Ibuprofen: Discovery, Development & Therapeutics

Ibuprofen: Discovery, Development & Therapeutics

By: Kim D. Rainsford (editor)Hardback

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Description

Ibuprofen has become one of the foremost pain-relieving medications world-wide with its proven safety and efficacy in a wide variety of painful and inflammatory conditions. It has also been widely investigated for application in a variety of painful and non-pain inflammatory states including cancer and neurodegenerative conditions, reflecting the unique and novel properties of the drug that would never have been foreseen from knowledge of the properties when it was initially discovered. * Edited by leading world expert with over 40 years record in research, teaching and as a scientific advisor in the field of anti-inflammatory/analgesic agents. Professor Kim Rainsford is also the founding Editor-in-Chief of the journal, Inflammopharmacology, as well as being an Associate Editor of The Journal of Pharmacy & Pharmacology. * Provides a thorough coverage of the medicinal chemistry and pharmaceutics of ibuprofen, and its pharmacokinetics in both humans and animals. * Includes molecular, pharmacological and toxicological studies, and discusses the safety and efficacy of non-prescription ibuprofen, including its side effects. Ibuprofen: Discovery, Development & Therapeutics provides a definitive reference on all the main aspects of the chemical and pharmaceutical properties, mechanisms of action and therapeutic uses of ibuprofen including its role in the prevention and treatment of rheumatic conditions, cancer and neurodegenerative conditions such as Alzheimer s and Parkinson s diseases. The book has its origins in a volume first published in 1999, since when there have been considerable advances in research and clinical studies on ibuprofen in the treatment of many inflammatory and even non-inflammatory states. This book will prove invaluable to scientists, clinicians, pharmacists and all those who need to know about the actions and uses of anti-inflammatory and analgesic drugs.

