Oral Antidiabetics

J Oral Antidiabetics Contributors H.J. Ahr, S.L. Ali, J.M. Amatruda, E.M. Bardolph, H. Bischoff, H.H. Blume, E.-M. Bomhard, E. Brendel, L. Groop, F. Hartig, A. Hasselblatt, L.S. Hermann, B. Junge, J. Kobberling, H.P. Krause, J. Kuhlmann, K.H. Langer, H.E. Lebovitz, P.J. Lefebvre, M. Matzke, M.L. McCaleb, G. Neugebauer, M. Noel, P. Ochlich, U. Panten, H.J. Ploschke, H. Pliimpe, E. Prugnard, W. Puls, W. Rebel, A.J. Scheen, H. Schlecker, F.H. Schmidt, B.S. Schug, E. Schiitz, C. Schwanstecher, M. Schwanstecher, S. Seip, J. Stoltefuss, R.H. Taylor, N.F. Wiernsperger, W. Wingender, C. Wiinsche Editors Jochen Kuhlmann and Walter Puls Springer if. Contents CHAPTER 1 Introduction J. KUHLMANN 1 References 5 CHAPTER 2 Pathophysiology of Type 2 Diabetes Mellitus A.J. SCHEEN and P.J. LEFEBVRE. With 5 Figures 7 A. Introduction 7 I. Heterogeneous Disease 7 II. Genetic Background 8 III. Environmental Factors 8 B. Abnormalities of the Glucose-Insulin Feedback Loop 9 I. Insulin Secretion 10 1. How to Measure Insulin Secretion? 11 2. Abnormal Plasma Concentrations 12 3. Abnormal Kinetics Response 13 4. Varia 14 II. Insulin Sensitivity 14 1. Hepatic Glucose Production 14 2. Splanchnic Glucose Uptake 16 3. Peripheral (Muscle) Glucose Uptake 16 4. Adipose Tissue Lipolysis 18 5. Increased Glucagon Secretion 19 6. Varia 19 C. Possible Causal Defects 19 I. Insulin Secretion 19 1. B-Cell Number 19 2. Insulin Gene 20 3. Amylin 21 4. GLUT 2 21 5. Glucokinase 21 XII Contents 6. Accumulation of B-Cell Glycogen 22 7. Varia 22 II. Insulin Sensitivity 23 1. Insulin Pre-receptor Level 23 2. Insulin Receptor Level 24 3. Insulin Post-receptor Level 25 4. Varia ,. 28 D. Role of Associated Obesity 29 I. Impact of Obesity on Insulin Secretion 29 II. Impact of Obesity on Insulin Sensitivity 29 III. Lipid Oxidation and Insulin Resistance 30 IV. From Obesity to Type 2 Diabetes 30 E. Dynamic Interaction Between Insulin Action and Insulin Secretion 31 I. What Is the Primary Defect? 31 II. Transient Compensatory Mechanisms 32 III. Role of Glucose Toxicity 33 IV. Vicious Circle Leading to Severe Hyperglycaemia 33 F. Conclusions 34 References 35 CHAPTER 3 Non-Pharmacological Management of Non-Insulin-Dependent Diabetes J. KOBBERLING 43 A. Dietary Management 43 I. General Basis for Recommendations 43 II. Total Energy Intake 44 1. Overweight NIDDM Patients 44 2. Normal Weight NIDDM Patients 45 III. Carbohydrates 46 1. Dietary Fibres 46 2. Simple Sugars 48 3. Glycaemic Index of Various Carbohydrates 48 IV. Dietary Fat 49 V. Dietary Protein 50 VI. Other Dietary Factors 51 1. Sodium 51 2. Alcohol 51 3. Vitamins, Minerals and Trace Elements : 51 VII. Dietary Specialities for Diabetics 52 1. Sweeteners : 52 2. Diabetic Foods 52 Contents XIII VIII. Problems and Techniques of Dietary Advice 52 IX. Dietary Recommendations in "Non-Western" Societies ... 53 1. India and Southeast Asia 53 2. Japan 54 3. China 55 4. Africa 55 B. Exercise 55 I. Insulin-Dependent Diabetes 56 II. Non-Insulin-Dependent Diabetes 56 1. Short-Term Effects 56 2. Long-Term Effects 57 III. Recommendations 58 References 59 Section I: Sulfonylureas CHAPTER 4 Sulfonylureas and Related Compounds: Chemistry and Structure-Activity Relationships H. PLUMPE. With 1 Figure 65 A. Introduction 65 B. Sulfonylureas 7 66 I. Variation of R1 66 II. Variation of R2 69 C. Sulfonylsemicarbazides 69 D. Sulfonylaminopyrimidines 