Hindmarch et al. (169)

Nicholson et al. (170) db, pc, co

db, pc, co

db, pc, co

Design

F 80 F 120 F 180 L 10 Pr 30 P F 120 F 180 Pr 10 P

F 120 qd ⫻ 5d F 240 qd ⫻ 5d F 60 bid ⫻ 5d F 120 bid ⫻ 5d Cl 2 bid ⫻ 5d P

Drug/dose (mg)

Time postdose (h)

DSS; tracking; vigilance; MSLT; subjective

CFF; CRT; subjective assessment (LARS); actigraphy

0.5, 1.5, 2.5, 3.5, 5, 6.5, 8

1.5, 3, 6, 9, 12, 24

Critical tracking; 1.5–2.5 except drivCRT; sustained ating (3–4), on days tention; actual driv1, 4, and 5 ing test

Tests

F both doses same as P. Pr impaired DSS, tracking and vigilance; also ↑ objective and subjective sleepiness

F at any dosage did not impair driving performance whereas Cl did. F 120 and F 240 and Cl, after AM single dose, adversely affected critical tracking on day 1 but not on days 4, 5. F at all doses and L were same as P with all tests. Pr ↓ CFF, CRT, LARS, actigraphy

Results

bid, twice daily; CFF, critical flicker fusion; Cl, clemastine; co, crossover; CRT, choice reaction time; d, days; db, double-blind; F, fexofenadine; h, hours; LARS, linear analog rating scale; P, placebo; pc, placebo-controlled; Pr, promethazine; qd, once daily; DSS, digit-symbol substitution; MSLT, multiple sleep latency test; ↑, enhance/increase; ↓, impair/decrease; L, loratadine.

24

No. of volunteers

Objective CNS Studies of Fexofenadine

Vermeeren and O’Hanlon (115)

Reference

Table 6

Effects on CNS 361

362

Welch et al.

Figure 4 Effects of a single dose of loratadine, triprolidine, and placebo on tests of pilot simulated aircraft flying. A. Objective; results of Vigilance and Tracking test (VigTrack), mean and standard error of percentage on omissions (i.e., errors). B. Subjective; results of Stanford Sleepiness Scale (SSS), mean and standard error of subjective ratings. Arrow indicates time of drug administration. Note that triprolidine showed significant detrimental effects on both objective and subjective measures; loratadine had no effect (i.e., same as placebo). (From Ref. 45.)

12

12

15

Mattila et al. (172)

Mattila et al. (173)

Brookhuis et al. (143) db, pc, co

db, pc, co

db, pc, co

db, pc, co

sb

E 10, 20, 30 qd ⫻ 5d Tr 10 SR ⫻ 5d P

E 20 qd ⫻ 6d P

E 20 qd ⫻ 6 d P

E 10 E 20 Cl 2

E 10, 50 P

Drug/dose (mg)

Actual driving performance; subjective

EEG vigilance (relative delta power), matching paradigm, pursuit rotor, pursuit tracking, subjective ratings DSS, CFF, Madox; body balance; nystagmus, simulated driving, VAS DSS, CFF, Madox; body balance, simulated driving, VAS

CFF; CRT; VAS

Tests

2, 6

1.5, 3, 4.5, 6

2, 4, 6

2.5, 4.5, 6.5

1, 2, 4, 6, 8, 24

Time postdose (h)

E did not affect performance, borderline subjective drowsiness noted at 3 h E did not ↓ driving performance; Tr did. Tr also affected subjective ratings; E did not

E did not affect performance or cause subjective changes

E 10 and 50 did not ↓ CFF performance but did mildly ↓ CRT; E50 but not E 10 caused some drowsiness on VAS Cl, not E, ↓ vigilance, ↓ tracking, ↑ subjective drowsiness; maximum effect at 4.5–5.5 h

Results

CFF, critical flicker fusion; Cl, clemastine; co, crossover; CRT, choice reaction time; DSS, digit–symbol substitution; d, days; db, double-blind; E, ebastine; EEG, electroencephalogram; h, hours; P, placebo; pc, placebo-controlled; qd, once daily; sb, single-blind; SR, sustained-released; Tr, triprolidine; VAS, visual analog scale; ↑, enhance/increase; ↓, impair/decrease.

16

9

Hopes et al. (97)

Vincent et al. (116)

No. of volunteers

Reference Design

Objective CNS Studies of Ebastine

Table 7

Effects on CNS 363

18

24

Vuurman et al. (117)

No. of volunteers

db, pc, co

db, pc, co

Design

Objective CNS Studies of Mizolastine

Kerr et al. (99)

Reference

Table 8

M5 M 10 M 20 M 40 Cl 2

M5 M 15 M 45 T 60 Tr 10 P

Drug/dose (mg)

CFF, tracking, divided attention, memory search, CRT, vigilance studies; actual driving; subjective (VAS)

CFF, CRT, tracking, memory tests (Stroop, Sternberg), subjective (LARS)

Tests

2–3, 3.45–4.45 (driving only), 5.30–6.30 (other tests)

1, 3, 5, 8, 24

Time postdose (h)

M 5, 15 did not affect performance tests or subjective ratings whereas M 45 and Tr did ↓ performance in various psychomotor measures. T negatively affected CFF only M 5, M 10 had no effect on psychomotor tests, driving and subjective ratings. M 40 ↓ driving and performance tests and ↑ subjective drowsiness similar to Cl; M 20 had effects intermediate to M 5, 10 and M 40

Results

364 Welch et al.

18

Patat et al. (175) db, pc, co

db, pc, co

db, pc, co CFF, CRT, DSS, free recall memory (immediate and delayed), VAS

1) CFF, CRT, tapping, arithmetic calculation, body sway, VAS 2) Short-term, long-term memory

1) Driving (actual and simulated) 2) CFF, adaptive tracking, divided attention

M 10 Cl 2 P

M 10 qd ⫻ 8d P Loraz 2 or P on d 6 or 8 only, with M

M 10 qd ⫻ 7d C 10 qd ⫻ 7d P Alc or P, single dose, d 5 or 7, 2h post-dose of M, C, or P

1) 4, 7.3 (actual), 3.2, 6.5 (simulated) 2) 1.5, 2.6, 4.5, 6, 7.8

1) 2, 4, 6, 8 2) 3

4, 8

M produced no effects on performance, memory, or subjective ratings of drowsiness whereas Cl significantly ↓ performance (CFF, CRT) M 10 at steady state devoid of effects on measures of performance and memory, and subjective ratings; Loraz caused marked ↓ of almost all objective and subjective tests M and C had no effect on driving or CFF; both did cause minimal but significant changes in tracking and divided attention tasks at certain time points post-dose. Alc caused significant ↓ in all psychomotor and driving tests

Alc, alcohol; C, cetirizine; CFF, critical flicker fusion; Cl, clemastine; co, crossover; CRT, choice reaction time; db, double-blind; DSS, digit–symbol substitution; LARS, linear analog rating scale; Loraz, lorazepam; M, mizolastine; P, placebo; pc, placebo-controlled; qd, once daily; VAS, visual analog scale; d, days; ↑, enhance/increase; ↓, impair/decrease; h, hours.

16

15 (elderly females, ages 66–77)

Patat et al. (174)

Patat et al. (107)

Effects on CNS 365

Ketotifen Hindmarch and Parrott (70) 50

18

12

Acrivastine Cohen et al. (91)

Ramaekers and O’Hanlon (110)

No. of volunteers

db, pc

db, pc, co

db, pc, co

Design

K 1 bid Ch 4 tid Meb 50 tid Cl 1 bid Pr 25 od

Ac 8 Ac 16 Ac 24 Ac/Ps 8/60 T 60 T 120 T 180 D 50 P

Ac 4, 8, 16 Tr 2, 5 P

Drug/dose (mg)

CRT; CFF; sleep evaluation

Driving tests

Adaptive tracking performance; reaction time; VAS

Tests

1.5–2.75 3.25–4.50

1.5, 3

Time postdose (h)

Objective CNS Studies of Acrivastine, Ketotifen, and Levocabastine (Topical Ophthalmic)

Reference

Table 9

K did not ↓ psychomotor behavior but did ↑ ease of getting to sleep; Ch ↓ CFF; Ch and Pr affected sleep and produced early morning ‘‘hangover’’

Ac did not ↓ adaptive tracking or reaction time; both doses of Tr ↓ adaptive tracking and ↑ reaction time, and also caused subjective effects Ac ↓ driving performance in a doserelated fashion. D also significantly ↓. T at all doses and Ac/Ps did not cause any effect on driving

Results

366 Welch et al.

12 db, pc, co

db, pc, co

db, pc, co

sb, pc

Le (0.5 mg/ml) 2 drops/eye qid ⫻ 1 wk P Le (0.5 or 2.0 mg/ml) 2 drops/eye and nostril Tr 10 P

K2 T 60 L 10 A 10 C 10 D 50 P

K 1 bid ⫻ 3 wks P

CFF; CRT; simulated car tracking; Stemberg memory scanning; word recognition; subjective LARS

CFF; CRT; VAS

EEG ⫻ 15 min predose, 3 and 6 h postdose on 8 study days P300; subjective somnolence (SSS)

5

5

2–2.5

3, 6

Tr but not Le impaired CFF, memory task, caused subjective somnolence

Le did not affect any tests (but no positive control)

Peak sedation effect on day 3 gradually ↓ thereafter; no positive control No effect on P300 latency, like D did, but did ↑ subjective somnolence compared to baseline and P

A, astemizole; Ac, acrivastine; bid, twice daily; C, cetirizine; CFF, critical flicker fusion; Ch, chlorpheniramine (chlorphenamine); Cl, clemastine; co, crossover; CRT, choice reaction time; d, days; db, double-blind; EEG, electroencephalogram; h, hours; K, ketotifen (oral); L, loratadine; Le, levocabastine; Meb, mebhydrolin; P, placebo; P300, P300 event-related potential; pc, placebo-controlled; Pr, promethazine; Ps, pseudoephedrine; qid, four times daily; sb, single-blind; SSS, Stanford Sleepiness Scale; tid, three times daily; Tr, triprolidine; VAS, visual analog scale; wks, weeks; ↑, enhance/increase; ↓, impair/decrease; T, terfenadine; D, diphenhydramine; LARS, linear analog rating scale.

