Comparative Pathophysiology and Toxicology of Cyclooxygenases

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.

PREFACE xi

INTRODUCTION: DISCOVERY OF CYCLOOXYGENASES AND HISTORICALPERSPECTIVE 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 Tract23

Effects of Aminonicotinic Acid Derivative ns–NSAIDs on the GITract 26

Effects of Pyrazolone Derivative ns–NSAIDs on the GI Tract27

Effects of Salicylic Acid Derivative ns–NSAIDs on the GI Tract28

Effects of Anthranilic Acid Derivative ns–NSAIDs on the GI Tract30

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 Toxicity38

Role of Cyclooxygenase Potency 39

Species Differences in NSAID–Associated Susceptibility to GIInjury 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 MechanismsAfter Mucosal Injury 46

Effects on Leukocyte Adhesion Molecules and Trafficking 49

Effects of GI Physiological Local pH, Gut Absorption, andFasting 50

NSAID Topical Effect–Mediated Injury 51

Changes in GI Motility, Microcirculation, and Enterobacteria52

Decreased Phosphatidylcholine Levels 53

Impaired Drug Metabolism 54

Role of Toll–like Receptor (TLR)–4/MyD88 and Enteric Bacteria54

Role of Uncoupling of Mitochondrial Oxidative Phosphorylation56

Role of Peroxisome Proliferator–Activated Receptor 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 Skeleton72

Role of Prostaglandins in Skeleton Metabolism 78

The Process of Bone Healing and Potential Role of Prostaglandins85

Inflammatory Response 85

Bone Resorption 88

Bone Formation 90

COX–1 and COX–2 Expression in Bone, Tendon, and Ligament DuringRepair 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 Aspectsof 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 System165

Conclusions 166

References 167

CHAPTER 4 CARDIOVASCULAR SYSTEM 180

Introduction 180

Comparative Physiological and Anatomical Aspects of theCardiovascular System 181

The Heart 181

Cardiovascular Blood Flow 183

Cardiac Conduction System and Blood Pressure 183

Heart Rate 186

Renin Angiotensin Aldosterone in the CardiovascularSystem 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 CardiovascularSystem 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 andBlood 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 OcularSystem 228

Role of Prostaglandins in the Ocular System 238

COX–1 Expression in the Eye Under Normal and PathologicalConditions 245

COX–2 Expression in the Eye Under Normal and PathologicalConditions 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 theRespiratory System 270

Role of Prostaglandins in the Respiratory System 275

COX–1 Expression in the Respiratory System Under Normal andPathological Conditions 283

COX–2 Expression in the Respiratory System Under Normal andPathological 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 SAFERNSAIDs 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

ZAHER A. RADI is a Research Fellow and ToxicologicAnatomic Pathologist in Drug Safety R&D at Pfizer WorldwideResearch & Development. He has published over fifty–fiveresearch papers and review articles, in addition to book chaptersand numerous abstracts and presentations.