J

Oral AntidiabeticsContributors

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

IntroductionJ. KUHLMANN 1

References 5

CHAPTER 2

Pathophysiology of Type 2 Diabetes MellitusA.J. SCHEEN and P.J. LEFEBVRE. With 5 Figures 7

A. Introduction 7I. Heterogeneous Disease 7

II. Genetic Background 8III. Environmental Factors 8

B. Abnormalities of the Glucose-Insulin Feedback Loop 9I. Insulin Secretion 10

1. How to Measure Insulin Secretion? 112. Abnormal Plasma Concentrations 123. Abnormal Kinetics Response 134. Varia 14

II. Insulin Sensitivity 141. Hepatic Glucose Production 142. Splanchnic Glucose Uptake 163. Peripheral (Muscle) Glucose Uptake 164. Adipose Tissue Lipolysis 185. Increased Glucagon Secretion 196. Varia 19

C. Possible Causal Defects 19I. Insulin Secretion 19

1. B-Cell Number 192. Insulin Gene 203. Amylin 214. GLUT 2 215. Glucokinase 21

XII Contents

6. Accumulation of B-Cell Glycogen 227. Varia 22

II. Insulin Sensitivity 231. Insulin Pre-receptor Level 232. Insulin Receptor Level 243. Insulin Post-receptor Level 254. Varia , . 28

D. Role of Associated Obesity 29I. Impact of Obesity on Insulin Secretion 29

II. Impact of Obesity on Insulin Sensitivity 29III. Lipid Oxidation and Insulin Resistance 30IV. From Obesity to Type 2 Diabetes 30

E. Dynamic Interaction Between Insulin Actionand Insulin Secretion 31

I. What Is the Primary Defect? 31II. Transient Compensatory Mechanisms 32

III. Role of Glucose Toxicity 33IV. Vicious Circle Leading to Severe Hyperglycaemia 33

F. Conclusions 34References 35

CHAPTER 3

Non-Pharmacological Managementof Non-Insulin-Dependent DiabetesJ. KOBBERLING 43

A. Dietary Management 43I. General Basis for Recommendations 43

II. Total Energy Intake 441. Overweight NIDDM Patients 442. Normal Weight NIDDM Patients 45

III. Carbohydrates 461. Dietary Fibres 462. Simple Sugars 483. Glycaemic Index of Various Carbohydrates 48

IV. Dietary Fat 49V. Dietary Protein 50

VI. Other Dietary Factors 511. Sodium 512. Alcohol 513. Vitamins, Minerals and Trace Elements : 51

VII. Dietary Specialities for Diabetics 521. Sweeteners : 522. Diabetic Foods 52

Contents XIII

VIII. Problems and Techniques of Dietary Advice 52IX. Dietary Recommendations in "Non-Western" Societies . . . 53

1. India and Southeast Asia 532. Japan 543. China 554. Africa 55

B. Exercise 55I. Insulin-Dependent Diabetes 56

II. Non-Insulin-Dependent Diabetes 561. Short-Term Effects 562. Long-Term Effects 57

III. Recommendations 58References 59

Section I: Sulfonylureas

CHAPTER 4

Sulfonylureas and Related Compounds:Chemistry and Structure-Activity RelationshipsH. PLUMPE. With 1 Figure 65

A. Introduction 65B. Sulfonylureas 7 66

I. Variation of R1 66II. Variation of R2 69

C. Sulfonylsemicarbazides 69D. Sulfonylaminopyrimidines 69E. Various Nonmarketed Compounds of Interest 69F. Conclusions 71References 71

CHAPTER 5

Sulfonylureas: Physicochemical Properties, Analytical Methodsof Determination and BioavailabilityS.L. A L I , H.H. BLUME, and B.S. SCHUG. With 15 Figures 73