69 E. Various Nonmarketed Compounds of Interest 69 F. Conclusions 71 References 71 CHAPTER 5 Sulfonylureas: Physicochemical Properties, Analytical Methods of Determination and Bioavailability S.L. ALI, H.H. BLUME, and B.S. SCHUG. With 15 Figures 73 A. Introduction 73 B. Physical Properties 73 I. Description 73 II. Melting Point 73 XIV Contents III. Solubility 73 1. Acetohexamide 76 2. Acetylcarbutamide 76 3. Carbutamide 77 4. Chlorpropamide 77 5. Glibenclamide 77 6. Glimepiride 77 7. Glipizide 77 8. Gliquidone 77 9. Glisoxepide 77 10. Metahexamide 78 11. Tolazamide 78 12. Tolbutamide 78 IV. Dissociation Constants 79 V. Crystal Shape and Structure 79 1. Acetohexamide 79 2. Glimepiride 80 3. Tolbutamide 80 C. Ultraviolet Spectrum 82 D. Infrared Spectrum 82 E. Nuclear Magnetic Resonance Spectrum 86 F. Mass Spectrum 86 G. Color and Identification Reactions 88 I. Acetohexamide, Glibornuride, Gliquidone 91 II. Carbutamide 91 III. Chlorpropamide 91 IV. Glibenclamide 91 V. Tolbutamide 91 H. Stability and Degradation 92 I. Acetohexamide 92 II. Chlorpropamide 92 III. Glibenclamide 92 IV. Glimpiride 93 V. Glisoxepide 93 VI. Tolbutamide 93 I. Methods of Analysis 94 I. Titrimetry 94 1. Acetohexamide 94 2. Carbutamide 94 3. Chlorpropamide 95 4. Glibenclamide 95 5. Glipizide 95 6. Glisoxepide 95 7. Tolazamide 95 8. Tolbutamide 95 Contents XV II. Ultraviolet Spectrophotometry 96 1. Acetohexamide 96, 2. Carbutamide 96 3. Chlorpropamide 96 4. Glibenclamide 96 5. Glipizide 96 6. Tolbutamide 97 III. Colorimetric Methods 97 1. Carbutamide 97 2. Glibenclamide 97 3. Tolbutamide 98 IV. Fluorimetry 98 V. Miscellaneous Methods 98 J. Chromatographic Methods 98 I. Paper Chromatography 99 II. Thin-Layer Chromatography 99 III. Gas-Liquid Chromatography and Mass Spectrometry 99 1. Acetohexamide 99 2. Chlorpropamide 99 3. Glibenclamide 103 4. Tolazamide 103 5. Tolbutamide 103 IV. High-Performance Liquid Chromatography 104 1. Acetohexamide, Chlorpropamide, Glibornuride, Gliclazide, Tolazamide 104 2. Carbutamide 106 3. Glibenclamide, Glipizide 106 4. Glimepiride 107 5. Glisoxepide 108 6. Tolbutamide 108 K. Bioavailability 108 1. Acetohexamide Ill 2. Chlorpropamide Ill 3. Glibenclamide (Glyburide) 113 4. Gliclazide 115 5. Glimepiride 117 6. Glipizide 117 7. Gliquidone 118 8. Glisoxepide 119 9. Tolazamide 119 10. Tolbutamide 119 References 121 XVI Contents CHAPTER 6 Mode of Action of Sulfonylureas U. PANTEN, M. SCHWANSTECHER, and C. SCHWANSTECHER. With 3 Figures 129 A. Introduction 129 B. Actions on Pancreatic /? Cells 130 I. Stimulation of Insulin Secretion 130 II. Inhibition of the KATP Channel 131 III. Location of the Sulfonylurea Receptor 134 IV. Properties of the Binding Sites for Sulfonylureas 135 V. Structure of Compounds Interacting with the Sulfonylurea Receptor 140 C. Actions on Non-/? Cells in Pancreatic Islets 143 D. Actions on Neurons 144 E. Actions on Cardiac Cells 145 F. Actions on Smooth Muscle 147 G. Actions on Skeletal Muscle 147 H. Actions on Miscellaneous Cells 148 I. Conclusions 148 References 149 CHAPTER 7 Sulfonylureas: Pharmacokinetics in Animal Experiments A. HASSELBLATT ...: 161 A. Introduction 161 B. Absorption of Sulfonylurea Derivatives After Oral Administration 162 I. Species Differences in the Rate of Absorption 162 II. Kinetics of Absorption of Sulfonylureas and Effects of Food and Other Drugs 163 III. Dependence of Absorption on Galenic Formulation 164 C. Distribution of Sulfonylurea Derivatives in the Organism 164 I. Space of Distribution of Sulfonylurea Derivatives 164 II. Protein Binding of Sulfonylureas and Interaction with Other Compounds on Plasma Protein-Binding Sites . 