Preface XIII 1 General Aspects 3 1.1 History 5 1.1.1 From Willow Bark to Salicylic Acid 5 1.1.1.1 Anti-Inflammatory and Analgesic Effects of Willow Bark and Leaves 5 1.1.

1.2 Salicylates as the Active Ingredients of Willow Bark and Other Natural Sources 6 1.1.1.3 Chemical Synthesis of Salicylic Acid 6 Summary 8 References 8 1.1.2 Synthesis of Acetylated Salicylic Acid and First Medical Use 9 1.1.

2.1 The Invention of Acetylated Salicylic Acid 9 1.1.2.2 Introduction of Acetylsalicylic Acid into the Clinics 15 Summary 16 References 16 1.1.3 Search for Pharmacological Modes of Action 18 1.1.

3.1 Salicylates and Energy Metabolism of the Cell 18 1.1.3.2 Aspirin and Prostaglandin Formation 19 1.1.3.3 Aspirin and COX-2 21 Summary 23 References 23 1.

1.4 Clinical Applications: A Piece of History 25 1.1.4.1 Anti-Inflammatory/Analgesic Actions 25 1.1.4.2 Antiplatelet/Antithrombotic Actions and the Bleeding Tendency 26 1.

1.4.3 Aspirin and the History of Prevention of Myocardial Infarction and Stroke 27 Summary 30 References 30 1.1.5 Current Research Topics 32 1.1.5.1 Clinical Research 32 1.

1.5.2 Basic Research 33 Summary 39 References 39 1.2 Chemistry 41 1.2.1 Structures and Chemical Properties of Salicylates 41 1.2.1.

1 Salicin: The Natural Salicylate 41 1.2.1.2 Salicylates in Clinical Use 41 1.2.1.3 Aspirin Formulations 43 Summary 45 References 46 1.2.

2 Determination of Salicylates 47 1.2.2.1 Gas-Liquid Chromatography 47 1.2.2.2 High-Performance Liquid Chromatography 47 1.2.

2.3 Spectrophotometry 47 Summary 49 References 49 2 Pharmacology 51 2.1 Pharmacokinetics 54 2.1.1 Absorption and Distribution 54 2.1.1.1 Absorption and Bioavailability 54 2.

1.1.2 Aspirin Formulations 57 2.1.1.3 Distribution and Plasma Levels 60 2.1.1.

4 Modifying Factors 62 Summary 63 References 64 2.1.2 Biotransformation and Excretion 66 2.1.2.1 Aspirin Esterases 66 2.1.2.

2 Biotransformations of Salicylic Acid 70 2.1.2.3 Excretion of Salicylates 71 Summary 72 References 72 2.2 Cellular Modes of Action 75 2.2.1 Inhibition of Cyclooxygenases 76 2.2.

1.1 COX-Isoforms, Substrates, and Regulation 76 2.2.1.2 Inhibition/Modulation of Cyclooxygenases by Aspirin 78 2.2.1.3 The Different Pharmacology of Aspirin and NSAIDs 82 2.

2.1.4 Modulation of COX-2 Gene Expression 84 2.2.1.5 Further Actions of Salicylates on Lipid Mediators 85 Summary 85 References 86 2.2.2 COX-Independent Actions of Aspirin on Cell Function 89 2.

2.2.1 Salicylates in the Plant Kingdom 89 2.2.2.2 Transacetylation Actions by Aspirin 89 2.2.2.

3 Aspirin and Nitric Oxide Formation 91 2.2.2.4 Salicylates and Kinases 92 2.2.2.5 Salicylates and Transcription Factors 96 Summary 98 References 99 2.2.

3 Energy Metabolism 101 2.2.3.1 Different Pharmacodynamics of Aspirin and Salicylates 101 2.2.3.2 Fatty Acid β-Oxidation 102 2.2.

3.3 Uncoupling of Oxidative Phosphorylation 106 2.2.3.4 Metabolic Actions of Salicylates and Reye''s Syndrome 108 Summary 109 References 110 2.3 Actions on Organs and Tissues 113 2.3.1 Hemostasis and Thrombosis 113 2.

3.1.1 General Aspects 113 2.3.1.2 Platelets 115 2.3.1.

3 Endothelial Cells 123 2.3.1.4 Plasmatic Coagulation 128 2.3.1.5 Fibrinolysis 128 Summary 129 References 130 2.3.

2 Inflammation, Pain, and Fever 136 2.3.2.1 General Aspects 136 2.3.2.2 Inflammation 137 2.3.

2.3 Pain 142 2.3.2.4 Fever 147 Summary 149 References 150 2.3.3 Aspirin and Malignancies 153 2.3.

3.1 General Aspects 153 2.3.3.2 Pathophysiology 154 2.3.3.3 Modes of Aspirin Action 156 2.

3.3.4 COX-Related Actions of Aspirin 157 2.3.3.5 Non-COX-Related Antitumor Actions of Aspirin 160 Summary 162 References 162 Contents VII 3 Toxicity and Drug Safety 167 3.1 Systemic Side Effects 170 3.1.

1 Acute and Chronic Toxicity 170 3.1.1.1 General Aspects 170 3.1.1.2 Pathophysiology and Clinical Symptoms of Acute Overdosing 172 3.1.

1.3 Treatment 175 3.1.1.4 Habituation 177 Summary 177 References 178 3.1.2 Bleeding Time and Bleeding Risk 180 3.1.

2.1 Aspirin and Bleeding Time 180 3.1.2.2 Mode of Aspirin Action 181 3.1.2.3 Aspirin-Related Bleeding Risk in Long-Term Prevention and Acute Surgical Interventions 184 3.

1.2.4 Prevention and Treatment of Bleedings 186 Summary 187 References 188 3.1.3 Safety Pharmacology in Particular Life Situations 191 3.1.3.1 Pregnancy and Fetal Development 191 3.

