Disulfiram and its Metabolite, Diethyldithiocarbamate: Pharmacology and status in the treatment of alcoholism, HIV infections, AIDS and heavy metal toxicity

460 Pages·1992·32.46 MB·English

by  Peter K. Gessner

Disulfiram and its
Metabolite, Diethyldithiocarbamate
Disulfiram and its
Metabolite,
Diethyldithiocarbamate
Pharmacology and status in the treatment
of alcoholism, HIV infections, AIDS and
heavy metal toxicity
Peter K. Cessner
Professor of Pharmacology and Therapeutics
School of Medicine and Biomedical Sciences
State University of New York at Buffalo
Buffalo, New York
eresa Cessner
Ţ
Research Professor of Pharmacology
Roswefl Park Graduate Division
State University of New York at Buffalo
Roswefl Park Cancer Institute
Buffalo, New York
SPRINGER-SCIENCE+BUSINESS MEDIA, B.V.
First edition 1992
C 1992 Peter K. Gessner and Teresa Gessner
Typeset in lo!.I12pt Garamond by Interprint Ltd, Malta
by 1] Press, Padstow, Comwall
ISBN 978-94-010-5028-9
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Library of Congress Cataloging-in-Publication data
Gessner, Peter K, 1931-
Disulfiram and its metabolite diethyldithiocarbamate pharmacology and
status in the treatment of alcoholism, HIV infections, AIDS and heavy
metal toxicity / Peter K. Gessner, Teresa Gessner.
p. cm.
Inc1udes bibliographical references and index.
ISBN 978-94-010-5028-9 ISBN 978-94-011-2328-0 (eBook)
DOI 10.1007/978-94-011-2328-0
1. Disu1f1ram-Physiological effect. 2. Diethyldithiocarbamate
Physiologica1 effect. 3. Diethyldithiocarbamate - Therapeutic use -
Testing. 1. Gessner, Teresa, 1933- II. Title.
RM666.DS83G47 1991
616.86'1061-dc20 91-19580
CIP
Contents
Figure acknowledgements xi
Preface xiii
Glossary xv
1 INTRODUCTION AND SCOPE OF MONOGRAPH 1
1.1 Introduction 1
1.2 Scope of monograph 3
1.3 Earlier reviews 5
2 RELEVANT PHYSICAL AND CHEMICAL PROPERTIES 7
2.1 Introduction and general properties 7
2.2 Acid-catalyzed decomposition 8
2.3 Formation of metal complexes 9
3 REACTIONS OF DISULFIRAM AND DIETHYLDITHIO-
CARBAMATE WITH BLOOD CONSTITUENTS 13
3.1 Introduction 13
3.2 Formation of copper complexes 14
3.3 Formation of mixed disulfides 15
3.4 Uptake of disulfiram by blood cells 17
3.5 Summary 19
4 ASSAY METHODS FOR DISULFIRAM AND METABOLITES
IN BIOLOGICAL MATERIALS 21
4.1 Introduction 21
4.2 General considerations 22
4.3 Specific methods 25
4.4 Other methods 26
vi Contents
5 METABOLISM OF DISULFIRAM AND DIETHYLDITHIO-
CARBAMATE 29
5.1 Introduction 29
5.2 Formation of mixed disulfides with generation of
diethyldithiocarbamate 30
5.3 Formation of disulfiram from diethyldithiocarbamate 32
5.4 Formation of the copper complex 34
5.5 S-glucuronide of diethyldithiocarbamic acid 34
5.6 Formation of carbon disulfide and diethylamine 36
5.7 Metabolism of carbon disulfide and formation of
carbonyl sulfide 37
5.8 The methyl ester of diethyldithiocarbamic acid 38
5.9 The methyl ester of diethylmonothiocarbamic acid 40
5.10 Other metabolites 41
6 PHARMACOKINETIC ASPECTS OF THE DISPOSITION OF
DISULFIRAM AND METABOLITES 43
6.1 Introduction 44
6.2 Methods 44
6.3 Urinary excretion of disulfiram metabolites 51
6.4 Pulmonary excretion of disulfiram metabolites 54
6.5 Plasma disulfiram and metabolites following its
administration 56
6.6 Diethyldithiocarbamate and metabolites following its
administration 60
7 HEAVY METALS: EFFECTS OF DIETHYLDITHIOCARBAMATE AND
DISULFIRAM ADMINISTRATION 65
7.1 Introduction 65
7.2 Thallium 69
7.3 Zinc 71
7.4 Cadmium 73
7.5 Lead 79
7.6 Nickel 81
7.7 Copper 85
7.8 Mercury 88
7.9 Platinum 90
7.10 Polonium 93
8 DISULFIRAM AND DIETHYLDITHIOCARBAMATE AS ENZYME
INHIBITORS 95
8.1 Introduction 96
8.2 Inhibition of drug metabolizing enzymes 102
Contents vii
8.3 Inhibition of dopamine j3-hydroxylase 120
8.4 Inhibition of superoxide dismutase 126
8.5 Inactivation of glutathione peroxidase 133
8.6 Effect of catalase 135
9 INHIBITION OF ALDEHYDE DEHYDROGENASE 137
9.1 Introduction 137
9.2 Phenomenology of the inhibition by disulfiram 145
9.3 Mechanism of the inhibition 150
9.4 Role of disulfiram metabolites 154
9.5 Inhibition of aldehyde dehydrogenases in blood 158
9.6 Inhibition of metabolism of endogenous aldehydes 162
9.7 Aldehyde and xanthine oxidases 166
10 THE DISULFIRAM-ETHANOL REACTION 167
10.1 Introduction 167
10.2 Discovery and therapeutic application 168
10.3 Pharmacological characteristics 171
