Comparative Pathophysiology and Toxicology of Cyclooxygenases

Description

The first thorough review of cyclooxygenase inhibitors, including their toxicity mechanisms and toxicopathological risks

Cyclooxygenases (COXs) are enzymes responsible for the formation of an important class of biological mediators called prostanoids. Prostanoids such as prostaglandins mediate inflammatory and anaphylactic reactions. For those suffering from inflammation and pain, the pharmacological inhibition of COXs, with non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, can provide relief. Yet the use of NSAIDs can trigger toxicological effects as well, leading to potential health risks.

Comparative Pathophysiology and Toxicology of Cyclooxygenases provides a comprehensive overview of how COX inhibitors affect various bodily systems, specifically the toxicity mechanisms triggered when the COX enzyme is inhibited. The book provides an introduction to the discovery of cyclooxygenases, their use as therapeutic agents, as well as an historical perspective. Shedding light on the differences in expression, pathophysiology, and toxicology of COX inhibitors across species, the book offers a systematic examination of the effects and pathophysiology of COX inhibitors and their mechanisms of toxicity, beginning with the GI tract. Subsequent chapters cover:

• The pathophysiology of COX inhibition on bone, tendon, and ligament healing
• COX inhibitors and renal system pathophysiology and mechanisms of toxicity
• The pathophysiologic role of COX inhibition in the ocular system
• COX inhibition and the respiratory and cardiovascular systems

The book also sheds light on the latest research devoted to developing COX inhibitors with no adverse side-effects. The first book to offer a thorough comparative look at the toxicological effects of COX inhibitors throughout the body, this invaluable resource will help advance the research and development of safer and more effective COX drugs.

