Receptors and Centrally Acting Drugs Pharmacokinetics and Drug Metabolism (eBook)

Front Cover 1
Receptors and Centrally Acting Drugs 4
Copyright Page 5
Table of Contents 8
Preface 6
Section 3: RECEPTORS AND CENTRALLY ACTING DRUGS 14
PART 1: TRANSMISSION AND RECEPTORS 16
CHAPTER 1. ON THE SCOPE AND MECHANIOSMS OF LOCAL CONTROL OF NEUROTRANSMITTER SECRETION FROM INDIVIDUAL VARICOSITIES OF THE SYMPATHETIC NERVES OF THE GUINEA-PIG AND MOUSE VAS DEFERENS 
18 
INTRODUCTION 18
SCOPE OF LOCAL CONTROL OF SECRETORY ACTIVITY OF INDIVIDUAL VARICOSITIES 19
LEVELS OF LOCAL CONTROL OF TRANSMITTER SECRETION IN SYMPATHETIC NERVES 22
MECHANISMS OF PREJUNCTIONAL CONTROL 23
TENTATIVE CONCLUSIONS 25
REFERENCES 26
CHAPTER 2. THE TOPOGRAPHY OF CHOLINERGIC TRANSMISSION 
28 
OUTPUT OF ACH PER IMPULSE 31
CONCLUDING REMARKS 33
REFERENCES 33
CHAPTER 3. SUBTYPES OF MUSCARINE RECEPTORS IN THE GUINEA-PIG ILEUM 34
FACILITATION OF ACETYLCHOLINE RELEASE THROUGH STIMULATION OF M 1 RECEPTORS 
35 
CONCLUSION 36
REFERENCES 36
CHAPTER 4. PRESYNAPTIC ALPHA-2 ADRENOCEPTORS 38
INTRODUCTION 38
CURRENT CLASSIFICATION OF ALPHA-ADRENOCEPTÖRS 38
LOCALIZATION OF ALPHA-2 ADRENOCEPTORS 39
FUNCTIONAL ROLE OF ALPHA-2 ADRENOCEPTORS 40
REFERENCES 42
CHAPTER 5. POSTSYNAPTIC ALPHA-2 ADRENOCEPTORSAND CHEMICAL TRANSMISSION 
44 
INTRODUCTION 44
POSTSYNAPTIC ALPHA-2 ADRENOCEPTORS 45
CONCLUDING REMARKS 52
ACKNOWLEDGEMENT 52
REFERENCES 52
CHAPTER 6. THE EFFECT OF NONDEPOLARIZING MUSCLE RELAXANTS ON TRANSMITTER RELEASE AT PERIPHERAL CHOLINERGIC RECEPTOR SITES 
58 
References 60
CHAPTER 7. SUBSENSITIVITY OF PRESYNAPTIC AND SUPERSENSITIVITY OF POSTSYNAPTIC DOPAMINERGIC RECEPTORS AS A RESULTOF REPEATED ADMINISTRATION OF ANTIDEPRESSANT DRUGS 
62 
INTRODUCTION 62
METHODS 62
RESULTS 63
DISCUSSION 67
REFERENCES 69
CHAPTER 8. MODULATION OF NEUROTRANSMITTER RECEPTORS AND DRUG RECOGNITION SITES BY REPEATED DOSES OF (–)DEPRENYL 
72 
Abolishment of postsynaptic dopamine receptor supersensitivity by repeated injections with (-)deprenyl 
73 
Reduced stimulation of the norephinephrine sensitive adenylate cyclase and decrease of ß-adrenergic receptor density 
75 
Summarizing our data we can conclude, that repeated, low doses of (-) depreny 
78 
References 78
CHAPTER 9. THE EFFECT OF ANTIMUSCARINIC DRUGS ON AGGRESSIVE BEHAVIOUR AND CONVULSIONS EVOKED BY CARBACHOL UNITARY CONCEPT OR DIFFERENT SENSITIVITIES OF CENTRAL CHOLINOCEPTORS 
82 
Carbachol- and McN-A-343-induced Gross Behavioural Effects 83
