Use of trimebutine maleate for the prophylaxis and treament of inflammatory gastrointestinal tract diseases

Abstract

The invention relates to pharmaceutics, and more particularly to gastroenterology, and can be used for the prophylaxis or treatment of inflammatory diseases of the gastrointestinal tract. What is described is the use of trimebutine maleate to achieve a maximum change in the level of the proinflammatory cytokines IL-1, IL-6, TNF-α, NF-κB and the anti-inflammatory cytokine IL-10 in the gastrointestinal tract for the prophylaxis or treatment of acute and chronic inflammatory diseases of the gastrointestinal tract.

Description

[0001] USES OF TRIMEBUTINE MALEATE FOR

[0002] PREVENTION AND TREATMENT OF INFLAMMATORY

[0003] GASTROINTESTINAL TRACT DISEASES

[0004] FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0005] The invention relates to pharmaceuticals, in particular gastroenterology, and can be used for the prevention or treatment of inflammatory diseases of the gastrointestinal tract.

[0006] LEVEL OF TECHNOLOGY

[0007] Among acute and chronic diseases of the gastrointestinal tract (GIT), conditions associated with inflammation processes play an important role. They can develop as a result of a violation of the microbiological balance in the small and large intestines, genetic predisposition, exogenous effects and other pathological factors.

[0008] One of the most common inflammatory gastrointestinal diseases in the population is irritable bowel syndrome (IBS), a chronic functional gastrointestinal disorder that affects 9 to 23% of the population worldwide. The percentage of patients seeking medical care for IBS approaches 12% in primary care practices and is by far the largest subgroup seen in gastroenterology clinics

[0001] .

[0009] IBS is characterized by changes in bowel habits, accompanied by discomfort, tension or pain in the abdomen, myalgia, bloating, bowel disturbances, and psychoemotional sensations of a serious disorder in the patient's bowel habits. Changes in gastrointestinal motility, visceral hypersensitivity, post-infectious reactivity, brain-gut interactions, changes in fecal flora, bacterial overgrowth, food sensitivity, carbohydrate malabsorption, and intestinal inflammation may all contribute to the pathogenesis of IBS. Functional gastrointestinal disorders, the most well-known of which, in addition to IBS, is functional dyspepsia (FD), occupy a significant place among the "functional somatic syndromes", along with chronic fatigue syndrome and fibromyalgia, with which they often overlap.A number of other comorbid conditions may occur more frequently than expected in patients with IBS, including gastroesophageal reflux, genitourinary disorders, fibromyalgia, headache, back pain, and a variety of psychological symptoms [2].

[0010] The etiology of the disease remains poorly understood, as a large number of pathological factors may be simultaneously involved in its development. There is no single physiopathological mechanism that could explain its causes, but there are at least three interrelated factors that act in a manner that varies from one individual to another: i) altered gastrointestinal reactivity, ii) motility or secretion in response to luminal irritants (food, bloating, inflammation, bacterial factors) or environmental stimuli

[0011] (psychosocial stress) that cause symptoms of diarrhea or constipation, and iii) intestinal hypersensitivity with increased visceral sensation and pain. In addition to the above factors, more and more data are emerging on the role of immune activation in the development of IBS, which is mainly shown in studies investigating the mechanisms that contribute to the development of inflammation or

[0012] PERSISTENT changes in the immune cells of the mucosa, enterochromaffin and mast cells, enteric nervous system and gastrointestinal microbiota. Cytokine imbalance of pro- and anti-inflammatory cytokines (as well as polymorphisms in cytokine genes) in the systemic circulation and intestinal mucosa can also characterize the manifestations of IBS.