1.3.2 The Elderly Patient 193 Summary 195 References 195 3.2 Organ Toxicity 198 3.2.1 Gastrointestinal (GI) Tract 198 3.2.1.

1 General Aspects 198 3.2.1.2 Pathophysiology of Aspirin-Induced GI Injury 199 3.2.1.3 Mode of Aspirin Action 201 3.2.

1.4 Clinical Studies 205 3.2.1.5 Aspirin and Other Drugs 209 Summary 211 References 211 3.2.2 Liver 216 3.2.

2.1 General Aspects 216 3.2.2.2 Pathophysiology and Mode of Aspirin Action 216 3.2.2.3 Clinical Studies 217 Summary 217 References 218 3.

2.3 Kidney 219 3.2.3.1 General Aspects 219 3.2.3.2 Analgesic Nephropathy and its Pathophysiology 219 3.

2.3.3 Mode of Aspirin Action 220 3.2.3.4 Clinical Studies - Individuals without Kidney Diseases 221 3.2.3.

5 Clinical Studies - Individuals with Preexisting Kidney Diseases 223 Summary 225 References 226 3.2.4 Audiovestibular System 228 3.2.4.1 General Aspects 228 3.2.4.

2 Pathophysiology of Aspirin-Induced Hearing Loss and Tinnitus 228 3.2.4.3 Mode of Aspirin Action 228 3.2.4.4 Clinical Studies 230 Summary 231 References 231 3.3 Hypersensitivity to Aspirin and Reye''s Syndrome 233 3.

3.1 Aspirin-Exacerbated Respiratory Disease (AERD, "Aspirin-Induced Asthma") 233 3.3.1.1 History, Epidemiology, and Pathophysiology 233 3.3.1.2 Mode of Aspirin Action 237 3.

3.1.3 Clinical Studies 239 3.3.1.4 Aspirin and Other Drugs 240 Summary 240 References 241 3.3.2 Urticaria/Angioedema and Stevens-Johnson and Lyell''s Syndrome 244 3.

3.2.1 Urticaria/Angioedema 244 3.3.2.2 Stevens-Johnson Syndrome and Lyell''s Syndrome 245 Summary 245 References 245 3.3.3 Reye''s Syndrome 247 3.

3.3.1 Clinics, Laboratory and Morphological Findings 248 3.3.3.2 Etiology and Pathogenesis 249 3.3.3.

3 Clinical Studies 252 3.3.3.4 Actual Situation 256 Summary 258 References 259 4 Clinical Applications of Aspirin 263 4.1 Thromboembolic Diseases 268 4.1.1 Coronary Vascular Disease 269 4.1.

1.1 General Aspects 269 4.1.1.2 Thrombotic Risk and Mode of Aspirin Action 271 4.1.1.3 Clinical Trials: Primary Prevention in Apparently Healthy Individuals 275 4.

1.1.4 Clinical Trials: Primary Prevention in Individuals with Vascular Risk Factors 279 4.1.1.5 Clinical Trials: Cardiovascular Prevention in Patients with Stable Angina 284 4.1.1.

6 Clinical Trials: Acute Coronary Syndromes (ACS) 285 4.1.1.7 Clinical Trials: Long-Term Secondary Prevention 288 4.1.1.8 Clinical Trials: Coronary Artery Bypass Graft Surgery (CABG) and Other Surgical Interventions 291 4.1.

1.9 Aspirin and Other Drugs 292 4.1.1.10 Actual Situation 297 Summary 298 References 299 4.1.2 Cerebrovascular Diseases 307 4.1.

2.1 General Aspects 307 4.1.2.2 Thrombotic Risk and Mode of Aspirin Action 308 4.1.2.3 Clinical Trials: Primary Prevention 312 4.

1.2.4 Clinical Trials: Secondary Prevention 314 4.1.2.5 Aspirin and Other Drugs 318 4.1.2.

6 Actual Situation 323 Summary 324 References 325 4.1.3 Peripheral Arterial Disease 330 4.1.3.1 General Aspects 330 4.1.3.

2 Thrombotic Risk and Mode of Aspirin Action 330 4.1.3.3 Clinical Trials: Primary Prevention 332 4.1.3.4 Clinical Trials: Secondary Prevention 334 4.1.

3.5 Clinical Trials: Peripheral Transluminal Angioplasty (PTA) and Surgical Interventions 336 4.1.3.6 Aspirin and Other Drugs 337 4.1.3.7 Actual Situation 339 Summary 339 References 339 4.

1.4 Venous Thrombosis 343 4.1.4.1 General Aspects 343 4.1.4.2 Thrombotic Risk and Mode of Aspirin Action 343 4.

1.4.3 Clinical Trials: Primary Prevention 344 4.1.4.4 Clinical Trials: Secondary Prevention 348 4.1.4.

5 Aspirin and Other Drugs 350 4.1.4.6 Actual Status 350 Summary 351 References 351 4.1.5 Preeclampsia 354 4.1.5.

1 General Aspects 354 4.1.5.2 Thrombotic Risk and Mode of Aspirin Action 354 4.1.5.3 Clinical Trials: Early Studies 358 4.1.

5.4 Clinical Trials: Reasons for Data Variability 359 4.1.5.5 Actual Situation 363 Summary 364 References 365 4.1.6 Aspirin "Resistance" (High On-Aspirin Treatment Platelet Reactivity) 369 4.1.

6.1 General Aspects 369 4.1.6.2 Definition and Types of Pharmacological Aspirin "Resistance" (HTPR) 370 4.1.6.3 Detection of Aspirin "Resistance" and Possible Pitfalls in Its Determination 371 4.

1.6.4 Phen.