Rombaut et al. (113)

12

15

Simons et al. (57)

Levocabastine (topical ophthalmic) Arriaga and Rombaut (186)

7

Vollmer et al. (68)

Effects on CNS 367

368

Welch et al.

so topical ophthalmic and nasal formulations have been developed. Levocabastine does not cause somnolence or impair performance when given via these routes to healthy volunteers (113, 186, 187) (Table 9).

X.

HIGHER THAN USUAL DOSAGES OF SECOND-GENERATION H 1-ANTIHISTAMINES

Some second-generation H 1-antagonists, when given at dosages higher than those recommended by the manufacturer, may cause some CNS dysfunction. This was first noted by Bhatti and Hindmarch (161) when studying the CNS effects of terfenadine, at a dosage of 240 mg instead of the usual 60–120 mg/day. The finding of impairment with higher than usual dosages of terfenadine was not seen in all studies (65, 160). Dose-related effects have been found for other secondgeneration H 1-antagonists including loratadine (40 mg) (54, 86), cetirizine (20 mg) (72, 160, 188), ebastine (50 mg) (116), and mizolastine (20 mg, 40 mg, and 45 mg) (99, 117, 189, 190). A series of studies of actual driving performance using a weaving index as an indicator of sedation found significant driving impairment after two- to three-times higher than currently recommended dosages of various newer H 1-antagonists (loratadine, terfenadine, cetirizine, acrivastine, mizolastine, and ebastine) (191). In contrast, higher than usual dosages of fexofenadine (i.e, up to 240 mg) have not been reported to cause any CNS impairment (41, 115, 170, 171). The observation that CNS effects can be seen as the dosage of most second-generation H 1-antagonists is increased points out how CNS penetration of this category of H 1-antagonists is still possible at high enough dosages. Nevertheless, at recommended dosages the therapeutic benefit/risk ratio for sedation by these new H 1-antagonists is vastly superior to that of the older compounds.

XI. COMPARISON AMONG H 1-ANTIHISTAMINES Before second-generation antihistamines were available, investigators tried to determine if certain first-generation H 1-antagonists were less sedating than others. Clemastine is one H 1-antagonist that was claimed to induce less sedation than other first-generation H 1-antagonists; however, the results of a placebo-controlled comparison study with hydroxyzine and azatadine refuted this contention (100). Other comparison studies with first-generation H 1-antagonists have been done (70, 192), but the information gleaned from them is limited since the studies were never repeated, and the findings only pertain to the specific H 1-antagonists studied. Clearly, there can be differences among older H 1-antagonists in terms of their CNS effects, but these are usually not consistent or predictable, and are

Effects on CNS

369

more likely a function of the individual variation from patient to patient in their sensitivity to have, perceive, or report these adverse effects. Traditional clinical practice advised that if sedation was occurring from an H 1-antagonist in one of the six classes of first-generation H 1-antagonists, the patient should be given a trial of an agent from another class because of the possibility that the sedation would be less; however, no scientific basis for this recommendation can be found in the literature. The availability of the second-generation H 1-antagonists with an absent or much reduced tendency to cause sedation has made this kind of practice both inappropriate and unnecessary. There is also only limited comparative information among the secondgeneration H 1-antagonists regarding objective CNS effects. Most studies of these agents have been designed using the single second-generation H 1-antagonist of interest, a positive control (a first-generation H 1-antagonist known to cause CNS impairment) and negative (placebo) control, with no additional second-generation H 1-antagonist comparator. Because the battery of objective tests used to study these medications varies greatly from one study to another, it is difficult to draw conclusions about relative CNS effects by comparing the results from these various single-agent studies. Studies of many of the second-generation H 1-antagonists reveal limited or no sedative effects, so one would not expect comparison studies to be very informative. Indeed, most of the comparative studies that have been reported, usually just studying two of the second-generation H 1-antagonists at a time, have not revealed significant differences between agents (47, 78, 99, 104, 105, 175). Most of the rare exceptions were studies that found either a small difference, or a difference with only one of the many objective tests done (53, 54, 65), or used a second-generation H 1-antagonist comparator (e.g., ketotifen, acrivastine, cetirizine) known to be more sedating than the others in this class (e.g., terfenadine, astemizole, loratadine) (110, 156, 164). Simons et al. evaluated six different H 1-antagonists (five second-generation agents, with diphenhydramine as the positive control) at one time in a single-dose, placebo-controlled, crossover study using an objective EEG test for somnolence and a visual analog scale (VAS) for subjective rating in 15 healthy subjects. No significant differences were found in the change in the P300 event-related potential and in the VAS score among the five second-generation H 1-antagonists studied (loratadine, cetirizine, astemizole, terfenadine, and ketotifen) (Fig. 5) although patients taking cetirizine and ketotifen, similarly to patients taking diphenhydramine, had a significant change in VAS relative to placebo (178). Hindmarch and Shamsi (41) reviewed the extensive literature on sedating effects of H 1-antagonists and categorized the tests for CNS impairment in the various studies of first- and secondgeneration H 1-antagonists as ones that demonstrated impairment vs. no impairment. They calculated a ratio of the number of tests in which significant impairment was found over the number of tests in which no impairment was detected,

370

Welch et al.

Figure 5 Percentage change from baseline in the P300 event-related potential 2.5 h after terfenadine 60 mg, cetirizine 10 mg, loratadine 10 mg, astemizole 10 mg, ketotifen 2 mg, diphenhydramine 50 mg, and placebo. Note that no significant differences were found among the second-generation H 1-antihistamines, while diphenhydramine demonstrated significant changes suggestive of sedation. *p ⬍ 0.05 compared to baseline and placebo. (From Ref. 57.)

representing the likelihood that a given antihistamine would cause sedative effects. Fexofenadine and ebastine had the best ratio in favor of not inducing CNS effects; triprolidine and diphenhydramine had the worst.

XII. CNS EFFECTS OF COMBINATION H 1-ANTIHISTAMINES/DECONGESTANTS Decongestants, used to relieve the symptoms of upper respiratory tract congestion and obstruction, are commonly used in combination with H 1-antagonists. These sympathomimetic agents promote vasoconstriction and improve nasal patency, thereby complementing the effects of H 1-antagonists in allergic rhinitis, which are predominantly to decrease the symptoms of nasal itch, sneezing, and rhinorrhea. Decongestants are pharmacologically related to epinephrine and amphetamine, and therefore can cause CNS stimulation, resulting in restlessness, insomnia, ap-

Effects on CNS

371

prehension, and tremor in certain sensitive patients. It has been theorized that the use of a decongestant in combination with a first-generation H 1-antagonist could potentially cancel out the sedative effects of the H 1-antagonist, an expectation commonly held by physicians using combination preparations in the presecond-generation H 1-antagonists era. However, when this was tested with triprolidine-d (triprolidine 2.5 mg plus pseudoephedrine 60 mg three times daily) using EEG monitoring, it could not be documented; the combination product caused significantly more patient-reported daytime sedation and drowsiness than either placebo or astemizole-d (193). The finding that sedation usually predominates has been reported for years by patients using either an over-the-counter or a prescription agent that contains both an H 1-antagonist of the first-generation type and a decongestant. With the advent of second-generation H 1-antagonists with reduced sedating properties, the fixed-dose combination of a second-generation H 1-antagonist with a decongestant, not surprisingly, is associated with a high incidence of patient reports of CNS stimulation (1,194–196). The impact of these combination agents on objective measures of CNS function has not been studied optimally, but a limited number of investigations have shown either no effect or actual improvement of objective performance (193, 195). Given the above, the convenience of having a single tablet or capsule of a fixed H 1-antagonist/decongestant combination has to be weighed against the increased potential of adverse subjective CNS stimulation effects due to the decongestant component.

XIII. COADMINISTRATION OF H 1-ANTIHISTAMINES AND ALCOHOL OR CNS-ACTIVE SUBSTANCES Objective psychomotor testing and tests of actual driving performance have confirmed that alcohol (0.50–0.75 g/kg) or diazepam 10 mg, administered concurrently with a first-generation H 1-antagonist such as clemastine, chlorpheniramine, cyproheptadine, or diphenhydramine, potentiates the CNS dysfunction produced by the H 1-antagonist (79, 87, 92, 102, 120, 197, 198). It is presumed that other CNS-active medications, including antidepressants and hypnotics, also potentiate CNS dysfunction produced by older H 1-antagonists, although this has not been well documented objectively. In contrast, in most studies, second-generation H 1-antagonists have not potentiated the adverse CNS effects of alcohol or the benzodiazepines (diazepam, lorazepam) (63, 79, 80, 102, 106, 111, 115, 120, 161, 162, 166, 172–175) (Table 10) (Fig.6). The degree of somnolence and impairment of CNS function associated with recommended daily doses of most second-generation H 1-antagonists in combination with alcohol or benzodiazepines is similar to that produced by alcohol or benzodiazepines alone.

