The Effect of Novel Anti-inflammatory Drugs on the Cyclooxygenase Enzymes and Recovery of Mucosal Barrier Function

Abstract

The non-steroidal anti-inflammatory drugs (NSAIDs) are a large group of drugs that are commonly used for the treatment of pain and inflammation in the veterinary species. The NSAIDs inhibit the action of the cyclooxygenase (COX) enzymes, COX-1 and COX-2, to reduce the production of prostaglandins. However, their use is associated with adverse effects, particularly in the gastrointestinal tract which may be related to the inhibition of COX-1. To reduce the incidence of these effects, NSAIDs have been designed to selectively inhibit COX-2 while allowing physiologic prostaglandin production by COX-1. The first experiments of this thesis aimed to determine the effect of three NSAIDs in the horse. Flunixin meglumine is commonly used to treat pain and endotoxemia associated with colic in the horse. Deracoxib and firocoxib have been shown to be COX-2 selective in the dog. This study used in vitro whole blood assays to determine the effect of flunixin meglumine, deracoxib, and firocoxib on the COX enzymes. Using this model, flunixin meglumine was shown to non-selectively inhibit COX-1 and COX-2 in the horse. In contrast, deracoxib and firocoxib selectively inhibited COX-2 in the horse. Using an in vitro equine whole blood assay, the next project determined that the novel NSAID robenacoxib is COX-2 selective in the horse. The effect of robenacoxib and flunixin meglumine on the recovery of ischemic-injured equine jejunum was then compared using an equine ex vivo model. While flunixin meglumine significantly inhibited the production of prostaglandin E2 (PGE2) and the recovery of barrier function, robenacoxib allowed barrier function to recovery and production of PGE2. The mechanism of action of the novel anti-inflammatory compound AHI-805 is currently unknown. Using an in vitro equine whole blood model, the effect of AHI-805 on COX-1 and COX-2 was determined. While AHI-805 did not inhibit COX-1, it did significantly inhibit the action of COX-2. The effect of AHI-805 on the recovery of mucosal barrier function in ischemic injured equine jejunum was determined using an equine ex vivo model. Treatment of ischemic injured equine jejunum with AHI-805 significantly inhibited the recovery of mucosal barrier function. Furthermore, in this ex vivo model AHI-805 significantly inhibited the action of both COX-1 and COX-2.