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Handbook of Experimental Pharmacology

Volume 84

Editorial Board

G.v. R. Born, London P. Cuatrecasas, Research Triangle Park, NC R. Rerken, Berlin A. Schwartz, Cincinnati, OR

Antituberculosis Drugs

Contributors K. Bartmann . H. Iwainsky . H. H. Kleeberg . P. Mison H. A. Offe . H. Otten . D. Tettenborn . L. Trnka

Editor K. Bartmann

Springer -Verlag Berlin Heidelberg New York London Paris Tokyo

Professor Dr_ med_ KARL BARTMANN

Julius-Lucas-Weg 67 D-5600 Wuppertal 1

With 68 Figures

ISBN-13 :978-3-642-72875-4 e-ISBN-13: 978-3-642-72873-0 001: 10.1007/978-3-642-72873-0

Library of Congress Cataloging-in-Publication Data. Antituberculosis drugs. (Handbook of experimental pharmacology; v. 84) Includes bibliographies and index. 1. Antitubercular agents. 2. Tuberculosis-Chemotherapy. I. Bartmann, K. (Karl) II. Series. [DNLM: 1. Antitubercular Agents. W1 HA51L v. 84/QV 268 A633] QP905.H3 vol. 84 615'.1 s 87-20782 [RC311.3.C45] [616.9'95061] ISBN-13: 978-3-642-72875-4 (U.S.)

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. Duplication of this pUblication or parts thereofis ouly permitted under the provisions of the German Copyright Law of September 9, 1965, in its version ofJune 24, 1985, and a copyright fee must always be paid. Violations faU under the prosecution act of the German Copyright Law.

© Springer-Verlag Berlin Heidelberg 1988 Softcover reprint of the hardcover 1st edition 1988

The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.

Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature.

2122/3130-543210

List of Contributors

K. BARTMANN, Julius-Lucas-Weg 67, D-5600 Wuppertal1

H.IwAINSKY, Forschungsinstitut fUr Lungenkrankheiten und Tuberkulose, Karower Str.11, GDR-1115 Berlin-Buch

H. H. KLEEBERG, Tuberculosis Research Institute, Private Bag X 385, Pretoria 0001, South Africa

P. MI~N, Research Institute for Technical Development, Kobateky 1400, Prag 4, Czechoslovakia

H. A. OFFE, Charlottenburger Str. 19jC 512, D-3400 Gottingen-Geismar

H. OTTEN, Institut fUr Chemotherapie, Bayer AG, Postfach 91709, D-5600 Wuppertal1

D. TETTENBORN, Bayer AG, Forschung und Entwicklung Medizin, Aprather Weg, Postfach, D-5600 Wuppertal 1

1. TRNKA, Research Institute for Tuberculosis and Respiratory Diseases, 18071 Praha 8 - Bulovka, Czechoslovakia

Preface

This volume deals specifically with those antituberculosis drugs which passed the preclinical phase and have been or are used in the treatment of tuberculosis and other mycobacterial diseases (except leprosy) in at least some parts of the world. Despite this restriction, there are 14 such drugs, and as a result this volume has reached rather large proportions. To prevent it from becoming even larger and more unwidely, most derivatives of antituberculotics have been omitted, especially where it is claimed that they provide only better bioavailibility or tolerability. Only in the chapter on the chemotherapy of diseases due to so-called atypical mycobacteria is the clinical use of the drugs described to a certain extent. In addition to antituberculotics, also discussed are antimicrobials which have been found to be effective against these mycobacteria.

The sequence in which the drugs are described is historical, reflecting not the time of discovery but rather the first clinical application. This order was selected for reasons which are now no longer relevant.

In this volume less emphasis is placed on detection, biological or synthetic production of antituberculotics, and structure-activity relationships. In contrast, emphasis is put on the degree, type, and mechanism of antimyco bacterial activity, pharmacokinetics, and biotransformation in animals and man, on experimental pharmacodynamics, and on the toxicity of antituberculotics used therapeutically. Thus, all the information which is today designated "preclinical data" is dealt with in extenso. Also described in detail is how, slowly and over many years, experimental chemotherapy of tuberculosis has become increasingly adapted to clinical problems as models have been elaborated which are more and more representative and offer a more reliable basis for predictions. Animal experiments have played an indispensable role in this research and have saved numerous human lives.

With respect to the rationale of and the results obtained during the development of therapeutic regimens, the reader may profit from referring in the subject index to the entries "treatment of infected animals - combined; intermittent; in phases; preventive."

During the time covered by this volume (about 1945-1985), the classification of microorganisms has been refined, and consequently names have been changed to a considerable extent. When it proved impossible to reliably transpose old classifications and nomenclature into the current systems, the author's nomenclature is used.