18

20

36

Riedel et al. (111)

Doms et al. (166)

1) 12 2) 12

db, pc, co

db, pc, co

db, pc, co

db, pc, co

db, pc, co

7

Hindmarch and Bhatti (79)

Cohen et al. (92)

Bateman et al. (162)

db, pc, co

Design

20

No. of volunteers

A 30 Ch 12 P Alc 0.5 g/kg T 60 L 10, 20 Tr 10 ⫾Alc P C 10 P ⫾Alc 0.6 g/kg

1) Ac 8 ⫾ Alc D 50 ⫾ Alc P⫹P 2) Ac 4 ⫹ Alc Ac 8 ⫹ Alc T 60 ⫹ Alc T 120 ⫹ Alc P

T 60, 120, 240 D 100 P Diaz 10 Alc 0.75 g/kg A 10 qd ⫻ 7 d P⫻7d Vodka 100ml on 7th d

Drug/dose (mg)

Psychomotor; learning; memory; attention; conc.; coordination; VAS; subjective health; anxiety

Actual driving (weaving index); self-reported sedation

CFF; CRT; car tracking (simulated); VAS; subjective

Psychomotor reaction time; pursuit rotor; visual discrimination; VAS Adaptive tracking; reaction time; eye movement; body sway; VAS

Psychomotor skills, including reaction time; CFF; subjective

Tests

Not stated

4

6

1, 2.5, 5.5, 7.5

6

4

Time postdose (h)

Objective CNS Studies of H 1-Antihistamines Administered with Alcohol or Diazepam/Lorazepam

Moser et al. (102)

Reference

Table 10

C ⫽ P, no ↓ of performance; no interaction with Alc; C did not change Alc kinetics or vice versa

Tr, but not T or L, caused weaving comparable to that seen with blood Alc of 0.05%

1) Ac 8 alone did not ↓ CNS performance; Ac ⫹ Alc ↓ performance but less than D ⫹ Alc 2) Effects of Ac (4 and 8) ⫹ Alc and T ⫹ Alc did not differ suggesting Ac effect in combination with Alc is small Ch, but not A, affected tests; Alc potentiated Ch but not A

D ↓ subjective, not objective, scores. T did not at any dose. D potentiated adverse effects of Diaz and D. T 120 did not Alc ↓ performance; no ↑ effect with A; A did not alter Alc kinetics

Results

372 Welch et al.

12

12

16

12

Mattila et al. (172)

Ramaekers et al. (63)

Mattila et al. (173)

1) 20 2) 16

O’Hanlon (80)

Bhatti and Hindmarch (161)

1) 12 2) 16

Gaillard et al. (120)

db, pc, co

db, pc, co

db, pc, co

db, pc, co

1) db, pc 2) db, pc

db, pc

Actual driving performance; EEG; subjective

DSS; CFF; Maddox; nystagmus; simulated driving; body balance; VAS

E 30 qd ⫻ 7d P Diaz 15 (day 7 only)

DSS; CFF; Maddox; nystagmus; simulated driving; body balance; VAS

E 20 qd ⫻ 7d P Alc 0.8 g/kg on day 7 L 10 C 10 P ⫾Alc 0.72 g/kg

Car driving (simulated); CFF; CRT; LARS (subjective)

Car driving (high speed, open road, 10 km); highway circuit, weaving index

Reaction time; tracking; memory; subjective (VAS)

2) T 60 L 10 Tr 10 P 3) T 60 bid ⫻ 4d P Alc T 60, 120, 240 P ⫾Alc 0.5 g/kg

1) L 10 T 60 Cl 1 2) ⫹Diaz 5

E alone at day 6, E ⫹ Diaz on day 7; 1.5, 3, 4.5, 6

0.5–5

E alone at day 6; E ⫹ Alc on day 7; 2, 4, 6

1.5, 3

1, 3

6

In contrast to T 60 or 120, T 240 alone ↓ driving; T 60, 120 did not potentiate Alc effects. T 240 ⫹ Alc same as T 240 E did not ↓ performance on day 6 but Alc did on day 7; E did not potentiate the effect of Alc C alone and L, C or P ⫹ Alc affected the EEG and ↑ weaving motion, speed, and subjective drowsiness; L did potentiate effects of Alc. Effects of Alc and C were additive. Alc had a greater effect than C E did not ↓ performance objectively or subjectively on day 6; on day 7 Diaz ↓ performance in objective and subjective tests; E did not enhance effects of Diaz

1) L & T no effect; Cl ↓ performance on tracking test, ↑ subjective drowsiness 2) Diaz no effect with any drug or with placebo Tr impaired driving; T and L did not ↓ driving; T did not potentiate Alc

Effects on CNS 373

18

24

Patat et al. (175)

Vermeeren and O’Hanlon (115) db, pc, co

db, pc, co

db, pc, co

Design 1) CFF; CRT; tapping; arithmetic calculation; body sway; VAS 2) short-term, long-term memory 1) Driving (actual and simulated) 2) CFF; adaptive tracking; divided attention

Critical tracking; CRT; sustained attention; actual driving test

M 10 qd ⫻ 7 d C10 qd ⫻ 7 d P Alc or P, d 5 or d 7 2 h post dose of M, C, or P F 120 qd ⫻ 5 d F 240 qd ⫻ 5 d F 60 bid ⫻ 5 d F 120 bid ⫻ 5 d Cl 2 bid ⫻ 5 d P Alc on day 5

Tests

M 10 qd ⫻ 8 d P Loraz 2 or P on d 6 or 8 with M

Drug/dose (mg)

1.5–2.5 except driving (3–4) on days 1, 4, and 5

1) 4, 7.3 (actual), 3.2, 6.5 (simulated) 2) 1.5, 2.6, 4.5, 6, 7.8

1) 2, 4, 6, 8 2) 3

Time postdose (h)

M 10 devoid of any effects on performance, memory, subjective ratings. Loraz caused marked ↓ of almost all tests. M did not potentiate effects of Loraz. M and C had no effect on driving or CFF. Alc caused significant ↓ of all psychomotor and driving tests. M and C did not potentiate adverse effects of Alc. F did not impair driving performance or most psychomotor tests at any dose, nor did it potentiate the effects of Alc; F actually attenuated alcohol’s adverse effect on driving.

Results

A, astemizole; Ac, acrivastine; Alc, alcohol; bid, twice daily; C, cetirizine; CFF, critical flicker fusion; Ch, chlorpheniramine (chlorphenamine); Cl, clemastine; co, crossover; CRT, choice reaction time; CTT, critical tracking test; d, days; D, diphenhydramine; db, double-blind; Diaz, diazepam; DSS, digit-symbol substitution; E, ebastine; EEG, electroencephalogram; F, fexofenadine; h, hours; H, hydroxyzine; K, ketotifen; L, loratadine; LARS, linear analog rating scale (subjective sedation); Loraz, lorazepam; M, mizolastine; P, placebo; pc, placebo-controlled; qd, once daily; T, terfenadine; Tr, triprolidine; VAS, visual analog scale; ↑, enhance/increase; ↓, impair/decrease.

16

No. of volunteers

Objective CNS Studies of H 1-Antihistamines Administered with Alcohol or Diazepam/Lorazepam—Continued

Patat et al. (174)

Reference

Table 10

374 Welch et al.

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375

Figure 6 Mean degree of weaving in a standardized actual driving test undertaken 1.5– 4 h after administration of a morning dose of drug on days 1, 4, and 5. On day 5, subjects were given a moderate alcohol dose along with study drug. Drugs used: clemastine 4 mg bid, placebo, fexofenadine 120 mg qd, fexofenadine 60 mg bid, fexofenadine 240 mg qd, fexofenadine 120 mg bid. Asterisks over bars indicate level of significance for drug– placebo differences. *p ⬍ 0.05; **p ⬍ 0.01. Note that clemastine significantly impaired driving performance on days 1 and 4; fexofenadine did not affect driving on day 1, and appeared actually to improve driving (i.e., less weaving compared to placebo) on day 4. Alcohol given on day 5 impaired driving but it was not potentiated by clemastine or by fexofenadine. Fexofenadine 120 mg bid appeared to attenuate the effect of alcohol on driving. (From Ref. 115.)

