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Rakhmatullaeva Gulnoza Kutpidinovna, Khamraev Abror Asrorovich, Yakubov Abdujalol Vaxobovich, Medical Sciences, Tashkent Medical Academy E-mail: [email protected]
INFLUENCE OF SOME PROTON POMP INHIBITORS, CYTOPROTECTIVE AGENTS AND THEIR COMBINATIONS ON CONDITION OF GASTRIC MUCOSAL BARRIER IN INDOMETHACIN INDUCED GASTROPATHY
Abstract: In experimental model of Indomethacin Induced Gastropathy, treatment with Proton Pomp Inhibitors(PPIs) and Cytoprotective agents influence on process of mucosal defense differently. Omeprazole decreases, rabeprazole, de-nole and pepsan-P increase, while sucralfate does not impact on synthesis of mucosal barrier. Thus, combination of omeprazole with cytoprotective agents is not expedient. Administration of rabeprazole with de-nole as well as pepsin-P has shown the best pharmacological synergism.
Keywords: indomethacin induced gastropathy, proton pomp inhibitors, cytoprotective agents, treatment.
Over the last decades safe usage of non steroid antiinflammatory drugs (NSAIDs), prevention and treatment of gastrointestinal complications are under great attention [3]. Considering the pathogenesis of NSAID-gastropathy, nowadays there are two group of drugs for treatment and prophylaxis: anti-secretor and cytoprotective drugs. H2 histamine blockers are not the best choice for this purpose, taking into account that they are inferior than proton pomp inhibitors [1]. PPIs take a leading position among all the drugs for treating gastropathies, therefore they are comfortable for use, effective and safe compared to other group of medications[2]. Analyses have shown that there is no answer to the question-"Which PPIs are the most efficient in therapy of gastropathy and do they all influence on process of cytoprotection in a same way?"
Usually, alongside with PPIs, misoprostol, de-nole and sucralfate are used for therapy. Misoprostol is synthetic analog of prostaglandin E2 which was intended to cure and prevent NSAIDs- induced gastropathy. However, misoprostol significantly inferior than PPIs and not excluded from several side effects as practice and latest guidelines show. It puts their usage as a first line drugs under question [3].
Efficacy of de-nole and sucralfate in treatment of NSAIDs induced gastropathy was proven in clinical trials by R. Mal-agela and co-authors [4], A. E. Karataeva and co-authors [5].
At the same time, lacks information about compared effectiveness of cytoprotectors and their usage in combination with PPIs in therapy [4]. In this aspect efficacy of new cyto-protector Pepsan-P appeals great attention.
Aim of the study: To investigate influence of some PPIs, cytoprotectors and their combinations to the condition of mucosal barrier of the stomach in indomethacin induced gastropathy (IIG).
Materials and methods: Experiment is conducted on white male rats of mixed population with body mass of 150200 gr. NSAID gastropathy is induced by indomethacin via oral insertion in dosage of 2,5 mg/kg within 5 days [6]. Research run in 14 animal groups: 1stgroup.- intact, 2nd group.-animals with IIG,3rd group.-animals with IIG without therapy; 4-8th groups.-animals with IIG receiving omeprazole, rabeprazole, de-nole, sucralfate, pepsan -P. 9-14th groups-animals with IIG receiving combination of PPIs and cytoprotec-tors- omeprazole with de-nole; omeprazole with sucralfate; omeprazole with pepsan-P; rabeprazole with sucralfate; rabeprazole with de-nole; rabeprazole with pepsan-P respectively.
Each group had 6 rats. Drugs were inserted orally in form of water suspension within 10 days on following dosage: omeprazole 50 mg/kg [7], rabeprazole 5 mg/kg [8], de-nole 10 mg/kg [9], sucralfate 400 mg/kg [10], pepsan-P 1500 mg/kg [11]. Condition of the mucosal barrier explored via amount of insoluble glikoproteins (IGP) in suspension from mucosal liquid of stomach. Content of sialic acid measured by L. I. Linevik method [12], amount offucosa by method of P. D. Rabinovich and co-authors [13]. Concentration of common protein tested by method of O. H. Lowry and co-authors [14].