[0013] The impact of developing intestinal pathology causes persistent low-grade systemic inflammation and inflammation in the intestinal mucosa, which is characterized by an altered composition of circulating cells, infiltration of immune cells of the mucosa and an increase in the production of various cytokines in patients with IBS. It has been established that an imbalance between pro- and anti-inflammatory cytokines plays an important role in the pathogenesis

[0014] IBS, which has been confirmed by numerous studies. Pro- and anti-inflammatory cytokines are important modulators of the immune response and also play an important role in the development of intestinal inflammation. Cytokine production is under genetic control, and an imbalance in the level of cytokine secretion can cause a predisposition to the disease along with clinical symptoms. There is evidence of the development of persistent inflammation in IBS, confirmed by a number of studies that found low levels of anti-inflammatory cytokines in patients with IBS or other studies that found high levels of anti-inflammatory cytokines or an imbalance of anti-inflammatory cytokines and the proportion of anti-inflammatory cytokines [3]. Recent studies have also shown an increase in the innate immune response in patients with IBS by assessing the expression and activation of Toll-like receptors.The obtained data suggest that activation of the immune response may play a key role in the pathogenesis of IBS. In particular, proinflammatory cytokines synthesized by macrophages, T-lymphocytes and endothelial cells are of great importance in the pathogenesis of inflammatory diseases. Over time, immune complexes appear in the blood, which affect other organs and tissues: skin, organs of vision, musculoskeletal system, hematopoietic system. The process of changing the level of systemic cytokines or mucosal cytokines, as well as polymorphism of their genes, apparently play a significant role. The pathophysiology of this process is associated with several conditions, such as changes in visceral sensitivity, food sensitivity, changes in the host intestinal microbiome, as well as disturbances in signal transmission at the brain-intestine level [4].

[0015] When a patient develops IBS, according to the data obtained, there is a tendency for high levels of anti-inflammatory cytokines, such as TNF-α, IL-, to be present in the bloodstream and in intestinal tissues.

[0016] 1β, IL-b, IL-8, and decreased levels of anti-inflammatory cytokines

[0017] IL-10, which inhibits the release of proinflammatory cytokines as well as antigen presentation. Some of these cytokines reduce the risk of IBS, such as anti-inflammatory cytokines such as IL-10, and some of them are associated with the development of IBS, such as proinflammatory cytokines that always promote inflammatory response such as IL-1, IL-6, IL-8, IL-12, IL-18 and TNF-α etc. The main proinflammatory cytokines associated with IBS are IL-1, IL-β and TNF-α [5].

[0018] It is known from the state of the art that one of the common drugs used since 1969 for the treatment of IBS, which affects the peripheral enkephalinergic receptors involved in digestion, is trimebutine.

[0019] The trimebutine molecule is 2-dimethylamino-2-phenylbutyl ester of 3,4,5-trimethoxybenzoic acid and its salt with maleic acid (maleate). Trimebutine is mainly administered orally in various solid dosage forms, including tablets, both rapidly disintegrating and with a delayed release. Since trimebutine is poorly soluble in water, its soluble salt, maleate, was obtained and introduced into clinical practice to increase its bioavailability. Trimebutine is used in the form of maleate for the treatment of digestive dysfunction such as abdominal pain, dyspepsia, nausea or vomiting, irritable bowel syndrome, or for the treatment of functional gastrointestinal disorders; and is manufactured and marketed as tablets, injections, granules for suspension, in the form of suppositories and oral suspension.The area of ​​application of trimebutine, in addition to IBS, is the treatment of various types of acute and chronic inflammatory diseases of the gastrointestinal tract.

[0020] Despite the wide variety of such diseases, the pathogenesis of most of them is similar to the mechanisms of development of the inflammatory process. The use of trimebutine maleate for the treatment of IBS does not change normal motility and activity of the intestine, but regulates abnormal hypo- and hyperactivity, increasing the number of long bursts in patients with constipation and decreasing in patients with predominant diarrhea. Trimebutine maleate accelerates gastric emptying and shortens the lag period (i.e., the period before the onset of constant gastric emptying) [6]. Trimebutine maleate is also indicated for individuals with postoperative paralytic ileus to accelerate the resumption of peristalsis after abdominal surgery.