XIV. SUMMARY An extensive body of research exists on CNS effects of H 1-antagonists. There is great interest in this area due to the well-known adverse CNS effects associated with first-generation H 1-antagonists, and the many new second-generation agents claiming to have nonsedative properties. Because the CNS effects of H 1antagonists are complex and cannot be reflected in one measurement, a variety of assessments of CNS function are required. These range from the subjective (e.g., self-rating of drowsiness) to the objective (e.g. 24 h EEG sleep latency, P300), and from the simple (e.g., critical flicker fusion) to the complex (e.g., actual driving). When these tests are applied to the evaluation of the H 1-antagonists currently available, it is clear that there is a real distinction between the older first-

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generation H 1-antagonists and the newer second-generation ones. At the recommended dosages, all the second-generation H 1-antagonists are clearly less sedating in more patients than their predecessors. These newer medications do not cross the blood–brain barrier readily; are highly specific for H 1-receptors; have little to no anticholinergic, antiserotoninergic, or anti-alpha-adrenergic effects; and do not enhance the adverse CNS effects of alcohol or other CNS-active substances such as the benzodiazepines. Since most second-generation H 1-antagonists are found to be relatively nonsedating, their benefit/risk ratios will be determined more by their other properties such as non-CNS adverse effects (e.g., potential to cause cardiac arrhythmias), potency, onset of action, duration of action, ease of administration, and cost. The future role and usefulness of the older sedating H 1-antagonists, given the availability of the safer second-generation agents, are unclear at the present time. When H 1-antagonist treatment is indicated, physicians should recommend an effective H 1-antagonist with a favorable clinical pharmacology profile and a wide margin of safety in patients of all ages. The common, often subclinical, adverse CNS effects produced by the old H 1-antagonists remain a major concern and, therefore, these compounds are no longer medications of choice in the treatment of allergic rhinitis, allergic conjunctivitis, or urticaria.

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12 Potential Cardiac Toxicity of H 1-Antihistamines Yee Guan Yap and A. John Camm St. George’s Hospital Medical School, London, England

I.

INTRODUCTION

Antihistamines are among the most frequently prescribed drugs worldwide for the treatment of allergic disorders, particularly in developed countries (1). The use of first-generation antihistamines, such as diphenhydramine, hydroxyzine, chlorpheniramine, brompheniramine, and cyproheptadine, is limited by their sedative and anticholinergic properties. The second-generation, nonsedating antihistamines (e.g., terfenadine, astemizole, loratadine, cetirizine, acrivastine, mizolastine) are relatively free of these side effects; however, since the 1990s there have been some reports of syncope, torsade de pointes (TdP), and sudden death in patients taking the nonsedating antihistamines terfenadine and astemizole. As a result of these reports, regulatory approval for terfenadine and astemizole has since been suspended in many countries. The cardiac safety profile of the H 1antihistamines is now being monitored by regulatory agencies in many countries. Although the occurrence of cardiotoxic effects in some patients taking terfenadine and astemizole (1–12) has led to the speculation that other nonsedating antihistamines may induce similar cardiotoxic effects, these potential adverse effects are not a class property of antihistamines, as will be discussed below.

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II. HISTORICAL PERSPECTIVE In a few cases, proarrhythmia from terfenadine and astemizole was due to overdose: the drugs were taken at doses considerably in excess of that recommended by the manufacturer (1–6). In many cases, the cardiotoxicity of terfenadine or astemizole was noted at usual doses of the drugs, but involved concurrent use of other drugs that inhibit cytochrome P-450 CYP 3A4 drug metabolism (imidazole antifungals and macrolide antibiotics) or patients with impaired liver function or congenital long QT syndrome (7, 9, 10, 12). The reports are exemplified by that of Simons et al., who described a case of ventricular tachyarrhythmia after a 10 mg dose of astemizole (8). Monahan et al. reported an episode of TdP with the recommended therapeutic dose of terfenadine in association with ketoconazole and cefaclor (10). Broadhurst et al. described QT prolongation and TdP with astemizole in a patient with Romano-Ward congenital long QT syndrome (9). Others reported a case of Mobitz-type 2 heart block with TdP after astemizole overdose and QT prolongation and ventricular ectopics with a therapeutic dose of terfenadine in a patient with liver cirrhosis (7). Furthermore, coadministration of these nonsedating antihistamines with drugs that prolong the QT interval by the same or other mechanisms (e.g., antiarrhythmics, antipsychotics, tricyclic antidepressants) also increases their adverse effect on cardiac repolarization (11, 12).

III. MECHANISM OF DRUG-INDUCED QT PROLONGATION AND TdP A.

Normal Ionic and Molecular Basis of the Cardiac Action Potential

The cardiac action potential is generated by the transmembrane movement of several ions, including Na ⫹, Ca 2⫹, and K ⫹. Like all living cells, the inside of cardiac cells is negatively charged compared to the outside (resting transmembrane potential ⫽ ⫺80 mV to ⫺90 mV); however, cardiac cells are excitable and, when appropriately stimulated, the ionic channels in the cell membrane open and close sequentially. Depending on their voltages and time dependencies, the movement of ions back and forth leads to changes in the transmembrane potential, and hence a generation of action potential. The initial depolarization (phase 0) is triggered by a rapid influx of sodium ions (I Na), which changes the cell potential from ⫺90 mV to ⫹30 mV (13, 14). The transient outward (I to) potassium current subsequently is responsible for the slight repolarization immediately after the overshoot (phase 1). During the following plateau phase (phase 2), the cell potential is maintained by the influx of calcium ions (I Ca). The inflow of sodium and calcium ions into cells where their concentrations are low elicits and maintains the depolarization, resulting in the P wave (atrial level) and QRS complex (ven-

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Figure 1 Cardiac ionic currents and their relationship with the action potential. (Modified from Ref. 12.)

tricular level) on the surface electrocardiogram (ECG). The repolarization phase (phase 3) of the myocytes is driven predominantly by outward movement of the potassium currents, carried by the rapid (I Kr) and slow (I Ks) components of the delayed rectifier potassium channel. This ionic movement gives rise to the T wave on the ECG, as the cellular potentials return in sequence to their resting states. The diastolic depolarization (phase 4) results from a combination of the decay of the outward delayed rectifier IKr and IKs currents, which maintains the resting potential at approximately ⫺90 mV, and the activation of a specific inward pacemaker current (I f ) and the inward sodium background leak current (I NaB). A variety of other different potassium channel subtypes are also present in the heart (15) (Fig. 1) and blockade of each of these potassium channels has a different effect on the action potential (Fig. 2). B. Mechanism of Acquired QT Prolongation and TdP Disturbances in any of these ionic movements, in particular of the potassium ions, may cause arrhythmias. There are at least eight different potassium channel subtypes in the heart (16). They differ in their voltage-, rate-, and time-dependent opening and closing characteristics and by their regulation and response to drugs. Each of them may be a target for drug effect. Furthermore, each potassium channel has a different effect on the action potential (Figs. 1, 2) and various potassium channels may not be equally expressed in all species, individuals, or tissues. The principal K ⫹ currents participating in the repolarization of the action potential in

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Figure 2 Alteration in the action potential with individual blockade of some potassium channels.

the human ventricular myocardium under normal conditions are the delayed rectifier K ⫹ current (I Kr and I Ks) (17), the inward rectifier I Ki (18), and the transient outward K ⫹ current I TO (19). I Kr seems to play the most important role in determining the duration of action potential. The drug-induced proarrhythmias are mostly mediated by drugs that suppress the I Ki and I Kr channels that govern the rapid repolarization phase (17). I Ki is a time-independent but voltage-dependent outward current. I Ki determines and stabilizes the resting membrane potential near the equilibrium potential for potassium and also contributes to the final phase of repolarization of the action potential. I Ki is also termed the inward rectifying current, as it allows current to flow more easily in the inward direction (18). Initial evidence suggested that the blockade of I Ki might be responsible for antihistamine-induced TdP (20). The inhibition of I Ki prolongs the rapid repolarization phase of the action potential, and an increase in the vulnerable period, enhancing the chances of aberrant excitation and arrhythmia in the presence of these drugs (20). Suppression of I Ki by nonsedating antihistamines is particularly

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marked when the plasma concentration of potassium is already abnormal (e.g., hypokalemia, ischemia); however, subsequent evidence showed that the magnitude of the block of I Ki by antihistamines such as terfenadine, astemizole, and ebastine is less than 30% at a supratherapeutic concentration of 0.3–1.0 µM, much less than their effect on I Kr (21, 22). The blockage of I Ki by an antihistamine will only provoke arrhythmias under conditions in which the QT interval has already been prolonged by other pharmacological, ionic, or pathological conditions (20, 21) or after overdose (20). Therefore, the major cardiac adverse effects of antihistamines are more likely to be mediated by the strong blockade of I Kr channel (21, 22), which is also most susceptible to influence from underlying heart disease, sex, saturated metabolism, and coadministration of other QT-prolonging drugs.

Figure 3 Arrhythmogenic mechanism of torsade de pointes.

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Blockade of the I Kr current results in the prolongation of action potential duration and slowing of the repolarization. It manifests clinically as a prolonged QT interval and a lower-amplitude T wave on the surface ECG. The prolongation of repolarization may result in bifid T wave and also lead to activation of an inward depolarization current, known as an early after-depolarization (23), which is responsible for the increased amplitude of U wave on the ECG and may promote repetitive triggered activity. When accompanied by markedly increased dispersion of repolarization, often induced by the same drug, this may induce reentry and provoke TdP, which is then sustained by further re-entry or spiral wave activity (24) (Fig. 3). Such phenomena are more readily induced in the His-Purkinje network and also from M cells, a subset of myocardial cells from the midventricular myocardium (25). One reason for this may be that resting membrane potential in Purkinje fibers is more positive than that in the ventricles and the blockade of I Kr channel is voltage-dependent, with greater block in depolarized tissue (26). This may then lead to dispersion of refractoriness between the two tissue types, which is potentially arrhythmogenic. The M cells are located deep in the subepicardium and are electrophysiologically different from those of epicardium and endocardium but intermediate between those of muscles and Purkinje fibers. Compared to subendocardial or subepicardial cells, M cells show much more pronounced action potential prolongation, easier induction of early after-depolarization, and development of triggered activity more readily in response to I Kr blockade (24, 25). This property results in a marked dispersion of repolarization (i.e., heterogeneous recovery of excitability), creating a zone of functional refractoriness in the mid-myocardial layer, which is probably the basis of the re-entry that sustains TdP.