Gaps in the information about the toxicology and/or biotransformation and pharmacokinetics of some of the antituberculotics, especially the older ones,

VIII Preface

should not be a cause of concern. We have followed the principle that all available data must be reported, but in the early days preclinical investigations were not as sophisticated as they are today and produced relatively little data. On the other hand, drugs like the tetracyclines, which have a very limited use in tuberculosis but widespread application against infections caused by rapidly growing bacteria, have undergone numerous tests and a great deal of data is available which must all be taken into account. For these types of drugs the reader can also consult other volumes of the Handbook of Experimental Pharmacology: volume 62 on aminoglycoside antibiotics, volume 67 on beta-Iactam-antibiotics, and volume 78 on tetracyclines.

Tuberculosis is one of the few infectious diseases which require combined chemotherapy. Combinations of drugs are discussed in the section on the last mentioned single drug in the combination. For instance, combinations of isoniazid with p-aminosalicylic acid or streptomycin are dealt with in the section on isoniazid, but combinations of isoniazid with ethambutol or rifampicin in the sections on the latter drugs.

Abbreviations have generally been used for the antituberculotics. A list of these abbreviations is given on p. XXIV.

A severe barrier to obtaining comprehensive information is the multiplicity of languages used for scientific communication. The contributors have tried to take into consideration relevant publications in English, German, French, other Romance languages such as Italian, Spanish, and Rumanian, and in several Slavic languages such as Czech, Polish, and Russian. Because of their different mother tongues, the authors have been able to help each other in covering many languages, as the lists of references show.

It has taken a long time to complete this book. At times it was unclear whether we would ever be successful. Handbook-writing has, for most authors, become an almost unmanageable task as all are burdened with too many duties, mostly of a nonscientific nature. The editor wishes to express his sincere and warm thanks to the contributors, who not only finished their papers but, despite all difficulties, also updated them to the level of knowledge in 1985-1986.

Contributors and editor offer, many thanks to Professor Dr. HANS HERKEN for being our ever patient and encouraging representative of the Editorial Board over the many years as the authors struggled with their manuscripts.

The editor gratefully acknowledges a grant from Bayer AG for the translation of a considerable part of the book into English.

K. BARTMANN

Contents

CHAPTER 1

Historical Introduction and Chemical Characteristics of Antituberculosis Drugs. H. A. OFFE. With 1 Figure. . . . . . . . . . . 1

A. p-Aminosalicylic Acid (PAS) . . . . . . . . . . . . . 1 B. Streptomycin (SM) - Dihydrostreptomycin (DHSM). . . 2 C. Thiosemicarbazone (TSC) [Thioacetazone, Thiacetazone,

p-Aminobenzaldehyde] .......... 5 D. Pyrazinamide (PZA) - Morphazinamide (MZA). 7 E. Isoniazid (INH) . . . . . . . . . . 8 F. Tetracyclines. . . . . . . . . . . . 12

I. Oxytetracycline (Terramycin, OTC) 12 II. Tetracycline (TC) . . . . . . 14

G. Viomycin (VM). . . . . . . . . . . 15 H. Cycloserine (CS) - Terizidone (TZ) . . 17 I. Thioamides: Ethionamide (ETH) - Protionamide (PTH) 19 J. Kanamycin (KM). . 21

K. Thiocarlide (DATC) . 23 L. Capreomycin (CM) 25

M. Ethambutol (EMB) . 26 N. Rifampicin (RMP) . 28

References will be found on each end of Paragraphs

CHAPTER 2

Experimental Evaluation of Efficacy L. TRNKA, P. MISoN, K. BARTMANN, and H. OTTEN. With 8 Figures 31

A. Introduction. L. TRNKA and P. MISoN . . . . . . . . . . 31 B. Methods, Tneir Limitations, Advantages, and Disadvantages

L. TRNKA and P. MISoN . . . . . . . . . . . . . . . . 34 I. In-vitro Tests . . . . . . . . . . . . . . . . . . 34

1. Determination of Minimal Inhibitory Concentrations (MIC) 34 2. Cross-Resistance 36 3. Type of Action . . . . 37

II. Animal Experiments . . . 38 III. Cell- and Tissue Cultures . 44

References. . . . . . . . . . 46

X Contents

C. Drugs and Treatment Regimens. . . . . . . . . . . . . 51 I. p-Aminosalicylic Acid (PAS). L. TRNKA and P. MISON 51

1. Antimicrobial Spectrum in Vitro 51 2. Antimycobacterial Activity . . . . 51

Activity in Artificial Media in Vitro 51 Bacterial Resistance . . . . . . 54 Type of Action . . . . . . . . 56

Effects in Cell and Tissue Cultures. 57 Activity in Experimental Tuberculosis and Development of Resistance in Vivo 57

