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Allergic Reactionsto DrugsContributorsM. Alexander • H. E. Amos • K. E. Andersen • A. ArnaudE. S. K. Assem • J. Aubert • H. Bundgaard • J. CharpinM. C. Conroy • A. L. de Week • J. Dewdney • L. DostalovaA.A. Fisher • L. Gamba • J.-P. Girard • H. Hedin • R. HoigneL. Juhlin • D. Kraft • H. I. Maibach • P. Middleton • C.W ParkerJ. Pepys • W. Richter • W. Schalch • C H. SchneiderK. H. Schulz • F. Stocker • A. Szczeklik • S. Zawodnik

Editors

A.L. de Week and H. Bundgaard

UNIVERSITATS-BIBLIOTHEK

Springer-Verlag Berlin Heidelberg New York Tokyo 1983

Contents

Section I: General Aspects of Drug Allergies

CHAPTER 1

lmmunochemical Basis of Allergic Reactions to DrugsC. H. SCHNEIDER

A. Introduction 3I. Definitions 3

II. Miscellaneous Parameters in Sensitization 41. Chemical Characteristics of the Antigen 52. Antigen Metabolism 63. Genetic Aspects 7

B. Cellular and lmmunochemical Elements in Antigenicity 8I. Cellular Aspects 8

II. Antigenic Determinants Reacting with Antibody 9III. Antigenic Determinants in Cellular Reactions 13

C. Antigenicity and Drugs 14I. Agents of Intrinsic Immunogenicity 14

II. Low Molecular Weight Drugs as Immunogens 161. The Formation of Antigenic Determinants 162. The Formation of Complete Immunogens 20

III. Immunogenic Complexes not Involving Covalent Linkage BetweenHapten and Carrier 21

IV. Molecular Parameters in Elicitation and Inhibition of AllergicReactions 24

References 27

CHAPTER 2

Chemical and Pharmaceutical Aspects of Drug AllergyH. BUNDGAARD. With 23 Figures

A. Introduction: Routes of Formation of Drug Antigens 37B. Immunologically Active Macromolecular Contaminants of Penicillins . 39C. Polymerization of /?-Lactam Antibiotics 41

I. Penicillin Polymers 411. Formation and Structure of Polymers 42

X Contents

2. Immunologic Effects of Polymers 523. Prevention of Penicillin Polymerization 54

II. Cephalosporin Polymers 55D. Reactions Between Penicillins and Pharmaceutical Adjuvants 56E. Chemically Reactive Impurities and Degradation Products 59

I. Acetylsalicylic Acid 60II. Phenindione 62

III. Phenylbutazone 63IV. Corticosteroids 64V. Penicillins 65

References 67

CHAPTER 3

Immunopathological Mechanisms and Clinical Aspectsof Allergic Reactions to DrugsA. L. DE WECK. With 4 Figures

A. Introduction 75B. Chemical Properties Involved in the Allergenic Potential of Drugs . . 77

I. Formation of Immunogenic Conjugates 78II. Reactive Derivatives and Metabolites 79

III. Requirements for Allergens Eliciting Antibody-Mediated Reactions 80IV. Requirements for Allergens Eliciting Cell-Mediated

(Delayed-Type) Allergic Reactions 81V. Impurities and Galenic Factors Involved in Sensitization . . . . 81

C. Induction of Immune Responses to Drugs: Main Factors Involved . . 82I. Factors Involving the Sensitizing Drug 82

1. Chemical Structure and Reactivity 822. Cross-Sensitization 833. Dose, Duration, and Number of Courses of Therapy . . . . 834. Mode of Administration 83

II. Factors Involving the Patient 841. The Immune System and the Regulation of Immune Responses

to Drugs 842. Age and Sex 853. Genetic Factors 854. Underlying Diseases 865. Variable Relationship Between the Immune Response to a Drug

and the Incidence of Clinical Allergic Symptoms 87D. Immunopathological Mechanisms of Allergic Reactions to Drugs . . . 89