[0021] [7]. Trimebutine maleate has moderate affinity for opiate receptors that act on peripheral delta-mu and kappa receptors [8]. Trimebutine maleate is also believed to act directly on gastrointestinal smooth muscle by inhibiting the influx of Ca 2+ , reduces the amplitude of external K* currents by inhibiting both Ca 2+ - both independent and dependent types K + channels [9].

[0022] The sodium channel blocking activity of trimebutine maleate results in inhibition of glutamate release and indicates a potential therapeutic effect of this compound in pain relief

[0010] .

[0023] Documents characterizing the use of trimebutine are known from the prior art.

[0024] Document EP 1244441 (A1) describes the use of trimebutine (2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxybenzoate hydromaleate) for the preparation of a medicinal product for the prevention and / or treatment of somatic pain. The disadvantage of this application is the focus on the use of trimebutine for the relief of pain conditions, without taking into account cases of therapy for the development of an inflammatory process that is not accompanied by pain syndrome.

[0025] Document RU2770301 (C2) describes the use of a polymorphic form of trimebutine maleate for the treatment of gastrointestinal tract diseases, where the said pharmaceutical composition contains a therapeutically effective amount of a polymorphic form of trimebutine maleate. The disadvantage is the use, without obtaining the desired end result of combating the development of concomitant inflammatory processes in the gastrointestinal tract.

[0026] Document RU2581920 (C2) describes a pharmaceutical composition adapted for oral administration containing trimebutine or its salts. The said composition is used to prevent or treat irritable bowel syndrome, including recurring gastrointestinal discomfort or pain. The disadvantage of this COMPOSITION is the use of trimebutine as a regulator of gastrointestinal peristalsis, regardless of the possible anti-inflammatory effect.

[0027] Document WO 1995001803 describes the use of trimebutine for the treatment of gastric pain and pathological symptoms such as gastroesophageal reflux, indigestion due to excess food intake, dyspepsia and constipation, without achieving the desired end result of combating the inflammatory process developing against the background of these conditions.

[0028] The publication by Trukhan D.I. et al.

[0013] describes trimebutine maleate as an opioid agonist that acts on peripheral delta, mu, and kappa receptors located on smooth muscle cells throughout the gastrointestinal tract, and also describes the use of trimebutine maleate for the treatment of functional gastrointestinal disorders. A disadvantage of the application is that the use of trimebutine maleate for the prevention of relapses or treatment of acute and chronic inflammatory diseases of the gastrointestinal tract is not disclosed.

[0029] The closest possible application is described in the publication

[0030] Langhgari, Naser-Aldin et al.

[0012] , which discloses the use of opiates for the prevention of relapses or treatment of acute and chronic inflammatory diseases of the gastrointestinal tract. However, the use of trimebutine maleate for the prevention of relapses or treatment of acute and chronic inflammatory diseases of the gastrointestinal tract is not disclosed.

[0031] The objective of the proposed invention is to identify and use new properties of trimebutine maleate when used in a daily dosage of 600 mg for the treatment of acute and chronic inflammatory diseases of the gastrointestinal tract by achieving maximum levels of proinflammatory cytokines IL-

[0032] 1, IL-6, TNF-alpha, Nf-kb and anti-inflammatory cytokine IL-10 in the gastrointestinal tract.

[0033] The technical result of the proposed invention is an unexpectedly discovered effect of the influence of trimebutine maleate in a daily dosage of 600 mg on achieving maximum levels of proinflammatory cytokines IL-1, IL-6, TNF-alpha, Nf-kb and anti-inflammatory cytokine IL-10 in the gastrointestinal tract.

[0034] The stated problem is solved by the fact that it is proposed to use trimebutine mateate in a daily dose of 600 mg to achieve the maximum change in the level of proinflammatory cytokines IL-1, IL-6, TNF-alpha, Nf-kb and anti-inflammatory cytokine IL-10 in the gastrointestinal tract, characterized in that the level of proinflammatory cytokines IL-1, IL-6, TNF-alpha, Nf-kb decreases, and the level of anti-inflammatory cytokine IL-10 increases.

