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Amtolmetin guacyl (MED15) is a new non-steroidal anti-inflammatory drug (NSAID) which shares anti-inflammatory, analgesic and antipyretic activity with the other drugs of the NSAID family but which shows, unexpectedly, strong gastroprotective activity similar to misoprostol. This effect has been attributed to the presence in its molecule of a vanillic moiety responsible for stimulation of capsaicin receptors present throughout the length of the gastrointestinal tract. MED15 shows antispasmodic activity in the bowel against a number of agonists and compares favourably with reference compounds. In in vivo indomethacin-induced rat ileitis, MED15 heals better than 5-aminosalicylic acid and sulfasalazine, as well as down-regulating intestinal wall myeloperoxidase content. In acetic acid-induced colitis in the rat, levels of malondialdehyde were found to be more markedly reduced with MED15 than with 5-aminosalicylic acid. In contrast with the effect in the stomach, MED15 protective effect in the bowel appears to be unrelated to nitric oxide (NO) production. The MED15 enteroprotective effect is related to stimulation of intestinal capsaicin receptors as demonstrated by the loss of protective effect in the presence of capsazepine, a specific receptor antagonist of capsaicin. In conclusion, following the favourable results obtained in animal models and notwithstanding the pharmacological effects typical of an NSAID, MED15 may rationally be proposed for the treatment of various human colitis conditions and Crohn's disease.

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.

A new de-N-acetylated glycosphingolipid termed WILD20, a breakdown product of GM1 obtained through alkaline hydrolysis, and characterized by nuclear magnetic resonance, mass spectrometry and elementary analysis, was found to inhibit phospholipase A2 via phosphokinase C translocation blockade. The substance inhibited various tumour cell lines in vitro, in synergy with doxorubicin and cisplatin. In vivo, it showed an antitumoral effect when both the tumour cells and WILD20 were injected at the same site (peritoneal cavity). Tumour cells, incubated with WILD20, showed a dose-dependent decrease of oncogenicity without impairment of viability. WILD20 also down-regulated tumour cell adherence to laminin and fibronectin. When peritumorally administered, WILD20 impaired tumour growth and potentiated the peritumoral effects of recombinant interleukin 2. The results obtained merit exploration of the therapeutical possibilities of this agent in human cancer patients.

Gal beta 1-->3GalN beta 1-->4Gal(3<--2 alpha Neu)beta 1-->4Glc beta-->1Sph (WILD20), a new glycosphingolipid, a breakdown product of the monosialoganglioside GM1 obtained through alkaline hydrolysis, shows dose-dependent platelet anti-aggregating properties in vitro and in vivo. This effect is agonist- and species-independent. The family of lysosphingolipids, to which the compound belongs, is present in platelets particularly after thrombin treatment. WILD20 antiplatelet effect is due to the interference with ADP or thrombin-induced aggregation, probably via phospholipase A2 (PLA2) blockade; the substance is also effective when arachidonic acid is used as an agonist. Serotonin blood levels are also reduced. The substance, orally active at dosages of 0.1-0.01 mg/kg as antiplatelets agent, prolonged bleeding time without interfering with the coagulative or fibrinolytic processes.

A comparison of the effects of methadone and morphine on phagocytic physiology was carried out in mice, using a number of tests, to estimate the risk of using methadone in maintenance protocols for opiates addicts. Results indicate that methadone, like morphine, reduces (a) R.E.S. activity and (b) PMN superoxide anion production, while unlike morphine it (a) does not produce haematologic changes, (b) does not exacerbate C. albicans infections, (c) does not inhibit phagocytosis and killing by murine polymorphonuclear leukocytes and macrophages, or by rabbit alveolar macrophages, and (d) does not reduce spleen and liver weight. These results are in strict agreement with those previously found in human subjects receiving controlled administration of morphine or methadone. Compared to morphine methadone therefore appears to have a lower toxic potentiality.