RU2749435C1 - Method for treatment of enteral insufficiency in inflammatory and traumatic injuries of peritoneum - Google Patents

Abstract

FIELD: medicine; veterinary medicine; biology.SUBSTANCE: method for treatment of enteral insufficiency in inflammatory and traumatic injuries of the peritoneum includes the injection of a p38 MAP kinase blocker.EFFECT: invention allows the treatment of enteral insufficiency, while it is highly effective and allows one to manage without additional devices for the injection of the drug.6 cl, 4 dwg, 3 ex, 3 tbl

Description

The proposed invention relates to the field of medicine, veterinary medicine and biology.

It is known that intact cells of the intestinal mucosa provide a barrier to prevent the movement of intraluminal bacteria and toxins into the blood. In peritonitis, an inflammatory reaction in the intestinal wall and ischemia / hypoxia of the intestinal mucosa interfere with this function. In turn, the increased permeability of the intestinal mucosa leads to the translocation of endotoxins and bacteria, a systemic inflammatory response and, ultimately, to the syndrome of multiple organ dysfunction.

Known methods for the treatment of enteral insufficiency, which, along with the surgical aid, include the use of nasogastrointestinal intubation using probes for early enteral nutrition, enterosorption, general hyperbaric oxygenation and intraintestinal oxygen therapy (Kosinets V.A.Enteral insufficiency syndrome: pathogenesis, modern principles of diagnosis and treatment // News surgery. 2008. T. 16, No. 2. S. 130-138).

A known method for the treatment of enteric insufficiency, including the conduct of standard postoperative intensive therapy for stimulation of intestinal motility, as well as "traditional drug therapy" (proserin, metoclopramide) and prolonged epidural blockade and the introduction of the drug serotonin adipinate at a dose of 20-30 to 40-60 mg per day (Great BM Assessment of the clinical efficacy of the drug serotonin adipinate in the treatment and prevention of enteric insufficiency syndrome in generalized peritonitis // Surgery. 2016. No. 9. S. 76-82. Doi: 10.17116 / hirurgia2016976-82).

The disadvantages of this method include the lack of influence on the morphological state of the layers of the intestinal wall.

An experimental method for the treatment of enteral insufficiency is also known, including the intravenous injection into the superior mesenteric vein of 6% HES 130 / 0.4 (hydroxyethyl Starch) (Fresenius Kabi, Germany) 4 hours after modeling of peritonitis. Rabbits were used as experimental animals. In this case, the modeling of peritonitis was carried out by installing a catheter in the ascending part of the colon, which ensured the flow of intestinal contents into the abdominal cavity. The infusion rate was 1 ml / kg ^-1 / min ^-1 , infusion was carried out for 30 minutes (Lu WH, Jin XJ, Jiang XQ Wang Z, Wu JY, Shen GG. Resuscitation with hydroxyethyl starch 130 / 0.4 attenuates intestinal injury in a rabbit model of sepsis Indian J Pharmacol 2015; 47: 49-54).

The disadvantages of this method include the short duration of the development of the pathological process, which does not allow assessing the effectiveness of the treatment and its impact on the outcome of the disease.

The closest in technical essence to the present invention is a method for correcting enteral insufficiency in peritonitis, including performing a laparotomy, eliminating the source of peritonitis, and sanitizing the abdominal cavity.

In this case, an intestinal probe is installed in the patient to monitor intra-abdominal pressure and electrostimulation of the duodenum. At the end of the laparotomy, laparoports are installed on the anterior abdominal wall. Intraoperatively, repeated washing of the lumen of the small intestine with an aqueous solution of chlorhexidine or furacilin, isotonic sodium chloride solution with the addition of broad-spectrum antibiotics to pure waters is carried out. At the end of the procedure, 200 ml of Remaxol solution is poured into the intestinal lumen, the abdominal cavity is drained, the wound is sutured. In the postoperative period, electrical stimulation of the duodenum is performed. An antiseptic solution is injected through the laparoports and an ultrasonic sanitation of the abdominal cavity is carried out in the antiseptic environment, changing the solution to clean waters. Then an antiseptic is aspirated and a solution of "Remaxol" is injected into the abdominal cavity 2 times a day, 200.0 ml, with a course of at least 3 days (Pat. 2657376 Russian Federation, MKI A61M 1/28, A61K 31/194, A61R 41/00 ; Salakhov E.K., Vlasov A.P. Method of correction of enteric insufficiency in peritonitis Patentee: Salakhov E.K .; filed. 08.11.2016; publ. 13.06.2018, bull. No. 17).

The disadvantages of the known method include the repeated administration of the drug, both into the intestinal lumen and into the abdominal cavity, and the need to use special devices for the administration of the drug solution - laparoports, intestinal probes.

Also, the disadvantages of the known method include the use of the Remaxol solution, which is not intended for intra-abdominal and intra-enteric use, while this solution does not contain components with anti-inflammatory activity.

It is known to use Remaxol for the treatment of patients with impaired liver function due to its acute or chronic damage (toxic, alcoholic, drug hepatitis), as well as in the complex treatment of viral hepatitis, in addition to etiotropic therapy (source https://www.rlsnet.ru /tn_index_id_42256.htm, access date 04/14/2020).

