Table of Contents
Preface XI
1 General Aspects 3
1.1 History 5
1.1.1 Willow Bark and Leaves as Antipyretic, Anti-Inflammatory Analgesics 5
1.1.2 Salicylates as the Active Ingredient of Willow Bark and Other Natural Sources 6
1.1.3 Synthesis of Acetylsalicylic Acid and First Clinical Studies 7
1.1.4 Mode of Aspirin Action 12
1.1.5 Anti-Inflammatory/Analgesic Actions of Aspirin 14
1.1.6 Aspirin in the Cardiovascular System 15
1.1.7 Current Research Topics 17
1.2 Chemistry 25
1.2.1 Structures and Chemical Properties of Salicylates 25
1.2.1.1 Salicylates in Clinical Use 25
1.2.1.2 Aspirin Formulations 27
1.2.2 Determination of Salicylates 30
1.2.2.1 Gas-Liquid Chromatography 30
1.2.2.2 High-Performance Liquid Chromatography 30
1.2.2.3 Spectrophotometry 30
2 Pharmacology 33
2.1 Pharmacokinetics 35
2.1.1 Absorption and Distribution 36
2.1.1.1 Absorption 36
2.1.1.2 Particular Aspirin Formulations 40
2.1.1.3 Distribution 40
2.1.1.4 Modifying Factors 42
2.1.2 Biotransformation and Excretion 46
2.1.2.1 Biotransformation of Aspirin 46
2.1.2.2 Biotransformations of Salicylic Acid 48
2.1.2.3 Excretion of Salicylates 49
2.1.2.4 Modification of Biotransformations and Excretion of Salicylates 50
2.2 Cellular Modes of Action 53
2.2.1 Inhibition of Cyclooxygenases 54
2.2.1.1 Acetylation of Cyclooxygenases and Traditional NSAIDs 55
2.2.1.2 Modulation of COX-2 Gene Expression 61
2.2.1.3 Further Actions of Salicylates on Arachidonate Metabolism 62
2.2.2 COX-Independent Actions on Cell Function 66
2.2.2.1 Kinases 67
2.2.2.2 Transcription Factors 69
2.2.2.3 Oxidative Stress and Nitric Oxide 73
2.2.2.4 Immune Responses 75
2.2.3 Energy Metabolism79
2.2.3.1 Fatty Acid β-Oxidation 80
2.2.3.2 Uncoupling of Oxidative Phosphorylation 82
2.2.3.3 Toxic Actions of Salicylates on the Liver 84
2.3 Actions on Organs and Tissues 88
2.3.1 Hemostasis and Thrombosis 89
2.3.1.1 Platelets 90
2.3.1.2 Endothelial Cells 95
2.3.1.3 Plasmatic Coagulation 98
2.3.1.4 Fibrinolysis 98
2.3.2 Inflammation, Pain, and Fever 105
2.3.2.1 Inflammation 106
2.3.2.2 Pain 110
2.3.2.3 Fever 113
2.3.3 Aspirin and Malignancies 120
2.3.3.1 COX-Related Antitumor Effects of Aspirin 120
2.3.3.2 Nonprostaglandin-Related Antitumor Actions of Aspirin 122
2.3.3.3 Nonspecific Actions of Salicylates 124
3 Toxicity and Drug Safety 129
3.1 Systemic Side Effects 131
3.1.1 Acute and Chronic Toxicity 132
3.1.1.1 Occurrence and Symptoms 132
3.1.1.2 Treatment 136
3.1.1.3 Habituation 139
3.1.2 Bleeding Disorders 142
3.1.2.1 Prolongation of Bleeding Time by Aspirin 142
3.1.2.2 Aspirin-Related Bleeding Risk in Surgical Interventions 144
3.1.2.3 Aspirin, Other Drugs, and Alcohol 146
3.1.2.4 Prevention and Treatment of Bleedings 146
3.1.3 Safety Pharmacology in Particular Life Situations 150
3.1.3.1 Pregnancy and Fetal Development 150
3.1.3.2 The Elderly Patient 153
3.2 Organ Toxicity 157
3.2.1 Gastrointestinal Tract 157
3.2.1.1 Pathophysiology of GI Injury 158
3.2.1.2 Prostaglandins and Gastric Mucosal Protection 160
3.2.1.3 Mode of Aspirin Action 161
3.2.1.4 Helicobacter pylori 164
3.2.1.5 Clinical Studies 166
3.2.1.6 Aspirin and Other Drugs 170
3.2.2 Kidney 179
3.2.2.1 Analgesic Nephropathy 179
3.2.2.2 Mode of Aspirin Action 180
3.2.2.3 Clinical Studies 181
3.2.3 Liver 187
3.2.3.1 Drug-Induced Liver Injury 187
3.2.3.2 Mechanisms of Aspirin Action 187
3.2.3.3 Aspirin and Other Drugs 188
3.2.4 Audiovestibular System 191
3.2.4.1 Pathophysiology of Hearing and Equilibrium Disturbances 191
3.2.4.2 Mode of Aspirin Action 191
3.2.4.3 Aspirin, Arachidonic Acid, and Prostaglandins 193
3.2.4.4 Clinical Trials 193