10.4 Blood acetaldehyde determination 177
10.5 The acetaldehyde hypothesis 178
10.6 Quest for animal models of the reaction 184
10.7 Effect of disulfiram on ethanol metabolism 191
10.8 The dopamine j3-hydroxylase hypothesis 193
10.9 Effect of ethanol in animals pretreated with disulfiram
metabolites 199
10.10 Treatment of the disulfiram--ethanol reaction 201
11 DISULFIRAM THERAPY OF ALCOHOL ABUSE 205
11.1 Introduction 205
11.2 Goals of disulfiram therapy 209
11.3 Disulfiram treatment components correlated with
reduction of drinking days 209
11.4 Disulfiram therapy paradigms 214
11.5 Election of and continuation in treatment 223
11.6 Characteristics of disulfiram's therapeutic effects 224
11.7 Side effects of disulfiram therapy 232
11.8 Chemical compliance monitoring 244
11.9 Disulfiram implants 245
12 IMMUNOMODULATORY EFFECTS OF
DIETHYLDITHIOCARBAMAT E 247
12.1 Introduction 248
12.2 Stimulation of antibody response to sheep red blood
cells 249
Contents
VIII
12.3 Enhancement of mitogen-induced
lymphoproliferation 251
12.4 Effect on lymphoproliferative response to alloantigens 255
12.5 Interaction with asymmetrical neocortical lesions 256
12.6 Effects on cell-mediated cytotoxicity 257
12.7 Effect on delayed-type hypersensitivity reaction 261
12.8 Induction of T-cell differentiation 261
12.9 Effect on lymphocyte populations in vivo 267
12.10 Effects on mononuclear phagocytic cells 272
12.11 Experimental therapeutics 273
12.12 Immunomodulatory effects of related compounds 275
12.13 Conclusions 275
13 CLINICAL STATUS OF DIETHYLDITHIOCARBAMAT E AS AN
IMMUNOSTIMULANT 279
13.1 Introduction 279
13.2 In the treatment of HIV infections and AIDS 280
13.3 In gastrointestinal surgery patients 290
13.4 As a therapeutic agent in autoimmune disease 290
13.5 In patients with neoplastic disease 291
13.6 As an adjuvant for influenza vaccination 292
13.7 Summary 292
14 MODULATION OF VARIOUS BIOLOGICAL PHENOMENA 295
14.1 Cytotoxicity 295
14.2 Modulation of the effects of oxidative stress 301
14.3 Modulation of the effects of radiation and
hyperthermia 306
15 MODULATION OF CANCER CHEMOTHERAPY 313
15.1 Introduction 313
15.2 Preclinical studies 315
15.3 Clinical studies 328
15.4 Conclusions 334
16 TOXICOLOGY 335
16.1 Introduction 335
16.2 Acute toxicity 336
16.3 Chronic toxiCity 341
16.4 Effects on liver 342
16.5 Testing for mutagenicity 343
16.6 Testing for carcinogenicity 344
16.7 Testing for teratogenic and reproductive toxicity 345
Contents ix
Appendix - The road to Anatabuse - Professor Erick Jacobsen 347
References 353
Author and citation index 413
Subject index
Figure
acknowledgements
Figure 7.2 Dr. A Oskarsson, Toxicology Laboratory, National Food
Administration, Sweden and Dr. H. Lindahl. Redrawn with permission
from, Toxicology Letters, 49, 87 (1989). © Elsevier Science Publishers,
The Netherlands.
Figure 8.1 Dr. F. Green, Department of Pharmacology, Pennsylvania
State University College of Medicine and Dr. G.E Miller. Adapted with
permission from, Biochemical Pharmacology, 32, 2433 (1983), Per
gamon Press pIc.
Figure 1O.1a Dr. R. Preisig, Institut fur klinische Pharmakologie, Univer
sitat Bern and Dr. Ch. Beyeler. Adapted with permission from Alcohol
ism, Clinical and Experimental Research, 9, 118-24 (1985). © The
Research Society on Alcoholism and Schweizerische Medizinische
Wochenschrift, 117, 52-60 (1987) © Schwabe & Co. AG.
Figure 10.2 Dr. K.O. Lindros, Research Laboratories of the State Alcohol
Monopoly, Finland. Reprinted with permission from, Alcoholism, Cli
nical and Experimental Research, 5,528-30 (1981). © The Research
Society on Alcoholism.
Figure 13.2 Dr. E.M. Hersh, Arizona Cancer Center, Reprinted with
permission from Journal of the American Medical Association, 265,
1538-44. © 1991 American Medical Association.
Figure 14.1 Dr. D. Rigas, School of Medicine, University of Oregon
xii Figure acknowledgements
Health Sciences Centre, Redrawn with permission from Biochemical
and Biophysical Research Communications, 88, 373-9. © Academic
Press.
Figure 14.2 Dr. R.G. Evans, Fricke Radiobiology Research Laboratories,
Rochester, Maine. Adapted with permission from International Jour
nal of Radiation Oncology, Biology and Physics, 9, 1635 (1983),
Pergamon Press pIc.
Appendix The Road to Antabuse by E. Jacobsen. Reprinted with
permission. Dr. A Konar, AlS Dumex Ltd., Copenhagen.