I. Antibody-Mediated Reactions 891. Anaphylactic Reactions 892. Cytotoxic Reactions 923. Immune Complex Reactions 93

II. Cell-Mediated (Delayed-Type) Reactions 94III. Reactions by Photosensitivity 96IV. Pseudoallergic Reactions 97

Contents XI

1. Mast Cell and Basophil Degranulation by ComplementComponents (Anaphylatoxins) 97

2. Liberation of Histamine Through NonimmunologicMechanisms 98

3. Pseudoallergic Reactions to Drugs Interfering withProstaglandin Synthesis 99

E. Clinical Forms of Allergic Reactions to Drugs 100I. Anaphylactic Shock 100

II. Serum Sickness 103III. Fever 105IV. Hematologic Reactions 106

1. Hemolytic Anemia 1072. Agranulocytosis 1093. Thrombocytopenia I l l4. Eosinophilia 112

V. Hepatic Disorders 113VI. Renal Diseases 114

VII. Reactions Affecting the Respiratory Tract 1161. Asthma 1162. Infiltrative and Fibrotic Pulmonary Reactions 116

VIII. Drug-Induced Autoimmunity 118IX. Vasculitis 120X. Digestive Tract and Other Manifestations 120

XI. Skin Manifestations 121References 121

CHAPTER 4

Cutaneous Manifestations of Drug AllergyK. H.SCHULZ

A. Pathogenesis and Classification 136I. Anaphylaxis, Urticaria, Angioedema 137

II. Late Urticarial Reactions 138III. Serum Sickness 139IV. Maculopapular Rashes 139V. Erythema Multiforme and Stevens-Johnson Syndrome . . . . . 140

VI. Allergic Vasculitis 141VII. Erythema Nodosum 143

VIII. Purpura 143IX. Purpura Pigmentosa Progressiva 144X. Fixed Eruptions 145

XL LyelFs Syndrome (Toxic Epidermal Necrolysis) 148XII. Drug-Induced Lupus Erythematosus 151

XIII. Allergic and Photoallergic Contact Dermatitis 152B. Diagnosis of Allergic Drug Reactions Involving the Skin 154References 156

XII Contents

CHAPTER 5

Allergy of the Respiratory Tract to Low Molecular Weight Chemical AgentsJ. PEPYS

A. Introduction 163B. Inorganic Chemicals 164

I. Halide Complex Salts of Platinum 1641. Allergy to Complex Platinum Salts 1652. lmmunochemical Analysis of Allergenicity of Platinum Salts . . 1653. Inhalation Tests with Platinum Salts 1694. Serological Findings 170

IL Nickel Sulphate 172III. Allergy to Potassium and Sodium Persulphate 172

C. Chemical Organic Dusts 173I. Amprolium Hydrochloride 173

II. Chloramine-T 173III. Piperazine Hydrochloride 174IV. Antibiotic Dusts: Ampicillin, Benzylpenicillin, 6-Aminopenicillanic

Acid and Related Substances 174V. Salbutamol 176

VI. Azo and Anthraquinone Dyes 176D. Organic Chemical Fumes and Vapours 176

I. Aminoethylethanolamine 177II. Diisocyanates 177

1. Reactions to Diisocyanates Other than TDI 1782. Modes of Action of TDI 1783. Antibodies to Other Diisocyanates 179

III. Epoxy Resin System Activating Agents 1791. Phthalic Anhydride-Specific IgE Antibodies 1802. Trimellitic Acid-Specific IgE and IgG Antibodies 181

IV. Miscellaneous Agents 181E. General Comments 181References 182

CHAPTER 6

Epidemiology of Drug Allergy: Drug MonitoringR. HOIGNE, F. STOCKER, and P. MIDDLETON. With 3 Figures

A. Introduction 187B. Methods of Epidemiology and Drug Monitoring 188

I. Comprehensive Inpatient (Intensive) Drug Monitoring 1891. Euler-Venn Diagram 1892. Weighted Attributions 191

II. Outpatient Drug Monitoring 192III. Spontaneous Reporting of Adverse Reactions to Drugs 192IV. Use of Record Linkage for Drug Surveillance 192

C. The Patient 193

Contents XIII

I. Disposition 1931. Allergy to Small Molecular Drugs 1932. Atopy and Adverse Drug Reactions: Drug Allergies 1933. Idiosyncrasy 1944. Intolerance 194

II. Basic Diseases 195D. Criteria Important to Epidemiology and Drug Monitoring 195

I. The Patient and the Adverse Reaction 1951. Characteristics of Clinical and Laboratory Adverse Reactions:

Distinction from Non-Drug Reactions 1952. Definition of Clinical Syndromes and Laboratory Findings . . 1973. Time Factors in Adverse Drug Reactions 1974. Frequency of Adverse Drug Reactions 2005. Degree of Importance of Adverse Drug Reactions 2016. Outcome and Duration of Adverse Drug Reactions 201

II. The Drug and Drug Groups 2011. Different Kinds of Drugs 2012. Method of Administration of Drug and Drug Allergic Reactions 202

E. Practical Consequences 202F. Summary 203References 203

CHAPTER 7

Diagnostic Procedures in Drug AllergyJ.-P. GIRARD and S. ZAWODNIK

A. Introduction 207B. Clinical Diagnosis 207C. Immunologic Diagnosis 208D. Skin Testing 209

I. Phenylbutazone - BSA Conjugates 209II. Penicillins 210

III. Patch Testing 212E. Laboratory Procedures for Investigating Type I Allergic Drug Reactions 212

I. Dosage of Serum IgE 212II. Radioallergosorbent Test (RAST) 213

III. Basophil Degranulation Test 214IV. Histamine Release from Sensitized Leukocytes . 215

F. In Vitro Investigation of Type II Reactions 215I. Drug-Induced Allergic Hemolysis 215

II. Drug-Induced Thrombocytopenia 2161. Inhibition of Clot Retraction 2162. Drug-Dependent Platelet Agglutination 2163. Complement Fixation Test for Drug-Induced Thrombocytopenia 216