The objective of the claimed invention is to develop a method for the treatment of enteral insufficiency in inflammatory and traumatic injuries of the peritoneum

The technical result of the proposed method is to simplify the treatment method, reduce its invasiveness and labor intensity.

The technical result is achieved by the fact that for the treatment / correction of enteral insufficiency, intracavitary administration of the drug is carried out.

The main differences of the proposed method are that p38 MAP kinase blockers are used as a drug, in particular:

1. SB203580 (4- (4'-Fluorophenyl) -2- (4'-methylsulfinylphenyl) -5- (4'-pyridyl) -imidazole);

2. SB239063 (trans-4- [4- (4-Fluorophenyl) -5- (2-methoxy-4-pyrimidinyl) -1H-imidazol-1-yl] cyclohexanol);

3. VX-745 (5- (2,6-Dichlorophenyl) -2- [2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one).

Distinctive techniques of the proposed method also consist in the fact that for the treatment of enteric insufficiency, one of the p38 MAP kinase blockers is injected into the serous cavity once in the form of a sterile solution and, depending on the type of blocker, at a concentration of 2-10 μg / ml, in a volume sufficient for wetting the entire surface of the serous membrane with the specified solution.

A distinctive technique is that the drug is administered to a subject in need of this, the condition or disease of which is accompanied by enteral insufficiency, while the p38 MAPK kinase blocker is administered into the serous cavity with a pharmaceutically acceptable carrier and / or excipient.

Comparative analysis of the proposed method and the prototype showed that the proposed method differs from the known by the above methods. These differences allow us to conclude that the proposed technical solution meets the criterion of the invention "novelty".

The authors of the proposed method have established the advantage of the proposed method over the known, which lies in the fact that the blocker p38 MAP kinase with a single administration provides the treatment of enteral insufficiency in peritonitis, both in the presence of surgical damage to the intestinal wall, and without it. The effectiveness of treatment is also shown, both without the use of antibiotics, and against the background of the use of antibiotics (tables 1, 2, 3; Fig. 2 and 4 of the Appendices to the description of the application).

It is known that p38 MAP kinase blockers are inhibitors of proinflammatory cytokine production (Badger AM, Bradbeer JN, Votta B. et al. Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein / p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function // J. Pharmacol. Exp. Ther. - 1996. - Vol. 279. - P. 1453-1461).

The authors of the proposed method are unknown and in the available literature no information has been found on the use of p38 MAP kinase blockers as an agent with activity against enteric insufficiency in inflammatory and traumatic injuries of the peritoneum.

The inventive method ensures the achievement of the technical result seen by the applicant, namely, the simplification of the method, due to a single administration of the drug; reducing its trauma and labor intensity, as well as reducing the risk of organ trauma, due to the lack of the use of special devices for the administration of a medicinal solution - laparoports, intestinal probes.

The foregoing allows us to conclude that the technical solution meets the “inventive step” criterion.

The method constituting the claimed invention is intended for use in medicine, veterinary medicine and biology. The possibility of its implementation is confirmed by the methods and means described in the application. The foregoing gives reason to believe that the claimed technical solution meets the criterion of the invention "industrial applicability".

The essence of the proposed method for the treatment of enteral insufficiency in peritonitis, inflammatory and traumatic injuries of the peritoneum is illustrated by examples of specific implementation. The examples below serve to illustrate but do not limit the invention.

Example 1.

Laboratory animals - Wistar rats weighing 220-250 g, 6 months old. - Peritonitis was simulated. The modeling was carried out by twice injecting into the abdominal cavity, with an interval of 6 hours, a mixture containing 0.6 × 10 ⁹ microbial bodies of E. coli ESBL and B. fragilis strain ISCST1982 (Fadeeva T.V., Shurygina I.A., Dremina N.N. ., Vetokhina A.V., Chepurnykh E.E., Shurygin M.G. Bacterial translocation in experimental peritonitis // Transbaikal Medical Bulletin. 2019. No. 4. P. 128-133). All invasive procedures were carried out in accordance with the rules of humane treatment of animals, which are regulated by the "Rules for work with the use of experimental animals" (Appendix to the order of the Ministry of Health of the USSR from 12.08.1977, No. 755). The conducted studies were approved by the Ethics Committee of the Institute of Chemistry of Chemistry.

The study was carried out on two groups of animals:

Control group 1 (25 animals): Introduction 1 day after modeling of peritonitis 3 ml nat. solution into the abdominal cavity. Removal of animals from the experiment was carried out for 12 hours and after 1, 3, 7, 14 days after modeling of peritonitis.

Experimental group 1 (15 animals): Introduction 1 day after modeling of peritonitis 3 ml of sterile solution of the blocker p38 MAP kinase SB203580 at a concentration of 10 μg / ml, once. Removal of animals from the experiment on days 3, 7 and 14 after modeling of peritonitis.

