Gastroprotective effects of amtolmetin guacyl: a new non-steroidal anti-inflammatory drug that activates inducible gastric nitric oxide synthase (original) (raw)
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Digestive Diseases and Sciences, 1999
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.
Autonomic and Autacoid Pharmacology, 2007
1 The in vivo effects of the non-steroid anti-inflammatory drug (NSAID) amtolmetin guacyl (AMG) on lipid peroxidation (LP) and on antioxidant enzyme and non-enzyme defence systems were investigated in models of stomach and colon damages, induced by other NSAIDs, by ethanol or by 2,4,6-trinitrobenzenesulfonic acid (TNBS).2 Indomethacin increased LP, glutathione peroxidase (GSH-PX) and glucose-6-phosphate dehydrogenase (Glu-6-P-DH) activities and decreased glutathione levels in gastric mucosa. Pretreatment with AMG normalized some of the parameters affected by indomethacin.3 Treatment of rats with ethanol for 0.5 h led to a decrease in glutathione levels as well as activities of glutathione reductase and Glu-6-P-DH in gastric mucosa. AMG, administered 0.5 h before ethanol, limited the adverse actions of ethanol.4 Amtolmetin guacyl failed to abolish the TNBS-induced changes in the followed-up parameters in colon mucosa and liver, but additional alterations (as with tolmetin) were not observed.5 The beneficial profile of AMG in the various experimental models of free radical-induced damage investigated in this study suggests the possibility that this drug might possess antioxidant activity.
Endogenous nitric oxide modulates ethanol-induced gastric mucosal injury in rats
Gastroenterology, 1995
Background~Aims: Endothelium-derived relaxing factor regulates vascular tone via vasodilation. The relative contribution of endogenous nitric oxide to the pathophysiology of ethanol-induced gastric mucosal microcirculatory disturbances was investigated in anesthetized rats. Methods: Macroscopic and microscopic gastric mucosal damage and gastric mucosal hemodynamics including blood flow and hemoglobin oxygen saturation (IS02) were assessed by pretreatment with a specific NO synthase inhibitor, N~-nitro-L-arginine (L-NNA), before and after intragastric administration of ethanol. Results: Pretreatment with L-NNA significantly increased macroscopic (7.7-fold) and microscopic damage caused by 30% ethanol. Concurrent administration of L-arginine, but not D-arginine, significantly reduced the increase in mucosal damage. Similar results were obtained with 60% ethanol. Pretreatment with L-NNA decreased both mucosal blood flow and IS02 in the basal period and enhanced decreases in both mucosal blood flow (2.7-fold) and IS02 (4.34old) induced by 30% ethanol compared with controls. Concurrent administration of L-arginine, but not D-arginine, significantly inhibited the effect of L-NNA on blood flow and IS02 in the basal period as well as after intragastric administration of 30% ethanol. Conclusions: Endogenous NO modulates ethanol-induced gastric mucosal injury through the regulation of gastic mucosal microcirculation.
2001
Amtolmetin guacyl (AMG) is a nonsteroidal antiinflammatory drug (NSAID) of high therapeutic activity and free of damaging effects on the gastrointestinal tract. Since acute ulcer and nausea have been found to be associated with gastric dysrhythmias, cutaneous electrogastrography and ultrasonographic study of the gastric emptying time were performed simultaneously in 24 healthy volunteers before and for 180 min after a liquid meal with 0.5 g/kg body weight of alcohol in double-blind, placebo-controlled, crossover studies. Before the recording session, each subject had taken placebo, AMG, a standard NSAID, or a gastric protective drug for four days. Alcohol administration increased the tachygastria percentage while diclofenac, AMG, and misoprostol alone did not induce gastrointestinal symptoms and gastric dysrhythmias. As regards alcohol-induced gastric dysrhythmia, placebo and diclofenac showed a clear increase in tachygastria while AMG and misoprostol did not. AMG is able to induce a normalization of gastric dysrhythmia induced by alcohol administration probably due to its peculiar mechanism of action, which involves capsaicin and CGRP pathways.