[0035] ESSENCE OF THE INVENTION

[0036] In the process of studying the effect of trimebutine maleate on pro- and anti-inflammatory activity in the gastrointestinal tract, it was unexpectedly discovered that the use of trimebutine maleate is accompanied by the development of tissue-specific anti-inflammatory action, expressed in achieving the maximum change in the level of pro-inflammatory cytokines IL-1, IL-6, TNF-alpha, Nf-kb and anti-inflammatory cytokine IL-10 in the gastrointestinal tract.

[0037] Moreover, this action has a dose-dependent effect of trimebutine maleate. When using trimebutine maleate in a daily dose of 600 mg once or twice with an interval of 12 hours between doses, the most pronounced changes in the cytokine profile were observed.

[0038] (pro-inflammatory and anti-inflammatory cytokines), probably associated with the impact on the regulatory link Nf-kb, which were statistically significant.

[0039] TERMS and DEFINITIONS

[0040] All technical and special terms used in the description have the generally accepted meaning in this field of technology.

[0041] BRIEF DESCRIPTION OF DRAWINGS

[0042] The present invention is further illustrated by Fig. 1 and Fig. 2. Fig. 1 shows the main stages of an experimental study of the anti-inflammatory effect of trimebutine maleate in a model of irritable bowel syndrome in male Wistar rats.

[0043] Fig. 2 shows the results of visual registration of the necropsy picture in intact rats (normal control group) (2a); rats of the negative control group (pathology control group) (26: the number "1" indicates swelling, the number "2" - thinning of the mucosa, the number "3" - focal hemorrhages); rats that received trimebutine maleate at a dose of 52.3 mg / kg according to scheme 1 (2c); rats that received trimebutine maleate at a dose of 104.6 mg / kg according to scheme 2 (2d); rats that received trimebutine maleate at a dose of 209.2 mg / kg according to scheme 3 (2e).

[0044] DISCLOSURE OF INVENTION

[0045] In accordance with certain facts discovered in the present invention, the following embodiments are provided:

[0046] In a particular case, the indicated use of trimebutine maleate is used to treat irritable bowel syndrome.

[0047] In some cases, the use of trimebutine maleate differs in that trimebutine maleate is used as part of a medicinal product in the form of a tablet, granule for the preparation of a ready-made suspension.

[0048] Preferably, trimebutine maleate is administered to the patient in a daily dose of 600 mg.

[0049] Preferably, trimebutine maleate is administered to the patient according to a regimen of at least twice a day, 100-300 mg, with an interval of 8-12 hours between doses until a daily dosage of 600 mg is reached. Trimebutine maleate can be administered to the patient regardless of age.

[0050] It was unexpectedly found that the use of trimebutine maleate is accompanied by the development of tissue-specific anti-inflammatory action. Moreover, this action has a dose-dependent effect on trimebutine maleate. As will be shown below, when using trimebutine maleate at a daily dose of 600 mg once or twice with an interval of 12 hours between doses, the most pronounced changes in the cytokine profile (pro-inflammatory and anti-inflammatory cytokines) were observed, which were statistically significant.

[0051] The following are examples of the invention, which illustrate the invention, but do not cover all possible variants of its implementation and do not limit the invention.

[0052] EXAMPLES

[0053] The invention is illustrated by the following illustrative examples, which do not limit the claimed scope of protection.

[0054] Example 1. Effect of trimebutine maleate on tissue-specific pro-inflammatory activity

[0055] The study was performed on 60 male Wistar rats weighing 200-220 grams, aged 3 months. The animals were obtained from the laboratory animal nursery "Rappolovo" (Russia, Leningrad region) and were kept under controlled conditions of a living systems laboratory for the duration of the experiment. The conditions of maintenance were as follows: ambient air temperature - 22±2°C, relative humidity - 60±5%, with a 12-hour change of the daily cycle. Rats were placed in macrolon cages on granulated bedding made of hard wood with free access to water and food. The study was carried out in accordance with the recommendations of Directive 2010 / 63 / EU of the European Parliament and of the councЫl on the protection of animals used for scientific purposes, September 22, 2010 and ARRIVE guidelines

[0013] .

