Ibuprofen

Professor K.D Rainsford, Professor Emeritus of Biomedical Sciences, Sheffield Hallam University.

• List of Contributors xiiiPreface xv1 History and Development of Ibuprofen 1Kim D. RainsfordSummary 11.1 Introduction 11.2 Historical Background 51.3 Initial Stages 71.4 Compounds in Development 101.5 Ibufenac – Almost There, but for Liver Toxicity 121.6 More Setbacks 121.7 More Learning 121.8 Ibuprofen 121.8.1 First Clinical Trials 121.8.2 Gastrointestinal Safety 141.9 Achievements and Rewards at Last 151.10 Ultimate Recognition of Safety – OTC Status 171.11 Worldwide Developments 191.11.1 Evolving Applications of Ibuprofen 19Acknowledgements 20References 202 The Medicinal Chemistry of Ibuprofen 22Kenneth J. Nichol and David W. Allen2.1 Introduction 222.2 The Discovery of Ibuprofen 222.3 Synthetic Routes to Ibuprofen 272.4 Biological Activities of Ibuprofen Analogues 312.5 Metabolites of Ibuprofen 362.5.1 Metabolites and Enantiomer Inversion 362.5.2 Synthesis of Metabolites 372.6 Ibuprofen Enantiomers 382.7 Physicochemical Aspects 42Acknowledgements 43References 433 The Pharmaceutics of Ibuprofen 50Fred HigtonSummary 503.1 Physical and Chemical Characteristics of Ibuprofen 503.2 Products Available Worldwide 543.3 Solid Dose Presentations 543.3.1 Conventional Ibuprofen Tablets 563.3.2 In vitro/in vivo Testing 583.3.3 Sustained Release Preparations 603.3.4 Ibuprofen Fast Acting: Ibuprofen Salts and Derivatives 643.4 Liquids 673.5 Taste-Masking of Ibuprofen 673.6 Suppositories 693.7 Topical Presentations 703.8 Conclusion 72References 724 The Pharmacokinetics of Ibuprofen in Humans and Animals 81Fakhreddin Jamali and Dion R. BrocksSummary 814.1 Absorption 824.2 Distribution 834.2.1 Protein Binding 834.2.2 Tissue Distribution 884.3 Clearance 924.3.1 Metabolism of Ibuprofen 934.3.2 Excretion of Ibuprofen 1044.4 Interspecies Differences in Pharmacokinetics of (R)- and (S)-Ibuprofen 1054.5 Relationship between Effect and Plasma Concentrations 1064.5.1 Therapeutic Effects 1064.5.2 Toxic Effects 1074.6 Pharmacokinetics in Special Populations 1084.6.1 Pharmacokinetics and Analgesic Effects in Patients in Pain 1084.6.2 Febrile Children and Infants 1144.6.3 Postoperative Paediatric Patients 1154.6.4 Premature Infants 1154.6.5 Juvenile Arthritis 1164.6.6 Children with Cystic Fibrosis 1164.6.7 Elderly Adults 1174.6.8 Rheumatic Disease 1174.6.9 Renal Insufficiency 1184.6.10 Hepatic Disease 1194.6.11 Burn Patients 1194.6.12 Effect of Gender and Race 1194.6.13 Effect of Operational Stessors 1204.7 Drug Interactions 1204.7.1 Anti-ulcer Medications 1204.7.2 Zidovudine 1214.7.3 Codeine and Oxycodone 1214.7.4 Anti-hyperlipidemic Drugs 1214.7.5 Oral Contraceptive Steroids 1224.7.6 Self-interaction; Enantiomer–Enantiomer Interaction 1234.7.7 Effect of Ibuprofen on the Pharmacokinetics of Other Drugs 1234.7.8 Other Drugs 123References 1245 Pharmacology and Toxicology of Ibuprofen 132Kim D. RainsfordSummary 1325.1 Introduction 1335.2 Basic Pharmacology and Toxicology 1345.2.1 The Relevance of Data from Animal Models to the Clinical Situation in Humans 1345.2.2 Acute Anti-inflammatory Activity 1365.2.3 Chronic Anti-inflammatory Activity 1415.2.4 Analgesic Activity 1435.2.5 Antipyretic Activity 1495.2.6 General Toxicology 1495.2.7 Effects on Prostaglandin Production Related to Pharmacological Activities 1645.2.8 Effects on Leukotriene Production 1805.2.9 Smooth Muscle Contractility 1815.2.10 Effects on Nitric Oxide Production 1815.2.11 Leucocytes and Vascular