3. Concluding Remarks 62 References . . . . . . 62

II. Streptomycin (SM) - Dihydrostreptomycin (DHSM) L. TRNKA and P. MISON. . . . . . 68 1. Antimicrobial Spectrum in Vitro 68 2. Antimycobacterial Activity . . . 69

Activity in Artificial Media in Vitro 69 Bacterial Resistance to, and Dependence on SM . 71 Type of Action . . . . . . . . . . . . . . . 75 Effects in Combination with Other Antituberculotics . 75

Effects in Cell- and Tissue Cultures . . . . . . . . . 76 Activity in Experimental Tuberculosis and Development of Resistance in Vivo. . . . . 76

Continuous Monotherapy . . . 77 Intermittent Monotherapy . . . 81 SM in Combined Chemotherapy 81

3. Concluding Remarks . . . . . . 83 References . . . . . . . . . . . . 83

III. Thiosemicarbazones (TSC) [Thiacetazone, Thioacetazone] L. TRNKA. . . . . . . . . . . . 92 1. Antimicrobial Spectrum in Vitro 92 2. Antimycobacterial Activity . . . 92

Activity in Artificial Media in Vitro 92 Bacterial Resistance . . . . . . . 94 Type of Action . . . . . . . . . 96 Effects in Combination with Other Antituberculotics . 96

Effects in Cell- and Tissue Cultures . . . . . . . .. 97 Activity in Experimental Tuberculosis and Development of Resistance in Vivo . . . . . . 97

TSC in Combined Chemotherapy 99 3. Concluding Remarks 100 References . . . . . . . . . . . . 100

IV. Pyrazinamide (PZA) and Morphazinamide (MZA) L. TRNKA ........... . 1. Antimicrobial Spectrum in Vitro

103 103

Contents XI

2. Antimycobacterial Activity . . . . 104 Activity in Artificial Media in Vitro 104

Bacterial Resistance . . . . . . 106 Type of Action . . . . . . . . 107

Effects in Cell- and Tissue Cultures 107 Activity in Experimental Tuberculosis and Development of Resistance in Vivo . . . . . . 107

Monotherapy. . . . . . . . . 107 PZA in Combined Chemotherapy 110

3. Concluding Remarks 110 References . . . . . . . . . . . 11 0

V. Isoniazid (INH). K. BARTMANN . . 113 1. Antimicrobial Spectrum in Vitro 113 2. Antimycobacterial Activity . . . 113

Activity in Artificial Media in Vitro 113 Bacterial Resistance . . . . . . 116 Type of Action . . . . . . . . 119 Effects in Combination with Other Antituberculotics . 123

Effects in Cell- and Tissue Cultures . . . . . . . .. 123 Effects in Embryonated Eggs . . . . . . . . . . .. 123 Activity in Experimental Tuberculosis and Development of Resistance in Vivo . . . . . . . 124

Efficacy in Special Animal Models. . . . . . . .. 126 INH in Combined Chemotherapy . . . . . . . .. 127 Intermittent Treatment with INH Alone and in Combination 129 Treatment in Phases . 132

3. Concluding Remarks 133 References . . . . . . . 134

VI. Tetracyclines. L. TRNKA. . 145 1. Antimicrobial Spectrum in Vitro 145 2. Antimycobacterial Activity . . . 145


Effects in Cell- and Tissue Cultures . 148 Activity in Experimental Tuberculosis 148

3. Concluding Remarks 149 References . . . . . . . . . . . . . 149

VII. Viomycin (VM). L. TRNKA . . . . . . 150 1. Antimicrobial Spectrum in Vitro and in Vivo 150 2. Antimycobacterial Activity . . . . 151


Effects in Cell- and Tissue Cultures . . . . . . . .. 154

XII Contents

Activity in Experimental Tuberculosis 155 Monotherapy. . . . . . . . . 155 VM in Combined Chemotherapy 155


VIII. Cycloserine (CS) and Terizidone (TZ). H. OTTEN. 158 1. Cycloserine (CS) . . . . . . . 158

Antimicrobial Spectrum in Vitro 158 Antimycobacterial Activity . . . 158


Effects in Cell- and Tissue Cultures 161 Activity in Experimental Tuberculosis 161

Monotherapy. . . . . . . . . 161 CS in Combined Chemotherapy. 162

2. Terizidone (TZ). . . . . . . . . . 163 Activity in Experimental Tuberculosis 163 Activity in Artificial Media in Vitro 164

3. Concluding Remarks . . . . . . . 164 References . . . . . . . . . . . . . 164

IX. Thioamides: Ethionamide (ETH), Protionamide (PTH). H. OTTEN 167 1. Antimicrobial Spectrum in Vitro 167 2. Antimycobacterial Activity . . . . 168