[0056] CPK was modeled in rats by a single oral administration of acetic acid solution (AO Vekton) at a concentration of 0.6%

[0014] .

[0057] The effective dosage of trimebutine maleate was calculated using the interspecies dose conversion factor for rats. The doses equivalent to the maximum daily dose, ½ of the maximum daily dose, and twice daily dose were: 104.6 mg / kg; 52.3 mg / kg, and 209.2 mg / kg, respectively

[0015] .

[0058] Trimebutine maleate was administered according to the following regimens:

[0059] 1. Orally at a dose of 52.3 mg / kg per day for 7 days after modeling the pathology.

[0060] 2. Orally at a dose of 104.6 mg / kg per day for 7 days after modeling the pathology.

[0061] 3. Orally at a dose of 209.2 mg / kg per day for 7 days after modeling the pathology.

[0062] During the study, the following experimental groups of 12 individuals were formed:

[0063] 1. IN intact animals (rats without IBS pathology, positive control, (group 1);

[0064] 2. NK - negative control (rats with a model of IBS pathology, but without treatment, (group 2), 3. groups of animals with a model of IBS, receiving trimebutine maleate in various application regimens (groups 3, 4 and 5).

[0065] Rats were decapitated under chloral hydrate anesthesia (350 mg / kg, intraperitoneally), the necropsy picture was visually recorded and a segment of the large intestine was removed, homogenized in phosphate-buffered saline (in a ratio of 1:10), centrifuged at 10,000 g. The resulting supernatant was used to determine IL-6, TNF-a, IL-1, Nf-kb by ELISA.

[0066] The analyzed sample, avidin conjugated with horseradish peroxidase were added to each well of the microplate and incubated. After that, the TMB substrate solution was added: a color change will be observed in those wells that contain the antigen, the antibody to it conjugated with biotin, and avidin conjugated with the enzyme. The enzyme-substrate reaction was stopped by adding a sulfuric acid solution and the color change was measured spectrophotometrically at a wavelength of 450 nm on an Infinite f 50 Tesap ELISA reader (Austria). The concentration of IL-6, TNF-a, IL-1, IL-10, Nf-kb in the samples was determined by comparing the optical density of the samples with the optical density of standard samples. Species-specific reagent kits manufactured by Cloud Clone (USA) were used in the work.

[0067] Statistical analysis of the obtained data was performed using the STATISTICA 6.0 software package. The results were expressed as M ± SEM (mean ± standard error of the mean). Comparison of means was performed using ANOVA with the Tyocki post-hoc test in the case of data obeying the law of normal distribution, and the Kruskal-Wallis test, when the data distribution differed from normal. Normality of distribution was checked using the Shapiro-Wilk test. Differences between the studied groups were considered statistically significant at p

[0068] <0.05.

[0069] The results obtained are presented in Table 1.

[0070] Table 1 - Comparative assessment of pro-inflammatory reactions in different groups of animals

[0071] Note: # - reliable relative to the IN group (Tyoki test, p<0.05); * - reliable relative to the NC group (Tyoki test, p<0.05); A

[0072] - significantly relative to the group of animals receiving trimebutine maleate at a dose of 104.6 mg / kg (Tyoki test, p<0.05).

[0073] According to the obtained data, the NC group of rats showed a pronounced inflammatory reaction in the intestinal wall, as evidenced by an increase in the concentration of proinflammatory cytokines IL-6, TNF-α and IL-1, as well as Nf-kb by 4.3; 3.8; 2.9 and 3.3 times relative to similar indicators of intact animals (all indicators p < 0.05).

[0074] The results of necropsy of animals from the control group are presented in Figure 2. The positions indicate: 1 - swelling; 2 - thinning of the mucous membrane; 3 - focal hemorrhages.

[0075] Significant changes in the content of proinflammatory cytokines were observed when animals were given trimebutine maleate at a dose of 104.6 mg / kg according to scheme 2. Thus, in comparison with the NC group of rats, a decrease in the concentration of IL-6 was noted - by 60.5% (p<0.05), TNF-α - 50.3% (p<0.05) and IL-1 - 28.5% (p<0.05), Nf-kb - 31.3% (p<0.05).