A. Introduction 73B. Physical Properties 73

I. Description 73II. Melting Point 73

XIV Contents

III. Solubility 731. Acetohexamide 762. Acetylcarbutamide 763. Carbutamide 774. Chlorpropamide 775. Glibenclamide 776. Glimepiride 777. Glipizide 778. Gliquidone 779. Glisoxepide 77

10. Metahexamide 7811. Tolazamide 7812. Tolbutamide 78

IV. Dissociation Constants 79V. Crystal Shape and Structure 79

1. Acetohexamide 792. Glimepiride 803. Tolbutamide 80

C. Ultraviolet Spectrum 82D. Infrared Spectrum 82E. Nuclear Magnetic Resonance Spectrum 86F. Mass Spectrum 86G. Color and Identification Reactions 88

I. Acetohexamide, Glibornuride, Gliquidone 91II. Carbutamide 91

III. Chlorpropamide 91IV. Glibenclamide 91V. Tolbutamide 91

H. Stability and Degradation 92I. Acetohexamide 92

II. Chlorpropamide 92III. Glibenclamide 92IV. Glimpiride 93V. Glisoxepide 93

VI. Tolbutamide 93I. Methods of Analysis 94

I. Titrimetry 941. Acetohexamide 942. Carbutamide 943. Chlorpropamide 954. Glibenclamide 955. Glipizide 956. Glisoxepide 957. Tolazamide 958. Tolbutamide 95

Contents XV

II. Ultraviolet Spectrophotometry 961. Acetohexamide 96,2. Carbutamide 963. Chlorpropamide 964. Glibenclamide 965. Glipizide 966. Tolbutamide 97

III. Colorimetric Methods 971. Carbutamide 972. Glibenclamide 973. Tolbutamide 98

IV. Fluorimetry 98V. Miscellaneous Methods 98

J. Chromatographic Methods 98I. Paper Chromatography 99

II. Thin-Layer Chromatography 99III. Gas-Liquid Chromatography and Mass Spectrometry 99

1. Acetohexamide 992. Chlorpropamide 993. Glibenclamide 1034. Tolazamide 1035. Tolbutamide 103

IV. High-Performance Liquid Chromatography 1041. Acetohexamide, Chlorpropamide, Glibornuride,

Gliclazide, Tolazamide 1042. Carbutamide 1063. Glibenclamide, Glipizide 1064. Glimepiride 1075. Glisoxepide 1086. Tolbutamide 108

K. Bioavailability 1081. Acetohexamide I l l2. Chlorpropamide I l l3. Glibenclamide (Glyburide) 1134. Gliclazide 1155. Glimepiride 1176. Glipizide 1177. Gliquidone 1188. Glisoxepide 1199. Tolazamide 119

10. Tolbutamide 119References 121

XVI Contents

CHAPTER 6

Mode of Action of SulfonylureasU. PANTEN, M. SCHWANSTECHER, and C. SCHWANSTECHER.With 3 Figures 129

A. Introduction 129B. Actions on Pancreatic /? Cells 130

I. Stimulation of Insulin Secretion 130II. Inhibition of the KATP Channel 131

III. Location of the Sulfonylurea Receptor 134IV. Properties of the Binding Sites for Sulfonylureas 135V. Structure of Compounds Interacting

with the Sulfonylurea Receptor 140C. Actions on Non-/? Cells in Pancreatic Islets 143D. Actions on Neurons 144E. Actions on Cardiac Cells 145F. Actions on Smooth Muscle 147G. Actions on Skeletal Muscle 147H. Actions on Miscellaneous Cells 148I. Conclusions 148References 149