Activity in Artificial Media in Vitro 168 Type of Action . . . . . . . . 169 Bacterial Resistance . . . . . . 170

Effects in Cell- and Tissue Cultures 171 Activity in Experimental Tuberculosis and Development of Resistance in Vivo . . . 171

Continuous Monotherapy . . . . 171 Intermittent Monotherapy . . . 172 ETH in Combined Chemotherapy 172


X. Kanamycin (KM) and Amikacin. L. TRNKA 177 1. Kanamycin - Antimicrobial Spectrum in Vitro 177 2. Kanamycin - Antimycobacterial Activity . 178



Monotherapy. . . . . . . . . . 182 KM in Combined Chemotherapy . 182

3. Amikacin - Antimycobacterial Activity. 183 4. Concluding Remarks 183 References . . . . . . . . . . . . . . 183

Contents XIII

XI. Thiocarlide (DATC). L. TRNKA 185 1. Antimicrobial Spectrum in Vitro 185 2. Antimycobacterial Activity . . . 185



Monotherapy. . . . . . . . . . 188 DATC in Combined Chemotherapy 189

3. Concluding Remarks 189 References . . . . . . . . . . . 189

XII. Capreomycin (CM). H. OTTEN. . . 191 1. Antimicrobial Spectrum in Vitro 191 2. Antimycobacterial Activity . . . 191


Effects in Cell- and Tissue Cultures 192 Activity in Experimental Tuberculosis and Development of Resistance in Vivo . . . . . . 194

Monotherapy. . . . . . . . . 194 CM in Combined Chemotherapy 194

3. Concluding Remarks 196 References . . . . . . . . . . . 196

XIII. Ethambutol (EMB). H. OTTEN. . . 197 1. Antimicrobial Spectrum in Vitro 197 2. Antimycobacterial Activity . . . 198


Effects in Cell- and Tissue Cultures 200 Activity in Experimental Tuberculosis and Development of Resistance in Vivo . . . . . . . 200

Monotherapy. . . . . . . . . . 200 EMB in Combined Chemotherapy . 201

3. Concluding Remarks 203 References . . . . . . . . . . . . 203

XIV. Rifampicin (RMP). L. TRNKA . . . 205 1. Antimicrobial Spectrum in Vitro 205 2. Antimycobacterial Activity . . . 206

Activity in Artificial Media in Vitro 206 Bacterial Resistance . . . . . . . 210 Type of Action . . . . . . . . . 213 Effects in Combination with Other Antituberculotics . . 215

Effects in Cell- and Tissue Cultures . . . . . . . .. . 216

XIV Contents

Activity in Experimental Tuberculosis and Development of Resistance in Vivo . . . 217

Continuous Monotherapy . . . . . . . . . . 217 Intermittent Monotherapy . . . . . . . . . . 221 RMP in Combined Chemotherapy (Continuous, Intermittent, in Phases) 222

3. Concluding Remarks 225 References . . . . . . . . 225

CHAPTER 3

Experimental Evaluation of Chemoprophylaxis and Preventive Treatment in Animals. H. H. KLEEBERG . . . . . . 233

A. Definitions. . . . . . . . . . . . 233 B. Objectives of Laboratory Experiments 233 C. Results of Animal Experiments . . 234

I. Experiments with Monkeys. . 234 II. Experiments with Guinea Pigs 235

III. Experiments with Cattle . . 236 D. Discussion of Experimental Data 239

I. Technique of Infection. . 239 II. Infective Dose . . . . . 239

III. Animal Species Differences 240 IV. The Drug as Factor . . . 241

E. Preventive Treatment in Animals 243 I. Experiments with Guinea Pigs 244

II. Experimental Studies with Mice. 244 III. Mink and Rabbits. . . . . . 247 IV. Intermittent Treatment. . . . . 247 V. Preventive Treatment in Cattle . 248

F. Immunological Questions of Chemoprophylaxis and Vaccine Prophylaxis. . . . . . . . . . . . . . . . . . . . . . 251

Combination of Chemoprophylaxis and Immune Prophylaxis 252 INH Resistant BCG . 253

References . . . . . . . . . . . . . . . . . . . . . .. . 253

CHAPTER 4

Experimental and Clinical Activity of Antituberculosis Drugs and Other Antimicrobial Agents Against Mycobacteria Other than Tubercle Bacilli, Except M. Leprae. K. BARTMANN. . . . . . . 259

A. Introduction . . . . . . . . . . . . . . . . . . . . . 259 B. Possible Reasons for the Lower Sensitivity of MOTT to many

Antituberculotics Compared to M. tuberculosis . . . . . . . 262 C. Efficacy of Antituberculosis Drugs and Other Antimicrobial Agents