Antimuscarinic Drugs on Carbachol-Induced Aggression and Convulsions 85
Calcium and Magnesium Ions on Carbachol-Induced Aggression and Convulsions 88
Acknowledgements 89
REFERENCES 89
CHAPTER 10. CHOLINESTERASE INHIBITORS AND CORTICOSTEROIDS INTERACT WITH GENERAL ANAESTHETICS BY ALTERING CENTRAL CHOLINERGIC MECHANISMS 
94 
REFERENCES 97
CHAPTER 11. GABA RECEPTORS IN THE MYENTERIC PLEXUS FROM MORPHINE-TOLERANT GUINEA-PIGS 
98 
INTRODUCTION 98
METHODS 99
RESULTS AND CONCLUSIONS 99
Acknowledgments 100
REFERENCES 100
CHAPTER 12. THE EFFECT OF 1 -NORADRENALINE AND XYLAZINE ON THE RELEASE OF NORADRENALINE DURING K + -CHANNEL INHIBITION IS NOT MEDIATED VIA a2-ADRENOCEPTORS 
102 
INTRODUCTION 102
METHODS 102
RESULTS 102
DISCUSSION 103
REFERENCES 104
CHAPTER 13. DESIGN AND SYNTHESIS OF 5H-2,3-BENZODIAZEPINES 
106 
INTRODUCTION 106
SUMMARY 111
REFERENCES 112
CHAPTER 14. MODULATION OF 3H-NORADRENALINE RELEASE FROM ISOLATED HUMAN CYSTIC ARTERY 
114 
INTRODUCTION 114
MATERIAL AND METHODS 114
RESULTS 116
CONCLUSIONS 119
REFERENCES 119
CHAPTER 15. NEUROTRANSMISSION IN LARVALAND PARASITIC LIFE:A STUDY ON SCHISTOSOMA MANSONI 
120 
HISTAMINERGIC MEDIATION 120
DOPAMINERGIC MEDIATION 121
ADRENERGIC MEDIATION 121
CHOLINERGIC AND SEROTONINERGIC MEDIATION 121
PROPHYLAXIS BY HISTAMINERGIC MEDIATION 121
CONCLUSIONS 122
REFERENCES 122
CHAPTER 16. GABA-ERGIC MECHANISMS IN ANTICONVULSIVE ACTIVITY OF HYDROXYLAMINE AND HYDRAZINE DERIVATIVES OF BARBITURIC ACID 
124 
References 126
CHAPTER 17. EFFECT OF DRUGS CLASSIFIED AS a2-ADRENOCEPTOR AGONISTS AND ANTAGONISTS ON THE ELECTROSHOCK-INDUCED SEIZURES IN MICE 
128 
References 130
PART 2: GABA AND BENZODIAZEPINE RECEPTORS 
132 
CHAPTER 18. THE THEORY OF MULTIPLE CHEMICAL SIGNALS IN SYNAPTIC TRANSMISSION AS IT EMERGES FROM GABA/BENZODIAZEPINE INTERACTION 
134 
1. Introduction 134
2. Benzodiazepines and GABAergic transmission 136
3. Endacoids for benzodiazepine recognition sites 138
REFERENCES 142
CHAPTER 19. PHARMACOLOGICAL CHARACTERIZATION OF GABA AND BENZODIAZEPINE BINDING SITES LOCALIZED IN THE NON-JUNCTIONAL SYNAPTIC REGION 
146 
EXPERIMENTAL 150
REFERENCES 151
CHAPTER 20. INTERACTION OF DIFFERENT COMPOUNDS,HAVING ATYPICAL ANXIOLYTIC PROPERTIES WITH GABA-BENZODIAZEPINE RECEPTOR COMPLEX 
152 
REFERENCES 159
CHAPTER 21. GABA CONTRIBUTION TO THE EFFECT OF NARCOTIC ANALGETICS ON THE SPINAL CORD AND CEREBRAL CORTEX 
160 
I. The drugs' effects on bioelectric activity in the spinal afferent tracts 
161 