Nitric oxide enhances prostaglandin production in ethanol-induced gastric mucosal injury in rats
European Journal of Pharmacology, 1998
The interaction between endogenous nitric oxide NO , elicited by administration of Escherichia coli lipopolysaccharide, and cyclooxygenase system, in ethanol-induced injury in rat gastric mucosa, was investigated. Administration of graded doses of lipopolysaccharide reduced the gastric mucosal injury in response to ethanol. The ex vivo production of both nitrite and prostaglandin E was 2 6 Ž . Ž . increased in dose-related manner by lipopolysaccharide. Pretreatment with dexamethasone, L-N -1-Iminoethyl lysine dihydrochloride and L-N G -nitro arginine methyl ester inhibited the protection associated with lipopolysaccharide treatment and the ex vivo production of both, nitrite and prostaglandin E . The pretreatment with L-arginine counteracted the decrease of nitrite and prostaglandin E production 2 2 6 Ž . Ž . in lipopolysaccharide-treated rats in which nitric oxide synthesis was blocked by L-N -1-Iminoethyl lysine dihydrochloride . Administration of sodium nitroprusside and S-nitroso-N-acetyl-D,L-penicillamine caused a dose related enhancement in the accumulation of Ž . prostaglandin E . Indomethacin administration and N-2-Cyclohexyloxy-4-nitrophenyl methanesulfonamide were ineffective in suppress-2 ing lipopolysaccharide-mediated protection against ethanol-induced damage, and in suppressing ex vivo increase of nitrite whereas the ex vivo increase of prostaglandin E was prevented in a dose-related fashion. These results indicate that in ethanol-induced rat gastric injury, 2 endogenous NO elicited by lipopolysaccharide or released by NO donors is able to activate the cyclooxygenase pathway, and the protective effect of lipopolysaccharide is dependent upon NO formation. q
Life Sciences, 1999
The roles of ca sulfhydryls (SHs), prostag andins (PGs) in the gastroprotection by momordin Ic, an oleanohc acid P saicin-sensitive sensory nerves (CPSN), endogenous nitric oxide,(NG), oligoglycoside isolated from the fruit of Kochiu scoparia (L.) SCHRAD., on ethanol-induced astric mucosal lesions were investigated in rats. Momordin Ic (10 mg/kg, p.0.) potentially inhibited e t!i anolinduced gastric mucosal lesions. The effect of momordin Ic was markedly attenuated by the pretreatment with capsaicin (125 mg/kg in total, s.c., an ablater of CPSN), NC-nitro-L-argmme methyl ester (L-NAME, 70 mg/kg, i.p., an inhibitor of NO synthase), N-ethylmaleimide (NEM, 10 mg/kg, s.c., a blocker of SHs), or indomethacin (10 mg/kg, KC., an inhibitor of PGs bios nthesis). The attenuation of L-NAME was abolished by L-arginine (300 mg/kg, i.v., a substrate of K 0 synthase), but not by D-arginine (300 mg/k , i.v., the enatiomer of L-arginine). The effect of the combination of capsaicin with mdomethacin, d M, or L-NAME was not more potent than that of capsaicm alone. The combination of indomethacin and NEM, indomethacin and L-NAME, or indomethacin and NEM and L-NAME increased the attenuation of each alone. These results suggest that CPSN play an im rtant role in the astroprotection by momordin Ic on ethanol-induced gastric mucosal lesions, an s" endogenous PGs, g 0, and SHs interactively p tikipak, in rats.