Against the Various MOTT Species . . . . . . . . . . . . .. 262

Contents XV

I. Group I. Photochromogenic Mycobacteria 262 1. M. Kansasii (Yellow Bacillus, M. Luciflavum) . 262

Types of Disease . . . . . . . . . . . . . 262 Activity of Antituberculosis Drugs in Vitro 262 Activity of Other Antimicrobial Agents in Vitro 264 Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Animals . . . . . . 264 Treatment of Infections in Man 267

2. M. Marinum (M. Balnei). . . . 272 Types of Disease . . . . . . . 272 Activity of Antituberculosis Drugs in Vitro 272 Activity of Other Antimicrobial Agents in Vitro 272 Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Animals . . . . . . 273 Treatment of Infections in Man 273

3. M. Simiae . . . . . . . . . . 273 Types of Disease . . . . . . . 273 Activity of Antituberculosis Drugs in Vitro 274 Treatment of Infections in Man 274

4. M. Asiaticum. . . . . . . . . . . . . . 274 Types of Disease . . . . . . . . . . . . 274 Activity of Antituberculosis Drugs in Vitro 274 Treatment of Infections in Man . . . . 274

II. Group II. Scotochromogenic Mycobacteria. 274 1. Introductory Remarks Including Types of Disease 274 2. Publications on Group II Without Identification

of the Species . . . . . . . . . . . . . . . 274 Activity of Antituberculosis Drugs in Vitro 274 Activity of Other Antimicrobial Agents in Vitro 275 Activity of Antituberculosis Drugs in Animals 275 Treatment of Infections in Man . . . . 275

3. M. Flavescens . . . . . . . . . . . . 276 Types of Disease and Treatment in Man. 276

4. M. Gordonae. . . . . . . . . . . . . 277 Activity of Antituberculosis Drugs in Vitro 277 Activity of Other Antimicrobial Agents in Vitro 277 Treatment of Infections in Man . . . . . . . 277

5. M. Scrofulaceum (M. Marianum, M. Paraffinicum) . 277 Activity of Antituberculosis Drugs in Vitro 277 Activity of Other Antimicrobial Agents in Vitro 277 Treatment of Infections in Man 278

6. M. Szulgai. . . . . . . . . . . . . . . 278 Types of Disease . . . . . . . . . . . . 278 Activity of Antituberculosis Drugs in Vitro 278 Activity of Other Antimicrobial Agents in Vitro 278 Treatment of Infections in Man . . . . . . . 278

XVI Contents

7. M. Xenopi (M. Littorale, M. Xenopei) . . . . . . . .. 278 Types of Disease . . . . . . . . . . . . . . . . .. 278 Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Vitro. . . . . . . . 278 Treatment of Infections in Man . . . . . . . . . . .. 279

III. Group III . . . . . . . . . . . . . . . . . . . . . .. 279 1. M. Avium Complex, Including M. Avium and M. Intracellulare

("Battey Bacillus") . . . . . . . . . . . . . . 279 Introductory Remarks Including Types of Disease 279 Activity of Antituberculosis Drugs in Vitro 280 Activity of Other Antimicrobial Agents in Vitro 282 Activity of Antituberculosis Drugs in Animals 283 Treatment of Infections in Man . . . . . . . 284

2. M. Haemophilum . . . . . . . . . . . . . . 285 Types of Disease, Activity of Antituberculosis Drugs in Vitro, and Treatment of Infections in Man. . . . . . . . . . . . 285

3. M. Malmoense ..................... 288 Types of Disease, Activity of Antituberculosis Drugs in Vitro, and Treatment of Infections in Man. . . . . . . . 288

4. M. Nonchromogenicum Complex (Including M. Non-chromogenicum, M. Terrae, M. Novum, M. Triviale) . 288 Types of Disease, Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Vitro, and Treatment of Infections in Man 288

5. M. Ulcerans (M. Buruli) . . . . . . . . . 289 Types of Disease . . . . . . . . . . . . 289 Activity of Antituberculosis Drugs in Vitro 289 Activity of Other Antimicrobial Agents in Vitro 289 Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Animals . . . . . . 289 Treatment of Infections in Man . . . . . . . . . 290

IV. Group IV . . . . . . . . . . . . . . . . . . . . 291 1. M. Fortuitum Complex (Including M. Fortuitum and

M. Chelonei with Subspecies Abscessus) . . . . . . 291 Types of Disease . . . . . . . . . . . . . . . . 291 Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Vitro and in Vivo . . 291 Treatment of Infections in Man 292

2. M. Smegma tis . . . . . . . . 293 Types of Disease . . . . . . . 293 Activity of Antituberculosis Drugs and Other Antimicrobial Agents in Vitro and in Vivo . . . . . . . . . . . 293

