Untitled

Abstract

The effect of the nonsteroidal antiinflammatory drug (NSAID) amtolmetin guacyl (AMG) on the gastric mucosa was studied in the rat by means of histological and functional techniques. AMG administered at 50-300 mg/kg intragastrically was virtually devoid of gastrolesive properties after either acute or repeated treatment. By contrast, its metabolite, tolmetin (TOL, 15-60 mg/kg, intragastrically) caused dose-dependent gastric damage after both treatments. Light and electron microscopy revealed that AMG induced minimal changes in the surface epithelium layer, without signs of vasocongestion or leukocytes adherence. AMG (50 mg/kg intragastrically) did not change basal gastric potential difference (PD), whereas acetylsalicylic acid and ibuprofen induced falls in PD of 22 and 27 mV, respectively. AMG (50 mg/kg intragastrically) reduced by 60% the fall in PD induced by 50% ethanol; this inhibition was dependent on the incubation time, and was maximal when AMG was given 4 hr before ethanol. AMG (100 mg/kg intragastrically) induced an increase in NO synthase type 2 (NOS2) activity, which was significantly different from control values, when AMG was administered 4 hr before the test. The metabolites of AMG, tolmetin, MED 5, and guaiacol were ineffective. Pharmacokinetic analysis of the residence time of AMG in the different areas of the gastrointestinal tract, revealed that AMG remains in the gastrointestinal tract at least for 4 hr, the time necessary for a maximal induction of NOS2 and for maximal protection against ethanol-induced damage. In conclusion, these data indicate that the nonsteroidal antiinflammatory drug amtolmetin guacyl is devoid of gastrolesive properties; this gastro-sparing effect seems to involve the production of nitric oxide, which can counteract the damaging effects due to prostaglandin inhibition. The presence in the stomach of the native molecule of amtolmetin guacyl seems to be necessary for the protective effect observed.

An Open-Label Multicenter Observational Study of the Efficacy, Tolerability, and Safety of the Nonsteroidal Anti-Inflammatory Drug Amtolmetin Guacil in Patients With Knee Osteoarthritis and Dyspepsia

“…Имеются данные о том, что АМГ обладает сходной эффективностью с неселективными в отношении ЦОГ НПВП и селективным ингибитором ЦОГ2 целекоксибом, но лучшей переносимостью со стороны органов ЖКТ [16][17][18][19][20]. Полагают, что этот благоприятный эффект АМГ связан с наличием в структуре молекулы остатков ванилина, которые стимулируют рецепторы капсаицина и образование пептида, связанного с геном кальцитонина, что в свою очередь способствует образованию оксида азота, обладающего «гастропротективной» активностью [21,22]. Полагают, что активация рецепторов капсаицина имеет место после прямого контакта препарата со слизистой оболочкой желудка, поэтому для реализации максимальной «гастропротективной» активности АМГ следует принимать натощак.…”

Morphological Features of Rat Gastric Mucosa after Acute and Chronic Treatment with Amtolmetin Guacyl: Comparison with Non-Selective and COX-2-Selective NSAIDs

“…depending on the experimental model) in the rat [17]. In the present study the TOL doses chosen were based on previous work [10], demonstrating a dose-dependent ulcerogenic effect in the rat. Equimolar doses of AMG were administered.…”

“…Among the various approaches carried out to prevent NSAID-induced gastropathy, cyclooxygenase-2 (COX-2)-selective inhibitors (already on the market) [4, 5]and nitric oxide (NO)-releasing NSAIDs (now in clinical trials) [6, 7]seem to be the more attractive therapeutic option. The mechanism shown by amtolmetin guacyl (AMG), a prodrug of tolmetin (TOL), is based on NO-mediated gastro-protective effects, and in previous animal and clinical studies AMG has demonstrated very good gastric tolerability combined with therapeutic efficacy comparable to that shown by conventional NSAIDs [8, 9, 10, 11, 12]. The reduced ulcerogenic potential of AMG is not related to a higher selectivity for the COX-2 isoenzyme, this compound being a non-selective inhibitor of both isoforms.…”

“…Previous studies in the rat have revealed that AMG is able to increase the activity and the expression of the inducible isoform of NO synthase (iNOS) in the gastric mucosa [13]. The increase in NO production also explains the gastro-protective activity of this drug against the gastric damage induced by ethanol [10], indomethacin and acetylsalicylic acid [13, 14]. …”

Analgesics and Antipyretics, 2. Nonsteroidal Anti‐inflammatory Drugs

“…Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs are a new and promising goup of analgesic and anti-inflammatory compounds. NO release is found as a mechanistically not yet resolved property of a few new COX-1 inhibitors such as amtolmetin [40] or it can be induced by adding a NO releasing moiety (e.g., nitroxybutyl) to existing COX-inhibitors [41]. The most advanced compounds are NO-naproxen and NO-flurbiprofen (NCX-2216).…”