Permeability 1825.2.12 Leukocyte Functions 1885.2.13 Immune Functions 1915.2.14 Effects on Articular Joint Integrity 1925.2.15 Miscellaneous Biochemical and Cellular Actions 1945.3 Experimental Therapeutics 1965.3.1 Endotoxin Shock 1965.3.2 Acute Lung Injury Induced by Exposure to Chemicals 1985.3.3 Acute Myocardial Injury and Coronary Functions 1995.3.4 Cerebral Injury 2015.3.5 Tourniquet Shock Ischemia 2025.3.6 Transcutaneous Hypoxia 2025.3.7 Cytokines and Surgical Stress 2035.3.8 Pleurisy from Delayed Hypersensitivity Reaction 2035.3.9 Abdominal Adhesions 2035.3.10 Uveitis 2045.4 Clinical Pharmacology and Toxicology 2045.4.1 Experimental Inflammation 2045.4.2 Experimental Pain 2055.4.3 Effects on Platelet Aggregation and Thrombosis 2065.4.4 Gastrointestinal Injury and Bleeding 2085.4.5 Hypersensitivity and Other Immunological Reactions 2105.4.6 Gynaecological and Obstetric Uses 2115.4.7 Effects on Lung Inflammation in Cystic Fibrosis 2125.4.8 Malignant Conditions 2125.4.9 Prevention of Cataract 2135.5 Conclusions 214References 2146 Therapeutics of Ibuprofen in Rheumatic and Other Chronic and Painful Diseases 237Walter F. Kean, Kim D. Rainsford and the late William W. BuchananSummary 2376.1 Introduction 2386.2 Overview of Clinical Pharmacology 2396.2.1 Pharmacokinetics Relevant to Therapy of Inflammatory Diseases and Pain 2406.2.2 Anti-inflammatory and Analgesic Activities 2456.2.3 Criteria for Determining Therapeutic Responses 2476.3 NSAID-Related Adverse Drug Reactions and Toxicity 2486.3.1 Gastrointestinal Side-Effects 2486.3.2 Cardiovascular Reactions 2516.3.3 Hepatic Reactions 2516.3.4 Renal Adverse Reactions 2516.3.5 Miscellaneous Reactions 2536.4 Rheumatoid Arthritis 2546.4.1 Early Studies at Low Doses 2556.4.2 Later Higher]Dose Studies 2576.5 Juvenile Idiopathic (Rheumatoid) Arthritis 2616.6 Primary and Secondary Osteoarthritis 2626.6.1 Acceleration of Cartilage and Bone Destruction 2726.6.2 Therapeutic Aspects 2736.6.3 Comparisons with Coxibs 2746.7 Formulations 2766.8 Variability in Response 2766.9 Relation of Drug Kinetics to Clinical Response 2776.10 Low Back Pain 2786.11 Shoulder Pain 2796.12 Reactive Arthritis (Reiter’s Syndrome) 2806.13 Psoriatic Arthritis 2806.14 Ankylosing Spondylitis 2806.15 Gout 2806.16 Fibromyalgia 2816.17 Haemophiliac Arthritis 2816.18 Postoperative Pain 2816.19 Sports Injuries 2826.20 Other Painful States 2836.21 Cancer 2846.22 Potential Non]analgesic Usage 2856.23 The Elderly 2856.24 Dexibuprofen 2866.25 Conclusions 286References 2877 Safety and Efficacy of Non-prescription, Over-the]Counter (OTC) Ibuprofen 313Kim D. RainsfordSummary 3137.1 Introduction 3137.2 Analysis of Clinical Trials 3157.2.1 Studies in Prospective Clinical Trials 3177.3 Epidemiological Studies and Case Reports 3277.4 Considerations for Special Groups 3307.4.1 Use of Drugs in the Elderly 3307.4.2 Safety in Pregnancy and Lactation 3317.4.3 Uses and Safety in Sport and Exercise 3347.5 Conclusions 336References 3368 Use of Ibuprofen in Dentistry 346Raymond A. Dionne, Sharon M. Gordon and Stephen A. CooperSummary 3468.1 Introduction 3468.2 Analgesia 3478.2.1 Preventive Analgesia 3488.2.2 Analgesic Activity of Ibuprofen Isomers 3498.2.3 Ibuprofen-Containing Combinations 3508.2.4 Ibuprofen Formulations 3548.3 Effects on Oedema 3558.4 Interactions with Plasma β-Endorphin 3568.5 Use for Chronic Temporomandibular Pain 3568.6 Recommendations for the Use of Ibuprofen in Dentistry 358References 3599 Gastrointestinal Adverse Reactions from