Antituberculosis Drugs

589 Pages·1988·31.679 MB·English

by  H. A. Offe (auth.), Professor Dr. med. Karl Bartmann (eds.)

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 pharma
cology; v. 84) Includes bibliographies and index. 1. Antitubercular agents. 2. Tuberculosis-Chemotherapy. I. Bart
mann, 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.)
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© 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
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Product liability: The publisher can give no guarantee for information about drug dosage and application thereof
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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 Wup
pertal1
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; inter
mittent; 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 nomen
clature 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 ........... . 103
1. Antimicrobial Spectrum in Vitro 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
Activity in Artificial Media in Vitro 145
Bacterial Resistance . . . . . . 147
Type of Action . . . . . . . . 147
Effects in Combination with Other Antituberculotics . 147
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
Activity in Artificial Media in Vitro 151
Bacterial Resistance . . . . . . 151
Type of Action . . . . . . . . 154
Effects in Combination with Other Antituberculotics . 154
Effects in Cell- and Tissue Cultures . . . . . . . .. 154
XII Contents
Activity in Experimental Tuberculosis 155
Monotherapy. . . . . . . . . 155
VM in Combined Chemotherapy 155
3. Concluding Remarks . . . . . . 156
References . . . . . . . . . . . . 156
VIII. Cycloserine (CS) and Terizidone (TZ). H. OTTEN. 158
1. Cycloserine (CS) . . . . . . . 158
Antimicrobial Spectrum in Vitro 158
Antimycobacterial Activity . . . 158
Activity in Artificial Media in Vitro 158
Bacterial Resistance . . . . . . 160
Type of Action . . . . . . . . 161
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
3. Concluding Remarks . . . . . . 175
References . . . . . . . . . . . . 176
X. Kanamycin (KM) and Amikacin. L. TRNKA 177
1. Kanamycin - Antimicrobial Spectrum in Vitro 177
2. Kanamycin - Antimycobacterial Activity . 178
Activity in Artificial Media in Vitro 178
Bacterial Resistance . . . . . . 179
Type of Action . . . . . . . . 181
Effects in Cell- and Tissue Cultures 181
Activity in Experimental Tuberculosis 182
Monotherapy. . . . . . . . . . 182
KM in Combined Chemotherapy . 182
3. Amikacin - Antimycobacterial Activity. 183
4. Concluding Remarks 183
References . . . . . . . . . . . . . . 183