CHAPTER 7

Sulfonylureas: Pharmacokinetics in Animal ExperimentsA. HASSELBLATT . . . : 161

A. Introduction 161B. Absorption of Sulfonylurea Derivatives After Oral

Administration 162I. Species Differences in the Rate of Absorption 162

II. Kinetics of Absorption of Sulfonylureas and Effectsof Food and Other Drugs 163

III. Dependence of Absorption on GalenicFormulation 164

C. Distribution of Sulfonylurea Derivatives in the Organism 164I. Space of Distribution of Sulfonylurea Derivatives 164

II. Protein Binding of Sulfonylureas and Interactionwith Other Compounds on Plasma Protein-Binding Sites . . 167

D. Accumulation of Sulfonylurea Derivativesin Different Organ Systems 169

I. Accumulation in the Liver '. 169II. Accumulation of Sulfonylurea Derivatives

in the Pancreatic Islets 169E. Elimination of Sulfonylurea Derivatives 171

Contents XVII

F. Influence of Other Drugs on Rate of Metabolism and Excretionof Sulfonylurea Drugs 175

G. Possible Implications of the Results from Animal Experimentson the Pharmacokinetics of Sulfonylurea Derivativesfor Clinical Applications in Humans 176

References 178

CHAPTER 8

Toxicology of SulfonylureasF. HARTIG, K.H. LANGER, W. REBEL, F.H. SCHMIDT,

and E. SCHUTZ 185

A. Introduction 185B. Acute Toxicity 185C. Chronic Toxicity 187

I. Carbutamide 1871. Rats 1872. Dogs 187

II. Tolbutamide 187III. Chlorpropamide .; 188

1. Rats and Mice 1882. Dogs 188

IV. Acetohexamide 189V. Tolazamide 189

VI. Glibenclamide 189VII. Gliclazide 189

VIII. Glipizide 190IX. Gliquidone 190X. Glibornuride 190

XI. Glisoxepide 1901. Subchronic and Chronic Toxicity in Rats 1902. Chronic Toxicity in Dogs 191

D. Reproduction Toxicology 191I. Glibenclamide 191

II. Glisoxepide 192III. Gliquidone 192IV. Glibornuride 192

E. Mutagenicity 192F. Other Toxicological Studies 193

I. In Vivo Studies 193II. In Vitro Studies 194

G. Conclusions 196References 196

XVIII Contents

CHAPTER 9

Clinical Pharmacology of SulfonylureasL. GROOP and G. NEUGEBAUER. With 3 Figures 199

A. Pharmacodynamics 199I. Mode of Action of Sulfonylureas 199

1. Effects on Insulin Secretion 199II. Hepatic Insulin Clearance 203

III. Other Pancreatic Effects 203IV. Extrapancreatic Effects 204V. Combination of Insulin and Sulfonylurea 205

VI. Rational Use of Sulfonylurea Drugs 206B. Pharmacokinetics 207

I. Similarities and Differences 207II. Timing of Drug Intake 208

III. Effect of Hyperglycemia 211IV. Dose- and Concentration-Response Relationship 211

1. First-Phase Insulin Secretion 2122. Second-Phase Insulin Secretion 2133. Fasting Blood Glucose 2134. Postprandial Blood Glucose 2145. Euglycemic and Hyperglycemic Clamp 215

V. Specific Pharmacokinetics 2161. Chlorpropamide 2162. Glibenclamide 2183. Gliclazide 2214. Glipizide 2235. Tolbutamide 2256. Tolazamide 2277. Glibornuride 2288. Gliquidone 2299. Acetohexamide 231

10. Glisoxepide 23211. Glyclopyramide 23212. Glymidine Sodium 23213. Carbutamide 23314. Glipentide 23415. Drugs Under Clinical Investigation 234

C. Safety and Tolerance 235I. Hypoglycemia 235

II. Sulfonylurea Failure 235III. Other Adverse Effects 236IV. Interactions 237

References 237

Contents XIX

Section II: Biguanides

CHAPTER 10

Chemistry and Structure-Activity Relationships of BiguanidesE. PRUGNARD and M. NOEL 263

A. Introduction 263I. The First Known Synthesis 263

II. The Golden Age 264III. Nomenclature 264IV. New Antihyperglycemic Biguanides 266

B. Chemistry 267I. Synthesis 267

1. Unsubstituted Biguanides 2692. N-Monosubstituted and N,N-Disubstituted

Biguanides 2693. N,N'-Substituted Biguanides 2704. N,N"-Substituted Biguanides 2705. N,N\N",N"'-Substituted Biguanides 271