Ibuprofen 363Kim D. Rainsford and Ingvar BjarnasonSummary 3639.1 Background and Introduction 3649.2 Current Status Concerning NSAID Ulceration 3659.2.1 Morbidity and Mortality 3669.3 Occurrence of Ulcers and Complications 3699.3.1 Epidemiological Studies 3699.3.2 Large-Scale Mega Trials 3769.4 Clinical Investigations on Comparative GI Effects of Ibuprofen 3789.4.1 Early Symptom-Based Studies in GI]Intolerant Subjects 3789.4.2 Procedures for Assessing GI Injury 3799.4.3 Upper GI Endoscopy 3809.4.4 NSAID-Enteropathy: Capsule and Device Assisted Intestinal Endoscopy and Other Techniques 3819.4.5 Radiochromium [51Cr]-Labelled Red Cell GI Blood Loss 3899.4.6 Intragastric and Occult Blood Loss and Reduced Haemoglobin 3949.5 Clinically-Relevant Pathogenesis of NSAID-Associated GI Injury 3959.5.1 Factors Affecting NSAID-Induced Gastroduodenal Injury 3959.5.2 Influence of Gastric Acidity 3979.5.3 Physicochemical Associations, Topical versus Systemic Actions of NSAIDs, Cyclo]oxygenases and Reduced Prostanoids 3999.5.4 Effects of NSAIDs on Gastric pH and Acid Secretion 4029.6 Procedures for Reducing GI Symptoms 4049.6.1 Ibuprofen Formulations 4049.6.2 Effects of Food or Drinks 4069.6.3 Mucus Protection Strategies 4099.6.4 Anti-ulcer Agents 4109.7 Overall Assessment of GI Safety of Ibuprofen 412References 41210 Hepatorenal Effects of Ibuprofen Compared with other NSAIDs and Paracetamol 432Kim D. Rainsford10.1 Introduction 43210.2 Hepatorenal Syndromes 43310.3 NSAID, Analgesic and DMARD-Induced Liver Injury 43310.3.1 Historical Associations of NSAIDs with Liver Toxicity 43310.3.2 Awareness of Liver Reactions with Modern NSAIDs 43410.3.3 Simultaneous Use of Potentially Hepatotoxic Medications 43910.4 Renal Adverse Reactions Form NSAIDs and Analgesics 44210.4.1 Renal Adverse Reactions from Ibuprofen 44410.5 Conclusions 446References 44611 Adverse Drug Reactions Attributed to Ibuprofen: Effects Other Than Gastrointestinal 452L.J. Miwa, M. Manenos and Judith K. Jones11.1 Introduction 45211.2 Allergy and Hypersensitivity 45311.2.1 Points to Consider when Evaluating Allergy-Type Reactions to NSAIDs 45311.2.2 Epidemiology of Allergy or Hypersensitivity with NSAIDs 45411.3 Adverse Dermatological Effects 45711.4 Hepatotoxicity 45811.5 Haematological Adverse Effects 46511.5.1 Neutropenia, agranulocytosis and aplastic anaemia 46511.5.2 Other Blood Disorders 46611.6 Renal Adverse Effects 46611.7 Cardiovascular Adverse Effects 47011.8 Adverse Effects on Reproduction 47711.8.1 Animal Studies of Teratogenic and Reproductive Effects 47711.8.2 Reports of Teratogenic Effects in Humans 47811.8.3 Perinatal Adverse Effects Associated with Therapeutic Use 47911.8.4 Other Reproductive Effects 48011.9 Endocrine and Metabolic Adverse Effects 48011.10 Central Nervous System Effects 48011.10.1 General CNS Effects 48011.10.2 Aseptic Meningitis 48111.10.3 Cognitive Dysfunction 48111.10.4 Psychiatric Adverse Effects 48111.11 Ocular Adverse Effects 48111.12 Infection-Related Adverse Event 48211.13 Drug Interactions 48211.13.1 NSAID–Anti-hypertensive Interactions 48311.13.2 NSAID–Diuretic Interactions 48411.13.3 NSAID–β-Adrenergic Blocker Interactions 48411.13.4 NSAID–Angiotensin-Converting Enzyme Inhibitor Interactions 48411.13.5 NSAID–Oral Anti-coagulant Interactions 48411.13.6 NSAID–Aminoglycoside Interactions 48511.13.7 NSAID–Oral Hypoglycemic Interactions 48511.13.8 NSAID–Cyclosporin Interactions 48511.13.9 NSAID–Lithium Interactions 48511.13.10 NSAID–Methotrexate Interactions 