Pharmaceutical Effects of Inhibiting the Soluble Epoxide Hydrolase in Canine Osteoarthritis

Osteoarthritis (OA) is a degenerative joint disease that causes pain and
bone deterioration driven by an increase in prostaglandins and
inflammatory cytokines. Current treatments focus on inhibiting
prostaglandin production, a pro-inflammatory lipid metabolite, with NSAID
drugs; however, other lipid signaling targets could provide safer and more
effective treatment strategies. Epoxides of polyunsaturated fatty acids
are anti-inflammatory lipid mediators that are rapidly metabolized by the
soluble epoxide hydrolase (sEH) into corresponding vicinal diols. sEH
inhibitors (sEHI) stabilize these biologically active, anti-inflammatory
lipid epoxides and are analgesic in both neuropathic and inflammatory pain
conditions. Additionally, increased diols have been observed in the
synovial fluid of humans with OA, warranting further research on the
biological role of this pathway in the progression of OA. Most
experimental studies testing the analgesic effects of sEH inhibitors have
used experimental rodent models which do not completely represent the
complex etiology of painful diseases. Here, we tested the efficacy of sEH
inhibitors in aged dogs with natural arthritis to provide a better
representation of the clinical manifestations of pain. Two sEHI were
administered orally, once daily for five days to dogs with naturally
occurring arthritis to assess efficacy and pharmacokinetics. Blinded
technicians recorded the behavior of the arthritic dogs based on
pre-determined criteria to assess pain and function. After five days,
EC1728 significantly reduced cumulative pain at a dose of 5 mg/kg compared
to vehicle controls. Pharmacokinetic evaluation showed concentrations
exceeding the enzyme potency in both plasma and synovial fluid. In vitro
data showed that epoxyeicosatrienoic acid (EETs), epoxide metabolites of
arachidonic acid, decreased inflammatory cytokines, IL-6 and TNF-α, in
canine chondrocytes challenged with IL1β to simulate an arthritic
environment. These results provide proof of concept that inhibiting the
sEH is a non-NSAID, non-opioid strategy for treating osteoarthritis.