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. Action of Alkalis 273 4. Action of Reducing Agents 273 5. Action of Oxidizing Agents 273 III. Cyclization Reactions 274 1. Cyclization with Derivatives of Carboxylic Acids 274 2. Cyclization with Carbonyl Compounds 274 3. Cyclization with /?-Difunctional Compounds 275 4. Cyclization with Benzil or Benzoin 276 5. Miscellaneous Cyclizations 276 IV. Metal-Biguanide Complexes 277 1. Synthesis and Structure 277 2. Pharmacological Activity of Complexes 279 3. Use of Biguanide Complexes in Analytical Procedures 280 C. Structure-Activity Relationships 280 References 282 XX Contents

CHAPTER 11 Physicochemical Properties and Analytical Methods of Determination of Biguanides E. PRUGNARD and M. NOEL. With 3 Figures 287 A. Physical Properties 287 I. General Properties 287 II. Dissociation.Constants 287 III. Spectroscopic Data 290 1. Ultraviolet Spectra 290 2. Infrared Spectra 291 3. Nuclear Magnetic Resonance Spectra 292 IV. Crystal Structures and Protonation Sites 292 1. Phenformin 292 2. Metformin 292 B. Quantitative Determination in Biological Medium 296 I. Detection of Antidiabetic Biguanides by Spectrophotometry 296 II. From Micrograms to Nanograms: The Chromatographic Revolution 296 1. Gas Chromatography 296 2. High-Performance Liquid Chromatography 298 3. Miscellaneous 300 References 302

CHAPTER 12 Preclinical Pharmacology of Biguanides N.F. WIERNSPERGER. With 13 Figures 305 A. Introduction 305 B. Absorption and Distribution 306 I. Absorption 306 II. Tissue Distribution 306 C. Efficacy 308 D. General Pharmacology 309 I. Blood Pressure 309 II. Varia 309 III. Hormones 310 IV. Antitumoral Properties 310 V. Vasculoprotective Effects 310 1. Macrocirculation 310 2. Microcirculation 312 3. Hypertension 313 Contents XXI

E. Organ Pharmacology 314 I. Gastrointestinal Tract 314 1. In Vitro 7.. 314 2. In Vivo 316 II. Pancreatic Hormone Secretion 318 1. In Vitro 318 2. In Vivo 319 III. Liver 319 1. In Vitro 319 2. In Vivo 321 IV. Adipose Tissue 323 1. In Vitro 323 2. In Vivo 323 V. Skeletal Muscle/Heart 324 1. In Vitro 324 2. In Vivo 324 VI. Other Tissues 327 1. Blood Cells 327 2. Varia 327 F. Lipid Metabolism 328 I. Lipogenesis 328 II. Lipolysis 328 III. Fatty Acids 328 IV. Triglycerides 329 V. Lipoproteins 329 VI. Cholesterol 329 G. Cellular Effects 330 I. Need for Insulin? 330 II. Potentiation of Insulin Actions 330 III. Mechanisms of Insulin Potentiation 332 1. Plasma Insulin 333 2. Insulin Receptor Binding/Phosphorylation 333 3. Postreceptor Mechanisms 334 4. Mechanisms Not Linked with Potentiation 334 5. Insulin-Independent Effects 336 IV. Biguanides: Membrane-Active Drugs 336 1. Supporting Arguments 337 2. Membrane Binding/Cellular Uptake 337 V. Intracellular Effects 341 VI. Conclusions 342 H. Conclusions 343 References 344 XXII Contents