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Contents

List of Contributors xiii Preface xv 1 History and Development of Ibuprofen 1 Kim D. Rainsford Summary 1 1.1 Introduction 1 1.2 Historical Background 5 1.3 Initial Stages 7 1.4 Compounds in Development 10 1.5 Ibufenac Almost There, but for Liver Toxicity 12 1.6 More Setbacks 12 1.7 More Learning 12 1.8 Ibuprofen 12 1.8.1 First Clinical Trials 12 1.8.2 Gastrointestinal Safety 14 1.9 Achievements and Rewards at Last 15 1.10 Ultimate Recognition of Safety OTC Status 17 1.11 Worldwide Developments 19 1.11.1 Evolving Applications of Ibuprofen 19 Acknowledgements 20 References 20 2 The Medicinal Chemistry of Ibuprofen 22 Kenneth J. Nichol and David W. Allen 2.1 Introduction 22 2.2 The Discovery of Ibuprofen 22 2.3 Synthetic Routes to Ibuprofen 27 2.4 Biological Activities of Ibuprofen Analogues 31 2.5 Metabolites of Ibuprofen 36 2.5.1 Metabolites and Enantiomer Inversion 36 2.5.2 Synthesis of Metabolites 37 2.6 Ibuprofen Enantiomers 38 2.7 Physicochemical Aspects 42 Acknowledgements 43 References 43 3 The Pharmaceutics of Ibuprofen 50 Fred Higton Summary 50 3.1 Physical and Chemical Characteristics of Ibuprofen 50 3.2 Products Available Worldwide 54 3.3 Solid Dose Presentations 54 3.3.1 Conventional Ibuprofen Tablets 56 3.3.2 In vitro/in vivo Testing 58 3.3.3 Sustained Release Preparations 60 3.3.4 Ibuprofen Fast Acting: Ibuprofen Salts and Derivatives 64 3.4 Liquids 67 3.5 Taste-Masking of Ibuprofen 67 3.6 Suppositories 69 3.7 Topical Presentations 70 3.8 Conclusion 72 References 72 4 The Pharmacokinetics of Ibuprofen in Humans and Animals 81 Fakhreddin Jamali and Dion R. Brocks Summary 81 4.1 Absorption 82 4.2 Distribution 83 4.2.1 Protein Binding 83 4.2.2 Tissue Distribution 88 4.3 Clearance 92 4.3.1 Metabolism of Ibuprofen 93 4.3.2 Excretion of Ibuprofen 104 4.4 Interspecies Differences in Pharmacokinetics of (R)- and (S)-Ibuprofen 105 4.5 Relationship between Effect and Plasma Concentrations 106 4.5.1 Therapeutic Effects 106 4.5.2 Toxic Effects 107 4.6 Pharmacokinetics in Special Populations 108 4.6.1 Pharmacokinetics and Analgesic Effects in Patients in Pain 108 4.6.2 Febrile Children and Infants 114 4.6.3 Postoperative Paediatric Patients 115 4.6.4 Premature Infants 115 4.6.5 Juvenile Arthritis 116 4.6.6 Children with Cystic Fibrosis 116 4.6.7 Elderly Adults 117 4.6.8 Rheumatic Disease 117 4.6.9 Renal Insufficiency 118 4.6.10 Hepatic Disease 119 4.6.11 Burn Patients 119 4.6.12 Effect of Gender and Race 119 4.6.13 Effect of Operational Stessors 120 4.7 Drug Interactions 120 4.7.1 Anti-ulcer Medications 120 4.7.2 Zidovudine 121 4.7.3 Codeine and Oxycodone 121 4.7.4 Anti-hyperlipidemic Drugs 121 4.7.5 Oral Contraceptive Steroids 122 4.7.6 Self-interaction; Enantiomer Enantiomer Interaction 123 4.7.7 Effect of Ibuprofen on the Pharmacokinetics of Other Drugs 123 4.7.8 Other Drugs 123 References 124 5 Pharmacology and Toxicology of Ibuprofen 132 Kim D. Rainsford Summary 132 5.1 Introduction 133 5.2 Basic Pharmacology and Toxicology 134 5.2.1 The Relevance of Data from Animal Models to the Clinical Situation in Humans 134 5.2.2 Acute Anti-inflammatory Activity 136 5.2.3 Chronic Anti-inflammatory Activity 141 5.2.4 Analgesic Activity 143 5.2.5 Antipyretic Activity 149 5.2.6 General Toxicology 149 5.2.7 Effects on Prostaglandin Production Related to Pharmacological Activities 164 5.2.8 Effects on Leukotriene Production 180 5.2.9 Smooth Muscle Contractility 181 5.2.10 Effects on Nitric Oxide Production 181 5.2.11 Leucocytes and Vascular Permeability 182 5.2.12 Leukocyte Functions 188 5.2.13 Immune Functions 191 5.2.14 