II. The drugs' effects on the cerebral cortex 164
Conclusions 168
References 170
CHAPTER 22. ALLOSTERIC INTERACTIONS AT CONVULSANT SITES COUPLED TO GABA RECEPTOR IONOPHORES 
172 
RESULTS AND DISCUSSION 172
REFERENCES 174
CHAPTER 23. THE EFFECT OF 2,3-BENZODIAZEPINES ON THEBENZODIAZEPINE-GABA-PICROTOXIN/BARBITURATE-CI-ION CHANNEL COMPLEX 
176 
REFERENCES 178
CHAPTER 24. ACTH AND RELATED PEPTIDES AS PSYCHOACTIVE AND NEUROACTIVE DRUGS 
180 
ABSTRACT 180
REFERENCES 187
CHAPTER 25. PHARMACOLOGICAL ACTIONS OF MODIFIED CASOMORPHINS 
192 
REFERENCES 197
CHAPTER 26. MURAMYL PEPTIDES: IMMUNOMODULATORS AND CENTRALLY ACTING DRUGS 
198 
REFERENCES 202
CHAPTER 27. SPONTANEOUS RELEASE OF HISTAMINE FROM MAST CELLS 
204 
Results 204
Conelusions 207
REFERENCES 208
CHAPTER 28. ADENYL CYCLASE (AC) AND GUANYL CYCLASE (GC)-COUPLED HISTAMINE (HA) RECEPTORS IN THE BRAIN 
210 
SUMMARY 210
1. HA-sensitive AC systems in the brain 210
2. HA-sensitive AC systems in the hypothalamus 210
3. HA-sensitive GC systems in the brain 214
REFERENCES 215
PART 3: HETEROGENEITY OF OPIATE RECEPTORS 218
CHAPTER 29. POSSIBLE INVOLVEMENT OF THE SPINAL DYNORPHINERGIC SYSTEM IN NOCICEPTIVE MECHANISMS 
220 
INTRODUCTION 220
MATERIALS AND METHODS 221
RESULTS 221
DISCUSSION 226
ACKNOWLEDGEMENTS 228
REFERENCES 229
CHAPTER 30. AFFINITY LABELING OF OPIOID RECEPTOR SUBUNITS BY 3H-D-ALA2-LEU5-ENKEPHALIN CHLOROMETHYL KETONE 
230 
INTRODUCTION 230
MATERIALS AND METHODS 230
RESULTS 230
DISCUSSION 232
REFERENCES 234
CHAPTER 31. CHARACTERISTICS OF OPIATE A AND B RECEPTORS STIMULATED OR INHIBITED BY INTRATHECALLY ADMINISTERED OPIATES IN THE RAT 
236 
Abstract 236
Introduction 236
Results and discussion 237
Influence on acetylcholine release 239
Influence on the urination of normally hydrated rats 243
References 244
CHAPTER 32. PHYSICAL SEPARATION OF k-OPIOID BINDING SITE FROM FROG BRAIN 
246 
REFERENCES 248
CHAPTER 33. TRANSGANGLIONIC EFFECT OF BASIC PEPTIDES ON THE PRIMARY NOCICEPTIVE ANALYZER 
250 
ABSTRACT 250
INTRODUCTION 250
MATERIALS AND METHODS 252
RESULTS 252
DISCUSSION 255
REFERENCES 257
CHAPTER 34. OPIOID EFFECTS IN HUMAN GRANULOCYTES (PMN) 258
Shape changes and motility 258
Receptor studies 261
Comparison to other PMN-stimulators 262
REFERENCES 263
CHAPTER 35. DISPLACEMENT STUDIES AMONG DIFFERENT OPIOID AGONISTS 
266 
INTRODUCTION 266
RESULTS AND CONCLUSIONS 266
REFERENCES 269
CHAPTER 36. RELATIONSHIPS BETWEEN THE SUGGESTED OPIOID RECEPTORS 
270 
Methods and materials 271