II. Stability Degradation 2721. Thermal Decomposition 2722. Action of Mineral Acids 2723. Action of Alkalis 2734. Action of Reducing Agents 2735. Action of Oxidizing Agents 273

III. Cyclization Reactions 2741. Cyclization with Derivatives of Carboxylic Acids 2742. Cyclization with Carbonyl Compounds 2743. Cyclization with /?-Difunctional Compounds 2754. Cyclization with Benzil or Benzoin 2765. Miscellaneous Cyclizations 276

IV. Metal-Biguanide Complexes 2771. Synthesis and Structure 2772. Pharmacological Activity of Complexes 2793. Use of Biguanide Complexes

in Analytical Procedures 280C. Structure-Activity Relationships 280References 282

XX Contents

CHAPTER 11

Physicochemical Properties and Analytical Methodsof Determination of BiguanidesE. PRUGNARD and M. NOEL. With 3 Figures 287

A. Physical Properties 287I. General Properties 287

II. Dissociation.Constants 287III. Spectroscopic Data 290

1. Ultraviolet Spectra 2902. Infrared Spectra 2913. Nuclear Magnetic Resonance Spectra 292

IV. Crystal Structures and Protonation Sites 2921. Phenformin 2922. Metformin 292

B. Quantitative Determination in Biological Medium 296I. Detection of Antidiabetic Biguanides

by Spectrophotometry 296II. From Micrograms to Nanograms: The Chromatographic

Revolution 2961. Gas Chromatography 2962. High-Performance Liquid Chromatography 2983. Miscellaneous 300

References 302

CHAPTER 12

Preclinical Pharmacology of BiguanidesN.F. WIERNSPERGER. With 13 Figures 305

A. Introduction 305B. Absorption and Distribution 306

I. Absorption 306II. Tissue Distribution 306

C. Efficacy 308D. General Pharmacology 309

I. Blood Pressure 309II. Varia 309

III. Hormones 310IV. Antitumoral Properties 310V. Vasculoprotective Effects 310

1. Macrocirculation 3102. Microcirculation 3123. Hypertension 313

Contents XXI

E. Organ Pharmacology 314I. Gastrointestinal Tract 314

1. In Vitro 7. . 3142. In Vivo 316

II. Pancreatic Hormone Secretion 3181. In Vitro 3182. In Vivo 319

III. Liver 3191. In Vitro 3192. In Vivo 321

IV. Adipose Tissue 3231. In Vitro 3232. In Vivo 323

V. Skeletal Muscle/Heart 3241. In Vitro 3242. In Vivo 324

VI. Other Tissues 3271. Blood Cells 3272. Varia 327

F. Lipid Metabolism 328I. Lipogenesis 328

II. Lipolysis 328III. Fatty Acids 328IV. Triglycerides 329V. Lipoproteins 329

VI. Cholesterol 329G. Cellular Effects 330

I. Need for Insulin? 330II. Potentiation of Insulin Actions 330

III. Mechanisms of Insulin Potentiation 3321. Plasma Insulin 3332. Insulin Receptor Binding/Phosphorylation 3333. Postreceptor Mechanisms 3344. Mechanisms Not Linked with Potentiation 3345. Insulin-Independent Effects 336

IV. Biguanides: Membrane-Active Drugs 3361. Supporting Arguments 3372. Membrane Binding/Cellular Uptake 337

V. Intracellular Effects 341VI. Conclusions 342

H. Conclusions 343References 344

XXII Contents

CHAPTER 13

Toxicology of BiguanidesF. SCHMIDT, F. HARTIG, W. REBEL, and P. OCHLICH. With 3 Figures .. 359

