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Usmanova Shakhnoza Erkinovna, Independent researcher of Tashkent Medical Academy,
Republic of Uzbekistan Yakubov Abdujalol Vahabovich, Head of the department of Clinical Pharmacology Hamraev Abror Asrarovich, professor of the department of Internal Medicine № 2 of Tashkent Medical Academy Republic of Uzbekistan
E-mail: [email protected]
INFLUENCE OF SOME I-APF ON CYTOPROTECTION MECHANISMS IN INDOMETHATSIN-INDUCED GASTROPATHYARTHRITIS
Abstract: On the experimental model of indomethacin-induced gastropathy in rats, the effect ofACE inhibitors, omeprazole, saitotec and their combinations on the mucosal barrier of the stomach was studied. It was found that with indomethacin-induced gastropathy indomethacin significantly suppresses the synthesis of insoluble glycoproteins in the mucous barrier and reduces the number of functioning mucus cells. ACE inhibitors have a cytoprotective effect in the treatment of indomethacin gastropathy. The most effective was captopril, the cytoprotective effect of which is equal to that of omeprazole and saitoteka.
With the combined use of omeprazole with ACE inhibitors and with the cytotext their cytoprotective pharmacodynamic effect increases as additive synergism. The most effective combination of omeprazole with captopril and omeprazole with saitotekom.
Keywords: indomethacin, gastropathy, cytoprotection, treatment.
One of the most important problems associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) is their damaging effect on the gastrointestinal tract, which can lead to serious complications. According to various sources, gastroduo-denal side effects can be observed in 20-40% of patients who regularly take NSAIDs. In 10-30% of them with esophagogas-troduodeno-scopy ulcers of the stomach and duodenum are detected. In this connection, in the last decade, special attention has been paid to the problem of the safe use of NSAIDs, the prevention and treatment of gastrointestinal side effects. However, methods for the prevention and effective treatment of NSAID-induced gastropathies have not been fully developed [3].
Prospective drugs for treatment are angiotensin converting enzyme (ACE inhibitors). It has been established that they stimulate the synthesis of prostaglandins. We assumed that they have a similar effect in the gastrointestinal tract. This can be confirmed by the results of a study by A. A. Gidoyatova et al. [5], who noted the ulcerative effect of enalapril and reniteca in the treatment of patients with heart failure with concomitant peptic ulcer. Similar data are cited by S. A. Alekseenko et al. [2] who established the ulcerative effect of enalapril in patients with hypertension and concomitant peptic ulcer.
Purpose ofthe study. Comparative evaluation of the effect of some ACE inhibitors, misoprostol, omeprazole and their combinations on the mucosal barrier ofthe stomach in indomethacin gastropathy in animals with experimental rheumatoid arthritis.
Object and methods of research. The effect of ACE inhibitors, omeprazole, misoprostol and the combination of omeprazole with ACE inhibitors and misoprostol on the gastric mucosa was studied in 78 male rats with a mixed population of160-200 g, which were on the usual diet ofthe vivarium. The animals were divided into 13 groups of 6 animals each: 1st group - intact, 2nd group - animals with experimental rheumatoid arthritis (ERA.), 3rd - animals with ERA. and indometacin gastropathy (GERA), 4th - GERA + H2O (without treatment), 5th - GERA + enalapril, 6th - GERA + lisinopril, 7th - GERA + + captopril, 8th - GERA + omeprazole, 9th - GERA + misoprostol, 1- I - GERA + omeprazole + enalapril, 11th - GERA + + omeprazole + lisinopril, 12th - GERA. + omeprazole + captopril, 13th - GERA. + omeprazole + misoprostol.
The preparations used were administered per os in the form of an aqueous suspension in 10 days in the following doses: enalapril 10 mg/kg, lisinopril 8 mg/kg, captopril 7.5 mg/kg, omeprazole 50 mg/kg, misoprostol 0.2 mg/kg. In a combined application, the same doses were used. The experimental model of rheumatoid arthritis was reproduced with a single injection of 0.2 ml Freund's adjuvant in the animal's back right foot. Indomethacin-induced gastropathy was induced by administration of indomethacin per os as an aqueous suspension at a dose of 2.5 mg/kg for 5 days.
