The mechanism of action of amtolmetin guacyl, a new gastroprotective nonsteroidal anti-inflammatory drug.

Amtolmetin guacyl (2-methoxyphenyl-1-methyl-5-p-methylbenzoyl-pyrrol-2-acetamido acetate) (MED15) is a new nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic and antipyretic properties similar to the traditional drugs, but with unexpected gastroprotective effects. In an in vivo rat model, amtolmetin guacyl administered orally demonstrates inhibition of gastric acid secretion following stimulation by various agonists, and up-regulation of gastric bicarbonate production. Pretreatment with MED15 also shows a significant reduction of indomethacin-induced gastric damage in the rat. The reason behind this behaviour appears to be bound to the presence in the MED15 molecule of a vanillic moiety known to stimulate capsaicin receptors. In fact, the antisecretive effect of MED15 is blocked by capsazepine (a specific capsaicin receptor antagonist). This effect is confirmed by the interference found with anti-histamine H(1) drugs. Owing to the connection between capsaicin and calcitonin gene-related peptide (CGRP), a possible effect of MED15 on CGRP receptors was hypothesized, considering the leading role played on gastric mucosa by the predominant sensory neuropeptide of the stomach wall, CGRP. In fact, the anti-secretive and gastroprotective effect of MED15 is abolished by CGRP-(8-37) (the specific CGRP receptor antagonist). The unmodified MED15 molecule is found throughout the gastroenteric tract for long periods of time following oral administration, as further confirmation of the mechanism of action being based on the presence of the vanillic moiety at receptor level.