Box 2 | Nonsteroidal anti-inflammatory drugs for canine arthritis 

In humans, nonsteroidal anti-inflammatory drugs (NSAIDS) — which inhibit the production of prostaglandins by targeting the enzyme cyclooxygenase (COX), thereby disrupting the inflammatory cascade — have been used to ameliorate the symptoms of arthritis for many years. However, prostaglandins also have functions such as the protection of the gastric mucosa, and so inhibition of their formation can lead to gastrointestinal toxicity. In the early 1990s, it was discovered that the COX enzyme has two isoforms, COX-1 and COX-2 (Ref. 22). Simply speaking (although the finer points are still a matter of considerable debate), COX-1 is constitutively active and produces normal regulatory and protective prostaglandins, whereas COX-2 is inducible and produces prostaglandins at sites of inflammation. On the basis of these different roles of the isoforms, it was proposed that drugs that had greater specificity for COX-2 than traditional NSAIDs — such as aspirin, which inhibits both COX-1 and COX-2 — might retain their anti-inflammatory effects but have reduced gastrointestinal toxicity. This led to the development of COX-2-selective inhibitors²², such as celecoxib and rofecoxib, which are now widely used in the treatment of arthritis.

Although more than 50 NSAIDs have been approved for use in humans, significant species-to-species differences in efficacy and, in particular, toxicity profiles have limited their direct extrapolation to animals. Nevertheless, the development of NSAIDS for canine arthritis has followed a similar pattern to that in humans. Non-selective NSAIDS, such as aspirin, have been used for many years²³. In the 1990s, carprofen (see figure), which is fairly selective for COX-2 over COX-1 in in vitro assays (10–100-fold in vitro, depending on the assay used^24-26) was approved. And, more recently, the highly selective (>1,000-fold in vitro²⁶) COX-2 inhibitor deracoxib (see figure), which is a relative of celecoxib and rofecoxib, but which has a more predictable duration of action and dose response in dogs, has also been introduced.

The recent approval of the NSAID tepoxalin (see figure) for canine arthritis further highlights how the fruits of human drug development programmes can be translated into novel animal drugs (indeed, in some cases, drugs that are successful in animals in preclinical tests, but turn out not to have a suitable biological profile in humans, might have the potential to be 'reborn' as animal drugs). Tepoxalin not only inhibits COX-1 and COX-2, but also 5-lipooxygenase, another important enzyme in the inflammatory cascade, and, like other compounds in this class, was developed as a potential human drug on the basis that such a dual inhibitory profile might offer high efficacy with little toxicity²⁷. However, although dual inhibitors have reached late-stage human clinical trials, none has yet been approved, and so the novel therapeutic approach of dual inhibition has become available for use in animals before humans.

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