III. Drug-Induced Agranulocytosis 2161. Serologic Methods 2162. Lymphocyte Stimulation 217

XIV Contents

G. Laboratory Procedures to Detect Serum-Sickness Syndrome (Type III) 217I. Determination of Immune Complexes 218

II. Determination of Circulating Antibodies 218H. Laboratory Diagnosis of Type IV Reactions or Delayed Hypersensitivity 219

I. Lymphocyte Transformation Test 220II. Leukocyte Migration Inhibition Test 222

J. Conclusions 223References 223

CHAPTER 8

Prevention and Treatment of Drug AllergiesA. L. DE WECK

A. Evaluation of the Allergenic Potential of Drugs 227B. Preventive Measures in Drug Allergy 229C. Prevention of Allergic Reactions by Accurate Diagnosis of Drug Allergy

in the Allergic Patient 230D. Specific Inhibition of Antibody-Mediated Reactions to Drugs . . . . 234E. Symptomatic Treatment of Allergic Reactions to Drugs 235F. Hyposensitization and Induction of Long-Lasting Immunological

Tolerance to Drugs 235References 237

Section II: Allergic Reactions to Specific Drugs

CHAPTER 9

Major Drugs Acting on the Central Nervous SystemC. W. PARKER

A. General Anesthetics 243I. Halothane 243

II. Other General Anesthetics 245III. Intravenous Anesthetic Agents 245

B. Sedatives, Hypnotics, and Tranquillizers 245I. Phenothiazines 245

II. Barbiturates 247III. Others . 247

C. Narcotics 247D. Anti-Epileptic Drugs 250E. Ethanol 251F. Anti-Depressive Drugs 252G. Stimulants and Hallucinogens 252H. L-Dopa 252J. Relaxants 252

K. Analgesic Agents 253References 255

Contents XV

CHAPTER 10

General and Local AnaestheticsE. S. K. ASSEM. With 6 Figures

A. Hypersensitivity Reactions to Intravenous Anaesthetics 259I. Clinical Manifestations 259

II. Predisposing Factors 259III. Relative Incidence with Various Agents 260

1. Barbiturates 2602. Eugenols 2603. Steroid Anaesthetics 260

B. Hypersensitivity Reactions to Volatile General Anaesthetics 266I. Halothane-Associated Liver Damage 266

1. Incidence 2672. Evidence in Support of an Allergic Mechanism 2673. Reactions to Other Halogenated Volatile Anaesthetics . . . . 2684. Possible Role of Idiosyncrasy in Hepatitis Associated with

Halogenated Volatile Anaesthetics 269C. Allergy to Local Anaesthetics 269

I. Structural Basis 269II. Investigation of Reactions to Local Anaesthetics 270

1. Skin Tests 2702. Other In Vivo Tests 2703. In Vitro Allergy Tests 271

References 273

CHAPTER 11

Analgesics and Nonsteroidal Anti-Inflammatory DrugsA. SZCZEKLIK. With 2 Figures

A. Classification and Mode of Action of Analgesics and NonsteroidalAnti-Inflammatory Drugs .- 277

B. Prevalence of Adverse Drug Reactions 280C. Clinical Manifestations of Adverse Reactions 280

I. Systemic Anaphylaxis 280II. Aspirin-Induced Asthma 280

1. Definition 2802. Prevalence 2803. Pathogenesis 2814. Clinical Symptoms and Laboratory Findings 2825. Diagnosis 2846. Prevention and Therapy 285

III. Asthma Relieved by Aspirin 285IV. Urticaria and Angioedema 286

1. Intolerance to Aspirin 2862. Hypersensitivity to Pyrazolone Drugs 287

V. Other Skin Reactions Produced by Analgesics 288VI. Liver Damage 289

XVI Contents

VII. Kidney Injury 289VIII. Hypersensitivity in Lupus Erythematosus 291

IX. Blood Dyscrasias 2911. Agranulocytosis and Pancytopenia 2912. Aspirin-Induced Thrombocytopenia 292

X. Peripheral Neuropathies 293References 293

CHAPTER 12

Neuromuscular Blocking DrugsE. S. K. ASSEM. With 8 Figures

A. Introduction 299B. In Vivo Diagnostic Procedures 300

I. Skin Tests 300II. Response to an Intravenous Test Dose 301

C. In Vitro Tests 301I. Histamine Release from Leucocytes 301

II. Passive Sensitisation Experiments 302III. Lymphocyte Transformation Test 302IV. Serum IgE Measurements 303

D. Mechanism of Reactions to Depolarising Agents (Suxamethonium) . . 303I. Clues from Case Histories and Other Clinical Findings 303