3. M. Thermoresistibile. . . . . . . . . . . . . . . 294 Types of Disease, Activity of Antituberculosis Drugs, and Treatment of Infection in Man 294

References . . . . . . . . . . . . . . . . . . . . . . . 294

Contents

CHAPTER 5

Experimental Pharmacology and Toxicology of Antituberculosis Drugs D. TETTENBORN. With 7 Figures

A. Introduction . . . . . . . . . . B. The Drugs . . . . . . . . . . .

I. p-Aminosalicylic Acid (PAS) 1. Respiration, Circulation, Heart 2. Acute Toxicity . . . . . . . 3. Subchronic and Chronic Toxicity References . . . . . . . . . . .

II. Streptomycin - Dihydrostreptomycin (SM - DHSM) 1. Respiration, Circulation, Heart. . . . . . . .

XVII

· 307

· 307 · 307 · 307 · 308 · 308 · 309 · 311

311 311

2. Neuromuscular Blocking Effects of SM, DHSM, and Other Basic Antibiotics. . . . .

3. Smooth Muscles ...... . 4. Ganglion Blocking Effects. . . 5. Further Pharmacologic Effects . 6. Acute Toxicity. . . . . . ..

Attempts at Reducing the Acute Toxicity 7. Subchronic Toxicity ........ . 8. Ototoxicity of the Aminoglycoside Antibiotics

Morphology. . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . Causes: Pharmacokinetics and Biochemical Effects Species Related Sensitivity Differences and Differences in the Activity of the Various Antibiotics Attempts to Reduce Ototoxicity

9. Nephrotoxicity ..... . 10. Reproductive Toxicity . . 11. Biochemical Effects of SM References . . . . . . ...

III. Thiosemicarbazone - Thiacetazone, Thioacetazone (TSC) 1. Acute Toxicity. . . . . . . . . 2. Subchronic and Chronic Toxicity. 3. Liver Toxicity . . . . . . . . .

References . . . . . . . . . . . . IV. Pyrazinamide (PZA) and Morphazinamide (MZA)

1. Pyrazinamide (PZA) ..... Respiration and Blood Pressure Acute and Subchronic Toxicity. Liver Toxicity, Carcinogenicity. References . . . . . . . . .

2. Morphazinamide (MZA) . . . Acute and Subchronic Toxicity. References

V. Isoniazid (INH) . . . . . . . . .

312 313 314 314 314 315 316

· 317 317 319 319

324 324 325 326 326 327

· 332 · 332

333 · 333 · 334 · 334 · 334

334 334 335 335 336 336 336

· 336

XVIII

1. Respiration, Circulation, Heart. 2. Smooth Muscles . . . . . . 3. Other Pharmacological Effects . 4. Central Stimulation Effects . . 5. INH and Vitamin B6 Metabolism 6. INH and the y-Aminobutyric Acid Metabolism. 7. Protective Action of Various Substances. 8. Acute Toxicity. . . . . . . . . 9. Subchronic and Chronic Toxicity.

10. Liver Toxicity . . 11. Neurotoxic Effects . . 12. Ototoxicity . . . . . 13. Reproductive Toxicity 14. Carcinogenic Effects 15. Cytostatic Effects 16. Mutagenic Effects . . 17. Lathyrogenic Activity. References . . . . . . .

VI. Tetracyclines: Tetracycline, Oxytetracycline (TC, OTC) 1. Respiration, Circulation, Heart. . . . . . . . 2. Neuromuscular Blocking Effects of Tetracyclines 3. Smooth Muscles . 4. Acute Toxicity. . 5. Subacute Toxicity 6. Liver Toxicity . . 7. Nephrotoxicity. . 8. Effects on the Intestinal Epithelium. 9. Tetracyclines and Bone Metabolism.

10. Reproductive Toxicity . . . . 11. Inhibition of Protein Synthesis . 12. Ototoxicity . 13. Phototoxicity References . . .

VII. Viomycin (VM) . 1. Respiration, Blood Pressure 2. Neuromuscular Blocking Effect 3. Ganglion Blocking Effect. 4. Smooth Muscles 5. Acute Toxicity . 6. Subacute Toxicity 7. Nephrotoxicity 8. Ototoxicity. . . References . . . .

VIII. Cycloserine (CS) and Terizidone (TZ) 1. D-Cycloserine (CS) . . . . .

Respiration, Circulation, Heart Smooth Muscles ..... .