Effects on Articular Joint Integrity 192 5.2.15 Miscellaneous Biochemical and Cellular Actions 194 5.3 Experimental Therapeutics 196 5.3.1 Endotoxin Shock 196 5.3.2 Acute Lung Injury Induced by Exposure to Chemicals 198 5.3.3 Acute Myocardial Injury and Coronary Functions 199 5.3.4 Cerebral Injury 201 5.3.5 Tourniquet Shock Ischemia 202 5.3.6 Transcutaneous Hypoxia 202 5.3.7 Cytokines and Surgical Stress 203 5.3.8 Pleurisy from Delayed Hypersensitivity Reaction 203 5.3.9 Abdominal Adhesions 203 5.3.10 Uveitis 204 5.4 Clinical Pharmacology and Toxicology 204 5.4.1 Experimental Inflammation 204 5.4.2 Experimental Pain 205 5.4.3 Effects on Platelet Aggregation and Thrombosis 206 5.4.4 Gastrointestinal Injury and Bleeding 208 5.4.5 Hypersensitivity and Other Immunological Reactions 210 5.4.6 Gynaecological and Obstetric Uses 211 5.4.7 Effects on Lung Inflammation in Cystic Fibrosis 212 5.4.8 Malignant Conditions 212 5.4.9 Prevention of Cataract 213 5.5 Conclusions 214 References 214 6 Therapeutics of Ibuprofen in Rheumatic and Other Chronic and Painful Diseases 237 Walter F. Kean, Kim D. Rainsford and the late William W. Buchanan Summary 237 6.1 Introduction 238 6.2 Overview of Clinical Pharmacology 239 6.2.1 Pharmacokinetics Relevant to Therapy of Inflammatory Diseases and Pain 240 6.2.2 Anti-inflammatory and Analgesic Activities 245 6.2.3 Criteria for Determining Therapeutic Responses 247 6.3 NSAID-Related Adverse Drug Reactions and Toxicity 248 6.3.1 Gastrointestinal Side-Effects 248 6.3.2 Cardiovascular Reactions 251 6.3.3 Hepatic Reactions 251 6.3.4 Renal Adverse Reactions 251 6.3.5 Miscellaneous Reactions 253 6.4 Rheumatoid Arthritis 254 6.4.1 Early Studies at Low Doses 255 6.4.2 Later Higher ]Dose Studies 257 6.5 Juvenile Idiopathic (Rheumatoid) Arthritis 261 6.6 Primary and Secondary Osteoarthritis 262 6.6.1 Acceleration of Cartilage and Bone Destruction 272 6.6.2 Therapeutic Aspects 273 6.6.3 Comparisons with Coxibs 274 6.7 Formulations 276 6.8 Variability in Response 276 6.9 Relation of Drug Kinetics to Clinical Response 277 6.10 Low Back Pain 278 6.11 Shoulder Pain 279 6.12 Reactive Arthritis (Reiter s Syndrome) 280 6.13 Psoriatic Arthritis 280 6.14 Ankylosing Spondylitis 280 6.15 Gout 280 6.16 Fibromyalgia 281 6.17 Haemophiliac Arthritis 281 6.18 Postoperative Pain 281 6.19 Sports Injuries 282 6.20 Other Painful States 283 6.21 Cancer 284 6.22 Potential Non ]analgesic Usage 285 6.23 The Elderly 285 6.24 Dexibuprofen 286 6.25 Conclusions 286 References 287 7 Safety and Efficacy of Non-prescription, Over-the ]Counter (OTC) Ibuprofen 313 Kim D. Rainsford Summary 313 7.1 Introduction 313 7.2 Analysis of Clinical Trials 315 7.2.1 Studies in Prospective Clinical Trials 317 7.3 Epidemiological Studies and Case Reports 327 7.4 Considerations for Special Groups 330 7.4.1 Use of Drugs in the Elderly 330 7.4.2 Safety in Pregnancy and Lactation 331 7.4.3 Uses and Safety in Sport and Exercise 334 7.5 Conclusions 336 References 336 8 Use of Ibuprofen in Dentistry 346 Raymond A. Dionne, Sharon M. Gordon and Stephen A. Cooper Summary 346 8.1 Introduction 346 8.2 Analgesia 347 8.2.1 Preventive Analgesia 348 8.2.2 Analgesic Activity of Ibuprofen Isomers 349 8.2.3 Ibuprofen-Containing Combinations 350 8.2.4 Ibuprofen Formulations 354 8.3 Effects on Oedema 355 8.4 Interactions with Plasma -Endorphin 356 8.5 Use for Chronic Temporomandibular Pain 356 8.6 Recommendations for the Use of Ibuprofen in Dentistry 358 References 359 9 Gastrointestinal Adverse Reactions from Ibuprofen 363 Kim D. Rainsford and Ingvar Bjarnason Summary 363 9.1 Background and Introduction 364 9.2 Current Status