II. lmmunochemical Considerations on the Nature of the Allergen . . 304III. Leucocyte Histamine Release by Suxamethonium 305

1. Effect of Serum 3052. Dose-Response Relationships 3053. Effect of Acetylcholine on the Response to Suxamethonium . . 3074. Effect of Non-Depolarising Blockers on Histamine Release by

Suxamethonium 3075. Effect of Calcium on Histamine Release 307

IV. Histamine Release as a Manifestation of Idiosyncrasy . . . . . . . 308E. Mechanism of Reactions to Non-Depolarising Agents 308

I. General Structural Features Associated with Histamine Release. . 308II. Relation of Leucocyte Histamine Release to Skin Wheal and Flare

Responses and Related Phenomena 309III. Calcium Dependence of Histamine Release 309IV. Effect of Acetylcholine on Histamine Release by Non-Depolarising

Agents 311V. Relation Between Allergy and Idiosyncrasy 311

References 311

CHAPTER 13

Drugs Used TopicallyK. E. ANDERSEN and H. I. MAIBACH

A. Epidemiology 313B. Clinical Aspects of Contact Allergy 314

Contents XVII

C. lmmunochemical, Pharmaceutical, and Pharmacologic Aspects . . . . 315D. Diagnostic Tests 316E. Anti-Psoriasis Agents 317