Contents

336 337 337 337 338 339 340 341 341 344 345 347 347 348 350 350 352 352 358 358 358 358 359 359 360 361 362 362 363 364 365 365 365 369 369 369 369 369 369 370 370 371 371 372 372 372 372

Contents

Central Nervous Effects ... Other Pharmacological Effects Acute Toxicity .. Subchronic Toxicity . . . . Chronic Toxicity ..... Nephrotoxicity, Ototoxicity. Local Tolerability.

2. Terizidone (TZ) ..... . Acute Toxicity . . . . . . Subacute and Chronic Toxicity

References . . . . . . . . . . IX. Thioamides (Ethionamide, Protionamide)

1. Ethionamide (ETH) . . . . . . . . Circulation, Heart. . . . . . . . . Acute, Subchronic and Chronic Toxicity Reproductive Toxicity Carcinogenicity . . . . . . .

2. Protionamide (PTH). . . . . Acute and Subchronic Toxicity Reproductive Toxicity Carcinogenicity

References . . . . . . X. Kanamycin (KM) . . .

1. Respiration, Circulation, Heart 2. Neuromuscular Blocking Effects. 3. Smooth Muscles . . . . . 4. Other Pharmacologic Effects . . 5. Acute Toxicity . . . . . . . . 6. Subchronic and Chronic Toxicity 7. Ototoxicity. . . . . 8. Nephrotoxicity . . . 9. Reproductive Toxicity References . . . .

XI. Thiocarlide (DATC) . 1. Acute Toxicity . . 2. Subacute Toxicity . 3. Chronic Toxicity . 4. Reproductive Toxicity References . . . . . .

XII. Capreomycin (CM) 1. Respiration, Circulation, Heart 2. Acute Toxicity . . . 3. Chronic Toxicity .. 4. Reproductive Toxicity 5. Ototoxicity. . 6. Nephrotoxicity References . . .

XIX

372 373 373 375 375 376 376 376 376 377 377 377 377 377 378 378 379 379 379 379 380 380 381 381 381 381 382 382 383 384 384 385 385 387 387 387 387 387 388 388 388 388 389 389 389 389 390

xx

XIII. Ethambutol (EMB) 1. Acute Toxicity . 2. Chronic Toxicity 3. Reproductive Toxicity 4. Ototoxicity. . 5. Pharmacology . References . . . .

XIV. Rifampicin (RMP) . 1. Acute Toxicity . 2. Subchronic Toxicity 3. Chronic Toxicity . 4. Microsomal Enzyme Induction 5. Reproductive Toxicity 6. Ototoxicity. . 7. Carcinogenicity . . . 8. Mutagenicity . . . . 9. Interactions with Other Drugs References . . . . . . . . . .

Contents

390 390 390 392 393 393 393 394 394 394 395 395 395 396 397 397 397 397

CHAPTER 6

Mode of Action, Biotransformation and Pharmacokinetics of Antituberculosis Drugs in Animals and Man H. IWAINSKY. With 52 Figures . . . . . . . . . . . 399

A. General Part . . . . . . . . . . . . . . . . 399 I. Mode of Action of Antituberculosis Drugs . 400

1. Type of Effect and Primary Site of Attack . 400 2. Transport of Antituberculotics to the Site of Action . 403 3. Mode of Action of Antituberculosis Drugs . . . . . 404

Nucleic Acid and Protein Synthesis as Primary Site of Attack 405 Biosynthesis of the Microbial Cell Wall as Primary Site of Attack ....... .

II. Biotransformation . . . . . . 1. Site of the Biotransformation 2. Possible Reactions. . . . . 3. Factors Influencing Biotransformation 4. Influence of the Inductive Effect of RMP on the

407 407 407

. 409

. 409

Biotransformation of Other Drugs. . . . . . . . 410 5. Antituberculosis Treatment and Biotransformation. . 411

III. Pharmacokinetics . . . . . . . . . . 412 1. Absorption of Antituberculosis Drugs . . . . . 412 2. Factors Influencing the Absorption . . . . . . 414

Changes in Absorption due to a Different Mode of Administration . . . . . . . . . . . . . . . 414 Influence of Structural Modifications of the Drugs. . 415 Influence of Galenic Processing . . 416 Influence of Food Consumption. . . . . . . . . . 417

Contents XXI

3. Binding of Antituberculosis Drugs to Proteins and Blood Cells 418 4. Distribution of Antituberculosis Drugs in the Body 420 5. Excretion of Antituberculosis Drugs . 423

Routes of Excretion . . . . . . 423 Influence of Age . . . . . . . 423 Influence of Kidney Function . . 424 Influence of Liver Diseases . . . 427

6. Factors Influencing the Pharmacokinetics of Antituberculosis Drugs. . . . . . . . . . . . . . . . . . . 429 Influence of Sex and Age. . . . . . . . . . . . . 429 Influence of Administration Intervals and Dose . . . 430 Influence of Combination of Antituberculosis Drugs . 430