Concerning NSAID Ulceration 365 9.2.1 Morbidity and Mortality 366 9.3 Occurrence of Ulcers and Complications 369 9.3.1 Epidemiological Studies 369 9.3.2 Large-Scale Mega Trials 376 9.4 Clinical Investigations on Comparative GI Effects of Ibuprofen 378 9.4.1 Early Symptom-Based Studies in GI ]Intolerant Subjects 378 9.4.2 Procedures for Assessing GI Injury 379 9.4.3 Upper GI Endoscopy 380 9.4.4 NSAID-Enteropathy: Capsule and Device Assisted Intestinal Endoscopy and Other Techniques 381 9.4.5 Radiochromium [51Cr]-Labelled Red Cell GI Blood Loss 389 9.4.6 Intragastric and Occult Blood Loss and Reduced Haemoglobin 394 9.5 Clinically-Relevant Pathogenesis of NSAID-Associated GI Injury 395 9.5.1 Factors Affecting NSAID-Induced Gastroduodenal Injury 395 9.5.2 Influence of Gastric Acidity 397 9.5.3 Physicochemical Associations, Topical versus Systemic Actions of NSAIDs, Cyclo ]oxygenases and Reduced Prostanoids 399 9.5.4 Effects of NSAIDs on Gastric pH and Acid Secretion 402 9.6 Procedures for Reducing GI Symptoms 404 9.6.1 Ibuprofen Formulations 404 9.6.2 Effects of Food or Drinks 406 9.6.3 Mucus Protection Strategies 409 9.6.4 Anti-ulcer Agents 410 9.7 Overall Assessment of GI Safety of Ibuprofen 412 References 412 10 Hepatorenal Effects of Ibuprofen Compared with other NSAIDs and Paracetamol 432 Kim D. Rainsford 10.1 Introduction 432 10.2 Hepatorenal Syndromes 433 10.3 NSAID, Analgesic and DMARD-Induced Liver Injury 433 10.3.1 Historical Associations of NSAIDs with Liver Toxicity 433 10.3.2 Awareness of Liver Reactions with Modern NSAIDs 434 10.3.3 Simultaneous Use of Potentially Hepatotoxic Medications 439 10.4 Renal Adverse Reactions Form NSAIDs and Analgesics 442 10.4.1 Renal Adverse Reactions from Ibuprofen 444 10.5 Conclusions 446 References 446 11 Adverse Drug Reactions Attributed to Ibuprofen: Effects Other Than Gastrointestinal 452 L.J. Miwa, M. Manenos and Judith K. Jones 11.1 Introduction 452 11.2 Allergy and Hypersensitivity 453 11.2.1 Points to Consider when Evaluating Allergy-Type Reactions to NSAIDs 453 11.2.2 Epidemiology of Allergy or Hypersensitivity with NSAIDs 454 11.3 Adverse Dermatological Effects 457 11.4 Hepatotoxicity 458 11.5 Haematological Adverse Effects 465 11.5.1 Neutropenia, agranulocytosis and aplastic anaemia 465 11.5.2 Other Blood Disorders 466 11.6 Renal Adverse Effects 466 11.7 Cardiovascular Adverse Effects 470 11.8 Adverse Effects on Reproduction 477 11.8.1 Animal Studies of Teratogenic and Reproductive Effects 477 11.8.2 Reports of Teratogenic Effects in Humans 478 11.8.3 Perinatal Adverse Effects Associated with Therapeutic Use 479 11.8.4 Other Reproductive Effects 480 11.9 Endocrine and Metabolic Adverse Effects 480 11.10 Central Nervous System Effects 480 11.10.1 General CNS Effects 480 11.10.2 Aseptic Meningitis 481 11.10.3 Cognitive Dysfunction 481 11.10.4 Psychiatric Adverse Effects 481 11.11 Ocular Adverse Effects 481 11.12 Infection-Related Adverse Event 482 11.13 Drug Interactions 482 11.13.1 NSAID Anti-hypertensive Interactions 483 11.13.2 NSAID Diuretic Interactions 484 11.13.3 NSAID -Adrenergic Blocker Interactions 484 11.13.4 NSAID Angiotensin-Converting Enzyme Inhibitor Interactions 484 11.13.5 NSAID Oral Anti-coagulant Interactions 484 11.13.6 NSAID Aminoglycoside Interactions 485 11.13.7 NSAID Oral Hypoglycemic Interactions 485 11.13.8 NSAID Cyclosporin Interactions 485 11.13.9 NSAID Lithium Interactions 485 11.13.10 NSAID Methotrexate Interactions 485 11.13.11 Ibuprofen Aspirin Interactions 486 11.14 Future Needs 486 References 487 12 Human Toxicity of Ibuprofen 500 Glyn Volans Summary 500 12.1 Introduction 500 12.2 Mechanism of