I. Tar 317II. Dithranol 317

III. Corticosteroids 318IV. Salicylic Acid 318V. Mechlorethamine 318

VI. 6-Aminonicotinamide 318VII. Thioxolone 319

VIII. 1,8,9-Triacetoxyanthracene 319IX. Tretinoin 319X. 8-Methoxypsoralen 319

F. Local Anesthetics 320I. Benzocaine 320

II. The Amide Group of Local Anesthetics 320III. Propanidid 321IV. Proxymetacaine 321V. Falicain 321

VI. Benzamine Lactate 322G. Antipruritic Agents 322

I. Antihistamines 322II. Phenol and Resorcinol 322

III. Menthol 323IV. Crotamiton 323V. Nitrofurylaminothiadazoles 323

VI. Oxypolyethoxydodecane 323VII. Dimethisoquin 323

VIII. Zirconium Compounds 323IX. Fragrances and Preservatives in Antipruritic Agents 324

H. Antiperspirants 324I. Aluminum Salts . 324

II. Formaldehyde 324III. Glutaraldehyde 324IV. Anticholinergic Agents 325V. Zirconium Salts 325

J. Local Antibiotics and Chemotherapeutics 325I. Neomycin 325

II. Gentamycin 327III. Penicillin 327IV. Chloramphenicol 328V. Bacitracin 328

VI. Polymyxin-B Sulfate 328VII. Tetracyclines 328

VIII. Erythromycin 329IX. Sulfonamide 329X. Nitrofurazone 329

XVIII Contents

XL Clindamycin 330XII. Sodium Fusidate 330

XIII. Streptomycin 331XIV. Virginiamycin 331XV. Xanthocillin 331

XVI. Mafenide 331XVII. Sulfur 332

XVIII. Halogenated Hydroxyquinolines 332K. Antifungal Agents 333

I. Nystatin 333II. Variotin 333

III. Undecylenic Acid 333IV. Imidazole Derivatives 333V. Tolnaftate 334

VI. Dibenzthione 334VII. Pyrrolnitrin 334

VIII. Zinc Pyrithone 334L. Steroids 335

I. Corticosteroids 335II. Dianabol Cream 336

III. Estrogens 336M. Antiseptics and Disinfectants 336

I. Quaternary Ammonium Compounds 337II. Chlorhexidine 338

III. Hexachlorophene 338IV. Dichlorophene 338V. Triphenylmethane Dyes 339

VI. Acridine Dyes 339VII. Rivanol 340

VIII. Fenticlor 340IX. Formaldehyde 340X. Tetramethylthiuram Disulfide 341

XL Hexomedine 341XII. Iodine and Iodides 341

XIII. Alcohols 341XIV. Triclosan 342•XV. Triclocarban 342

XVI. TEGO 342XVII. Glutaraldehyde 343

XVIII. Mercurials 343XIX. Silver Nitrate 343

N. Preservatives 343I. Parabens 344

II. Propylene Glycol 345III. SorbicAcid 345IV. Chlorocresol and /?-Chloro-m-xylenol 346V. Chloracetamide 346

Contents XIX

VI. Nordihydroguaiaretic Acid 346VII. BHA and BHT 347

VIII. Propyl Gallate 347IX. Imidazolidinyl Urea 347X. Other Preservatives 347

O. Vitamins 347I. Tretinoin 347

II. Thiamine 348III. a-Tocopherol 348IV. Other Vitamins 348

P. Photocontact Dermatitis 348I. Halogenated Salicylanilides 349

II. Chloro-2-phenylphenol 349III. Bithionol 350IV. Hexachlorophene 350V. Fenticlor 350

VI. Multifungin 350VII. Jadit 350

VIII. Chlorhexidine 351IX. Esters of /?-Aminobenzoic Acid 351X. Sulfonamides and Phenothiazines 351

XI. Digalloyl Trioleate 351XII. Captan 351

XIII. Coal Tar 352XIV. 8-Methoxypsoralen 352XV. 6-Methylcoumarin 352

XVI. Hydrocortisone 352Q. Vehicle Constitutents 352

I. Petrolatum 353II. Lanolin 353

III. Emulsifiers . 354IV. Aliphatic Alcohols . 355V. Polyethylene Glycol 355

VI. Glycerol 356VII. Propylene Glycol 356

VIII. Ethylenediamine Hydrochloride 356IX. Ethylsebacate 356X. Freons 356

R. Perfumes 357S. Plant-Derived Topical Drugs 358

I. 8-Methoxypsoralen 358II. Arnica Tincture 358

III. Camomile 359IV. Coumarin 359V. Tincture of Benzoin 359

VI. Podophylin 359VII. Rosin (Colophony) 359

XX Contents

VIII. Gums 359IX. Vegetable Turpentine 359X. Wood and Coal Tar 360

XL Propolis 360T. Miscellaneous Agents 360

I. 5-Fluorouracil 360II. Tromantidine Hydrochloride 360

III. Idoxuridine 361IV. Neutral Red 361V. Suntan Preparations 361

VI. Dihydroxyacetone 362VII. Hydroquinone and Derivatives 362

VIII. Resorcinol 363IX. Benzoyl Peroxide 363X. Epinephrine and Derivatives 363

XL Pyrazolone Compounds 364XII. Bufexamac 364

XIII. Nitroglycerin 364XIV. Allylthiocarbamide 364XV. Heparinoid 364

XVI. TEA-Coco Hydrolyzed Protein 364XVII. Metoprolol 365

U. Conclusions 365References 365

CHAPTER 14

AntihistaminesA. A. FISHER

A. Introduction 379B. The Nature and Classification of the Antihistamines . . . . . . . . 379C. The Role of Tartrazine in Allergic Antihistamine Reactions 380D. The Nitrogen-Linked Ethylenediamines 381

I. The Asthmatic Patient and Ethylenediamine Sensitivity 382II. Industrial Dermatitis due to Ethylenediamine Sensitivity 382

1. Epoxy Resin Dermatitis 3822. Machine Worker's Dermatitis 382

III. The Relationship of the Hydroxyzines to Ethylenediamine . . . . 383IV. The Relationship of the Piperazine (Cyclizine) Antihistamines to

Ethylenediamine 383E. The Oxygen-Linked Ethanolamine Antihistamines 383

I. Systemic "Endogenic" Contact Dermatitis to Ethanolamines . . . 384II. Photoallergic Dermatitis due to Diphenhydramine 384

F. The Phenothiazines 384I. Promethazine Hydrochloride 384

II. Cross-Reactions Between the Phenothiazine Antihistamines andOther Phenothiazine Compounds 385

Contents XXI

III. Exposure of Medical and Nursing Personnel to Phenothiazines . . 385IV. Exposure of Veterinarians and Farmers to Phenothiazines . . . . 386V. Exposure to Methylene Blue 386

VI. Varieties of Allergic Reactions to Phenothiazine Compounds . . . 386G. The Carbon-Linked Alkylamine (Propylamine) Antihistamines . . . . 388H. Miscellaneous Antihistamines 388J. Facial Dyskinesia from the Antihistamines 388

References 389

CHAPTER 15

Drugs Acting on the Cardiovascular SystemH. E. AMOS. With 9 FiguresA. Incidence of Hypersensitivity Reactions 391

I. Cardiac Glycosides 391II. Quinidine 391

III. Procainamide 392IV. Adrenergic Neuron Blocking Agents 392V. Hydralazine 394

VI. Beta-Adrenoceptor Blocking Drugs 394B. Clinical Aspects of the Adverse Effects 394

I. Drug-Induced Lupus Erythematosus 394II. Thrombocytopenia 395

III. Hemolytic Anemia 396IV. Cutaneous Manifestations 396V. Specific Organ Damage Induced by Cardiovascular Drugs . . . 397

1. Liver 3972. Heart 397

VI. Oculomucocutaneous Syndrome 3981. Cutaneous Manifestations 3982. Eye Lesions 3993. Sclerosing Peritonitis 3994. Oral/Nasal Lesions . 3995. Hearing Impairment 3996. Fibrotic Reactions 400