A. Introduction 359B. General Pharmacology and Toxicology 359C. Acute and Chronic Toxicity 360

I. Phenethylbiguanide (Phenformin) 3601. Biochemical Deviations in Blood Serum

and Liver Mitochondria 3602. Serum Levels and Organ Distribution (Kidneys,

Duodenum, Liver and Organelles) 3633. Acute Toxicity 3654. Chronic Toxicity 366

II. Butylbiguanide (Buformin) 3671. Acute Toxicity 3672. Chronic Toxicity 367

III. Dimethylbiguanide (Metformin) 3671. Acute Toxicity 3672. Subchronic and Chronic Toxicity 3683. Mutagenicity, Fertility and Teratogenicity 3694. Carcinogenicity Studies 369

D. Comparative Evaluations and Critical Remarks 370References 370

CHAPTER 14

Clinical Pharmacology of BiguanidesL.S. HERMANN. With 1 Figure • 373

A. Introduction 373B. Pharmacodynamics 374

I. Antihyperglycaemic Effect 374II. Weight-Stabilizing Effect 377

III. Lipid-Lowering Effect 3781. Triglycerides, Cholesterol and Lipoproteins 3782. Free Fatty Acids and Glycerol 380

IV. Insulin-Sensitizing Effect 3811. Insulin Secretion 3812. Insulin Levels 3823. Insulin Action and Insulin Resistance 383

V. Vascular Effects ' 3881. Blood Pressure and Renal Effects 3882. Fibrinolysis, Haemorrheology and Thrombosis 388

VI. Gastrointestinal Effects 390

Contents XXIII

C. Effects on Metabolic Pathways in Human Diabetes 391I. Glucose Metabolism 391

II. Lactate Metabolism 393III. Lipid Metabolism 394

D. Indications 395E. Contraindications and Precautions 395F. Combination Therapy 396

I. Metformin Plus Sulphonylurea 396II. Metformin Plus Insulin 397

G. Pharmacokinetics 397H. Safety and Tolerance 398

I. Lactic Acidosis 398II. Gastrointestinal and Other Adverse Effects 399

I. Interactions 400References 400

Section III: Glucosidase Inhibitors

CHAPTER 15

Chemistry and Structure-Activity Relationshipsof Glucosidase InhibitorsB. JUNGE, M. MATZKE, and J. STOLTEFUSS. With 63 Figures 411

A. Introduction 411B. Pseudoglucosylamines 412

I. Validamine, Valienamine, and Valiolamine 412II. N-Substituted Valiolamine Derivatives 417

III. Acarviosin Derivatives 419IV. Acarbose 421V. Higher Pseudo-oligosaccharides 426

C. Polyhydroxypiperidines and Polyhydroxypyrrolidines 427I. Nojirimycin 427

II. 1-Deoxynojirimycin 429III. N-Substituted Derivatives of 1-Deoxynojirimycin 432IV. Branched and Chain-Extended Deoxynojirimycin

Derivatives 4441. Derivatives Branched at C-l 4442. Derivatives Branched at C-5 4463. Derivatives Chain-Extended at C-6 '.... 449

V. Deoxy, Amino, and Halogen Derivatives 450VI. Polyhydroxypiperidines with Altered Configuration 453

VII. Bicyclic Derivatives of Deoxynojirimycin 454

XXIV Contents

1. Castanospermine 4542. Castanospermine Derivatives 457

VIII. Polyhydroxypyrrolidines 4601. Monocyclic Pyrrolidine Derivatives 4602. Bicyclic Pyrrolidine Derivatives 465

References 467

CHAPTER 16

Analytical Methods of Determination of Glucosidase InhibitorsH.J. PLOSCHKE, H. SCHLECKER, S. SEIP, and C. WUNSCHE.With 5 Figures 483

A. Chromatographic Techniques 483I. Analytical Methods 483

II. Preparative Methods 4841. Reverse-Phase Chromatography 4852. Ion-Exchange Chromatography 4873. Size-Exclusion Chromatography 4874. Adsorption Chromatography 4885. Craig Distribution 4886. Detection 490

