Evaluation of Drug Activities (eBook)

Front Cover 1
Evaluation of Drug Activities: Pharmacometrics 4
Copyright Page 5
Table of Contents 17
List of Contributors 6
Preface 10
Symbols and Abbreviations 14
Contents of Volume 1 16
PART I: General Principles CHAPTERS 1-7 20
CHAPTER 1. First Clinical Trials of Potential Drugs 22
A. Introductory 22
B. Qualitative Pharmacology 25
C. Metabolism 27
D. Toxicology 28
E. Chemical and Pharmaceutical Aspects 30
F. First Administration to Man 30
G. Technique 34
H. Choice of Subjects Ethical and Legal Aspects
J. Dosage 37
K. Conclusion 38
L. A Selected Bibliography on Therapeutic Trials 39
References 40
CHAPTER 2. A Plan for Evaluating Potential Drugs 42
A. Introductory 42
B. Choice of Objectives 43
C. Method of Approach 44
D. The Inventive Chemist 47
E. The Inventive Pharmacologist 48
F. Chronic Toxicity 59
G. Conclusions 60
References 62
Appendix: Statistics on Drug Evaluations 62
CHAPTER 3. Design, Statistical Analysis and Interpretation 68
A. Introductory 68
B. Basis of Statistical Inference 72
C. Some Common Types of Experimental Design 81
D. Some Distribution-free Statistical Tests 91
E. Further Sources 110
Tabular Appendixes 114
References 132
CHAPTER 4. Strain and Sex Differences in Response to Drugs 134
A. Introductory 134
B. Origin of Strain Differences 134
C. Basis for Differential Use of Strains 136
D. Practical Applications 139
References 145
CHAPTER 5. Some Limitations of Animal Tests 148
A. Restricted Induction 148
B. Factors Affecting Sensitivity 148
C. Transfer from Animals to Man 154
References 155
CHAPTER 6. Toxicity Tests 158
A. Introductory 158
B. Some limitations 160
C. Circumstances Necessitating Toxicity Tests 161
D. Materials 163
E. Acute Toxicity Tests 166
F. Short-term Chronic Tests 168
G. Final Toxicity Tests 170
H. Other Tests 176
J. Evaluation of Results 183
K. Conclusions 188
CHAPTER 7. Drug Dependence 190
A. Introductory 190
B. Elements of Drug Abuse 190
References 201
PART II: Particular Applications CHAPTERS 8-19 204
CHAPTER 8. Analgesics 206
A. Introductory 206
B. The Framework 207
C. Experimental Methods 211
D. Conclusions 223
References 224
CHAPTER 9. Local Anaesthetics 228
A. Objectives 228
B. Methods 228
References 236
CHAPTER 10. Tranquillisers and Sedatives 238
A. Introductory 238
B. Types of Test 240
C. Conclusions 258
References 259
CHAPTER 11. Antidepressives, Analeptics and Appetite Suppressants 262
A. Scope and Definitions 262
B. Antidepressives 262
C. Analeptics 269
D. Appetite Suppressants 276
References 280
CHAPTER 12. Hypnotics and General Anaesthetics 284
A. Introductory 284
B. Methods of Administration 284
C. End-points for Detecting Anaesthesia 288
D. Duration of Anaesthesia and Interaction with Other Drugs 292
E. Hypnotic Activity 295
F. Further Tests 300
G. Conclusions 302
References 307
CHAPTER 13. Anticonvulsants 310
A. Introductory 310
B. Methods 311
C. Conclusions 321
References 322
CHAPTER 14. AntiParkinsonian Agents 324
A. Introductory 324
B. Induced Tremor 324
C. Acetylcholine Antagonism 330
D. Electroencephalographic Changes 330
E. New Approaches 331
F. Conclusions 331
References 333
CHAPTER 15. Centrally Acting Skeletal Muscle Relaxants 336
A. Present Position 336
B. Initial Testing Methods 338
C. Secondary Testing Methods 340
D. Sites of Action 342
E. Conclusions 346
References 347
CHAPTER 16. Neuromuscular Blocking Agents 348
A. Introductory 348
B. Animal Species 350
C. Anaesthetics 354
D. Nerve-muscle Preparations 355
E. Site and Mechanism of Action 357
F. Conclusions 372
References 372
CHAPTER 17. Cardiovascular Activity of Sympathomimetic Amines 376
A. Introductory 376
B. Isolated Organs and Tissues 377
C. Whole Animals 385
References 390
CHAPTER 18. Depressants of Peripheral Sympathetic Nerve Function 392
I. SYMPATHETIC NERVE BLOCKADE 393
A. Classes of Sympathetic Nerve-blocking Agent 393
B. Adrenaline a- and ß-Receptors 394
C. Choice of Methods 396
D. General Methods 397
E. Methods Mainly for Investigating Ganglion-blocking Actions 423
F. Methods Mainly for Investigating Adrenergic Neurone-blocking Actions 427
G. Tests for Antagonism of Adrenaline at a-Receptor Sites 435
H. Tests for Antagonism of Adrenaline at ß-Receptor Sites 439
II. INHIBITION OF CATECHOLAMINE SYNTHESIS AND METABOLISM 444
A. Inhibitors of ( — )-Dopa Decarboxylase 446
B. Inhibitors of Dopamine ß-Oxidase 447
C. Inhibitors of Mono-amine Oxidase 448
References 449
CHAPTER 19. Antihypertensive Agents 454
A. Introductory 454
B. Repeated Measurement of Arterial Blood Pressure 456
C. Direct methods 458
D. Indirect Methods 459
E. Genetic Hypertension 464
F. Psychogenic Hypertension 464
G. Neurogenic Hypertension 466
H. Hypertension Caused by Deficient Diets 467
J. Hypertension Caused by Salt and Adrenocorticoids 468
K. Adrenal Regeneration Hypertension 469
L. Renal Hypertension 470
M. Other Methods 474
N. Angiotensin Antagonists 475
References 476