CHAPTER 13 Toxicology of Biguanides F. SCHMIDT, F. HARTIG, W. REBEL, and P. OCHLICH. With 3 Figures .. 359 A. Introduction 359 B. General Pharmacology and Toxicology 359 C. Acute and Chronic Toxicity 360 I. Phenethylbiguanide (Phenformin) 360 1. Biochemical Deviations in Blood Serum and Liver Mitochondria 360 2. Serum Levels and Organ Distribution (Kidneys, Duodenum, Liver and Organelles) 363 3. Acute Toxicity 365 4. Chronic Toxicity 366 II. Butylbiguanide (Buformin) 367 1. Acute Toxicity 367 2. Chronic Toxicity 367 III. Dimethylbiguanide (Metformin) 367 1. Acute Toxicity 367 2. Subchronic and Chronic Toxicity 368 3. Mutagenicity, Fertility and Teratogenicity 369 4. Carcinogenicity Studies 369 D. Comparative Evaluations and Critical Remarks 370 References 370

CHAPTER 14 Clinical Pharmacology of Biguanides L.S. HERMANN. With 1 Figure • 373 A. Introduction 373 B. Pharmacodynamics 374 I. Antihyperglycaemic Effect 374 II. Weight-Stabilizing Effect 377 III. Lipid-Lowering Effect 378 1. Triglycerides, Cholesterol and Lipoproteins 378 2. Free Fatty Acids and Glycerol 380 IV. Insulin-Sensitizing Effect 381 1. Insulin Secretion 381 2. Insulin Levels 382 3. Insulin Action and Insulin Resistance 383 V. Vascular Effects ' 388 1. Blood Pressure and Renal Effects 388 2. Fibrinolysis, Haemorrheology and Thrombosis 388 VI. Gastrointestinal Effects 390 Contents XXIII

C. Effects on Metabolic Pathways in Human Diabetes 391 I. Glucose Metabolism 391 II. Lactate Metabolism 393 III. Lipid Metabolism 394 D. Indications 395 E. Contraindications and Precautions 395 F. Combination Therapy 396 I. Metformin Plus Sulphonylurea 396 II. Metformin Plus Insulin 397 G. Pharmacokinetics 397 H. Safety and Tolerance 398 I. Lactic Acidosis 398 II. Gastrointestinal and Other Adverse Effects 399 I. Interactions 400 References 400

Section III: Glucosidase Inhibitors

CHAPTER 15 Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors B. JUNGE, M. MATZKE, and J. STOLTEFUSS. With 63 Figures 411 A. Introduction 411 B. Pseudoglucosylamines 412 I. Validamine, Valienamine, and Valiolamine 412 II. N-Substituted Valiolamine Derivatives 417 III. Acarviosin Derivatives 419 IV. Acarbose 421 V. Higher Pseudo-oligosaccharides 426 C. Polyhydroxypiperidines and Polyhydroxypyrrolidines 427 I. Nojirimycin 427 II. 1-Deoxynojirimycin 429 III. N-Substituted Derivatives of 1-Deoxynojirimycin 432 IV. Branched and Chain-Extended Deoxynojirimycin Derivatives 444 1. Derivatives Branched at C-l 444 2. Derivatives Branched at C-5 446 3. Derivatives Chain-Extended at C-6 '.... 449 V. Deoxy, Amino, and Halogen Derivatives 450 VI. Polyhydroxypiperidines with Altered Configuration 453 VII. Bicyclic Derivatives of Deoxynojirimycin 454 XXIV Contents

1. Castanospermine 454 2. Castanospermine Derivatives 457 VIII. Polyhydroxypyrrolidines 460 1. Monocyclic Pyrrolidine Derivatives 460 2. Bicyclic Pyrrolidine Derivatives 465 References 467

CHAPTER 16 Analytical Methods of Determination of Glucosidase Inhibitors H.J. PLOSCHKE, H. SCHLECKER, S. SEIP, and C. WUNSCHE. With 5 Figures 483 A. Chromatographic Techniques 483 I. Analytical Methods 483 II. Preparative Methods 484 1. Reverse-Phase Chromatography 485 2. Ion-Exchange Chromatography 487 3. Size-Exclusion Chromatography 487 4. Adsorption Chromatography 488 5. Craig Distribution 488 6. Detection 490 B. Spectroscopic Techniques 490 I. Nuclear Magnetic Resonance 490 II. Mass Spectrometry 492 References - 494

