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Gastrosparing Effect of New Antiinflammatory Drug Amtolmetin Guacyl in the Rat (Involvement of Nitric Oxide)

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Abstract

The effect of the nonsteroidal antiinflammatorydrug (NSAID) amtolmetin guacyl (AMG) on the gastricmucosa was studied in the rat by means of histologicaland functional techniques. AMG administered at 50-300 mg/kg intragastrically was virtuallydevoid of gastrolesive properties after either acute orrepeated treatment. By contrast, its metabolite,tolmetin (TOL, 15-60 mg/kg, intragastrically) caused dose-dependent gastric damage after bothtreatments. Light and electron microscopy revealed thatAMG induced minimal changes in the surface epitheliumlayer, without signs of vasocongestion or leukocytes adherence. AMG (50 mg/kg intragastrically) didnot change basal gastric potential difference (PD),whereas acetylsalicylic acid and ibuprofen induced fallsin PD of 22 and 27 mV, respectively. AMG (50 mg/kg intragastrically) reduced by 60% the fall in PDinduced by 50% ethanol; this inhibition was dependent onthe incubation time, and was maximal when AMG was given4 hr before ethanol. AMG (100 mg/kg intragastrically) induced an increase in NO synthase type 2(NOS2) activity, which was significantly different fromcontrol values, when AMG was administered 4 hr beforethe test. The metabolites of AMG, tolmetin, MED 5, and guaiacol were ineffective. Pharmacokineticanalysis of the residence time of AMG in the differentareas of the gastrointestinal tract, revealed that AMGremains in the gastrointestinal tract at least for 4 hr, the time necessary for a maximalinduction of NOS2 and for maximal protection againstethanol-induced damage. In conclusion, these dataindicate that the nonsteroidal antiinflammatory drugamtolmetin guacyl is devoid of gastrolesive properties;this gastrosparing effect seems to involve theproduction of nitric oxide, which can counteract thedamaging effects due to prostaglandin inhibition. Thepresence in the stomach of the native molecule ofamtolmetin guacyl seems to be necessary for theprotective effect observed.

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Authors
  1. Claudio Pisano
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  2. Daniela Grandi
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  3. Giuseppina Morini
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  4. Gabriella Coppelli
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  5. Loredana Vesci
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  6. Pietro Lo Giudice
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  7. Silvia Pace
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  8. Licia Pacifici
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  9. Antonio Longo
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  10. Gabriella Coruzzi
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  11. Paolo Carminati
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Pisano, C., Grandi, D., Morini, G. et al. Gastrosparing Effect of New Antiinflammatory Drug Amtolmetin Guacyl in the Rat (Involvement of Nitric Oxide). Dig Dis Sci 44, 713–724 (1999). https://doi.org/10.1023/A:1026653623516

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