B. Spectroscopic Techniques 490I. Nuclear Magnetic Resonance 490

II. Mass Spectrometry 492References - 494

CHAPTER 17

Pharmacology of Glucosidase InhibitorsW. PULS. With 3 Figures 497

A. Introduction 497B. Intestinal Digestion of Dietary Di-, Oligo- and Polysaccharides

by a-Glucosidases497

C. Exploratory Investigations on the Feasibilityof a-Glucosidase Inhibition 498

D. Primary Effects of Glucosidase Inhibitors 500E. Secondary Effects of Glucosidase Inhibitors 501

I. Investigations to Evaluate the Potencyof Glucosidase Inhibitors 501

II. Blood Glucose and Plasma Insulin 5031. Single-Dose Studies 5032. Repeated Administration 505

Contents XXV

III. Lipid Metabolism 5081. Blood Lipids 5082. Tissue Lipids 509

IV. Protein Metabolism 511V. Hormones 512

1. Pancreatic Insulin 5122. Catecholamines and Thyroid Hormones 5133. Other Hormones 513

VI. Vitamins and Trace Metals 514VII. Exocrine Pancreas 514

VIII. Small and Large Bowel 5151. Weight, Length and Microflora 5152. Enzyme Activity Alterations in the Small Intestine . . . . 5173. Enterohormones in the Intestinal Gut Wall 518

IX. Liver 5191. Glycogen 5192. Lipids 520

X. Heart 522XI. Skeletal Muscle 522

XII. Dangerous Late Complications 5231. Nephropathy 5232. Neuropathy 5243. Retinal Microangiopathy 525

References 525

CHAPTER 18

General Pharmacology of Glucosidase InhibitorsW. PULS 535

A. Introduction 535B. Neuropharmacological Studies 535C. Cardiovascular/Respiratory Studies 536D. Gastrointestinal Function Studies 536E. Haematological Studies 537F. Antigenic, Antiallergic and Pulmonary Activity 537G. Antibacterial, Antimycotic and Antiparasitic Activity 537H. Other Studies 537References 538

XXVI Contents

CHAPTER 19

Pharmacokinetics and Metabolism of Glucosidase InhibitorsH.P. KRAUSE and H.J. AHR. With 4 Figures 541

A. Introduction 541B. Acarviosin Derivatives 541

I. Acarbose 5411. Introduction 5412. Determination Methods 5423. Absorption 5424. Plasma Concentrations 5435. Protein Binding 5436. Distribution 5437. Metabolism 5448. Excretion 544

C. Valiolamine Derivatives 545I. AO-128 545

1. Introduction 5452. Determination Methods 5453. Absorption 5464. Plasma Concentrations of Total Radioactivity 5465. Plasma Concentrations of Unchanged AO-128 5466. Distribution 5467. Metabolism 5478. Excretion 547

D. Deoxynojirimycin-Derivatives 547I. Miglitol 547

1. Introduction 5472. Determination Methods 5483. Absorption 5484. Plasma Concentrations 5485. Protein Binding 5486. Distribution 5497. Metabolism 5498. Excretion 549

II. Emiglitate 5491. Introduction 5492. Absorption 5503. Plasma Concentrations 5504. Distribution 5505. Metabolism 5506. Excretion ; 551

III. Other Deoxynojirimycin Derivatives 5511. 1-Deoxymannojirimycin 5512. Af-methyl-1 -deoxynojirimycin 552

Contents XXVII

E. Comparative Discussion 552References 554

CHAPTER 20

Toxicology of Glucosidase InhibitorsE.M. BOMHARD. With 2 Figures 557

A. Acarbose 557I. General Toxicology 557

1. Acute Toxicity . . . ' . 5572. Subacute Intravenous Toxicity 5573. Subchronic Oral Toxicity 5584. Chronic Toxicity 559