CHAPTER 17 Pharmacology of Glucosidase Inhibitors W. PULS. With 3 Figures 497 A. Introduction 497 B. Intestinal Digestion of Dietary Di-, Oligo- and Polysaccharides by a-Glucosidases 497 C. Exploratory Investigations on the Feasibility of a-Glucosidase Inhibition 498 D. Primary Effects of Glucosidase Inhibitors 500 E. Secondary Effects of Glucosidase Inhibitors 501 I. Investigations to Evaluate the Potency of Glucosidase Inhibitors 501 II. Blood Glucose and Plasma Insulin 503 1. Single-Dose Studies 503 2. Repeated Administration 505 Contents XXV

III. Lipid Metabolism 508 1. Blood Lipids 508 2. Tissue Lipids 509 IV. Protein Metabolism 511 V. Hormones 512 1. Pancreatic Insulin 512 2. Catecholamines and Thyroid Hormones 513 3. Other Hormones 513 VI. Vitamins and Trace Metals 514 VII. Exocrine Pancreas 514 VIII. Small and Large Bowel 515 1. Weight, Length and Microflora 515 2. Enzyme Activity Alterations in the Small Intestine .... 517 3. Enterohormones in the Intestinal Gut Wall 518 IX. Liver 519 1. Glycogen 519 2. Lipids 520 X. Heart 522 XI. Skeletal Muscle 522 XII. Dangerous Late Complications 523 1. Nephropathy 523 2. Neuropathy 524 3. Retinal Microangiopathy 525 References 525

CHAPTER 18 General Pharmacology of Glucosidase Inhibitors W. PULS 535 A. Introduction 535 B. Neuropharmacological Studies 535 C. Cardiovascular/Respiratory Studies 536 D. Gastrointestinal Function Studies 536 E. Haematological Studies 537 F. Antigenic, Antiallergic and Pulmonary Activity 537 G. Antibacterial, Antimycotic and Antiparasitic Activity 537 H. Other Studies 537 References 538 XXVI Contents

CHAPTER 19 Pharmacokinetics and Metabolism of Glucosidase Inhibitors H.P. KRAUSE and H.J. AHR. With 4 Figures 541 A. Introduction 541 B. Acarviosin Derivatives 541 I. Acarbose 541 1. Introduction 541 2. Determination Methods 542 3. Absorption 542 4. Plasma Concentrations 543 5. Protein Binding 543 6. Distribution 543 7. Metabolism 544 8. Excretion 544 C. Valiolamine Derivatives 545 I. AO-128 545 1. Introduction 545 2. Determination Methods 545 3. Absorption 546 4. Plasma Concentrations of Total Radioactivity 546 5. Plasma Concentrations of Unchanged AO-128 546 6. Distribution 546 7. Metabolism 547 8. Excretion 547 D. Deoxynojirimycin-Derivatives 547 I. Miglitol 547 1. Introduction 547 2. Determination Methods 548 3. Absorption 548 4. Plasma Concentrations 548 5. Protein Binding 548 6. Distribution 549 7. Metabolism 549 8. Excretion 549 II. Emiglitate 549 1. Introduction 549 2. Absorption 550 3. Plasma Concentrations 550 4. Distribution 550 5. Metabolism 550 6. Excretion ; 551 III. Other Deoxynojirimycin Derivatives 551 1. 1-Deoxymannojirimycin 551 2. Af-methyl-1 -deoxynojirimycin 552 Contents XXVII