Toxicity in Overdosage 501 12.3 Epidemiological Reviews of the Effects of Ibuprofen in Overdosage 501 12.4 Reports of Deaths after Ibuprofen Overdose 502 12.5 Dose Response and Toxicokinetics 502 12.6 Gastrointestinal Effects 508 12.7 Renal Effects 509 12.7.1 Cases of Massive Overdose 509 12.7.2 Cases Affected by Additional Factors 509 12.8 Metabolic Effects 510 12.9 Central Nervous System (CNS) Effects 511 12.10 Cardiovascular Effects 511 12.11 Respiratory Effects 512 12.12 Haematological Effects 512 12.13 Skin Reactions 512 12.14 Ibuprofen Toxicity in Children 512 12.15 Ibuprofen in Pregnancy and Breast Feeding 513 12.16 Chronic Abuse of Ibuprofen 513 12.17 Conclusion 514 12.17.1 Management of Ibuprofen Overdosage 514 12.17.2 Continuing Surveillance 515 12.17.3 Comparative Human Toxicity Ibuprofen versus Other NSAIDs and Non ]opioid Analgesics 516 References 516 13 Ibuprofen in the Prevention and Therapy of Cancer 520 Randall E. Harris Summary 520 13.1 Introduction and Background 521 13.2 Ibuprofen, COX-1 and COX-2 522 13.3 COX-2 and the Inflammogenesis of Cancer 522 13.4 Preclinical Efficacy Studies of Ibuprofen and Cancer 523 13.4.1 Preclinical Efficacy Study of Ibuprofen Therapy for Breast Cancer 523 13.4.2 Preclinical Efficacy Study of Ibuprofen versus Retinoic Acid for the Prevention of Breast Cancer 523 13.4.3 Preclinical Efficacy Study of Celecoxib versus Ibuprofen for the Prevention of Breast Cancer 524 13.4.4 Other Animal Studies of NSAIDs and Cancer 524 13.5 Human Epidemiologic Studies of Ibuprofen for the Prevention of Cancers of the Breast, Colon, Prostate and Lung 525 13.5.1 Methods of Analysis 526 13.5.2 Comparative Results for Ibuprofen and Aspirin from Eepidemiologic Studies of Cancers of the Breast, Colon, Prostate and Lung 526 13.5.3 Comparison of Ibuprofen, Aspirin and Selective COX ]2 Inhibitors in Cancer Prevention 527 13.5.4 Meta-analyses of Epidemiologic Studies of NSAIDs for Cancer Prevention 528 13.5.5 Discussion of Meta-analyses of NSAIDs and Cancer 530 13.6 Therapeutic Studies of Non-selective COX-2 Inhibitors for Human Cancer 531 13.7 COX-2 and the Inflammogenesis of Cancer 533 13.7.1 COX-2 Blockade of Molecular Carcinogenesis 533 13.7.2 Role of COX-1 in Carcinogenesis 534 13.7.3 Other Molecular Targets of NSAIDs 535 13.8 Safety Profile of Ibuprofen 535 13.8.1 COX-1 and COX-2 Isoforms 535 13.8.2 Gastrointestinal and Renal Effects of Ibuprofen 535 13.8.3 Ibuprofen and Cardiovascular Disease 536 13.9 Future Perspectives for Cyclooxygenase Inhibitors in Cancer Chemoprevention 536 References 537 14 Ibuprofen in Prevention of Neurodegenerative Diseases 549 Kim D. Rainsford Summary 549 14.1 Introduction 550 14.2 Pathogenesis of AD 550 14.3 Early Clinical Observations of Effects of NSAIDs in AD 551 14.4 Cellular and Molecular Effects of Ibuprofen in AD 555 14.4.1 Actions of Ibuprofen in Rodent AD Models 556 14.4.2 In Vitro Effects and Molecular Actions of Ibuprofen in AD 558 14.4.3 Conclusions 559 14.5 Ibuprofen in Parkinson s Disease 559 14.5.1 Effects of Ibuprofen in Models of PD 561 14.6 Other Neuroprotective Effects of Ibuprofen 561 14.7 Conclusions 562 References 562 Appendix A Some Proprietary Brands and Preparations of Ibuprofen Available Worldwide 573 Kim D. Rainsford Appendix B References to Analytical Methods for Determination ofIbuprofen in Biological Fluids, Principally Plasma 583 Kim D. Rainsford Index 000

Product Details

  • publication date: 04/09/2015
  • ISBN13: 9781118743386
  • Format: Hardback
  • Number Of Pages: 624
  • ID: 9781118743386
  • weight: 1074
  • ISBN10: 1118743385

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