[0076] It should be noted that the concentration of IL-6 and TNF-α in animals that received trimebutine maleate at a dose of 104.6 mg / kg according to scheme 2 was significantly lower (p<0.05) than in rats that were administered trimebutine maleate at doses of 52.3 and 209.2 mg / kg according to schemes 2 and 3. The administration of trimebutine maleate at a dose of 104.6 mg / kg according to scheme 2 was not accompanied by the development of pathological changes in the gastrointestinal tract (Fig. 2).

[0077] At the same time, against the background of the introduction of trimebutine maleate to animals at a dose of 104.6 mg / kg according to scheme 1, a decrease (relative to untreated rats) was observed in the content of proinflammatory cytokines IL-6, TNF-a, IL-1 - NNAa by 32.4% (p < 0.05); 25.5% (p < 0.05), 25.4% (p < 0.05), respectively, and Nf-kb - by 30.4% (p < 0.05). According to the results of necropsy of animals receiving trimebutine maleate at a dose of 104.6 mg / kg according to scheme 1, no pathological changes were recorded (Fig. 2).

[0078] Based on the data obtained according to the study protocol, in the conditions of experimental IBS, it is noted that the use of trimebutine maleate is accompanied by the development of tissue-specific anti-inflammatory action. It is noted that this action has a dose-dependent effect on trimebutine maleate.

[0079] Thus, the optimal dose of trimebutine maleate can be considered 104.6 mg / kg per day for 7 days. When using trimebutine maleate in this dose, the most pronounced changes in the cytokine profile were observed, probably associated with the effect on the regulatory link Nf-kb (IL-1, TNF-a is activated), which were statistically significant, both in relation to untreated animals and rats that received trimebutine maleate in other doses and a different regimen from this one.

[0080] Example 2. Effect of trimebutine maleate on stimulation of anti-inflammatory activity

[0081] The study was conducted on 60 male Wistar rats weighing 200-220 grams, aged 3 months. The animals were obtained from the laboratory animal nursery "Rappolovo" (Russia, Leningrad region) and for the duration of the experiment were kept in controlled conditions of the laboratory of living systems. The conditions of maintenance were: ambient air temperature - 22±2°C, relative humidity - 60±5%, with a 12-hour change of the daily cycle. Rats were placed in macrolon cages on granulated bedding made of hard wood with free access to water and food. The study was carried out in accordance with the recommendations of Directive 2010 / 63 / EU of the European Parliament and of the council on the protection of animals used for scientific purposes, September 22, 2010 and ARRIVE guidelines

[0013] . IBS was modeled in rats by a single oral administration of a solution of acetic acid (AO Vekton) at a concentration of 0.6%

[0014] .

[0082] The effective dosage of trimebutine maleate was calculated using the interspecies dose conversion factor for rats. The doses equivalent to the maximum daily dose, ½ of the maximum daily dose, and twice daily dose were: 104.6 mg / kg; 52.3 mg / kg, and 209.2 mg / kg, respectively

[0015] .

[0083] Trimebutine maleate was administered according to the following regimens:

[0084] 4. Orally at a dose of 52.3 mg / kg per day for 7 days after modeling the pathology.

[0085] 5. Orally at a dose of 104.6 mg / kg per day for 7 days after modeling the pathology.

[0086] 6. Orally at a dose of 209.2 mg / kg per day for 7 days after modeling the pathology.

[0087] During the study, the following experimental groups of 12 individuals were formed:

[0088] 4. IN intact animals (rats without IBS pathology, positive control, (group 1);

[0089] 5. NK - negative control (rats with a model of IBS pathology, but without treatment, (group 2),

[0090] 6. groups of animals with a model of IBS, receiving trimebutine maleate in different application regimens (groups 3, 4 and 5).