E. Comparative Discussion 552 References 554

CHAPTER 20 Toxicology of Glucosidase Inhibitors E.M. BOMHARD. With 2 Figures 557 A. Acarbose 557 I. General Toxicology 557 1. Acute Toxicity ...'. 557 2. Subacute Intravenous Toxicity 557 3. Subchronic Oral Toxicity 558 4. Chronic Toxicity 559 II. Reproduction Toxicology 560 1. Fertility and General Reproductive Performance in Rats 560 2. Embryotoxicity/Teratogenicity in Rats 560 3. Peri-/Postnatal Study in Rats 560 4. Embryotoxicity/Teratogenicity in Rabbits 561 III. Genotoxicity/Mutagenicity 561 IV. Carcinogenicity 561 1. Rat 561 2. Hamster 569 3. Low-Carbohydrate/Emiglitate Lifetime Carcinogenicity Study in Sprague-Dawley Rats 571 V. Toxicokinetics 571 VI. Special Studies 573 1. Glycogen Storage in Rats 573 2. Cell Proliferation in Kidney Cortex 574 3. Electron Microscopic Investigations 575 4. Investigations of Effects on Endocrinium 575 5. Interaction with Other Oral Antidiabetics 575 VII. Assessment of the Carcinogenic Potential of Acarbose .... 576 1. Significance of Leydig Cell Tumours 576 2. Significance of Epithelial Kidney Tumours in Sprague-Dawley Rats 577 B. Emiglitate 579 I. General Toxicology 579 1. Acute Toxicity 579 2. Subacute Toxicity 580 3. Subchronic Toxicity 580 4. Chronic Toxicity 581 II. Reproduction Toxicology 582 XXVIII Contents

1. Fertility and General Reproductive Performance in Rats : 582 2. Embryotoxicity/Teratogenicity in Rats 582 3. Embryotoxicity/Teratogenicity in Rabbits 582 III. Genotoxicity/Mutagenicity 582 IV. Carcinogenicity 582 1. Rat 582 2. Mouse 584 V. Toxicokinetics 584 VI. Special Studies 584 C. Miglitol 585 I. General Toxicology 585 1. Acute Toxicity 585 2. Subacute Toxicity 585 3. Subchronic Toxicity 586 4. Chronic Toxicity 586 II. Reproduction Toxicology '. 587 1. Fertility and General Reproductive Performance in Rats 587 2. Embryotoxicity/Teratogenicity in Rats 587 3. Peri-/Postnatal Study in Rats 587 4. Embryotoxicity/Teratogenicity in Rabbits 587 III. Genotoxicity/Mutagenicity 588 IV. Carcinogenicity 588 1. Rat 588 2. Mouse- 588 V. Toxicokinetics 588 VI. Special Studies 591 D. Voglibose 592 I. General Toxicology 592 1. Acute Toxicity 592 2. Subacute Toxicity 592 3. Subchronic Toxicity 593 4. Chronic Toxicity 595 II. Reproduction Toxicology 596 1. Fertility and General Reproductive Performance in Rats 596 2. Embryotoxicity/Teratogenicity in Rats 596 3. Peri-/Postnatal Study in Rats 597 4. Embryotoxicity/Teratogenicity in Rabbits 598 5. Peri-/Postnatal Study in Rats Fed on a Glucose Diet 598 III. Genotoxicity/Mutagenicity 599 IV. Carcinogenicity 599 1. Rat 599 2. Mouse 600 Contents XXIX

V. Toxicokinetics 601 VI. Special Studies 601 1. Antigenicity in Guinea Pigs and Mice 601 2. Effect of Dietary Carbohydrates on the Oral Toxicity in Rats 601 3. Effect of Low-Protein Diet on Plasma Transaminases in Rats 602 E. Castanospermine 602 I. General Toxicology 602 1. Acute/Subacute Toxicity 602 II. Reproduction Toxicology 603 III. Genotoxicity/Mutagenicity 603 IV. Carcinogenicity 603 V. Toxicokinetics 603 VI. Special Studies 603 F. Common Toxicological Characteristics of Glucosidase Inhibitors 604 I. Reduced Glucose Utilization 605 II. Lysosomal Glycogen Storage 606 III. Accumulation of Undigested Carbohydrates in the Large Intestine , 607 References 608