Adaptive cytoprotection through modulation of nitric oxide in ethanol-evoked gastritis
World journal of gastroenterology : WJG, 2004
To assess the mechanisms of protective action by different mild irritants through maintenance of gastric mucosal integrity and modulation of mucosal nitric oxide (NO) in experimental gastritis rats. Either 200 mL/L ethanol, 50 g/L NaCl or 0.3 mol/L HCl was pretreated to normal or 800 mL/L ethanol-induced acute gastritis Sprague-Dawley rats before a subsequent challenge with 500 mL/L ethanol. Both macroscopic lesion areas and histological damage scores were determined in the gastric mucosa of each group of animals. Besides, gastric mucosal activities of NO synthase isoforms and of superoxide dismutase, along with mucosal level of leukotriene (LT)C4 were measured. Macroscopic mucosal damages were protected by 200 mL/L ethanol and 50 g/L NaCl in gastritis rats. However, although 200 mL/L ethanol could protect the surface layers of mucosal cells in normal animals (protection attenuated by NG-nitro-L-arginine methyl ester), no cytoprotection against deeper histological damages was found ...
European Journal of Pharmacology, 1999
In this study the effect of nitric oxide NO synthesis inhibition on ethanol-induced gastric damage was evaluated in bile duct-ligated, Ž. G sham-operated and unoperated rats. The animals were injected intraperitoneally with saline, L-arginine 200 mgrkg or N-nitro-L-arginine Ž. methylester L-NAME in doses of 5, 15 and 30 mgrkg, 30 min before ethanol administration. The animals were killed 1 h after ethanol administration and their stomachs were removed for measurement of gastric mucosal damage. The results showed that L-NAME significantly enhanced the development of gastric mucosal lesions in sham-operated and unoperated rats, while in bile duct-ligated animals, L-NAME decreased and L-arginine enhanced the potentiation of ethanol-induced gastric mucosal damage. The plasma level of nitrite and nitrate was also measured and was significantly higher in bile duct-ligated rats than in control groups. The results suggest that inhibition of NO synthase with L-NAME has different effects on ethanol-induced gastric damage in cholestatic groups and in normal rats and that these effects can be explained by overproduction of NO in bile duct-ligated animals.
Life Sciences, 2000
Studies on the effect of ninhydrin in the normal gastric mucosa and against the ethanol induced gastric injury were undertaken in rats in view of the presence of a carbonyl function as well as hydroxyl groups in its chemical structure. In spite of its potentials to generate hydroxyl radicals, it is deemed to possess antioxidant property by virtue of its electrophillic nature. Recent studies have shown gastroprotection to mediate through a reaction between the electrophillic compounds and sulfhydryl groups of the mucosa. Hence it was found worthwhile to evaluate the interaction between the oxidant and antioxidant functions in the structure of the same compound. The effects of ninhydrin pretreatment on gastric mucosal injuries caused by 80% ethanol, 25% NaCl and 0.2M NaOH were investigated in rats. The gastric tissue in ethanol-treated rats was analyzed for different histopathological lesions. In addition, the effects on ethanol-induced changes in the gastric levels of proteins, nucleic acids, non-protein sulfhydryl (NP-SH) and malondialdehyde (MDA) were also evaluated. Ninhydrin, as such, failed to induce any signiÞcant changes in normal gastric mucosa, while its pretreatment at oral doses of 5, 10 and 20 mg/kg was found to provide a dose-dependent protection against the ulcers induced by ethanol, NaOH and NaCl. The results of histopathological evaluation revealed a protective effect of ninhydrin on congestion, hemorrhage, edema, erosions and necrosis caused by ethanol. Furthermore, the pretreatment afforded a dose-dependent inhibition of the ethanol-induced depletion of proteins, nucleic acids, NP-SH and increase of MDA in the gastric tissue. The results obtained clearly demonstrate the anti-ulcerogenic activity of ninhydrin. The exact mechanism of action is not known. However, the carbonyl function in ninhydrin appears to achieve antioxidant balance and protect the gastric mucosa from the ethanol-induced gastric injury. Further studies are warranted to investigate the toxicity and detailed mechanism of action of this potent compound before any clinical trials, especially at the effective lower doses.