II. Reproduction Toxicology 5601. Fertility and General Reproductive Performance

in Rats 5602. Embryotoxicity/Teratogenicity in Rats 5603. Peri-/Postnatal Study in Rats 5604. Embryotoxicity/Teratogenicity in Rabbits 561

III. Genotoxicity/Mutagenicity 561IV. Carcinogenicity 561

1. Rat 5612. Hamster 5693. Low-Carbohydrate/Emiglitate Lifetime

Carcinogenicity Study in Sprague-Dawley Rats 571V. Toxicokinetics 571

VI. Special Studies 5731. Glycogen Storage in Rats 5732. Cell Proliferation in Kidney Cortex 5743. Electron Microscopic Investigations 5754. Investigations of Effects on Endocrinium 5755. Interaction with Other Oral Antidiabetics 575

VII. Assessment of the Carcinogenic Potential of Acarbose . . . . 5761. Significance of Leydig Cell Tumours 5762. Significance of Epithelial Kidney Tumours

in Sprague-Dawley Rats 577B. Emiglitate 579

I. General Toxicology 5791. Acute Toxicity 5792. Subacute Toxicity 5803. Subchronic Toxicity 5804. Chronic Toxicity 581

II. Reproduction Toxicology 582

XXVIII Contents

1. Fertility and General Reproductive Performancein Rats : 582

2. Embryotoxicity/Teratogenicity in Rats 5823. Embryotoxicity/Teratogenicity in Rabbits 582

III. Genotoxicity/Mutagenicity 582IV. Carcinogenicity 582

1. Rat 5822. Mouse 584

V. Toxicokinetics 584VI. Special Studies 584

C. Miglitol 585I. General Toxicology 585

1. Acute Toxicity 5852. Subacute Toxicity 5853. Subchronic Toxicity 5864. Chronic Toxicity 586

II. Reproduction Toxicology '. 5871. Fertility and General Reproductive Performance

in Rats 5872. Embryotoxicity/Teratogenicity in Rats 5873. Peri-/Postnatal Study in Rats 5874. Embryotoxicity/Teratogenicity in Rabbits 587

III. Genotoxicity/Mutagenicity 588IV. Carcinogenicity 588

1. Rat 5882. Mouse- 588

V. Toxicokinetics 588VI. Special Studies 591

D. Voglibose 592I. General Toxicology 592

1. Acute Toxicity 5922. Subacute Toxicity 5923. Subchronic Toxicity 5934. Chronic Toxicity 595

II. Reproduction Toxicology 5961. Fertility and General Reproductive Performance

in Rats 5962. Embryotoxicity/Teratogenicity in Rats 5963. Peri-/Postnatal Study in Rats 5974. Embryotoxicity/Teratogenicity in Rabbits 5985. Peri-/Postnatal Study in Rats Fed

on a Glucose Diet 598III. Genotoxicity/Mutagenicity 599IV. Carcinogenicity 599

1. Rat 5992. Mouse 600

Contents XXIX

V. Toxicokinetics 601VI. Special Studies 601

1. Antigenicity in Guinea Pigs and Mice 6012. Effect of Dietary Carbohydrates

on the Oral Toxicity in Rats 6013. Effect of Low-Protein Diet

on Plasma Transaminases in Rats 602E. Castanospermine 602

I. General Toxicology 6021. Acute/Subacute Toxicity 602

II. Reproduction Toxicology 603III. Genotoxicity/Mutagenicity 603IV. Carcinogenicity 603V. Toxicokinetics 603

VI. Special Studies 603F. Common Toxicological Characteristics

of Glucosidase Inhibitors 604I. Reduced Glucose Utilization 605

II. Lysosomal Glycogen Storage 606III. Accumulation of Undigested Carbohydrates

in the Large Intestine , 607References 608

CHAPTER 21

Clinical Pharmacology of Glucosidase InhibitorsE. BRENDEL and W. WINGENDER. With 4 Figures 611