CHAPTER 21 Clinical Pharmacology of Glucosidase Inhibitors E. BRENDEL and W. WINGENDER. With 4 Figures 611 A. Acarbose 611 I. Introduction 611 II. Pharmacodynamics 611 1. Effects on Blood Sugar and Insulin 611 2. Effects on Gastrointestinal Hormones and Exocrine Pancreatic Function 613 3. Effects on Lipids and Lipoproteins 614 III. Pharmacokinetics 614 IV. Safety and Tolerability 616 V. Interactions 617 B. Deoxynojirimycin Derivatives (Miglitol, Emiglitate) 618 I. Introduction 618 II. Pharmacodynamics 619 1. Effect on Blood Sugar and Insulin 619 2. Effects on Gastrointestinal Hormones 623 3. Effects on Lipids 623 III. Pharmacokinetics 624 IV. Safety and Tolerability 625 XXX , Contents

V. Interactions 626 C. Other Glucosidase Inhibitors 626 I. Introduction 626 II. Pharmacodynamics 626 References 628

CHAPTER 22 Clinical Evaluation of Glucosidase Inhibitors R.H. TAYLOR and E.M. BARDOLPH 633 A. Introduction 633 I. Carbohydrate Digestion 633 II. Diet and Glucosidase Inhibitors 634 III. Role of Glucosidase Inhibitors in Diabetes 635 B. Acarbose 635 I. Studies in Type I Diabetes 636 II. Studies in Type II Diabetes 637 1. Clinical Trials 637 2. Effect on Lipids 638 3. Studies Comparing Effects with Other Antidiabetic Agents 639 III. Other Clinical Studies 641 C. Deoxynojirimycin Derivatives 641 I. Studies in Type I Diabetes 642 II. Studies in Type II Diabetes 643 D. Other Glucosidase Inhibitors 644 E. Conclusions 645 References 646

CHAPTER 23 Oral Antidiabetic Drugs in Research and Development H. BISCHOFF and H.E. LEBOVITZ. With 11 Figures 651 A. Introduction 651 B. Stimulation and Modulation of Insulin Secretion 652 I. Depolarization of the B-Cell Membrane 653 1. Inhibitors of the ATP-Sensitive K+ Channel 653 a) Sulfonylurea Derivatives 653 b) Benzoic Acid Derivatives 655 c) Guanidine Derivatives 656 d) 2-Substituted Imidazoline Derivatives '. 657 2. Compounds with Uncertain Sites of Action 659 II. a2-Adrenoceptor Antagonism 661 III. Ca2+ Channel Modulation 662 Contents , XXXI

C. Suppression of Hepatic Glucose Production 663 I. Inhibition of Fatty Acid Oxidation 664 1. Inhibitors of Carnitine Acylcarnitine Translocase: Hydrazonopropionic Acid Derivatives 664 a) Pharmacological Properties 665 b) Effect on Gluconeogenesis and Mode of Action ... 666 c) Clinical Studies 668 2. Inhibitors of Carnitine Palmitoyltransferase I 668 a) Pharmacology and Effects on Gluconeogenesis .... 668 a) 2-Oxirane Carboxylic Acid Derivatives 668 P) Dioxolane Derivative 670 y) B-Aminobetaine Structures 670 b) Pharmacokinetics and Toxicology 671 c) Clinical Studies 672 D. Enhancement of Insulin Action 673 E. Mimicking of Insulin Action 678 F. Prevention of Deleterious Effects Caused by Glucose 680 I. Aldose Reductase Inhibitors 681 II. Aminoguanidine: An Inhibitor of Advanced Glycation End Product Formation 684 References 685

CHAPTER 24 New Approaches for the Treatment of Diabetes Mellitus J.M. AMATRUDA and M.L: MCCALEB 697 A. Prevention 697 I. Non-Insulin-Dependent Diabetes Mellitus 697 II. Insulin-Dependent Diabetes Mellitus 698 B. Obesity 700 I. Central Mechanisms 701 II. Peripheral Mechanisms 703 1. Increased Energy Expenditure 703 2. Decreased Fat Absorption 704 C. Insulin Sensitizers 704 I. Rationale 704 II. Specific Targets 705 III. Amylin and Amylin Blockers 706 D. Alternative Insulin Delivery 707 E. Gene Therapy 709 References 710

Subject Index 715