IV. MEASUREMENT OF QT INTERVAL When measuring the QT interval, the ECG is best recorded at a paper speed of 50 mm/s and an amplitude of 0.5 mV/cm using a multichannel recorder capable of simultaneous recording of all 12 leads. A tangent line to the steepest part of the descending portion of the T wave is then drawn. The intercept between the tangent line and the isoelectric line is defined as the end of T wave. The QT interval is measured from the beginning of the QRS complex to the end of the T wave on a standard ECG. Traditionally, lead II has been used for QT interval measurement because the vectors of repolarization in this lead usually result in a long single wave rather than discrete T and U waves. The QT interval is influenced by heart rate. At least three or four RR intervals preceding the QT interval should be measured for rate correction. Several formulas may be used to correct the QT interval for the biophysical effect of heart rate (QTc). The most commonly used are Fridericia’s cube-root for-

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mula (QTc ⫽ QT/RR 1/3) and Bazett’s square-root formula (QTc ⫽ QT/RR 1/2). Between the two, Bazett’s formula is more popular, but Fridericia’s correction is preferred because it is more accurate at the extremes of physiological heart rate. Newer repolarization parameters such as QT dispersion (maximum ⫺ minimum QT intervals) on the 12-lead surface ECG, which is considered to be an indirect measure of spatial heterogeneity of repolarization, may be useful in assessing drug efficacy and safety. In one important study, patients who received a class 1A antiarrhythmic drug who developed QT prolongation and suffered TdP had significantly increased precordial QT interval dispersion (27). In contrast, patients receiving amiodarone or class 1A antiarrhythmics without developing TdP did not have increased QT dispersion, although the QT interval was similarly prolonged (27). Thus, spatial heterogeneity/dispersion of the ventricular repolarization process may be required in addition to QT prolongation for the genesis of TdP. Although the use of QT dispersion in the assessment of drugs that prolong the QT interval needs further confirmation, it may provide information about the clinical significance of QT prolongation.

V.

DRUG-INDUCED QT PROLONGATION AND TdP

The blockade of the potassium channels prolongs the ventricular repolarization, which manifests clinically as a prolonged QT interval and other T- or U-wave abnormalities on surface electrocardiogram. Although these abnormalities of repolarization predispose to the development of TdP, there is no linear relationship between the degree of QT interval prolongation and the likelihood of development of TdP. Furthermore, TdP can occur without a prolonged QT interval, and it does not develop in all patients with long QT intervals (28). For instance, both quinidine and amiodarone are known to prolong the QT interval. While quinidine is a well-recognized cause of TdP, amiodarone is rarely associated with TdP. QT prolongation is generally considered when the QTc interval is greater than 440 milliseconds (ms) (men) and 460 ms (women) (29), using Bazett’s formula (Table 1). The suggested upper limit of normal QTc interval for adult males is 450 ms and for adult females is 470 ms. The severity of proarrhythmia at a given QT interval varies from drug to drug and from patient to patient. Although the QT interval is widely viewed as a surrogate marker of the arrhythmogenic potential of a drug, the extent of QT prolongation and risk of TdP with a given drug may not be linearly related to the dose or plasma level of the drug because patient factors (e.g., gender) and metabolic factors (e.g., electrolyte levels) are also important (see below). Apart from congenital long QT syndrome, there have been very few data available to quantify the magnitude of arrhythmic risk assess-

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Table 1 Normal Values of QTc Interval (corrected by Bazett’s formula) a Study Moss (29) Adult men Adult women Children (1–15 yr) CPMP (98) Adult men Adult women Concern about drug effect

QTc interval (Bazett’s) Normal ⬍430 ⬍450 ⬍440

Borderline Prolonged (top 1%) 430–450 ⬎450 450–470 ⬎470 440–460 ⬎460 QTc interval (Bazett’s) 450 (upper limit) 470 (upper limit) 500

a

Values given in milliseconds. CPMP, Committee for Proprietary Medicinal Products.

ment with particular values of QT prolongation, especially with drug-induced QT prolongation. Data from the Long QT Syndrome Registry showed that the risk of malignant ventricular arrhythmias is exponentially related to the length of QTc interval (29) (Fig. 4). In drug-induced QT prolongation, although no such relationship is known, a MEDLINE search of the English-language literature for 1980– 1992 on proarrhythmia (TdP, polymorphic ventricular tachycardia, atypical ventricular tachycardia, and drug-induced ventricular tachycardia) by cardiac drugs

Figure 4 ECG from a 24-year-old woman who presented with TdP while taking an H 1-antihistamine. After discontinuation of the drug, the QT interval remained prolonged (QTc ⫽ 573 ms), due to congenital long-QT syndrome.

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(a)

(b) Figure 5 (a) ECG of a 63-year-old female patient with thioridazine-induced ventricular fibrillation cardiac arrest while in hospital. She was successfully resuscitated and this is the ECG performed immediately after the cardiac arrest. Note the QTc interval was 619 ms and her serum potassium level at this time was 3.3 mmol/L. (b) ECG of the same performed 2 days after the cardiac arrest when the offending drug thioridazine has been removed for 2 days and her serum potassium level corrected to 4.4 mmol/L. Note that the QT interval has returned to normal (QTc ⫽ 399 ms).

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Figure 6 Rhythm strip in a patient with drug-induced TdP. Note the typical short– long–short initiating ventricular cycle before the onset of TdP and the classical ‘‘twisting of a point’’ of the cardiac axis during TdP.

known to prolong QT interval showed that among the 332 patients with proarrhythmia, only 25% had baseline QTc ⱖ470 ms, while 90% had QTc ⱖ500 ms when they developed arrhythmias (30). Thus, a maximal QTc value over 500 ms (Fig. 5) should cause concern about the potential for drug-induced TdP (Table 1). There is a characteristic initiating sequence prior to the onset of TdP, particularly in acquired TdP. The first ventricular complex of the sequence is usually a ventricular ectopic beat or the last beat of a salvo of ventricular premature beats (Fig. 6). This is then followed by a pause terminated by a sinus beat. The sinus beat frequently has a very prolonged QT interval and an exaggerated U wave. A premature ventricular beat then falls on, or is generated by, the exaggerated U wave of the sinus beat and precipitates TdP. It has been suggested that, in some patients, postpause accentuation of the U wave, if present, may be a better predictor of TdP than the duration of the QTc interval (31), particularly with drug-associated TdP. When an ectopic beat or brief tachycardia is followed by a pause, it is therefore important to examine the QT interval and morphology of T/U waves in the postextrasystolic sinus beat (31).

VI. PROPERTIES OF H 1-ANTIHISTAMINES DETERMINING PROARRHYTHMIC TOXICITY The association of nonsedating antihistamines and TdP has been reported mainly with terfenadine and astemizole. These H 1-antihistamines potentially exhibit their

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cardiac effects at therapeutic histamine receptor-blocking concentration, whereas others have only caused cardiac effects at supratherapeutic concentrations or have not caused any significant cardiac effects at all. Several factors that may be responsible for the varying cardiac action of antihistamines are reviewed below. A. Potassium Ion Channel Blockade Like class III antiarrhythmics, terfenadine and astemizole were found to prolong the monophasic action potential and QT interval, which led to the development of early after-depolarization and TdP through an inhibition of the I Kr channel (13, 32, 33). Not all nonsedating antihistamines block the I Kr channels to the same degree. Among the antihistamines evaluated, astemizole, terfenadine, and ebastine have shown blocking effects in I Kr channels expressed in Xenopus oocytes (22, 34, 35). Mizolastine also blocks I Kr channels expressed in Chinese hamster ovary cells, although in a reversible manner and at concentrations significantly higher than those corresponding to therapeutic free plasma levels (unpublished observations). Terfenadine and ebastine (22) but not mizolastine (36) can also block the slow delayed rectifier I Ks channel in guinea pig dissociated ventricular myocytes. Loratadine does not block cloned I Kr channels expressed in Xenopus oocytes (up to 10 µM), nor does it block I Kr channels in guinea pig ventricular myocytes (up to 3 µM). At higher concentrations, however, it can block both heterogeneously and constitutively expressed I Kr channels (37–39). In contrast, ceterizine, despite having similar antihistaminic potency in vivo with respect to other antihistamines, does not block the I Kr channel in heterogeneously expressed Xenopus oocytes (up to 30 µM) or prolong ventricular repolarization at the highest therapeutic level in a canine model of long QT syndrome (38, 39). Fexofenadine, the carboxylate metabolite of terfenadine, likewise had no IKr-blocking effect, even at a concentration 30 times greater than the concentration of terfenadine producing half-maximal effect (12, 32). Thus, there are significant differences in the ability of H 1-antihistamines to block the different members of the cardiac potassium channel family. It appears as if antihistamines such as terfenadine, which simultaneously suppress more than one channel involved in the lengthening of the action potential (i.e., IKr and I Ks) or which block I Kr at low concentration, possess a higher propensity to induce arrhythmias. Those that do not block the I Kr channels (e.g., fexofenadine) or block the channel with lower potency (e.g., loratadine) are less likely to be cardiotoxic. B. Physicochemical Properties Other drug-related factors such as the physicochemical properties of the antihistamines (e.g., diarylalkylamine moiety, quaternization of diphenhydramine, lipophilicity of the side chain) and their metabolic profile (e.g., tissue distribution) may also contribute to the cardiac toxicity of antihistamines. Like class III antiar-