Table of contents

• PREFACE xi
• INTRODUCTION: DISCOVERY OF CYCLOOXYGENASES AND HISTORICAL PERSPECTIVE 1
• Aspirin 1
• Prostaglandins 2
• Cyclooxygenases 4
• COX-2 Selective NSAIDs 7
• References 8
• CHAPTER 1 GASTROINTESTINAL TRACT 11
• Introduction 11
• Comparative COX-1 and COX-2 Expression in the GI Tract 13
• Effects of ns-NSAIDs on the GI Tract 15
• Effects of Arylpropionic Acid ns-NSAIDs on the GI Tract 17
• Effects of Enolic Acid (Oxicam) ns-NSAIDs on the GI Tract 22
• Effects of Acetic Acid Derivative ns-NSAIDs on the GI Tract 23
• Effects of Aminonicotinic Acid Derivative ns-NSAIDs on the GI Tract 26
• Effects of Pyrazolone Derivative ns-NSAIDs on the GI Tract 27
• Effects of Salicylic Acid Derivative ns-NSAIDs on the GI Tract 28
• Effects of Anthranilic Acid Derivative ns-NSAIDs on the GI Tract 30
• Effects of COX-1 Inhibitors on the GI Tract 30
• Effects of COX-2 s-NSAIDs on the GI Tract 31
• Pathophysiology and Mechanisms of NSAID-Associated GI Toxicity 38
• Role of Cyclooxygenase Potency 39
• Species Differences in NSAID-Associated Susceptibility to GI Injury 39
• GI Anatomical Differences 40
• Enterohepatic Recirculation and NSAID Toxicity 41
• Role of Xenobiotic Glucuronidation 42
• Aging and Stress and NSAID GI Effects 43
• Disruption of GI Physiological Mucosal Defense Mechanisms 44
• GI Disequilibrium 45
• Effects on Physiological GI Mucosal Cell Renewal Mechanisms After Mucosal Injury 46
• Effects on Leukocyte Adhesion Molecules and Trafficking 49
• Effects of GI Physiological Local pH, Gut Absorption, and Fasting 50
• NSAID Topical Effect-Mediated Injury 51
• Changes in GI Motility, Microcirculation, and Enterobacteria 52
• Decreased Phosphatidylcholine Levels 53
• Impaired Drug Metabolism 54
• Role of Toll-like Receptor (TLR)-4/MyD88 and Enteric Bacteria 54
• Role of Uncoupling of Mitochondrial Oxidative Phosphorylation 56
• Role of Peroxisome Proliferator-Activated Receptor γ 56
• Role of Mitogen-Activated Protein Kinases 57
• NSAID GI Injury-Associated Risk Factors 57
• Conclusions 57
• References 58
• CHAPTER 2 BONE–TENDON–LIGAMENT SYSTEM 72
• Introduction 72
• Comparative Physiological and Anatomical Aspects of the Skeleton 72
• Role of Prostaglandins in Skeleton Metabolism 78
• The Process of Bone Healing and Potential Role of Prostaglandins 85
• Inflammatory Response 85
• Bone Resorption 88
• Bone Formation 90
• COX-1 and COX-2 Expression in Bone, Tendon, and Ligament During Repair and in Pathological Conditions 91
• Effects of ns-NSAIDs on Bone Healing 96
• Effects of COX-2 s-NSAIDs on Bone Healing 103
• Effects of ns-NSAIDs on Ligament and Tendon Healing 112
• Effects of COX-2 s-NSAIDs on Ligament and Tendon Healing 113
• Conclusions 114
• References 115
• CHAPTER 3 RENAL SYSTEM 127
• Introduction 127
• Comparative Physiological, Developmental, and Anatomical Aspects of the Renal System 128
• Role of Prostaglandins in the Renal System 140
• COX-1 and COX-2 Expression in the Kidney 149
• Effects of ns-NSAIDs on the Kidney 154
• Effects of COX-2 s-NSAIDs on the Kidney 162
• Potential Mechanisms of NSAID Effects on the Renal System 165
• Conclusions 166
• References 167
• CHAPTER 4 CARDIOVASCULAR SYSTEM 180
• Introduction 180
• Comparative Physiological and Anatomical Aspects of the Cardiovascular System 181
• The Heart 181
• Cardiovascular Blood Flow 183
• Cardiac Conduction System and Blood Pressure 183
• Heart Rate 186
• Renin–Angiotensin–Aldosterone in the Cardiovascular System 187
• Natriuretic Peptides in the Cardiovascular System 188
• Cardiovascular Research and Animal Models 189
• Cardiovascular Atherosclerosis 191
• COX-1 and COX-2 Expression in the Cardiovascular System 192
• Pathophysiological Role of Prostaglandins in the Cardiovascular System 196
• Effects of NSAIDs on the Cardiovascular System 201
• Effects of COX-1 and COX-2 Inhibition on Myocardial Ischemia, Infarction, and Thrombosis 201
• Effects of COX-1 and COX-2 Inhibition on Coronary Blood Flow and Blood Pressure 211
• Effects of COX-1 and COX-2 Inhibition on Atherogenesis 215
• Conclusions 216
• References 216
• CHAPTER 5 OCULAR SYSTEM 228
• Introduction 228
• Comparative Physiological and Anatomical Aspects of the Ocular System 228
• Role of Prostaglandins in the Ocular System 238
• COX-1 Expression in the Eye Under Normal and Pathological Conditions 245
• COX-2 Expression in the Eye Under Normal and Pathological Conditions 248
• Effects of COX-2 s-NSAIDs in Ophthalmology 253
• Effects ns-NSAIDs in Ophthalmology 256
• Conclusions 259
• References 259
• CHAPTER 6 RESPIRATORY SYSTEM 270
• Introduction 270
• Comparative Physiological and Anatomical Aspects of the Respiratory System 270
• Role of Prostaglandins in the Respiratory System 275
• COX-1 Expression in the Respiratory System Under Normal and Pathological Conditions 283
• COX-2 Expression in the Respiratory System Under Normal and Pathological Conditions 288
• Effects of COX-2 s-NSAIDs on the Respiratory System 295
• Effects of ns-NSAIDs on the Respiratory System 299
• Conclusions 300
• References 301
• CHAPTER 7 CURRENT RESEARCH STRATEGIES FOR DESIGNING SAFER NSAIDs 309
• Nitric Oxide–Releasing NSAIDs 309
• Hydrogen Sulfide–Releasing NSAIDs 311
• NSAIDs Associated with Zwitterionic Phospholipids 311
• Chiral NSAIDs 313
• Trefoil Peptides 314
• Novel Mechanism of Action NSIADs 314
• mPGES-1 Inhibitors 316
• References 316
• INDEX 321

Author Information

ZAHER A. RADI is a Research Fellow and Toxicologic Anatomic Pathologist in Drug Safety R&D at Pfizer Worldwide Research & Development. He has published over fifty-five research papers and review articles, in addition to book chapters and numerous abstracts and presentations.