The state ofthe mucosal barrier of the stomach was assessed by determining the content offractions ofinsoluble glycoproteins
INFLUENCE OF SOME I-APF ON CYTOPROTECTION MECHANISMS IN INDOMETHATSIN-INDUCED GASTROPATHYARTHRITIS
(NGP). To conduct biochemical studies, animals were sacrificed by one-time decapitation under ether anesthesia. The stomach was removed, purified, washed with cold saline solution, and the prednis was removed. Then the mucous layer was scraped, weighed and suspended in distilled water at a rate of 30 mg/ml.
The content of sialic acids in the suspension was determined by the method of L. I. Linevika To determine fucose in the suspension, the NSG was used by the method proposed by P. D. Rabinovich et al. [6]. The protein content was determined by the O. H. Lowry [7].
The results were processed using Student's t-test by a standard Microsoft Excel software package. Differences were considered significant atp < 0.05.
The results of the research and their discussion. Table 1 presents the results of a study of the content of NHP fractions in the gastric mucosa in animals with GERA and the efficacy of the use of ACE inhibitors, omeprazole, misoprostol and their combinations with omeprazole. As the studies have shown, with ERA., the content of NGP fractions remains practically unchanged. In animals with indomethacin GERA., a significant decrease in NGP fractions was observed. The content of sialic acids in them was lower than in animals with ERA. by 69.5%.
The content of fucose and protein decreased respectively by 55.5% and 48.1%. These results were significantly lower than in the control group.
ACE inhibitors, omeprazole and misoprostol have a positive effect on the content of NHP fractions in the gastric mucosa. In animals treated with enalapril, the content of sialic acids was higher than in rats without treatment by 60.8%, fucose - by 34.5%, protein - by 29.7%. Similar results were obtained in animals treated with lisinopril and omeprazole.
In the treatment of GERA, captopril and misoprostol were the most effective. In animals treated with captopril, the content of sialic acids in comparison with the group without treatment increased by 136.2%, fucose - by 69.7%, protein - by 37.4%. However, despite a significant increase, the content of the studied NGV fractions remained lower than in the control group.
In the group with misoprostol, the content of sialic acids increased by 183.3%, fucose - by 87.3%, protein - by 44.1%. In the combined use of omeprazole with other drugs, the potentiation of their cytoprotective effect was recorded as an additive pharmacodynamic interaction.
Table 1.- The content of NHP fractions in the gastric mucosa with indomethacin gastropathy in animals with experimental rheumatoid arthritis
Group of animals Sialic acids mg per ml of suspension ^g per ml of Fucose suspension mg per ml of suspension Protein
Intact 4.12 ± 0.158 6.73 ± 0.125 15.22 ± 0.655
ERA 3.84 ± 0.155 6.25 ± 0.153 14.72 ± 0.593
GERA 1.22 ± 0.067 2.78 ± 0.100 7.65 ± 0.257
GERA + H2O (without treatment) 1.38 ± 0.072 2.85 ± 0.121 8.55 ± 0.352
GERA. + enalapril 2.22 ± 0.047* 3.82 ± 0.089* 9.92 ± 0.400
GERA. + lisinopril 2.47 ± 0.085* 4.12 ± 0.051* 10.12+0.397*
GERA + captopril 3.27 ± 0.041* 4.82 ± 0.106* 11.75 ± 0.546*
GERA. + omeprazole 3.52 ± 0.089* 4.12 ± 0.076* 10.22 ± 0.343*
GERA. + misoprostol 3.92 ± 0.122* 5.32 ± 0.089* 12.32 ± 0.483*
GERA. + omeprazole + enalapril 4.32 ± 0.074* 5.98 ± 0.147* 12.88 ± 0.584*
GERA. + omeprazole +lisinopril 4.52 ± 0.105* 6.72 ± 0.220* 13.98 ± 0.625*
GERA + omeprazole + captopril 5.98 ± 0.155* 8.72 ± 0.173* 16.78 ± 0.500*
GERA. + omeprazole + misoprostol 7.37 ± 0.133* 10.85 ± 0.466* 19.62 ± 0.569*
Note: * p < 0.05 compared to data of animals with GERA without treatment
In the group of animals treated with omeprazole with enalapril, in comparison with the group GERA + H2O, the content of sialic acids increased by 213%, fucose - by 110.5%, protein - by 50.8%. Almost the same interaction was observed in the treatment with omeprazole with lisinopril.