7. Serum-Concentrations of Antituberculosis Drugs as Parameter of Treatment Efficacy . 431 Coverage. . . . . . . . 432 Half-Life. . . . . . . 432 Area Under the Curve. . 432

IV. General Medical Relevance of the Results Obtained in the Field of Tuberculosis . . . . . . . . . . . . . 435 1. Studies on the Mode of Action . . . . . 436 2. Studies on Biotransformation Processes . 436 3. Studies on Pharmacokinetics . 438 References . . . . . . . . . . . . 438

B. Special Part - The Antituberculosis Drugs · 457 I. PAS. · 457

1. Mode of Action. · 457 2. Biotransformation . · 460 3. Pharmacokinetics · 463 References · 463

II. SM · 465 1. Mode of Action. · 465 2. Biotransformation . · 466 3. Pharmacokinetics · 466 References · 468

III. TSC . 471 1. Mode of Action. 471 2. Biotransformation. 471 3. Pharmacokinetics 472 References .472

IV. PZA . · 473 1. Mode of Action. 473 2. Biotransformation. · 473 3. Pharmacokinetics · 474 References · 475

XXII Contents

V. INH . . . . . . . . . . . . . . . . . .476 1. Mode of Action. . . . . . . . . . . . 476

Incorporation of INH in Mycobacteria. . 476 Biotransformation of INH by Mycobacteria . 476 Uptake of INH by Resistant Mycobacteria . 478 Mode of Action. . . . . . . . . . . . . . 479

2. Biotransformation. . . . . . . . . . . . 483 Biotransformation Patterns in Man and in Animals 483 Biotransformation and Antituberculotic Activity. . 485 Determination of INH and Its Biotransformation Products 485 Genetically Fixed Polymorphism of INH and Other Drugs 485 Possible Ways of Differentiating Between Rapid and Slow INH Biotransformation . . . . . . . . . . . . .. . 488 Biotransformation of INH Derivatives and INH Retard Preparations . . . . . . . . . . . . 489 Factors Affecting Biotransformation . . 490 Race Dependent Biotransformation . . 492 Biotransformation in Animals. . . . 492 Influence of Biotransformation on Efficacy and Side Effects. 494

3. Pharmacokinetics . 496 References . . . . . 497

VI. Tetracyclines . . . 508 1. Mode of Action. 508 2. Biotransformation . 508 3. Pharmacokinetics 509 References . . . . 511

VII. VM . . . . . . . 514 1. Mode of Action. 514 2. Biotransformation. 514 3. Pharmacokinetics 514 References . . . . 515

VIII. CS. . . . . . . . 515 1. Mode of Action. 515 2. Biotransformation. 516 3. Pharmacokinetics 517 References . . . . 519

IX. ETH/PTH . . . . 520 1. Mode of Action. 520 2. Biotransformation. 520

Possibilities of Assay of ETH, PTH and Their Biotransformation Products. . . . . . . . . 520 Reversible Conversion of ETH and PTH into the Corresponding Sulphoxides. . . . . . . . . . 521 Biotransformation Products of ETH and PTH 522 Biotransformation of ETH and PTH in Man and Animals 523

3. Pharmacokinetics 524 References . . . . . . . . . . . . . . . . . . . . .. 526

Contents

X. KM 1. Mode of Action. . 2. Biotransformation. 3. Pharmacokinetics References . . . .

XI. DATC ..... . 1. Mode of Action. 2. Biotransformation. 3. Pharmacokinetics References . . . .

XII. CM ...... . 1. Mode of Action. 2. Biotransformation . 3. Pharmacokinetics References . . . .

XIII. EMB ...... . 1. Mode of Action. 2. Biotransformation. 3. Pharmacokinetics References . . . .

XIV. RMP ..... . 1. Mode of Action. 2. Biotransformation .

Biotransformation Pattern in Man and in Animals. Modification of the Biotransformation Rate by Auto-Induction.

3. Pharmacokinetics References

Subject Index . . .

XXIII

527 527 527 528 529 530 530 530 530 531 532 532 532 532 533 533 533 535 537 539 541 541 543 543

544 545 550

555

List of Abbreviations for Antituberculotics and Some of Their Derivatives

Drug

Capreomycin Cycloserine Ethambutol Ethionamide Isoniazid Kanamycin Morphazinamide Oxytetracycline Para-aminosalicylic acid Protionamide Pyrazinamide Rifampicin Streptomycin Terizidone Tetracycline Thiocarlide Thiosemicarbazone (Thioacetazone, Thiacetazone) Viomycin

Abbreviation

CM CS EMB ETH INH KM MZA OTC PAS PTH PZA RMP SM TZ TC DATe TSC

VM

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