The Enantiomers of Etodolac, a Racemic Anti-inflammatory Agent, Play Different Roles in Efficacy and Gastrointestinal Safety

Abstract

The therapeutic effects of non-steroidal anti-inflammatory drugs (NSAIDs) include anti-pyretic, analgesic and anti-inflammatory effects, while their adverse effects are primarily gastrointestinal (GI) and renal toxicity. The major therapeutic and adverse effects are mediated by the inhibition of cyclooxygenase (COX), which catalyzes the rate-limiting step in the formation of prostanoids from arachidonic acid. [1][2][3] There are two membrane-bound COX isoenzymes, the constitutively expressed COX-1 and the highly inducible COX-2. 4) COX inhibitors include conventional NSAIDs and COX-2-selective inhibitors. Conventional NSAIDs, at therapeutic doses, are non-selective COX inhibitors and inhibit both isoenzymes. The anti-inflammatory benefits of NSAIDs are primarily due to COX-2 inhibition, while inhibition of COX-1 often elicits GI toxicity. Etodolac is widely known as a COX-2-selective inhibitor. 5-7) It has good clinical anti-inflammatory efficacy and a good safety profile for the GI tract. 8) Many NSAIDs are chiral and are marketed as the racemate (which contains equal amounts of each enantiomer). The anti-inflammatory activity of NSAIDs and their inhibition of prostaglandin synthetase is largely stereospecific in favor of the S-enantiomer. 9) Etodolac too is a racemate consisting of S-and R-enantiomers, and S-etodolac inhibits prostaglandin synthesis in sheep vesicular glands and decreases hind-paw volume in established adjuvant arthritic rats. 10) Neuropathic pain is a common symptom caused by injury to peripheral or central nerves, and it can result from pathological changes induced by metabolic disease, viral infection, traumatic injury or chemotherapeutically induced nerve damage. Clinically, neuropathic pain is characterized by mechanical and thermal allodynia, hyperalgesia and spontaneous ongoing pain that are often refractory to treatment. 11) Patients with neuropathic pain do not respond to NSAIDs, and resistance or insensitivity to opiates is common. 12) We recently reported that etodolac attenuates allodynia in a mouse model of neuropathic pain. 13) The mechanism of the anti-allodynic effects of etodolac has not yet been established, but COX inhibition is unlikely to be involved because the COX inhibitors indomethacin and celecoxib do not attenuate the allodynia. There is still a question which enantiomer of etodolac produces the anti-allodynic effect in mice. And there is also a question whether the ulcerogenic activity of etodolac is attributable to the S-enantiomer alone.In the present study, we evaluated the inhibitory effects of the enantiomers of etodolac on COX-1 and COX-2. We also investigated the beneficial actions of racemic etodolac and its enantiomers, especially their anti-inflammatory effects, antiallodynic effects and ulcerogenic activity, in mouse and rat models. S-Etodolac, but not R-etodolac, inhibited COX-2 and showed anti-inflammatory and anti-allodynic effects, while R-etodolac showed a gastroprotective effect that may explain the low GI toxicity of racemic etodolac. MATERIALS AND...

Etodolac Containing Topical Niosomal Gel: Formulation Development and Evaluation

“…Its therapeutic effects are due to its ability to inhibit prostaglandin synthesis (“as discussed by Inoue et al [1]”). Prostaglandins are the chemicals which are responsible for pain and the fever and tenderness that occur with inflammation.…”

Increased Gastric Mucus Secretion Alleviates Non-Steroidal Anti-Inflammatory Drug-Induced Abdominal Pain

“…However, since the change in mucus secretion and the acid/mucus ratio did not differ significantly between those individuals who had severe mucosal injury and those who did not (such as in those with MLS of ≥ 4) (data not shown), there could be other mechanisms underlying the apparent differences in the severity of the mucosal injury between individuals administered naproxen and those administered etodolac. Interestingly, a recent study reported that etodolac consists of 2 enantiomers, S-and R-etodolac, and that R-etodolac reduced HCl/ethanolinduced gastric damage in rats (Inoue et al 2011). The gastroprotective effects of R-etodolac may also be associated with a modulation of the gastric secretory function.…”

Etodolac Blocks the Allyl Isothiocyanate-Induced Response in Mouse Sensory Neurons by Selective TRPA1 Activation

“…We have previously reported that etodolac shows an antiallodynic effect in a mouse model of neuropathic pain [3]. The effect depends on the S -enantiomer of etodolac and appears to be mediated by a COX-independent pathway.…”

“…We have previously reported that etodolac, a nonsteroidal anti-inflammatory drug (NSAID) and selective cyclooxygenase-2 (COX-2) inhibitor, attenuates allodynia in a mouse model of neuropathic pain [2]. The mechanism of the antiallodynic effect of etodolac has not yet been established, but COX inhibition is unlikely to be involved because other COX inhibitors do not attenuate the allodynia [2,3]. …”