In groups of animals treated with omeprazole with cap-topril and omeprazole with misoprostol, the interaction of the preparations was more significant. The data obtained significantly exceeded the control values. In the treatment with
omeprazole with captopril, the content of sialic acids, fucose and protein increased by 333.3%, 207% and 96.5%, respectively. In the group of omeprazole with misoprostol, the level of these fractions increased by 433.3%, 281.7% and 129.6%, respectively. These results significantly exceeded the control figures.
Discussion. It is established that in full functioning NGP sialic acids and fucose play a special role. These carbohydrate components provide elasticity and viscosity of the mucous barrier. The results obtained from animals with GERA. allow us to
state that damage to the mucous barrier of the stomach is due to a decrease in the synthesis of NHP and its functional insufficiency, which is characterized by a change in rheological properties. In the literature, the negative effect of indomethacin on the mucosal barrier is due to inhibition of COX enzymes, suppression of prostaglandin production and subsequent disturbance of microcirculation. We assumed that this mechanism is not the only one. Probably, one of the reasons for the damaging effect of the drug is a disturbance in the bioregulatory system of L-arginine-nitric oxide as a universal mechanism in triggering mutually conditioned pathogenetic mechanisms of cell damage.
In the literature, there are convincing data on the ulcer healing effect of enalapril [2; 5]. The authors associate it with the stimulation of the synthesis of prostaglandins. We assume that this is one of the mechanisms of the positive effect of the drug, which is a consequence of the corrective effect of the drug on the NO-formation system. Studying the effect of captopril and lisinopril on the state of the gastric mucosa in patients with arterial hypertension and osteoarthritis, who take NSAIDs for a long time, E. L. Nikonov found that ACE inhibitors have a positive effect not only on the cardiovascular system, but also improve the morphofunctional parameters of the gastric mucosa S. Alekseenko et al. [2] argue that the mechanisms of the positive effect of preparations of the group ofACE inhibitors on the gastric mucosa require further study. Perhaps, they are associated with an increase in the level of endogenous prostaglandin E2 and its cytoprotective effect.
Among the ACE inhibitors that we used, captopril had the best cytoprotective effect, probably due to the presence of the sulfhydryl group in the chemical structure. As is known, the sulfhydryl group necessary for the synthesis of prostanoids and activation of the prostaglandin receptors affects the permeability ofmembranes and adheres to free radicals. This is confirmed
by Nafeesa Mohd Ismail et al. [8] who studied the effects of captopril and ranitidine on the content of prostaglandin E2, ma-lonic dialdehyde and the activity of glutathione reductase on the model of aspirin-induced gastropathy in rats. It was found that in contrast to ranitidine, captopril increases the level of glutathione reductase, prostaglandin E2 and significantly reduces the content of malonic dialdehyde in the gastric mucosa. It is known that natural amino acids containing sulfhydryl (L-cys-teine and methionine), as well as sulfhydryl-containing drugs, prevent erosion in the rat caused by ethanol caused by ethanol. This indicates the protective effect of sulfhydryl compounds on the gastric mucosa, as well as the possible mediated effect of these on gastric cytoprotection induced by prostaglandins.
The results obtained by us with the use of misoprostol are consistent with the data of other authors [4]. As R. A. Ab-dulkhakov [1], misoprostol, like endogenous prostaglandins, has the ability to enhance the formation of mucus and bicarbonate secretion, improve blood flow, stimulate the regeneration of the epithelium of the gastric mucosa, reduce the production of hydrochloric acid.
Conclusions
1. With indomethacin-induced gastropathy, the drug significantly suppresses the synthesis of insoluble glycoproteins in the mucus barrier.
2. ACE inhibitors have a cytoprotective effect in the treatment of indomethacin gastropathy. The most effective of them is captopril, the cytoprotective effect of which is equal to that of omeprazole and misoprostol.
3. With the combined use of omeprazole with ACE inhibitors and misoprostol, their cytoprotective pharmacodynamic effect increases in the form of additive synergism. The most effective combination of omeprazole with captopril and
omeprazole with misoprostol. References:
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