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Table 2 Physicochemical Properties Related to Pharmacokinetic Parameters of Nonsedating H 1-Antihistamines

Mizolastine Cetirizine Fexofenadine Loratadine Astemizole Terfenadine Ebastine

Lipophilicity (log P)

Estimated volume of distribution (L/kg)

2.9 3.5 5.3 5.7 5.8 6.9

1.4 0.5 9.0 18.0 45.0 27.0 7.2

Source: Modified from Ref. 41.

rhythmic agents, certain antihistamines possess a diarylalkylamine moiety that is believed to inhibit the potassium channels (13). Quaternization of diphenhydramine can result in a potent class I antiarrhythmic agent with long duration of action and notable tachycardia (13). Lipophilicity of the side chain (nitrogen substitution) is also important in the potassium channel-blocking activities of antihistamines (13). In this aspect, mizolastine and cetirizine are less lipophilic than loratadine, astemizole, ebastine, and terfenadine (41, 42) (Table 2) and do not contain either diarylalylamine or diphenhydramine moieties. There are also major differences in tissue distribution and myocardial fixation among H 1-antihistamines. In animal models, a low apparent volume of distribution seems to be associated with low tissue fixation (i.e., heart tissue levels lower than blood levels). For instance, heart/plasma ratios in animals are 4 in rats for terfenadine (43), 400 in dogs for astemizole (44), but only 0.5 for mizolastine in guinea pigs (unpublished data); however, for cetirizine, the tissue drug level is not necessarily lower than that of the serum level, at least in the skin. After ingestion of a single dose of 10 mg of cetirizine in humans, the concentration of cetirizine in the skin has been shown to be lower than the serum level from 1 to 9 hours but higher at 24 hours and equivalent at 168 hours (steady state) (45). Of note is that diphenhydramine overdose can lead to an abnormal repolarization including moderate QT prolongation, lower T-wave amplitude, as well as tachycardia (46, 47). Furthermore, diphenhydramine overdose has also been reported to cause death, seizures, pulmonary edema, and neuroleptic malignant syndrome (48–53). It is therefore important to note that the ability to cause QT prolongation and proclivity for producing TdP is seen only with some antihistamines and is not a class effect.

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C. Hepatic Metabolism Cytochrome P-450 enzymes, a superfamily of heme-containing proteins present within the endoplasmic reticulum, have low substrate specificity and are responsible for the oxidation of a wide variety of lipophilic substrates. Cytochrome P450 families 1, 2, and 3 (CYP1, CYP2, and CYP3) are involved in drug metabolism, with isoenzymes of CYP2B, CYP2C, CYP2D, and CYP3A being responsible for most drug oxidation. Most, but not all, of the nonsedating antihistamines are metabolized via the hepatic cytochrome P-450 CYP3A4 system (Table 3a); therefore, administration of these antihistamines to patients with compromised liver function or concomitant administration of drugs (e.g., imidazole antifungals, macrolide antibiotics) (Table 3b) or food (e.g., grapefruit juice) that inhibit the hepatic cytochrome P-450 CYP3A4 may result in the accumulation of the parent drug and the development of cardiotoxicity (11). For instance, terfenadine undergoes rapid first-pass metabolism by cytochrome P-450 hepatic enzymes (CYP 3A4) and is transformed into its active metabolite terfenadine carboxylate. Terfenadine carboxylate had no effect on the I Kr potassium channel, even at high concentrations (12); however, inhibition of the hepatic oxidative metabolism of terfenadine by imidazole antifungals (e.g., ketoconazole, itraconazole) or macrolide antibiotics (erythromycin, clarithromycin) will result in an accumulation and increased bioavailability of the cardiotoxic prodrug (13, 54). In addition, drugs such as erythromycin and ketoconazole can themselves prolong the QT interval as well as inhibit the metabolic activity of hepatic cytochrome P-450. Concomitant administration of terfenadine and any of these antimicrobial therapies will produce marked QT prolongation that correlates with plasma concentration of unmetabolized terfenadine and increases the risk of arrhythmia (55). Concomitant administration of terfenadine with drugs that can inhibit metabolic activity of hepatic cytochrome P-450 or those that prolong the QT interval must be avoided. With regard to astemizole, the P-450 isoenzyme CYP3A4 metabolizes the drug into two active metabolites, desmethylastemizole and norastemizole. The QT prolongation is caused by astemizole and desmethylastemizole (13). Ebastine, a highly lipophilic compound, is a prodrug, which is metabolized to a large extent through the cytochrome P-450 CYP3A4 and its effect on QT prolongation is enhanced after oral dosage by pretreatment with ketoconazole (56). Mizolastine is less dependent on cytochrome P-450 hepatic metabolism than astemizole, terfenadine, and ebastine. It has relatively little (1.5–50%) pharmacokinetic interaction with ketoconazole and erythromycin compared with the drugs mentioned above; the increase in mizolastine plasma concentrations observed with systemic ketoconazole led to plasma concentrations equivalent to those obtained with a 15–20 mg dose of mizolastine alone. The QT interval prolongation observed did not seem greater than that anticipated for ketoconazole alone. Cetirizine and fexofenadine differ from the other currently used nonsedat-

Table 3

Metabolism of Nonsedating H 1-Antihistamines

Nonsedating antihistamines and their major metabolic pathways Terfenadine Hepatic P-450 CYP3A4 Astemizole Hepatic P-450 CYP3A4 Ebastine Hepatic P-450 CYP3A4 and CYP2D6 Loratadine Hepatic P-450 CYP3A4 and CYP2D6 Mizolastine Mainly via glucuronidation (65%), less via hydroxylation (hepatic P-450 CYP 3A4 and 2A6) Fexofenadine 80% via the fecal route and 10% via the renal route Cetirizine 60% renal, 40% hepatic Drugs and foods that can inhibit hepatic cytochrome P-450 CYP3A4 enzymatic activity Imidazole antifungals Ketoconazole Itraconazole Fluconazole Metronidazole Macrolide antibiotics Erythromycin Clarithromycin Troleandomycin Josamycin Flurythromycin Ponsinomycin Antidepressants Fluvoxamine Fluoxetine Paroxetine Sertraline Nefazodone HIV protease inhibitors or non-nucleoside Amprenavir reverse transcriptase inhibitors Indinavir (NNRTI) Nelfinavir Ritonavir Saquinavir Delavirdine (NNRTI) Anti-ulcer drugs Ranitidine Cimetidine Omeprazole Ethinyl estradiol Estrogen Oral contraceptives Calcium antagonists Diltiazem Verapamil Nifedipine Tetracyclines Tetracycline Doxycycline Anti-tuberculosis drug Isoniazid Antimalarial Primaquine Antibiotic Quinupristin/dalfopristin Antiarrhythmic drug Amiodarone Antihypertensive drug Hydralazine Food Grapefruit juice

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ing antihistamines because they are not metabolized to the same extent (57). In adults, cetirizine is eliminated 60% unchanged via the renal route and 40% via the hepatic route. Patients with renal and hepatic impairment are advised to decrease the dosage. Fexofenadine is eliminated primarily by the fecal route (80%) and only 10% by the renal route (58). Consequently, the potential drug interactions are less relevant. Although renal disease rather than liver disease could result in elevated plasma concentrations, both cetirizine and fexofenadine are devoid of QT-prolonging effect. Grapefruit juice contains furanocoumarins (e.g., 6′, 7′-dihydroxybergamottin and its dimers), which are potent inhibitors of CYP3A4, and cause a rapid loss of enzyme activity of intestinal but not hepatic cytochrome CYP3A4 (57). In one study of six healthy subjects, when 60 mg terfenadine was given simultaneously with double-strength grapefruit juice for 7 days, all subjects had increased and quantifiable levels of unmetabolized terfenadine, accompanied by an increase in the QTc interval from 420 to 434 ms ( p ⬍ 0.05) (59). Although in most studies of drug–grapefruit interactions, double-strength grapefruit juice was given twice daily for a week, significant interaction between terfenadine and regular-strength grapefruit juice (60) or freshly squeezed juice (61) was also demonstrated. Thus, grapefruit juice can inhibit the metabolism of some nonsedating antihistamines by enzymes of the cytochrome P-450 CYP3A4 located in the gut wall and should therefore be avoided by patients taking these drugs.