Isolated longitudinal strip of gu1nea-p1g 1leum 271
Isolated mouse vas deferens 271
Isolated rat vas deferens 271
Isolated rabbit vas deferens 271
Isolated nictitating membrane of the cat 271
Results and discussion 272
The effect on the longitudinal muscle strip of guinea-pig ileum 272
Effect on the isolated rabbit vas deferens 273
Effect on the mouse vas deferens 273
Effect on the isolated nictitating membrane of the cat 276
Effects on the isolated rat vas deferens 277
Characterizations of opioid receptors of the organs tested 277
References 279
CHAPTER 37. COMPARISON OF THE EFFECT OF LOW DOSE MORPHINE (M) AND FENTANYL (F) ON CATECHOLAMINES DURING SCOLIOSIS SURGERY 
280 
METHODS 280
RESULTS 280
REFERENCES 282
CHAPTER 38. BEHAVIORALLY ACTIVE OXYTOCIN FRAGMENTS DIMINISH INTRAVENOUS SELF-ADMINISTRATION OF HEROIN IN HEROIN-TOLERANT RATS 
284 
INTRODUCTION 284
METHODS 284
RESULTS AND DISCUSSION 285
REFERENCES 287
CHAPTER 39. INFLUENCE OF OXYTOCIN AND AN ANALOG ANTAGONIST OF OXYTOCIN ON THE DEVELOPMENT OF ACUTE MORPHINE TOLERANCE IN MICE 
288 
INTRODUCTION 288
METHODS 288
TREATMENT 289
REFERENCES 290
CHAPTER 40. GLUCOCORTICOID-INDUCED CHANGES IN CENTRAL OPIATE AND ADRENERGIC MECHANISMS 
292 
REFERENCES 299
CHAPTER 41. INCREASED POTENCY OF NALOXONE AGAINST MORPHINE IN MICE PRETREATED WITH D-MET2,PRO5-ENKEPHALINAMIDE (EA): A DEMONSTRATION OF ACUTE CROSS-SENSITIZATION 
300 
Introduction 300
Materials and Methods 301
Materials 302
Results 302
Discussion 304
Summary 305
References 305
PART 4: DRUGS AND THE CENTRAL NERVOUS SYSTEM 308
CHAPTER 42. PHARMACOKINETIC—PHARMACODYNAMIC RELATIONSHIPS FOR MULTIPLE RECEPTOR INTERACTING DRUGS 
310 
Beil-shaped eurves 317
Multiphase dose-response curves 317
U-shaped curves 318
Evaluation of composed dose-(concentration)-response curves 318
References 322
CHAPTER 43. THE EFFECT OF NOVEL PSYCHOTROPIC DRUGS ON RAT BRAIN DOPAMINE- AND ALPHA-ADRENERGIC RECEPTOR BINDING IN VITRO 
324 
INTRODUCTION 324
MATERIALS AND METHODS 324
RESULTS AND DISCUSSION 325
REFERENCES 327
CHAPTER 44. STRESS, ADRENERGIC AGENTS AND INFECTION 328
INTRODUCTION 328
MATERIAL AND METHODS 329
DISCUSSION AND CONCLUSIONS 333
REFERENCES 333
CHAPTER 45. CLINICAL PHARMACOLOGY OF MABUTEROL A NEW BETA-2-SYMPATHOMIMETIC DRUG WITH BRONCHODILATING EFFECTS
336 
METHODS 336
RESULTS 338
DISCUSSION 338
SUMMARY 339
REFERENCES 339
CHAPTER 46. EFFECT OF DENERVATION ON THE MOVEMENT OF TAURINE IN SKELETAL MUSCLE 340
MATERIALS AND METHODS 340