[0091] Rats were decapitated under chloral hydrate anesthesia (350 mg / kg, intraperitoneally), the necropsy picture was visually recorded and a segment of the large intestine was removed, homogenized in phosphate-buffered saline (in a ratio of 1:10), centrifuged at 10,000 g. The resulting supernatant was used to determine IL-10. The analyzed sample, avidin conjugated with horseradish peroxidase were added to each well of the microplate and incubated. After this, a solution of TMB substrate was added: in those wells that contain the antigen, the antibody to it conjugated with biotin, and avidin conjugated with the enzyme, a color change will be observed. The enzyme-substrate reaction was stopped by adding a sulfuric acid solution and the color change was measured spectrophotometrically at a wavelength of 450 nm using an Infinite f 50 Тесаn ELISA reader (Austria). The concentration of IL-10 in the samples was determined by comparing the optical density of the samples with the optical density of standard samples.Species-specific reagent kits manufactured by Cloud Clone (USA) were used in the work. Statistical analysis of the obtained data was performed using the STATISTICA 6.0 software package. The results were expressed as M ± SEM (mean value ± standard error of the mean). Comparison of means was performed by the ANOVA method with the Tukey post-hoc test in the case of data obeying the law of normal distribution, and the Kruskal-test.

[0092] Wallis, when the data distribution is different from normal.

[0093] The normality of the distribution was tested using the Shapiro test.

[0094] Wilka. Differences between study groups were considered statistically significant at p < 0.05.

[0095] The results obtained are presented in Table 2.

[0096] Table 2 - Comparative assessment of pro-inflammatory reactions in different groups of animals

[0097] Note: # - reliable relative to the IN group (Tukey test, p<0.05); * - reliable relative to the NC group (Tukey test, p<0.05); A - reliable relative to the group of animals receiving trimebutine maleate at a dose of 104.6 mg / kg (Tukey test, p<0.05).

[0098] According to the obtained data, the IL-10 concentration in the NC group of rats was 45.5% (p<0.05) lower than in the intact group (Table 2). Visually, post mortem in rats with IBS, but without treatment, thinning of the intestinal wall, focal hemorrhages and bloating were noted (Fig. 2). The results of necropsy of intact animals are presented in Figure 2.

[0099] At the same time, against the background of the introduction of trimebutine maleate to animals at a dose of 104.6 mg / kg according to scheme 2, an increase in the concentration of IL-10 (anti-inflammatory cytokine) was observed - 29.1% (p<0.05). However, according to the results of necropsy of animals receiving trimebutine maleate at doses of 52.3 mg / kg and 209.2 mg / kg according to schemes 1 and 3, no pathological changes were recorded (Fig. 2).

[0100] The most pronounced changes in the IL-10 content were observed when animals were given trimebutine maleate at a dose of 104.6 mg / kg according to scheme 2. The IL-10 content in this group of animals increased by 56.4% (p<0.05).

[0101] Based on the conducted experimental studies, it is noted that trimebutine maleate has a pronounced anti-inflammatory pharmacodynamic property (manifested at a daily dosage in animals of 104.6 mg / kg), expressed in the activation of the “anti-inflammatory” link of immunity, and assessed by the corresponding cytokine - IL-10.

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[0117] 15. FDA Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.

Claims

CLAUSE OF THE INVENTION 1. Use of trimebutine maleate at a daily dose of 600 mg to achieve maximum change in the level of proinflammatory cytokines IL-1, IL-6, TNF-alpha, Nf-kb and anti-inflammatory cytokine IL-10 in the gastrointestinal tract.

2. Use according to paragraph 1, characterized in that the level of proinflammatory cytokines IL-1, IL-6, TNF-alpha, Nf-kb decreases, and the level of anti-inflammatory cytokine IL-10 increases.

3. Use according to paragraph 1, characterized in that trimebutine maleate is used according to a regimen of at least twice a day, 100-300 mg at an interval 8-12 hours between doses to achieve a daily dosage of 600 mg.

4. Use according to paragraph 1, characterized in that trimebutine maleate is used as part of a medicinal product in the form of a tablet or granule for the preparation of a ready-made suspension.

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