3.3 Non-Dose-Related (Pseudo)allergic Actions of Aspirin 197
3.3.1 Aspirin Hypersensitivity (Widal's Syndrome) 197
3.3.1.1 Pathophysiology and Clinics 197
3.3.1.2 Mode of Aspirin Action 199
3.3.1.3 Clinical Trials 201
3.3.2 Urticaria/Angioedema, Stevens-Johnson and Lyell Syndromes 205
3.3.2.1 Urticaria/Angioedema 205
3.3.2.2 Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (Lyell Syndrome) 206
3.3.3 Reye's Syndrome 208
3.3.3.1 Clinics, Laboratory, and Morphological Findings 209
3.3.3.2 Etiology 209
3.3.3.3 Clinical Studies 212
3.3.3.4 Actual Situation 217
4 Clinical Applications of Aspirin 223
4.1 Thromboembolic Diseases 227
4.1.1 Coronary Vascular Disease 228
4.1.1.1 Thrombotic Risk and Mode of Aspirin Action 229
4.1.1.2 Clinical Trials: Primary Prevention in Individuals Without Risk Factors 231
4.1.1.3 Clinical Trials: Primary Prevention in Individuals with Risk Factors 235
4.1.1.4 Clinical Trials: Stable Angina Pectoris 237
4.1.1.5 Clinical Trials: Secondary Prevention 238
4.1.1.6 Clinical Trials: Percutaneous Coronary Interventions 243
4.1.1.7 Clinical Trials: Coronary Artery Bypass Graft Surgery (CABG) 244
4.1.1.8 Aspirin and Other Drugs 246
4.1.1.9 Actual Situation 250
4.1.2 Cerebrovascular Diseases 260
4.1.2.1 Thrombotic Risk and Mode of Aspirin Action 261
4.1.2.2 Clinical Trials: Primary Prevention 263
4.1.2.3 Clinical Trials: Secondary Prevention 265
4.1.2.4 Aspirin and Other Drugs 267
4.1.2.5 Actual Situation 270
4.1.3 Peripheral Arterial Disease 276
4.1.3.1 Thrombotic Risk and Mode of Aspirin Action 276
4.1.3.2 Clinical Trials: Primary Prevention 278
4.1.3.3 Clinical Trials: Secondary Prevention 279
4.1.3.4 Clinical Trials: Peripheral Transluminal Angioplasty (PTA) 281
4.1.3.5 Aspirin and Other Drugs 282
4.1.3.6 Actual Situation 283
4.1.4 Venous Thrombosis 287
4.1.4.1 Thrombotic Risk and Mode of Aspirin Action 287
4.1.4.2 Clinical Trials 287
4.1.4.3 Actual Situation 288
4.1.5 Preeclampsia 290
4.1.5.1 Thrombotic Risk and Mode of Aspirin Action 290
4.1.5.2 Clinical Trials 293
4.1.5.3 Clinical Trials in Pregnancy-Induced Hypertension: Reasons for Data Variability 294
4.1.5.4 Actual Situation 298
4.1.6 Aspirin "Resistance" 303
4.1.6.1 Definition and Types of Pharmacological Aspirin "Resistance" 304
4.1.6.2 Detection of Aspirin "Resistance" 304
4.1.6.3 Pharmacological Mechanisms of Aspirin "Resistance" 307
4.1.6.4 Clinical Trials 310
4.2 Pain, Fever, and Inflammatory Diseases 322
4.2.1 Aspirin as an Antipyretic Analgesic 322
4.2.1.1 Fever, Pain, and Antipyretic/Analgesic Actions of Aspirin 323
4.2.1.2 Clinical Trials 326
4.2.1.3 Aspirin and Other Drugs 327
4.2.1.4 Actual Situation 328
4.2.2 Arthritis and Rheumatism 332
4.2.2.1 Pathophysiology and Mode of Aspirin Action 332
4.2.2.2 Clinical Trials 334
4.2.2.3 Aspirin and Other Drugs 335
4.2.2.4 Actual Situation 336
4.2.3 Kawasaki Disease 339
4.2.3.1 Pathophysiology and Mode of Aspirin Action 339
4.2.3.2 Clinical Trials 340
4.2.3.3 Aspirin and Other Drugs 341
4.2.3.4 Actual Situation 341
4.3 Further Clinical Indications 343
4.3.1 Colorectal Cancer 343
4.3.1.1 Etiology and Pathophysiology of Intestinal Adenomas, Colorectal Cancer, and Mode of Aspirin Action 344
4.3.1.2 Clinical Trials: Epidemiological Studies 346
4.3.1.3 Clinical Trials: Randomized Prospective Prevention Trials 349
4.3.1.4 Aspirin and Other Drugs 352
4.3.1.5 Actual Situation 352
4.3.2 Alzheimer's Disease 359
4.3.2.1 Pathophysiology and Mode of Aspirin Action 359
4.3.2.2 Clinical Trials 361
4.3.2.3 Aspirin and Other Drugs 363
4.3.2.4 Actual Situation 363
Appendix A 367
Appendix B 369
Index 371