RESULTS 341
DISCUSSION 342
REFERENCES 344
CHAPTER 47. SELECTIVE a1 RECEPTOR BLOCKER PRAZOSIN AND LIVER FUNCTIONS 
346 
REFERENCES 349
LIST OF CONTRIBUTORS 350
SUBJECT INDEX 358
Section 4: PHARMACOKINETICS AND DRUG METABOLISM 364
CHAPTER 1. AUTORADIOGRAPHIC DRUG DISTRIBUTION STUDIES 366
SECTIONING FOR OTHER PURPOSES 372
REFERENCES 374
CHAPTER 2. PHARMACOKINETIC ASPECTS OF THE MODE OF ACTION OF EGYT-475, A NEW ANTIDEPRESSIVE AGENT 
376 
Introduction 376
Materials and methods 376
Results and discussion 377
Summary 381
References 381
CHAPTER 3. MODEL-INDEPENDENT (SYSTEMIC) APPROACH IN PHARMACOKINETICS 384
NATURE OF THE SYSTEMIC APPROACH 385
SYSTEMIC PARAMETERS 386
STATISTICAL MOMENTS METHOD 389
DESCRIPTION OF THE METABOLITES KINETICS 390
CONCLUSION 390
CHAPTER 4. PHARMACOKINETICS, METABOLISM AND ELIMINATION AND THEIR RELATION TO THE EFFECTS AND TOXICITY OF SELECTED DRUGS AND CHEMICALS 
392 
PHARMACOKINETIC CONSIDERATIONS,FACTORS INFLUENCING DRUG LEVEL-TIME COURSE 
393 
PHARMACOKINETIC MODELS AND SOME OF THEIR APPLICATIONS 395
EFFECT OF BIOTRANSFORMATION ON DRUG ACTIVITY AND TOXICITY 396
RELATIONSHIP BETWEEN TOXICITY, PHARMACOKINETICS, METABOLISM AND ELIMINATION: BENZENE AND ACRYLONITRILE 398
REFERENCES 400
CHAPTER 5. EPIGENETIC IMPRINTING OF DRUG METABOLISM 402
INTRODUCTION 402
MATERIALS AND METHODS 404
RESULTS AND DISCUSSION 405
SUMMARY 408
REFERENCES 409
CHAPTER 6. THE ROLE OF MELANIN BINDING IN THE METABOLISM AND PHARMACOKINETICS OF DRUGS 
414 
Pharmacological and toxicological consequences 416
Pharmacokinetic approaches 416
Binding to substantia nigra (SN) melanin 417
REFERENCES 419
CHAPTER 7. ON THE PHARMACOKINETIC AND PHARMACODYNAMIC PROFILE OF THE NOVEL ANTIDEPRESSIVE, NOMIFENSINE 
422 
INTRODUCTION 422
METHODS 423
RESULTS AND CONCLUSIONS 423
REFERENCES 426
CHAPTER 8. THE PHARMACOKINETICS OF VINPOCETINE IN PATIENTS WITH IMPAIRED LIVER FUNCTION 
428 
INTRODUCTION 428
EXPERIMENTAL 428
DISCUSSION 431
REFERENCES 432
CHAPTER 9. THE ABSORPTION, TISSUE DISTRIBUTION AND ELIMINATION OF RGH-2957 (YUTACR) IN RATS 
434 
MATERIALS AND METHODS 434
RESULTS AND DISCUSSION 435
REFERENCES 437
CHAPTER 10. CHANGES IN DRUG METABOLISM BY STEROID TREATMENTS OF FEMALE RATS 
438 
SUMMARY 438
INTRODUCTION 438
METHODS 439
RESULTS 439
DISCUSSION 439
REFERENCES 441
CHAPTER 11. INFLUENCE OF ENZYME INDUCTION AND PARACETAMOL POISONING ON AMINOANTIPYRINE BLOOD LEVELS IN MICE 
444 
Materials and methods 444
Results 445
Discussion 447