A. Acarbose 611I. Introduction 611

II. Pharmacodynamics 6111. Effects on Blood Sugar and Insulin 6112. Effects on Gastrointestinal Hormones

and Exocrine Pancreatic Function 6133. Effects on Lipids and Lipoproteins 614

III. Pharmacokinetics 614IV. Safety and Tolerability 616V. Interactions 617

B. Deoxynojirimycin Derivatives (Miglitol, Emiglitate) 618I. Introduction 618

II. Pharmacodynamics 6191. Effect on Blood Sugar and Insulin 6192. Effects on Gastrointestinal Hormones 6233. Effects on Lipids 623

III. Pharmacokinetics 624IV. Safety and Tolerability 625

XXX , Contents

V. Interactions 626C. Other Glucosidase Inhibitors 626

I. Introduction 626II. Pharmacodynamics 626

References 628

CHAPTER 22

Clinical Evaluation of Glucosidase InhibitorsR.H. TAYLOR and E.M. BARDOLPH 633

A. Introduction 633I. Carbohydrate Digestion 633

II. Diet and Glucosidase Inhibitors 634III. Role of Glucosidase Inhibitors in Diabetes 635

B. Acarbose 635I. Studies in Type I Diabetes 636

II. Studies in Type II Diabetes 6371. Clinical Trials 6372. Effect on Lipids 6383. Studies Comparing Effects with Other Antidiabetic

Agents 639III. Other Clinical Studies 641

C. Deoxynojirimycin Derivatives 641I. Studies in Type I Diabetes 642

II. Studies in Type II Diabetes 643D. Other Glucosidase Inhibitors 644E. Conclusions 645References 646

CHAPTER 23

Oral Antidiabetic Drugs in Research and DevelopmentH. BISCHOFF and H.E. LEBOVITZ. With 11 Figures 651

A. Introduction 651B. Stimulation and Modulation of Insulin Secretion 652

I. Depolarization of the B-Cell Membrane 6531. Inhibitors of the ATP-Sensitive K+ Channel 653

a) Sulfonylurea Derivatives 653b) Benzoic Acid Derivatives 655c) Guanidine Derivatives 656d) 2-Substituted Imidazoline Derivatives '. 657

2. Compounds with Uncertain Sites of Action 659II. a2-Adrenoceptor Antagonism 661

III. Ca2+ Channel Modulation 662

Contents , XXXI

C. Suppression of Hepatic Glucose Production 663I. Inhibition of Fatty Acid Oxidation 664

1. Inhibitors of Carnitine Acylcarnitine Translocase:Hydrazonopropionic Acid Derivatives 664a) Pharmacological Properties 665b) Effect on Gluconeogenesis and Mode of Action . . . 666c) Clinical Studies 668

2. Inhibitors of Carnitine Palmitoyltransferase I 668a) Pharmacology and Effects on Gluconeogenesis . . . . 668

a) 2-Oxirane Carboxylic Acid Derivatives 668P) Dioxolane Derivative 670y) B-Aminobetaine Structures 670

b) Pharmacokinetics and Toxicology 671c) Clinical Studies 672

D. Enhancement of Insulin Action 673E. Mimicking of Insulin Action 678F. Prevention of Deleterious Effects Caused by Glucose 680

I. Aldose Reductase Inhibitors 681II. Aminoguanidine: An Inhibitor of Advanced Glycation

End Product Formation 684References 685

CHAPTER 24

New Approaches for the Treatment of Diabetes MellitusJ.M. AMATRUDA and M.L: MCCALEB 697

A. Prevention 697I. Non-Insulin-Dependent Diabetes Mellitus 697

II. Insulin-Dependent Diabetes Mellitus 698B. Obesity 700

I. Central Mechanisms 701II. Peripheral Mechanisms 703

1. Increased Energy Expenditure 7032. Decreased Fat Absorption 704

C. Insulin Sensitizers 704I. Rationale 704

II. Specific Targets 705III. Amylin and Amylin Blockers 706

D. Alternative Insulin Delivery 707E. Gene Therapy 709References 710

Subject Index 715