VII. EFFECTS OF NONSEDATING H 1-ANTIHISTAMINES ON QT INTERVALS The potential effects of any new H 1-antihistamine on human cardiac repolarization are carefully examined during its clinical development, mainly through the assessment of its potential to prolong the QT interval and the monitoring of potential cardiac events. Terfenadine increases the QT interval in a dose-dependent manner and QT interval prolongation has been shown to correlate with terfenadine concentration (62–64). This effect is significantly more marked in patients with cardiovascular disease (64). Compared to baseline, terfenadine 60 mg twice daily is associated with a QTc increase of 6 ms in normal subjects and a 12 ms increase in patients with cardiovascular disease (64). Astemizole and its metabolite desmethylastemizole prolong the QT interval but there is a lack of correlation among dosage, plasma concentration, and QT prolongation (13, 55). There has been no report of QT prolongation or ventricular arrhythmias with ebastine administered at therapeutic dosages or at a dosage three times the recommended level (60 mg/day) (55, 65). At a dosage five times the recommended level (100 mg/day), ebastine causes a small QT prolongation (10.3 ms

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and ⬍10%) that is not clinically meaningful, although it was statistically significant compared with placebo (65). A detailed study, however, showed that the minor QT prolongation with ebastine (and possibly with other drugs) is critically dependent on the precision of the rate correction formulas and influenced by the natural variability of the QTc interval. For instance, while all generalized heart rate correction formulas showed consistent QT prolongation with terfenadine, results were inconsistent with ebastine. Correction using Bazett’s formula suggested significant QT interval increase with ebastine, but correction using the Lecocq formula suggested a significant QT interval decrease. Even with an optimized heart rate correction formula (QTc ⫽ QT/RR 0.314) from pooled QT/RR regression during the drug-free state, the minor QT prolongation with ebastine was not consistent. The QTc changes in a four-way crossover study after a 7 day course of placebo, 60 mg ebastine, 100 mg ebastine, and 100 mg terfenadine were ⫺1.95 ⫾ 6.87 ms, p ⫽ N.S.; ⫺3.91 ⫾ 9.38 ms, p ⫽ 0.053; 0.75 ⫾ 8.23 ms, p ⫽ N.S.; 12.95 ⫾ 14.64 ms, p ⫽ 0.0003, respectively (M. Malik, personal communication). Thus, measurement imprecision and natural diurnal variability of the QTc interval can lead to a QTc variation of at least 4–5 ms, which can be critical when assessing minor drug-induced QT prolongation. In contrast, loratadine does not cause a significant QT prolongation even at supratherapeutic doses (66, 67). In one study, no patient had a QTc interval of more than 440 ms when given loratadine 40 mg (four times the recommended dosage) for 3 months (66). The clinical experience with mizolastine, particularly in potentially high-risk patients, is still limited. An overview of the QT interval monitoring performed during the clinical development of mizolastine showed that this second-generation H 1-antihistamine has no significant effect on cardiac repolarization in humans (68). Mizolastine was administered orally to healthy volunteers in single doses of up to 75 mg and in a repeated dosage of 40 mg daily (i.e., 7.5 and 4 times the recommended daily dosage, respectively) and at a dose of 10 or 15 mg in patients. In healthy volunteers, there was no increased incidence of QTc value ⬎440 ms or ∆QTc ⱖ40 ms compared with placebo. No dose-related increase in QTc interval was observed. In patients, the mean QTc interval changes from baseline were not significantly different between mizolastine and placebo. In volunteers or patients receiving mizolastine, there was little or no idiosyncratic QT interval prolongation and it did not induce changes in the T/U wave morphology. Cetirizine is the metabolite of hydroxyzine, a first-generation antihistamine, which at high dosages has been reported to be associated with T-wave changes (55). In studies conducted in healthy subjects, however, and even in supratherapeutic dosages of 20 or 60 mg daily, cetirizine was devoid of an effect on QT interval (69). There was likewise no dose-related increase in QT interval or significant increase in mean QT interval with fexofenadine, the carboxylate

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metabolite of terfenadine, in a dosage up to 240 mg twice a day for 12 months, compared with placebo (70). Extensive ECG data from more than 2100 patients receiving fexofenadine or placebo in controlled clinical trials recently demonstrated that fexofenadine does not increase the QT interval, even when administered chronically in doses 10 times higher than that recommended by the manufacturer (71). Pratt et al. reported that fexofenadine in dosages up to 800 mg once daily or 690 mg twice daily (recommended dosage: 60 mg twice daily) for 28 days resulted in no dose-related increases in QT interval. Longer-term studies indicated no statistically significant QTc increases compared with placebo in patients receiving fexofenadine 80 mg twice daily for 3 months, 60 mg twice daily for 6 months, or 240 mg once daily for 12 months. Clinical trials in patients with seasonal allergic rhinitis (n ⫽ 1160) treated with 40, 60, 120, or 240 mg twicedaily fexofenadine or placebo indicated no dose-related increases in QTc and no statistically significant increases in mean QTc compared with placebo. In controlled trials with approximately 6000 persons, no case of fexofenadine-associated TdP was observed (71). This is probably not surprising, given that fexofenadine does not block the I Kr potassium channel. Concerns were raised over a case report of fexofenadine-induced QT prolongation and ventricular arrhythmia (72). In this report, a 67-year-old man with hypertension and mild left ventricular hypertrophy had his carvedilol stopped due to itching. He was subsequently prescribed fexofenadine 180 mg daily and experienced QT prolongation and ventricular dysrrhythmia after 2 months of treatment (72). Although there was a temporal correlation between ECG-documented QT prolongation and institution of fexofenadine, the patient’s age, hypertension, ventricular hypertrophy, and sudden cessation of carvedilol themselves constitute risk factors for QT prolongation and ventricular arrhythmia. Thus, this single case report contrasts with the extensive clinical and experimental evidence that TdP is not a risk during exposure to fexofenadine. Azelastine has no electrocardiographic effects when administered at several times the recommended dosage or concomitantly with agents that inhibit its metabolism and elimination in human volunteers (73). The data in the public domain on azelastine and acrivastine are currently sparse, however, and further information on the cardiac safety of these drugs is needed. The effect of nonsedating antihistamines that are metabolized by cytochrome P-450 CYP3A4 on the QT interval is markedly increased when they are coadministered with an enzyme inhibitor. For instance, a mean of 82 ms increase in QTc interval at 12 h after dosing (i.e., at or near trough) was reported when terfenadine was coadministered with ketoconazole (54). When ebastine (20 mg/ day) was coadministered with ketoconazole (400 mg/day) in healthy subjects in multiple doses, there was a small but statistically significant increase in the QTc interval by 10 ms compared to that produced by ketoconazole alone (65). The

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majority of subjects receiving this combination exhibited ⬍5% increase in the mean QTc interval relative to baseline, and approximately 30% of subjects exhibited a 5–10% increase in the QTc interval (70). When ebastine (20 mg/day) was coadministered with erythromycin (2000 mg/day) to the same subjects in multiple doses in the same study, the QTc interval was likewise significantly increased by 10 ms compared with the QTc interval during administration of erythromycin alone (65). Three different studies have been carried out to assess the interaction between loratadine and the cytochrome P-450 CYP3A4 inhibitors ketoconazole, erythromycin, and cimetidine (74–76). Although ketoconazole was the most potent inhibitor of loratadine metabolism, followed by cimetidine and then erythromycin, no significant changes in QTc interval profile from baseline (approximately 400 ms) were demonstrated when any of the three drugs were tested in combination with loratadine (74–76). With mizolastine, the ECG parameters were not modified during coadministration with erythromycin compared to the effect of each coadministered drug alone. The minor QT interval prolongation observed during coadministration of ketoconazole with mizolastine (⬇ ⫹7 ms) might be attributable to the ketoconazole itself (77). The same explanation probably applied when ketoconazole (400 mg) was coadministered with cetirizine (20 mg, twice the recommended dose), producing a minor QT prolongation of 17.4 ms compared with 9.1 ms with cetirizine alone (78) Interaction studies showed no significant increases in QTc when fexofenadine 120 mg twice daily was administered in combination with erythromycin (500 mg three times daily) or ketoconazole (400 mg once daily) after dosing to steady-state (6.5 days) (72).

VIII. INCIDENCE OF CARDIAC EVENTS WITH COMMONLY PRESCRIBED NONSEDATING H 1-ANTIHISTAMINES The World Health Organization’s (WHO) adverse drug reaction database provides a source of data on spontaneous adverse drug reactions from 17 countries where nonsedating antihistamines are available. Data reported include total rate and rhythm disorders, selected reactions (QT prolongation, TdP, ventricular tachyarrhythmias, cardiac arrest, and supraventricular tachycardia), cardiac and sudden deaths. From 1986 to 1996 the following data were reported: 106 cases of selected reactions, 13 cardiac and sudden deaths for loratadine; 19 cases of selected reactions, 2 cardiac and sudden deaths for cetirizine; and 1 case of se-

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lected reaction and no incidence of cardiac and sudden death for acrivastine (79). When calculated as reports per million defined daily doses (DDD) sold, all three antihistamines have a very low reporting rate. Specifically, the reporting rates for cardiac and sudden deaths were approximately 0.005 for loratadine and 0.0008 for cetirizine and none for acrivastine compared with 0.038 for terfenadine. Although the reported incidences of deaths were themselves very low compared with terfenadine, the type of report and its analysis have attracted some criticism because of potential flaws and biases (80, 81). For instance, the report does not take into account the spontaneous rate of background cardiac events in the untreated population or the inclusion of a wide variety of undefined and unsubstantiated cardiac events in a composite numerator, rather than specific ventricular events of relevance to nonsedating antihistamines. This makes the analysis questionable (81). The Food and Drug Administration (FDA), which monitors, analyzes, and reviews individual reports and follow-up of cases of adverse drug reactions with antihistamines, did not find any definitive causal association between loratadine, cetirizine, or acrivastine and ventricular tachyarrhythmia up to 1997. It should be emphasized that apart from the specific contraindications described, the incidence of cardiotoxicity with antihistamines is extremely low in view of the widespread use of the drugs. Nevertheless, as antihistamines are prescribed for non-fatal disorders such as allergic rhinitis and chronic urticaria, the attributable risk must be assessed very critically. It will be very difficult to conduct a large controlled clinical study to examine the causal association between nonsedating antihistamines and ventricular arrhythmias. Any crude adverse event report must be put in perspective and used to detect trends and generate hypotheses that may guide surveillance and help plan future studies. The European Association of Allergology and Clinical Immunology (EAACI) published a guideline on the use of nonsedating antihistamines to avoid any unwanted arrhythmogenic effect associated with their use (82). It includes: avoidance of excessive dosage of antihistamines beyond that recommended by the manufacturer; avoidance of coadministration of drugs known to interfere with the hepatic metabolism of antihistamines; careful use of antihistamines in patients with liver impairment or at risk of cardiac arrhythmias (e.g., congenital long QT syndrome or atrioventricular block); selection of antihistamines that do not have quinidinelike actions and are not metabolized by hepatic cytochrome P-450 in patients at risk of cardiac arrhythmia. Nonsedating antihistamines are widely prescribed for the treatment of allergic disorders; however, the nonsedating antihistamines such as terfenadine and astemizole that block I Kr channels are now known to cause QT prolongation and TdP, particularly when given in overdosage, with concomitant ingestion of imidazole antifungals or macrolide antibiotics, or to at-risk patients including those with congenital long QT syndrome, cardiac disease, liver disease, or electrolyte

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disturbance. Many questions still need to be answered, such as the roles of other potassium channels (I Ks , I To , and I Ped ) and the relative expression of various potassium channels in different individuals, which may be important in the pathogenesis of TdP.