CHAPTER 12. BIOAVAILABILITY OF VARIOUS NIFEDIPINE DOSING FORMS IN BEAGLE DOGS 
450 
INTRODUCTION 450
MATERIALS AND METHODS 450
RESULTS AND DISCUSSION 451
REFERENCES 454
CHAPTER 13. PHARMACOKINETIC ASPECTS OF INTERACTION BETWEEN THIOPENTAL AND ANTIDEPRESSANT DRUGS 
456 
Methods 456
Results 457
Discussion 459
References 460
CHAPTER 14. XANTHOGENATES: SOME MECHANISMS OF CYTOCHROME-P-450 INHIBITION 
462 
MATERIALS AND METHODS 462
RESULTS AND DISCUSSION 463
REFERENCES 465
CHAPTER 15. 1-[3-TRIFLUOROMETHYL-PHENYL]-1-[5,6-DIHYDROXY-CYCLOHEXA-DIENE-2-YL] PROPANE-1-OL, A NEW METABOLITE OF FLUMECINOL IN HUMANS 
468 
INTRODUCTION 468
MATERIAL AND METHODS 469
HUMAN CLINICAL PROTOCOL 471
RESULTS 471
ACKNOWLEDGEMENTS 472
REFERENCES 472
CHAPTER 16. TOXINS AND PHARMACOKINETICS OF RIFAMPICIN 474
INTRODUCTION 474
MATERIAL AND METHODS 475
RESULTS 476
DISCUSSION AND CONCLUSIONS 478
REFERENCES 478
CHAPTER 17. ANTIPYRINE-CLEARANCE AND PARACETAMOL METABOLISM IN DIABETICS 
480 
INTRODUCTION 480
PATIENTS AND METHODS 480
RESULTS AND DISCUSSION 480
REFERENCES 482
CHAPTER 18. DRUG METABOLIZING PROCESSES IN EXPERIMENTAL HYPOTHYREOSIS AND HYPERTHYROXINEMIA IN RATS 
484 
Methods 484
Results and discussion 485
References 487
CHAPTER 19. MECILLINAM — PHARMACOKINETIC AND CLINICAL STUDY 
490 
RESULTS 491
CONCLUSIONS 495
CHAPTER 20. PHARMACOKINETICS OF SYNTROPIUM IN MAN STUDIED BY USING A RADIORECEPTOR ASSAY 
496 
ASSAY 496
RESULTS 500
REFERENCE 501
CHAPTER 21. COMPARISON OF MONOOXYGENASE ACTIVITIES,METAPOLITE PATTERNS AND DNA ADDUCTS IN VARIOUS MICROSOME-MEDIATED BENZO (a) PYRENE METABOLIZING SYSTEMS 
502 
INTRODUCTION 502
EXPERIMENTAL SYSTEM 502
RESULTS AND DISCUSSION 503
REFERENCES 505
CHAPTER 22. DISAPPEARANCE OF SEX DIFFERENCE IN PENTOBARBITONE SLEEPING TIME OF MICE HOUSED IN CAGES WITH WIRE GRID FLOOR 
506 
INTRODUCTION 506
MATERIALS AND METHODS 506
RESULTS 507
BEDDING USED 507
DISCUSSION 508
REFERENCES 509
CHAPTER 23. INVESTIGATION ON TIME-DEPENDENT PHARMACOKINETICS OF ADRIAMYCIN IN PATIENTS WITH DIFFERING LIVER STATUS 
510 
INTRODUCTION 510
PATIENTS AND METHODS 510
RESULTS AND DISCUSSION 511
REFERENCES 513
CHAPTER 24. INFLUENCE OF ACETYLATOR PHENOTYPE ON METABOLISM OF 5-AMINO-SALICYLIC ACID 
514 
ABSTRACT 514
INTRODUCTION 514
MATERIAL AND METHODS 514
RESULTS 515
DISCUSSION 515
REFERENCES 516
CHAPTER 25. STUDIES ON THE MELANIN AFFINITY OF p-BROMO-METHYL-AMPHETAMINE (V-111) AND OTHER AMPHETAMINE DERIVATIVES 
518 
References 521
LIST OF CONTRIBUTORS 522
SUBJECT INDEX 526