167 D. Accumulation of Sulfonylurea Derivatives in Different Organ Systems 169 I. Accumulation in the Liver '. 169 II. Accumulation of Sulfonylurea Derivatives in the Pancreatic Islets 169 E. Elimination of Sulfonylurea Derivatives 171 Contents XVII F. Influence of Other Drugs on Rate of Metabolism and Excretion of Sulfonylurea Drugs 175 G. Possible Implications of the Results from Animal Experiments on the Pharmacokinetics of Sulfonylurea Derivatives for Clinical Applications in Humans 176 References 178 CHAPTER 8 Toxicology of Sulfonylureas F. HARTIG, K.H. LANGER, W. REBEL, F.H. SCHMIDT, and E. SCHUTZ 185 A. Introduction 185 B. Acute Toxicity 185 C. Chronic Toxicity 187 I. Carbutamide 187 1. Rats 187 2. Dogs 187 II. Tolbutamide 187 III. Chlorpropamide .; 188 1. Rats and Mice 188 2. Dogs 188 IV. Acetohexamide 189 V. Tolazamide 189 VI. Glibenclamide 189 VII. Gliclazide 189 VIII. Glipizide 190 IX. Gliquidone 190 X. Glibornuride 190 XI. Glisoxepide 190 1. Subchronic and Chronic Toxicity in Rats 190 2. Chronic Toxicity in Dogs 191 D. Reproduction Toxicology 191 I. Glibenclamide 191 II. Glisoxepide 192 III. Gliquidone 192 IV. Glibornuride 192 E. Mutagenicity 192 F. Other Toxicological Studies 193 I. In Vivo Studies 193 II. In Vitro Studies 194 G. Conclusions 196 References 196 XVIII Contents CHAPTER 9 Clinical Pharmacology of Sulfonylureas L. GROOP and G. NEUGEBAUER. With 3 Figures 199 A. Pharmacodynamics 199 I. Mode of Action of Sulfonylureas 199 1. Effects on Insulin Secretion 199 II. Hepatic Insulin Clearance 203 III. Other Pancreatic Effects 203 IV. Extrapancreatic Effects 204 V. Combination of Insulin and Sulfonylurea 205 VI. Rational Use of Sulfonylurea Drugs 206 B. Pharmacokinetics 207 I. Similarities and Differences 207 II. Timing of Drug Intake 208 III. Effect of Hyperglycemia 211 IV. Dose- and Concentration-Response Relationship 211 1. First-Phase Insulin Secretion 212 2. Second-Phase Insulin Secretion 213 3. Fasting Blood Glucose 213 4. Postprandial Blood Glucose 214 5. Euglycemic and Hyperglycemic Clamp 215 V. Specific Pharmacokinetics 216 1. Chlorpropamide 216 2. Glibenclamide 218 3. Gliclazide 221 4. Glipizide 223 5. Tolbutamide 225 6. Tolazamide 227 7. Glibornuride 228 8. Gliquidone 229 9. Acetohexamide 231 10. Glisoxepide 232 11. Glyclopyramide 232 12. Glymidine Sodium 232 13. Carbutamide 233 14. Glipentide 234 15. Drugs Under Clinical Investigation 234 C. Safety and Tolerance 235 I. Hypoglycemia 235 II. Sulfonylurea Failure 235 III. Other Adverse Effects 236 IV. Interactions 237 References 237 Contents XIX Section II: Biguanides CHAPTER 10 Chemistry and Structure-Activity Relationships of Biguanides E. PRUGNARD and M. NOEL 263 A. Introduction 263 I. The First Known Synthesis 263 II. The Golden Age 264 III. Nomenclature 264 IV. New Antihyperglycemic Biguanides 266 B. Chemistry 267 I. Synthesis 267 1. Unsubstituted Biguanides 269 2. N-Monosubstituted and N,N-Disubstituted Biguanides 269 3. N,N'-Substituted Biguanides 270 4. N,N"-Substituted Biguanides 270 5. N,N\N",N"'-Substituted Biguanides 271 II. Stability Degradation 272 1. Thermal Decomposition 272 2. Action of Mineral Acids 272 3.

Load more