IX. OTHER FACTORS THAT MAY PROLONG VENTRICULAR REPOLARIZATION OR PREDICT TdP There are many causes of QT interval prolongation; however, by far the most common cause of QT prolongation is a drug. The drugs that can cause QT prolongation and TdP are listed in Table 4. Apart from drugs, other conditions likely to cause QT prolongation, some of which have already been discussed above, include: Organic heart disease (e.g., congenital long QT syndrome, ischemic heart disease, congestive heart failure, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocarditis, and Kawasaki syndrome) (83–87) Metabolic abnormalities (e.g., hypokalemia and, much less commonly, hypocalcemia and hypomagnesemia) (88–90) Bradycardia, atrioventricular and sinoatrial blocks (89, 92) Drug-related factors (e.g., narrow therapeutic window, multiple pharmacological actions including inhibition and induction of cytochrome P-450 enzymes, polypharmacy) (13, 33, 93) Female preponderance, which may be due to sex differences in specific cardiac ion densities (94, 95) Hepatic impairment (12)

X.

PREVENTION AND TREATMENT OF DRUG-INDUCED QT PROLONGATION

In clinical practice, adverse proarrhythmic effects of nonsedating antihistamines or the effects of any QT-prolonging drugs can be prevented by not exceeding the recommended dosage, and by avoiding their use in patients with pre-existing heart disease or risk factors as mentioned above, previous ventricular arrhythmias and/or electrolyte imbalance such as hypokalemia. Concomitant administration of drugs that inhibit cytochrome P-450 (e.g., imidazole antifungals, macrolide antibiotics) or those that can prolong the QT interval or cause electrolyte distur-

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Drugs That Can Prolong QT Interval and Lead to TdP (not a comprehensive list)

Antiarrhythmic drugs

Calcium channel blockers

Psychiatric drugs

Type 1A (TdP reported in all) Quinidine (TdP reported) Procainamide (TdP reported) Disopyramide (TdP reported) Ajmaline (TdP reported) Aprindine Type 1C (increase QT by prolonging QRS interval) Encainide Flecainide Propafenone Moricizine Type 3 (TdP reported in all) Amiodarone Dronedarone Sotalol d-sotalol Bretylium Ibutilide Dofetilide Semantilide Trecetilide Ersentilide Azimilide Tedisamil Almokalant Prenylamine (TdP reported, withdrawn) Bepridil (TdP reported, withdrawn) Terodiline (TdP reported, withdrawn) Thioridazine (TdP reported) Chlorpromazine (TdP reported) Haloperidol (TdP reported) Droperidol (TdP reported) Amitriptyline Nortriptyline Imipramine (TdP reported) Desipramine (TdP reported) Clomipramine Maprotiline (TdP reported) Doxepin (TdP reported) Lithium (TdP reported) Chloral hydrate Sertindole (TdP reported, withdrawn) Pimozide (TdP reported) Ziprasidone

410 Table 4

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Antihistamines

Antimicrobial and antimalarial drugs

Serotonin agonists/antagonists Immunosuppressants Antidiuretic hormones Other agents

Terfenadine (TdP reported, withdrawn) Astemizole (TdP reported, withdrawn) Diphenhydramine (TdP reported) Hydroxyzine Ebastine Mizolastine Erythromycin (TdP reported) Clarithromycin (TdP reported) Ketoconazole Pentamidine (TdP reported) Quinine Chloroquine (TdP reported) Halofantrine (TdP reported) Amantadine (TdP reported) Sparfloxacin Grepafloxacin (TdP reported, withdrawn) Pentavalent antimonial meglumine Ketanserin (TdP reported) Cisapride (TdP reported, withdrawn) Tacrolimus (TdP reported) Vasopressin (TdP reported) Adenosine Organophosphates Probucol (TdP reported) Papaverine (TdP reported) Cocaine

bance should be avoided. The serum potassium level should be checked regularly when the patient is taking potassium-depleting diuretics. Drugs that can prolong the QT interval should ideally be listed and regularly updated in a national drug formulary. Any adverse event suggestive of cardiac arrhythmias should be reported urgently to drug regulatory authorities and/or drug manufacturers. In our institution, we routinely give out an advice leaflet regarding the risk of QT prolongation and TdP to at-risk groups such as patients who are prescribed QT-prolonging drugs and those with congenital long QT syndrome (Fig. 7). Several websites provide information about the risk of QT prolongation with a particular drug, although none is comprehensive (Fig. 7). TdP is often self-limiting and associated with recurrent dizziness and syncope; however, it may progress to ventricular fibrillation and sudden death. The management of patients with drug-induced TdP includes identifying and withdrawing the offending drug(s), and identifying and correcting any electrolyte ab-

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Figure 7 Contents in St. George’s Hospital advice leaflet on long-QT syndrome and websites for checking QT-prolonging drugs.

normalities. The potassium level should be replenished to 4.5–5 mmol/L. The treatment of choice is intravenous infusion of magnesium sulfate (1–2 g). Magnesium, which has no direct effect on the QT interval, reduces the I Ca-L current and acts on the sodium/potassium-activated adenosine triphosphate system, which facilitates potassium influx into the cardiac cell and corrects the abnormal repolarization (96). In resistant cases, isoproterenol or temporary rapid atrial or ventricular cardiac pacing may be needed to increase the heart rate and shorten the QT interval (97). Temporary pacing works by decreasing the QT interval.

XI. REGULATORY PERSPECTIVE IN DRUG DEVELOPMENT Apart from antiarrhythmics, many drugs capable of inducing TdP are prescribed for noncardiac indications and are used for the treatment of relatively benign conditions. Regulatory authorities in the European Union (EU) are now concerned that the risk of cardiotoxicity should be identified and if possible quantified during the preclinical and clinical development of a drug. There are currently no contemporary guidelines from other regulatory authorities to address this issue; however, in 1997, the Committee for Proprietary Medicinal Products (CPMP) adopted a document entitled ‘‘Points to Consider: The Assessment of the Potential for QT Interval Prolongation by Non-Cardiovascular Medicinal Products’’ (96). This document should be viewed as a strong signal from the public health

Figure 8 The preclinical and clinical stages for testing the safety of new active substances (NAS) proposed in the CPMP document. (Summary from Ref. 98.)

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authorities that the problem of QT prolongation, especially caused by noncardiac drugs, is now thought to be extremely important, and to require careful scrutiny. Additional research and development are needed for any compound with the potential to prolong the QT interval. The CPMP document details the necessary preclinical and clinical stages required for testing the safety of new active substances (Fig. 8).

XII. SUMMARY Nonsedating H 1-antihistamines are widely prescribed for the treatment of allergic disorders because of their lack of sedative and anticholinergic effects; however, certain nonsedating antihistamines such as terfenadine and astemizole are now known to cause QT prolongation and TdP, particularly in overdosage or with concomitant ingestion of imidazole antifungals or macrolide antibiotics. Mechanistic studies showed that the cardiotoxic effects of some nonsedating antihistamines are due to the inhibition of repolarization potassium channels, particularly I Kr, which leads to prolongation of the action potential and QT interval, and the development of early after-depolarization, which triggers TdP. Patients at risk of developing TdP, such as those with congenital long QT syndrome, cardiac disease, liver disease, electrolyte disturbance, or those taking drugs that can prolong QT interval, should avoid nonsedating antihistamines that are also capable of prolonging the QT interval. Many questions still need to be answered, such as the role of other potassium channels (I Ks , I To , and I ped ) and the relative expression of various potassium channels in different individuals, which may be important in the pathogenesis of TdP with nonsedating antihistamines. There is also a lack of information on the cardiac actions of newer nonsedating antihistamines. The evidence so far indicates that the potential to cause ventricular arrhythmias is not a class effect and that loratadine, cetirizine, and fexofenadine are not associated with QT prolongation, TdP, or other ventricular arrhythmias. It is hoped that with a better understanding of the arrhythmogenic mechanism of nonsedating antihistamines, we will be able to identify patients at risk and prevent any cardiac toxicity associated with H 1-antihistamines, and ultimately, death.

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