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Comparison of the Effects of Deracoxib, Buffered Aspirin, and Placebo on the Gastric Mucosa of Healthy Dogs Kathleen A. Sennello Thesis submitted to the Graduate School of Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Master of Science In Veterinary Clinical Sciences Michael S. Leib DVM, MS, Chair Marion F. Ehrich MS, RPh, PhD William E. Monroe DVM, MS April 4, 2005 Blacksburg, VA Keywords: canine, gastric ulceration, non-steroidal anti-inflammatory drugs, cyclooxygenase, gastroscopy COMPARISON OF THE EFFECTS OF DERACOXIB, BUFFERED ASPIRIN, AND PLACEBO ON THE GASTRIC MUCOSA OF HEALTHY DOGS KATHLEEN A. SENNELLO ABSTRACT This study tested the hypothesis that administration of deracoxib, a cyclooxygenase-2 specific (COX-2) inhibitor, would result in lower gastric lesion scores than administration of buffered aspirin and gastric lesion scores similar to placebo when administered to healthy dogs for 28 days. Twenty-four, healthy, random source dogs were divided into three groups. Group I received buffered aspirin, 23.6 mg/kg PO q 8h, group II received deracoxib, 1.6 mg/kg PO q 24h and placebo twice daily PO q 8h after deracoxib administration, and group III received placebo PO q 8h. Gastroscopy was performed on days -7, 6, 14, and 28 of treatment. Four regions of the stomach (pylorus, incisura, cardia, and body) were evaluated separately and lesions scored on a scale of 1 (mucosal hemorrhage) to 12 (perforating ulcer) by an observer unaware of which treatments the dogs received. Dogs were observed every 8 hours for vomiting, diarrhea and anorexia. Feces were scored from 1-5 (scores <4 were considered diarrhea). Lesion scores for each group, at each location, and total scores, at each time period, were evaluated for the effects of time and treatment using a Kruskal-Wallis test. Total dog days of vomiting and dog days of diarrhea in each group were compared using a Wilcoxon rank sums test. Significance was determined at p<0.05. Significantly higher median total gastric lesion scores were found in the aspirin group compared to the deracoxib or placebo groups on days 6, 14, and 28. There were no significant differences in median total gastric lesion scores between the deracoxib or placebo groups at any time during the study. There was no location effect on gastric lesion scores and there was no significant change in gastric lesion scores over time in any of the groups during treatment. Significantly more dog-days of vomiting occurred in the aspirin group as compared to the deracoxib group. No significant differences were found between groups for dog-days of diarrhea. In this study, the administration of deracoxib to healthy dogs resulted in significantly lower gastric lesion scores compared to dogs receiving aspirin and lesion scores similar to those receiving placebo. iii ACKNOWLEDGEMENTS The author would like to recognize the Virginia Veterinary Medical Association Veterinary Memorial Fund and Virginia-Maryland Regional College of Veterinary Medicine for providing the funding to make this project possible. A special thanks to Dr Michael Leib who offered his expertise and encouragement with this project and all aspects of the author’s professional career. Thanks to Dr. David L. Panciera for his collaborative research and support. Thanks to John Strauss, Stephanie Milburn, and Karen Whitt for technical help. Thanks to Daniel Ward for his statistical expertise. Special thanks to Drs. Michael S. Leib, William E. Monroe, and Marion F. Ehrich for their cooperation, encouragement, and tireless review of the study design and document drafts. Their involvement undoubtedly improved the quality of this work. iv DECLARATION OF WORK PERFORMED I declare that I, Kathleen Sennello performed all work detailed in the materials and methods of this manuscript with the exception of the following procedures. The clinical pathology laboratory at Virginia-Manyland’s Regional College of Veterinary Medicine performed complete blood counts and serum biochemical profiles. The parasitology laboratory at Virginia-Maryland’s Regional College of Veterinary Medicine performed all zinc sulfate fecal flotations. Serum salicylate levels were performed by Montgomery Regional hospital and Cedra Corporation performed plasma deraxocib levels. v TABLE OF CONTENTS ABSTRACT…………………………………………………………………………........ii ACKNOWLEDGEMENTS………………………………………………………………iv DECLARATION OF WORK PERFORMED…………………………………………….v TABLE OF CONTENTS…………………………………………………………………vi LIST OF TABLES AND FIGURES……………………………………………………viii LIST OF ABBREVIATIONS…………………………………………………………….ix INTRODUCTION………………………………………………………………………...1 CHAPTER I: Literature Review A. Anatomy and physiology of gastroprotection………………………………….3 Gastric function…………………………………………………………....3 Gastric microanatomy…………………………………………………..