Results and explanation: Table 1 illustrates the effects of some PPIs and cytoprotectors on amount of insoluble glikoproteins of mucosal layer of stomach in indomethacin induced gastropathy.
It is evident from provided information that indometha-cin noticeably decreases synthesis of mucosal barrier components, such as IGP. Group of animals with IIG had 3 times less amount of sialic acid and fucosa, 1,5 less amount of total protein in suspension of gastric mucosa. Usage of omeprazole decreased synthesis of IGP. In this group observed following results: decrease of sialic acid to 40.6%, fucosa to 39.0%
and total protein to 27.4%, compared to non -treated group (IIG+H2O). Effect of rabeprazole was totally vice versa, it stimulated synthesis of IGP. Sialic acid concentration raised to 62.2%, fucosa to 106.9% and total protein to 35.7%.
Almost same results were with de-nole usage. Sialic acid level grew for 87,8%, fucosa for 94.9% and total protein for 40.7% differently from non-treated group.
Table 1. - Effects of some PPIs and cytoprotectors on amount of insoluble glikoproteins of mucosal layer of stomach in indomethacin induced gastropathy.
Animal groups Sialic acid (mkg/ml) fucosa (mkg/ml) Total protein (mkg/ml)
Intact 3.66 ± 0.24 6.45 ± 0.48 16.52 ± 0.99
IIG 1.29 ± 0.16 2.34 ± 0.14 10.48 ± 0.83
IIG+ H20 1.48 ± 0.10 2.18 ± 0.15 10.12 ± 0.79
IIG+ omeprazole 0.88 ± 0.07* 1.33 ± 0.09* 7.35 ± 0.29*
IIG+rabeprazole 2.40 ± 0.14* 4.51 ± 0.15* 13.74 ± 0.60*
IIG+de-nole 2.78 ± 0.21* 4.25 ± 0.15* 14.24 ± 0.60*
IIG+sucralfate 1.69 ± 0.14 2.53 ± 0.18 9.83 ± 0.79
IIG+pepsan-P 2.23 ± 0.12* 3.92 ± 0.22* 13.21 ± 0.95*
Note: * - P < 0.05 from group of non-treated (IIG + H20)
Group of animals treated with sucralfate had no significant changes compared to the group of without treatment, such as decreased amount of total protein and increased level of sialic acid, fucosa.
Use of pepsan-P showed stimulating effect on mucosal barrier. In this group level of IGP changed: sialic acid to 50.6%, fucosa to 79.8% and total protein grew to 30.5%.
Taking into account results ofmonotherapy, effectiveness of combined use PPIs with cytoprotectors presents great promises.
Results of use in combination omeprazole and rabeprazole with cytoprotectors and their effect on amount of IGP of gastric mucosal layer in IIG is shown in (table 2).
As it is evident from presented information, combination of omeprazole and de-nole inhibits stimulative effect of the latter. Apparently, combined therapy has no difference than monotherapy with omeprazole. Using omeprazole with sucralfate also does not have a stimulative influence on mucosal barrier IGP.
Table 2.- Effects of combined usage of omeprazole and rabeprazole with some cytoprotective agents on level of IGP of mucosal barrier in IIG.
Animal group Sialic acid (mkg/ml) Fucosa (mkg/ml) Total protein (mkg/ml)
IIG+ H20 1.48 ± 0.10 2.18 ± 0.15 10.12 ± 0.79
IIG + omeprazole + De-nole 0.91 ± 0.07* 1.24 ± 0.11* 7.53 ± 0.60*
IIG + omeprazole + sucralfate 0.80 ± 0.06* 1.15 ± 0.12* 6.89 ± 0.42*
IIG + omeprazole + pepsan-P 1.32 ± 0.11 1.85 ± 0.14 9.26 ± 0.72
IIG + rabeprazole De-nole 3.10 ± 0.18* 6.29 ± 0.26* 15.80 ± 0.55*
IIG + rabeprazole + sucralfate 2.54 ± 0.18* 4. 37 ± 0.23* 14.12 ± 0.85*
IIG + rabeprazole + pepsan-P 3.80 ± 0.29* 7.18 ± 0.58* 16.45 ± 0.96*
Note: * P < 0.05 from the group of non-therapy(lIG + H2O)
In the group of omeprazole with pepsan-P, the content of sialic acid increased by 58.0%, fucose by 39% and total protein by 26.0% compared to the indicator of the monotherapy group with omeprazole. At the same time, there was only a significant increase in sialic acid and fucose. According to the data presented in the table, it can be seen that in terms of the stimulation of the protective barrier, the best combination is cytoprotectors with rabeprazole.