48511.13.11 Ibuprofen–Aspirin Interactions 48611.14 Future Needs 486References 48712 Human Toxicity of Ibuprofen 500Glyn VolansSummary 50012.1 Introduction 50012.2 Mechanism of Toxicity in Overdosage 50112.3 Epidemiological Reviews of the Effects of Ibuprofen in Overdosage 50112.4 Reports of Deaths after Ibuprofen Overdose 50212.5 Dose–Response and Toxicokinetics 50212.6 Gastrointestinal Effects 50812.7 Renal Effects 50912.7.1 Cases of Massive Overdose 50912.7.2 Cases Affected by Additional Factors 50912.8 Metabolic Effects 51012.9 Central Nervous System (CNS) Effects 51112.10 Cardiovascular Effects 51112.11 Respiratory Effects 51212.12 Haematological Effects 51212.13 Skin Reactions 51212.14 Ibuprofen Toxicity in Children 51212.15 Ibuprofen in Pregnancy and Breast Feeding 51312.16 Chronic Abuse of Ibuprofen 51312.17 Conclusion 51412.17.1 Management of Ibuprofen Overdosage 51412.17.2 Continuing Surveillance 51512.17.3 Comparative Human Toxicity – Ibuprofen versus Other NSAIDs and Non]opioid Analgesics 516References 51613 Ibuprofen in the Prevention and Therapy of Cancer 520Randall E. HarrisSummary 52013.1 Introduction and Background 52113.2 Ibuprofen, COX-1 and COX-2 52213.3 COX-2 and the Inflammogenesis of Cancer 52213.4 Preclinical Efficacy Studies of Ibuprofen and Cancer 52313.4.1 Preclinical Efficacy Study of Ibuprofen Therapy for Breast Cancer 52313.4.2 Preclinical Efficacy Study of Ibuprofen versus Retinoic Acid for the Prevention of Breast Cancer 52313.4.3 Preclinical Efficacy Study of Celecoxib versus Ibuprofen for the Prevention of Breast Cancer 52413.4.4 Other Animal Studies of NSAIDs and Cancer 52413.5 Human Epidemiologic Studies of Ibuprofen for the Prevention of Cancers of the Breast, Colon, Prostate and Lung 52513.5.1 Methods of Analysis 52613.5.2 Comparative Results for Ibuprofen and Aspirin from Eepidemiologic Studies of Cancers of the Breast, Colon, Prostate and Lung 52613.5.3 Comparison of Ibuprofen, Aspirin and Selective COX]2 Inhibitors in Cancer Prevention 52713.5.4 Meta-analyses of Epidemiologic Studies of NSAIDs for Cancer Prevention 52813.5.5 Discussion of Meta-analyses of NSAIDs and Cancer 53013.6 Therapeutic Studies of Non-selective COX-2 Inhibitors for Human Cancer 53113.7 COX-2 and the Inflammogenesis of Cancer 53313.7.1 COX-2 Blockade of Molecular Carcinogenesis 53313.7.2 Role of COX-1 in Carcinogenesis 53413.7.3 Other Molecular Targets of NSAIDs 53513.8 Safety Profile of Ibuprofen 53513.8.1 COX-1 and COX-2 Isoforms 53513.8.2 Gastrointestinal and Renal Effects of Ibuprofen 53513.8.3 Ibuprofen and Cardiovascular Disease 53613.9 Future Perspectives for Cyclooxygenase Inhibitors in Cancer Chemoprevention 536References 53714 Ibuprofen in Prevention of Neurodegenerative Diseases 549Kim D. RainsfordSummary 54914.1 Introduction 55014.2 Pathogenesis of AD 55014.3 Early Clinical Observations of Effects of NSAIDs in AD 55114.4 Cellular and Molecular Effects of Ibuprofen in AD 55514.4.1 Actions of Ibuprofen in Rodent AD Models 55614.4.2 In Vitro Effects and Molecular Actions of Ibuprofen in AD 55814.4.3 Conclusions 55914.5 Ibuprofen in Parkinson’s Disease 55914.5.1 Effects of Ibuprofen in Models of PD 56114.6 Other Neuroprotective Effects of Ibuprofen 56114.7 Conclusions 562References 562Appendix A Some Proprietary Brands and Preparations of Ibuprofen Available Worldwide 573Kim D. RainsfordAppendix B References to Analytical Methods for Determination ofIbuprofen in Biological Fluids, Principally Plasma 583Kim D. RainsfordIndex 000