VII. Oculomucocutaneous Syndrome and ^-Blocking Drugs Other thanPractolol 4001. Propranolol 4002. Alprenolol 4013. Timolol 401

C. Immunopharmacological Aspects 401I. Cardiac Glycosides 401

1. Digitoxin 4012. Digoxin 4023. Gitaloxin 4024. Gitoxin 4035. Lanatoside C 4036 Ouabain 403

XXII Contents

7. Proscillaridin 403II. Quinidine 403

III. Procainamide 404IV. Hydralazine 405V. Beta-Adrenoceptor Blocking Drugs 407

VI. Methyldopa 410D. Clinical Immunological Aspects 410

I. Drug-Induced Lupus Erythematosus 411II. Thrombocytopenia 412

III. Oculomucocutaneous Syndrome 413IV. Mechanism of Practolol-Induced Tissue Damage 414V. Hemolytic Anemia 415

1. Stibophen 4162. Penicillin 4163. Methyldopa 417

E. Conclusion 417References 417

CHAPTER 16

Penicillins and CephalosporinsA. L. DE WECK. With 10 FiguresA. Introduction 423B. Penicillins 423

I. The Formation of Antigenic Determinants from P e n i c i l l i n s . . . . 4231. The Penicilloyl Determinant 4252. The Penicillenate Determinant 4303. Penicilloic Acid 4304. The Penicillanyl Determinant 4335. The Penamaldate and Penaldate Determinants 4346. The D-Penicillamine Determinant 4347. The Penicoyl Derivatives 4358. Penicillin Polymers 4359. Protein Impurities 438

10. Role of the Side Chain in Penicillin Allergy 441II. Clinical Aspects 443

1. Anaphylactic and Anaphylactoid Reactions 4432. Urticaria 4453. Serum-Like Disease 4454. Morbilliform Exanthema 4455. Hematologic Disorders 4476. Kidney and Vascular Disorders 4487. Other Manifestations 449

III. Epidemiology and Frequency of Allergic Reactions 449IV. Diagnostic Tests 450

1. Skin Tests 4512. Antibody Detection Techniques 4533. Cellular Tests 456

Contents XXIII

C. Cephalosporins 457I. Immunologic Aspects of Hypersensitivity to Cephalosporins . . . 458

1. Immunogenicity of the Cephalosporins 4582. Formation of Antigenic Determinants 4593. Role of the Side Chain in Immunological Reactivity 4594. Protein Impurities and Polymers 461

II. Clinical Aspects 461III. Epidemiology and Frequency of Allergic Reactions 462IV. Diagnostic Tests 462

D. Conclusions 464References 464

CHAPTER 17

Other AntibioticsD. KRAFT. With 8 Figures

A. Introduction 483B. Tetracyclines 483

I. Physicochemical and Pharmacologic Properties 483II. Immunochemistry and Immunology 484

III. Clinical Aspects 485IV. Results of Diagnostic Tests 487

1. Skin Tests 4872. Tetracycline-Specific Antibodies 4873. Tetracycline-Specific Lymphocyte Reactivity 488

V. Experimental Studies in Animals 488VI. Conclusions Concerning Possible Pathomechanisms 488

C. Chloramphenicol and Thiamphenicol 489I. Physicochemical and Pharmacologic Properties 489

II. Immunochemistry and Immunology 489III. Clinical Aspects 490IV. Results of Diagnostic Tests 491

1. Skin Tests 4912. Chloramphenicol-Specific Antibodies 4913. Chloramphenicol-Specific Lymphocyte Reactivity 492


D. Aminoglycosides 493I. Physicochemical and Pharmacologic Properties 493

II. Immunochemistry and Immunology 495III. Clinical Aspects 495

1. Streptomycin and Dihydrostreptomycin 4952. Deoxystreptamine Aminoglycosides 496

IV. Results of Diagnostic Tests 4961. Skin Tests 4962. Aminoglycoside-Specific Antibodies 4973. Aminoglycoside-Specific Lymphocyte Reactivity 497

