Symposium on Clinical Pharmacology (eBook)

Front Cover 1
Symposium on Clinical Pharmacology 4
Copyright Page 5
Table of Contents 6
INTRODUCTORY REMARKS 9
PART 1: PHARMACOLOGICAL FACTORS IN DRUG ACTION 9
CHAPTER 1. PHARMACOKINETICS AND DRUG EFFECT 10
Classical pharmacokinetic models 10
Physiological pharmacokinetic model 11
Methotrexate kinetics and effect 12
REFERENCES 16
CHAPTER 2. ABSORPTION, PROTEIN BINDING, DISTRIBUTION AND EXCRETION OF ANTINEOPLASTIC DRUGS 18
REFERENCES 28
CHAPTER 3. FACTORS AFFECTING BIOTRANSFORMATION AND ACTIVITY OF ANTITUMOR DRUGS 30
REFERENCES 42
CHAPTER 4. THE PRODUCT OF CONCENTRATION AND TIME 44
REFERENCES 53
CHAPTER 5. TRANSPORT OF TUMOR-INHIBITORY AGENTS ACROSS CELL MEMBRANES 56
REFERENCES 58
CHAPTER 6. PHARMACOLOGICAL CONSIDERATIONS IN THE CHEMOTHERAPY OF CENTRAL NERVOUS SYSTEM TUMORS 60
Components of drug distribution 60
Brain drug distribution and routes of administration 61
CONCLUSIONS 64
REFERENCES 65
PART 2: FACTORS INFLUENCING DRUG SELECTIVITY 9
CHAPTER 7. DESCRIPTIVE AND OPERATIONAL CYTOKINETICS 66
Descriptive cytokinetics of bone marrow and intestinal epithelium 67
Operational cytokinetics of bone marrow and intestine 68
Descriptive cytokinetics of tumors 69
Operational cytokinetics of tumors 71
Comparison between the descriptive and operational approaches to cytokinetics 72
C O N C L U S I O N S 75
REFERENCES 77
CHAPTER 8. ROLE OF ENZYMATIC ACTIVATION AND INACTIVATION IN DRUG SELECTIVITY 80
Purine and pyrimidine antimetabolites 81
Cyclophosphamide and dimethyl-triazeno-imidazole carboxamide 86
Other drugs inactivated in insensitive tissues 87
Inactivation followed by reactivation 88
CONCLUSIONS 88
REFERENCES 88
PART 3: MECHANISMS OF CLINICAL DRUG RESISTANCE 9
CHAPTER 9. GENERAL MECHANISMS OF CLINICAL RESISTANCE TO CANCER CHEMOTHERAPY 92
REFERENCES 96
CHAPTER 10. MECHANISMS OF CLINICAL DRUG RESISTANCE TO ALKYLATING AGENTS 98
CLASSES OF ALKYLATING AGENT AND MECHANISM OF ACTION 98
DEFINITION OF RESISTANCE 100
CONCLUSIONS 108
REFERENCES 108
CHAPTER 11. RESISTANCE TO FOLIC ACID ANTAGONISTS -CLINICAL ASPECTS 110
General considerations 110
Resistance to MTX in experimental tumors 111
Resistance to MTX in man 112
Prevention and exploitation of folate antagonist resistance 113
REFERENCES 114
CHAPTER 12. RESISTANCE TO PURINE ANALOGS 116
CONCLUSIONS 123
REFERENCES 124
CHAPTER 13. CLINICAL RESISTANCE TO ANTIPYRIMIDINE ANTICANCER DRUGS 128
Fluorouracil 130
Clinical pharmacologic attacks on pyrimidine-resistant tumors 135
REFERENCES 136
PART 4: COMBINATION CHEMOTHERAPY 9
CHAPTER 14. BIOCHEMICAL AND PHARMACOLOGICAL PRINCIPLES OF COMBINATION CHEMOTHERAPY 138
REFERENCES 147
CHAPTER 15. THERAPEUTIC SYNERGISM IN ANIMAL MODELS - INCREASED ANTITUMOR SPECIFICITY RESULTING FROM DIMINISHED TOXICITY FOR THE HOST 150
REFERENCES 159
CHAPTER 16. SCHEDULE-DEPENDENT SYNERGISM AND ANTAGONISM BETWEEN METHOTREXATE AND ASPARAGINASE 160
METHODS AND MATERIALS 160
RESULTS 161
DISCUSSION 169
REFERENCES 170
CHAPTER 17. NEW EXPERIMENTAL DRUG COMBINATIONS WITH POTENTIAL CLINICAL UTILITY 172
Combinations of alkylating agents 178
SUMMARY 183
REFERENCES 184
CHAPTER 18. NEW COMBINATIONS IN THE TREATMENT OF LUNG CANCER 186
REFERENCES 191
CHAPTER 19. CHEMOTHERAPY OF METASTATIC SARCOMAS USING COMBINATIONS WITH ADRIAMYCIN 192
RESULTS AND DISCUSSION 194
CONCLUSION 200
REFERENCES 201
PART 5: NEW INFORMATION ON MECHANISMS OF DRUG ACTION 9
CHAPTER 20. BLEOMYCIN AND PHLEOMYCIN - RECEPTIVITY OF TARGET SITES 202
General Properties 202
Locating antibiotic with mercury 204
How might mercury staining be used in bleomycin therapy? 213
REFERENCES 215
CHAPTER 21. ADRIAMYCIN-DAUNORUBICIN CELLULAR PHARMACODYNAMICS 216
REFERENCES 224
CHAPTER 22. THE VINCA ALKALOIDS 226
Structure-activity relationships 226
Biological actions of the vinca alkaloids 226
Biochemical mechanisms of action 227
Metabolism and distribution of the vinca alkaloids 229
CONCLUSION 230
REFERENCES 231
CHAPTER 23. REACTIONS AND EFFECTS OF NITROSOUREAS 234
REFERENCES 240
CONCLUDING REMARKS 242