…3 Gastric mucosal defense…………………………………………………..4 B. Gastric Ulceration…………………………………………………………...…8 Ulcer development and healing…………………………………………...8 Gastric ulceration in canine patients……………………………………..11 Helicobacter spp. induced gastric injury………………………………...11 Drug induced gastric injury……………………………………………...12 Studies demonstrating gastric injury due to corticosteroid use or concurrent corticosteroid and non-steroidal anti-inflammatory drug use in dogs…………………………………………………………………..…..15 C. Gastrointestinal injury, non-steroidal anti-inflammatory drugs and cyclooxygenase…………………………………………………………………..17 Cyclooxygenase 1 and 2…………………………………………………17 Studies demonstrating cyclooxygenase activity in dogs, cats and horses………………………………...........................................18 Aspirin as the prototypical cyclooxygenase-1 inhibitor…………………20 Studies utilizing aspirin-induced gastric injury in dogs…………………22 Cyclooxygenase-2 selective inhibitors…………………………………..24 Studies evaluating cyclooxygenase-2 preferential inhibitors in dogs ….26 Inconsistencies in the cyclooxygenase-1 and 2 theory……………..........28 D. Deracoxib……………………………………………………………………..30 Structure and function……………………………………………………30 Deracoxib: efficacy and safety studies…………………………………..31 CHAPTER II: Comparison of the Effects of Deracoxib, Buffered Aspirin, and Placebo on the Gastric Mucosa of Healthy Dogs. A. Introduction…………………………………………………………………..36 B. Materials and Methods……………………………………………………….38 C. Results……………………………………………………………………..…42 D. Discussion……………………………………………………………………45 CHAPTER III: Conclusions……………………………………………………..………51 FOOTNOTES……………………………………………………………………………52 REFERENCES………………………………………………………………..…………53 vi TABLES Table 1-Gastric lesion scoring scale…………………………………….……….66 FIGURES Figure 1-Submucosal hemorrhage……………………………………………….67 Figure 2-Gastric erosions………………………………………………………...68 Figure 3-Gastric ulcer…………………………………………………………....69 Figure-4 Median total gastric lesion scores……………………………………...70 Figure-5 Median total gastric lesion scores over time………………………...…71 APPENDIXES Appendix 1-Addendum on additional methods………………………………….73 Appendix 2-Regional and total gastric lesion scores for all dogs…………….…75 Appendix 3-Serum salicylate concentrations/Mean aspirin dosages…………….79 Appendix 4-Plasma deracoxib concentrations/Mean deracoxib dosages………..80 Appendix 5-Total dog-days of vomiting, diarrhea and anorexia……………...…81 Appendix 6-Fecal flotation results……………………………………………….82 VITA…………………………………………………………………………………..…83 vii LIST OF TABLES AND FIGURES Table 1. Gastric Lesion Scores…………………………………………………………..66 Figure 1. Pinpoint hemorrhages……………………………………………………….…67 Figure 2. Multiple erosions……………………………………………………………....68 Figure 3. Ulcer……………………………………………………………...……………69 Figure 4. Total median gastric lesion scores at each endoscopy day………………….…70 Figure 5. Median total gastric lesion scores over time……………………………..……71 viii LIST OF ABBREVIATIONS 5-HETE 5-Hydroperoxyeicosatretanoic acid 100X One-hundred times magnification AA Arachidonic acid BUN Blood urea nitrogen cAMP cellular AMP CLASS Celecoxib Long-term Arthritis Safety Study COX Cyclooxygenase COX-1 Cyclooxygenase-one COX-2 Cyclooxygenase-two FDA Food and drug administration GI Gastrointestinal h Hours H+ Hydrogen ion HCl Hydrochloric acid IC50 Inhibitory concentration 50 IL Interleukin IM Intramuscular iNOS Inducible nitric oxide synthase IV Intravenous Kg Kilograms LPS Lipopolysaccaride LT Leukotrienes Mg Milligrams MPSS Methylprednisolone sodium succinate NO Nitric oxide NSAID Non-steroidal anti-inflammatory drug PGE Prostaglandin E PGE2 Prostaglandin E-two PGF2α Prostaglandin F-two alpha PGI2 Prostaglandin I-two PO Per os q Every RMANOVA Repeated measures analysis of variance SC Subcutaneous TNFα Tumor necrosis factor-alpha TXB2 Thromboxane B-two VIGOR Vioxx Gastrointestinal Outcomes Research Group °C Degrees Celsius µg Microgram ix INTRODUCTION The use of non-steroidal anti-inflammatory drugs (NSAIDs) in animals has increased since the introduction of new products and identification of new indications for their use. NSAIDs are primarily recognized for their analgesic, anti-pyrexic, and anti- inflammatory properties and are used extensively for postoperative pain management (both orthopedic and selected soft tissue procedures).1 The most common indication for the use of chronic NSAIDs in the canine patient remains the treatment of pain and inflammation associated with osteoarthritis.2 Side effects recognized with the use of NSAIDs in the dog include gastrointestinal (GI) bleeding/ulceration, nephrotoxicity, hepatotoxicity, and platelet dysfunction.1,3-5 In the United States alone, the development of NSAID associated GI ulceration results in the deaths of 5,000-16,500