XXIV Contents


E. Polymyxins 498I. Physicochemical and Pharmacologic Properties 498


1. Skin Tests 5002. Polymyxin-Specific Antibodies 5003. Polymyxin-Specific Lymphocyte Reactivity 501


F. Rifamycins 501I. Physicochemical and Pharmacologic Properties 501


1. Skin Tests 5042. Rifamycin-Specific Antibodies 5043. Rifamycin-Specific Lymphocyte Reactivity 505


G. Macrolides 505I. Physicochemical and Pharmacologic Properties 505


1. Skin Tests 5072. Macrolide-Specific Antibodies 5083. Macrolide-Specific Lymphocyte Reactivity 508

V. Experimental Studies in Animals 508VI. Conclusions Concerning Possible Pathomechanisms . . . : . . . 508

H. Lincomycins 508I. Physicochemical and Pharmacologic Properties 508


1. Skin Tests 5102. Lincomycin-Specific Antibodies 5103. Lincomycin-Specific Lymphocyte Reactivity 510


J. Miscellaneous Antibiotics 511I. Vancomycin 511

II. Spectinomycin 511III. Novobiocin 511

References 512

Contents XXV

CHAPTER 18

Other Antibacterial DrugsM. ALEXANDER

A. Introduction 521

B. Sulfonamides Including Benzylpyrimidine Sulfonamides 521I. Physicochemical and Pharmacologic Properties 521


1. Skin Tests 5262. Sulfonamide-Specific Antibodies 5273. Sulfonamide-Specific Lymphocyte Reactivity 527


C. Nitrofurantoin 528I. Physicochemical and Pharmacologic Properties 528


1. Skin Tests 5312. Nitrofurantoin-Specific Antibodies 5313. Nitrofurantoin-Specific Lymphocyte Reactivity 532


D. Nalidixic, Pipemidic, and Oxolonic Acids 533I. Physicochemical and Pharmacologic Properties 533


1. Skin Tests 5352. Nalidixic, Pipemidic, and Oxolonic Acid-Specific Antibodies . . 5363. Nalidixic, Pipemidic, and Oxolonic Acid-Specific Lymphocyte

Reactions 536V. Experimental Studies in Animals 536

VI. Conclusions Concerning Possible Pathomechanisms 536

E. Isoniazid 537I. Physicochemical and Pharmacologic Properties 537


1. Skin Tests 5402. Isoniazid-Specific Antibodies 5413. Isoniazid-Specific Lymphocyte Reactivity 541


XXVI Contents

F. Ethambutol 542I. Physicochemical and Pharmacologic Properties 542


1. Skin Tests 5432. Ethambutol-Specific Antibodies 5433. Ethambutol-Specific Lymphocyte Reactivity 544


G. Sulfones 544I. Physicochemical and Pharmacologic Properties 544


1. Skin Tests 5452. Sulfone-Specific Antibodies 5453. Sulfone-Specific Lymphocyte Reactivity 545


H. Clofazimine 546I. Physicochemical and Pharmacologic Properties 546


1. Skin Tests 5472. Clofazimine-Specific Antibodies 5473. Clofazimine-Specific Lymphocyte Reactivity 547


References 548

CHAPTER 19Antifungal, Anthelmintic, and Antiprotozoal DrugsJ. DEWDNEY. With 9 Figures

A. Introduction 559

B. Antifungal Drugs 560I. Systemic Agents 560

II. Topical Agents 562

C. Anthelmintic Drugs 567I. Piperazines 567

II. Benzimidazole and Imidazothiazoles 569III. Diethylcarbamazine 571

Contents XXVII

D. Antiprotozoal Drugs 572I. Introduction 572

II. Quinine 572III. Other Antimalarial Drugs 574

References 574

CHAPTER 20

Solutions and Emulsions Used for Intravenous InfusionsW. RICHTER and H. HEDIN. With 7 Figures

A. Introduction 581

B. Plasma Substitutes 581I. Historical 581

II. General Physicochemical Properties 582III. General Clinical Aspects 582IV. Incidence 583

C. Plasma Protein Fractions 585I. Physicochemical and Pharmaceutical Aspects 585


1. Skin Tests 5872. Specific Antibodies 5873. Lymphocyte Transformation Test 587

V. Potential Pathomechanisms 588D. Dextran. 589

I. Physicochemical and Pharmaceutical Aspects 589II. Immunochemistry and Immunology 591

III. Clinical Aspects 591IV. Results of Diagnostic Tests . 592


V. Potential Pathomechanisms 594VI. Miscellaneous 596

E. Gelatin Derivatives 596I. Physicochemical and Pharmaceutical Aspects 596




XXVIII Contents

F. Hydroxyethylstarch 601I. Physicochemical and Pharmaceutical Aspects 601




G. Polyvinylpyrrolidone 604I. Physicochemical and Pharmaceutical Aspects 604

II. Immunochemistry and Immunology 605III. Miscellaneous 605

H. Parenteral Nutrition 606I. General Aspects 606

II. Sugars 6071. Glucose 6072. Galactose 6073. Invertose 6084. Mannitol 609

III. Amino Acids 6101. Physicochemical and Pharmaceutical Aspects 6102. Adverse Reactions, Including Potential Pathomechanisms . . . 610

IV. Fat Emulsions 6111. Physicochemical and Pharmaceutical Aspects 6112. Immunochemistry and Immunology 6113. Clinical Aspects 6124. Incidence 6135. Results of Diagnostic Tests 6136. Potential Pathomechanisms , . . . . 615

References 615

CHAPTER 21

Gastrointestinal DrugsL. JUHLIN

A. Introduction 629B. Antacids 629C. Gastric Antisecretory Drugs 629D. Laxatives 630E. Antidiarrheal Agents 632F. Anti-Inflammatory Drugs 632G. Miscellaneous Drugs 633References 634