In the treatment of IIG with a combination of rabeprazole and de-nol, synergism of the pharmacodynamic interaction
was observed. In this group, the content of sialic acid increased by 109.4%, fucose by 188.5%, total protein by 56.0% of the indicator of the group without treatment. Therapy with rabeprazole has shown following results: the increase in IGP fractions was 62.2%, 106.9% and 35.7%, respectively (P < 0.05).
In simultaneous use of rabeprazole and sucralfate, the stimulating effect of rabeprazole remained almost unchanged (P > 0.05).
The combination of rabeprazole with pepsan-R is the most effective. In this group, the pharmacodynamic synergism
of the drugs was more significant than in the rabeprazole and de-nol group. The content of sialic acid increased by 156.7%, fucose - by 229.3%, total protein by 62.5% compared to the group without treatment. These results were significantly superior than results of monotherapy with rabeprazole.
As it can be seen that, the proton pump inhibitors such as omeprazole and rabeprazole act in different directions on the synthesis of IGP. The inductive effect of rabeprazole convincingly indicates the superiority of the action of the drug on the mechanisms of synthesis and development of the mucous barrier, with regard to the stimulating effect of de-nola on the IGP, it must be assumed that this is due to its two main pharmacodynamic effects. Firstly, de-nol forms a type of protective barrier that prevents absorption of H + ions and promotes faster regeneration of damages in mucosal layer. Secondly, de-nol stimulates the local synthesis of prostaglandin E2, which helps to increase the synthesis of the mucosal barrier [15]. There are debate on the effect of sucralfate on the synthesis of IGP in some literature. Our results are consistent with the data of K. Stiener and co-authors. [16], F. Halter [17] and J. C. Soule [18], who argue that the cytoprotective features of sucralfate are determined solely by its local "protective" mechanisms. B. L. Slomiany and co-authors. [19] found in their investigation that under the action of sucralfate, the content of IGP in the gastric mucosa increases by 19.0%. However, other authors have questioned this point of view [20].
In our studies, the stimulating effect of pepsan-P on the synthesis of IGP has been established. Probably, this
effect of the drug in the treatment of IIG is linked to its other remarkable features. As it is known that pepsan-P has a noticeable antacid, anti-inflammatory and antioxidant effect [21]. It inhibits the release of histamine from the mast cells in the mucous membrane of the esophagus and stomach, reducing the formation of thromboxane A2 and reactive oxygen ions, therefore as a result reduces the local inflammation process.
It can be assumed that the pharmacodynamic syner-gism of rabeprazole with cytoprotectors is due to their similar effect on impaired mechanisms of mucosal barrier synthesis, at the same time, the combined use of omeprazole with cytoprotectors multidirectional, because of the prevail pharmacodynamic effect of omeprazole and the absence of synergism.
Conclusions:
1.Proton pomp inhibitors and cytoprotectors influence on mucosal defense process of stomach in indomethacin induced gastropathy differently.
2. Omeprazole decreases, rabeprazole, de-nole and pep-san-P increase, sucralfate does not impact on synthesis of mucosal barrier. Combined usage of omeprazole with cytoprotectors does not change inhibitive effect of omeprazole on mucosal barrier secretion.
3. Combination of rabeprazole with de-nole and pepsan-P shows pharmacological additive synergism, whilst combined usage of rabeprazole with sucralfate has no any pharmacological change in effectiveness.
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