Acemetacin antinociceptive mechanism is not related to NO or K+ channel pathways.

Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) used for the treatment of acute gout and inflammation. However, its use is limited due to side effects. Acemetacin is a prodrug of indomethacin that exhibits better gastric tolerability in preclinical and clinical trials. The aim of this study was to examine if the systemic administration of acemetacin involved the sequential participation of nitric oxide (NO) or K+ channel pathways to confer its antinociceptive effect, as compared to indomethacin. The antinociceptive effect of both drugs was studied with the formalin test. Equimolar doses of acemetacin or indomethacin were administered orally. The intraplantar administration of either L-NAME, glibenclamide, apamin or charybdotoxin plus indomethacin or acemetacin was studied using the formalin test and the anti-inflammatory and antihyperalgesic effects were measured. The antinociceptive effect of acemetacin or indomethacin was not significantly different when pretreatment with L-NAME, glibenclamide, apamin or charybdotoxin was done. The antihyperalgesic and antiinflammatory effects were also similar for both indomethacin and acemetacin. Our results suggest that the antinociceptive effect of indomethacin or acemetacin is not mediated by NO or K+ channel activation.

Lack of effects of acemetacin on signalling pathways for leukocyte adherence may explain its gastrointestinal safety.

BACKGROUND AND PURPOSE: Acemetacin is a non-steroidal anti-inflammatory drug which is rapidly bioconverted to indomethacin, but produces significantly less gastric damage than indomethacin. This study was performed to investigate several possible mechanisms that could account for the gastrointestinal tolerability of acemetacin. EXPERIMENTAL APPROACH: The gastric and intestinal damaging effects of acemetacin and indomethacin were examined in the rat. Effects of the drugs on blood levels of leukotriene B(4) and thromboxane B(2), on leukocyte-endothelial adherence in post-capillary mesenteric venules, and on gastric expression of tumour necrosis factor-alpha (TNF-alpha) were determined. The two drugs were also compared for gastric toxicity in rats pretreated with inhibitors of COX-2 and NOS. KEY RESULTS: Acemetacin induced significantly less gastric and intestinal damage than indomethacin, despite markedly suppressing COX activity. Indomethacin, but not acemetacin, significantly increased leukocyte adherence within mesenteric venules, and gastric expression of TNF-alpha. Pretreatment with L-nitro-arginine methyl ester or lumiracoxib increased the severity of indomethacin-induced gastric damage, but this was not the case with acemetacin. CONCLUSIONS AND IMPLICATIONS: The increased gastric and intestinal tolerability of acemetacin may be related to the lack of induction of leukocyte-endothelial adherence. This may be attributable to the reduced ability of acemetacin to elevate leukotriene-B(4) synthesis and TNF-alpha expression, compared to indomethacin, despite the fact that acemetacin is rapidly bioconverted to indomethacin after its absorption.

Mechanisms underlying the anti-inflammatory activity and gastric safety of acemetacin.

BACKGROUND AND PURPOSE: Acemetacin is regarded as a pro-drug of indomethacin and induces significantly less gastric damage but the reasons for this greater gastric safety of acemetacin are unclear. The anti-inflammatory effects of acemetacin have been attributed, at least in part, to its hepatic biotransformation to indomethacin. The aim of this study was to determine the effects of acemetacin and indomethacin in an in vivo model of acute inflammation and to examine the importance of biotransformation of acemetacin (to indomethacin) to its anti-inflammatory actions. EXPERIMENTAL APPROACH: The zymosan airpouch model was used in rats. Indomethacin or acemetacin (2.7-83.8 micromol kg(-1)) were administered orally or directly into the pouch. Leukocyte infiltration, prostaglandin (PG) E(2) and leukotriene (LT) B(4) levels in exudates, and whole blood thromboxane (TX) B(2) synthesis were measured. KEY RESULTS: Acemetacin was rapidly converted to indomethacin after its administration. Both acemetacin and indomethacin elicited comparable, dose-dependent reductions of leukocyte infiltration and of PGE(2) and TXB(2) synthesis. However, indomethacin induced more gastric damage than acemetacin and elevated LTB(4) production in the airpouch. CONCLUSIONS AND IMPLICATIONS: The similar effects of acemetacin and indomethacin on leukocyte infiltration and PG synthesis are consistent with rapid biotransformation of acemetacin to indomethacin. Some of this biotransformation may occur extra-hepatically, for instance in inflammatory exudates. Acemetacin probably exerts actions independent of conversion to indomethacin, given the different effects of these two drugs on LTB(4) production. Such differences may contribute to the relative gastric safety of acemetacin compared to indomethacin.