Contents XXIX

CHAPTER 22

Intolerance to Food and Drug AdditivesL. JUHLIN. With 1 Figure

A. Introduction 639B. Symptoms of Intolerance 639

I. Hyperkinetic Behavior Disturbance 639II. Contact Dermatitis 641

1. Dyes 6412. Antioxidants 6413. Preservatives 6424. Flavors 6425. Stabilizers 642

III. Recurrent Urticaria and Angioedema 642IV. Asthma, Rhinorrhea, and Nasal Polyps 645V. Purpura 646

VI. Other Symptoms of Intolerance 646C. Mechanisms 647D. Diagnosis of Intolerance 648E. Food and Drug Labeling 649References 650

CHAPTER 23

VitaminsW. SCHALCH and L. DOSTALOVA

A. Introduction 657I. The Drug-Equivalent Use of Vitamins 658

II. Allergic Reactions to Vitamins 664B. Vitamin A 666

I. Physicochemical and Pharmacologic Aspects 666II. Allergic Reactions to Vitamin A . 667

C. Vitamin B t . 668I. Physicochemical and Pharmacologic Aspects 668

II. Allergic Reactions to Vitamin B t 669D. Vitamin B2 671

I. Physicochemical and Pharmacologic Aspects 671II. Allergic Reactions to Vitamin B2 •• 672

E. Vitamin B6 672I. Physicochemical and Pharmacologic Aspects 672

II. Allergic Reactions to Vitamin B6 673F. Vitamin B12 673

I. Physicochemical and Pharmacologic Aspects 673II. Allergic Reactions to Vitamin B1 2 674

G. Vitamin C 675I. Physicochemical and Pharmacologic Aspects 675

II. Allergic Reactions to Vitamin C 676

XXX Contents

H. Biotin 677J. FolicAcid 677

I. Physicochemical and Pharmacologic Aspects 677II. Allergic Reactions to Folic Acid 678

K. Nicotinic Acid and Nicotinamide 678I. Physicochemical and Pharmacologic Aspects 678

II. Allergic Reactions to Nicotinic Acid and Nicotinamide 679L. Pantothenic Acid 679

M. Vitamin D 680N. Vitamin E 680

I. Physicochemical and Pharmacologic Aspects 680II. Allergic Reactions to Vitamin E 681

O. Vitamin K 682I. Physicochemical and Pharmacologic Aspects 682

II. Allergic Reactions to Vitamin K 682P. Conclusions 683References 684

CHAPTER 24

Corticotrophins and CorticosteroidsJ. CHARPIN, A. ARNAUD, and J. AUBERT. With 6 Figures

A. Frequency of Accidents due to Corticotrophins 691B. Clinical Aspects of Allergic Reactions to ACTH ,. . 692C. Etiology and Physiopathology of Accidents 694D. Diagnosis of Allergy to ACTH 697E. Therapy 698F. Allergy to Corticosteroids 698

I. Neurologic Symptoms 698II. Contact Dermatitis 698

III. Anaphylactoid Reactions 698References 699

CHAPTER 25Hypersensitivity Reactions to HormonesM. C. CONROY and A. L. DE WECK

A. Protein and Polypeptide Hormones 703I. lmmunochemical and Pharmacological Aspects 703

II. Clinical Aspects 704III. Results of Diagnostic Tests 705

B. Prostaglandins 706I. lmmunochemical and Pharmacological Aspects 706


Contents XXXI

C. Adrenocorticosteroids 707I. lmmunochemical and Pharmacological Aspects 707


1. Cutaneous Tests 7082. Direct Challenge 708

D. Sex Steroids and Oral Contraceptive Drugs 708I. lmmunochemical and Pharmacological Aspects 708


E. Conclusion 710References 710

CHAPTER 26

Allergy to InsulinJ. AUBERT and J. CHARPIN

A. Epidemiology and Frequency of Allergic Reactions 713B. Clinical Aspects 713C. Immunological, Pharmaceutical, and Pharmacological Aspects . . . . 7 1 3D. Results of Diagnostic Tests 714E. Special Considerations 714References 715

CHAPTER 27

Radiologic Contrast MediaJ.-P. GIRARD and L. GAMBA

A. Introduction 717B. Chemical Structures of Contrast Media 717C. Clinical Manifestations 718D. Pathogenic Mechanisms 718

I. Hypersensitivity Mechanisms 718II. Direct Histamine Release 720

III. Activation of Complement Factors 720IV. Inhibition of Acetylcholine Esterase 721

E. Diagnostic Tests 722I. Skin Tests . 722

II. Lymphocyte Transformation Test 722III. Provocation Tests 722

F. Prevention 723I. Risk Factors 723

II. Premedication 723References 724

Subject Index 727

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