For histological examination, the intestines were fixed in FineFIX solution (Milestone, Italy), embedded in paraffin, sections were stained with hematoxylin-eosin. The degree of damage to the intestinal mucosa was assessed using the Chiu C.J. et al., 1970 (Chiu CJ, McArdle AH, Brown R., Scott HJ, Gurd FN Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal // Arch Surg. 1970. V. 101 , No. 4. P. 478-483. DOI: 10.1001 / archsurg.1970.01340280030009). The results of the study (mean ± mean error) are shown in Table 1.

The data given in Table 1 indicate the early appearance of morphological signs of enteric insufficiency - 12 hours after modeling of peritonitis, as well as a significant improvement in indicators in experimental group 1 compared with control group 1.

Example 2.

Laboratory animals - Wistar rats weighing 220-250 g at the age of 6 months. conduct modeling of peritonitis. To do this, a laparotomy is performed, the cecum is removed into the wound, and in the avascular zone of the dome of the cecum, an incision of the serous-muscular membrane up to 1 cm long is made.Then the intestinal wound is sutured with a continuous twisted suture, after which a suspension containing 0.5 ml 10 ⁹ microbial bodies of E. coli and B.fragilis, after which the laparotomic wound is sutured (Pat. 2716482, Russian Federation, IPC G09B 23/28, А61В 17/00 Method for modeling peritonitis. Chepurnykh EE, Shurygina I.A. ., Fadeeva T.V., Grigoriev E.G .; No. 2019109595, filed on 01.04.2019, published on 11.03.2020. Bulletin No. 8).

The study used 36 animals, which were divided into 2 groups:

Control group 2 (18 animals): Introduction 1 day after modeling of peritonitis 3 ml nat. solution into the abdominal cavity, once.

Experimental group 2 (18 animals): Introduction 1 day after modeling of peritonitis 3 ml of sterile solution of the blocker p38 MAP kinase VX-745 at a concentration of 2 μg / ml, once.

On the 3rd, 7th and 14th days after modeling of peritonitis, the animals were subjected to autopsy. The intestines were fixed in FineFIX solution (Milestone, Italy), embedded in paraffin, stained sections with hematoxylin-eosin, and histological examination. The degree of enteric insufficiency was assessed using a special scale Chiu C.J. et al., 1970 (Chiu C.J., McArdle AH, Brown R., Scott HJ, Gurd FN Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal // Arch Surg. 1970. V. 101, No. 4. P. 478-483. DOI: 10.1001 / archsurg.1970.01340280030009).

The studies were carried out in compliance with the principles set forth in the Convention for the Protection of Vertebrate Animals Used for Experimental and Other Purposes (Strasbourg, France, 1986), as well as in accordance with the rules of humane treatment of animals, which are regulated by the "Rules for Conducting Work with the Use of Experimental Animals" (Appendix to the order of the Ministry of Health of the USSR dated 12.08.1977, No. 755).

It was found that in animals of control group 2, the severity of damage to the mucous membrane, which is the morphological equivalent of enteric failure, increased with a maximum at 14 days, when the average value of the damage index was 4.17 points. In figure 1, position A shows the damage to the mucous membrane in the animal of the control group 2 on the 14th day after modeling of peritonitis, estimated at 5 points, staining with hematoxylin and eosin, magnification 40x.

In animals of experimental group 2, the severity of damage to the intestinal mucosa at all times was lower than in control group 2. Figure 2, position B shows damage to the mucous membrane in an animal of experimental group 2 on the 14th day after modeling peritonitis, estimated at 3 points, stained with hematoxylin and eosin, magnification 40x.

The significance of differences in the severity of mucosal damage between the Control 2 and Experimental 2 groups is shown in Table 2 (mean ± mean error).

From the data in Table 2, it follows that the severity of damage to the mucous membrane, which is equivalent to the severity of enteric failure, assessed using a special scale Chiu C.J. et al., 1970 on the 14th day in the Experimental 2 group was significantly lower than in the Control 2 group.

Example 3.

Laboratory animals - Wistar rats weighing 220-250 g, 6 months old. - Peritonitis was simulated similarly to example 2. The study used 36 animals, which were also divided into 2 groups:

Control group 3 (18 animals): Introduction 1 day after modeling of peritonitis 3 ml nat. solution into the abdominal cavity. Intramuscular administration of an antibiotic (Cefoperazone + Sulbactam 47 mg / day), starting from 1 day after the introduction of microorganisms into the abdominal cavity - 2 times a day for 5 days.

Experimental group 3 (18 animals): Introduction 1 day after modeling of peritonitis 3 ml of sterile solution of the blocker p38 MAP kinase SB239063 at a concentration of 10 μg / ml, once. Intramuscular administration of an antibiotic (Cefoperazone + Sulbactam 47 mg / day), starting from 1 day after the introduction of microorganisms into the abdominal cavity - 2 times a day for 5 days.

On the 3rd, 7th and 14th days after modeling of peritonitis, the animals were subjected to autopsy. The intestine was subjected to fixation in FineFIX solution (Milestone, Italy), embedding in paraffin, staining of sections with hematoxylin-eosin, and histological examination. The degree of damage to the intestinal mucosa was assessed using the Chiu C.J. et al., 1970.

It was found that in control group 3, the severity of enteric insufficiency increased in dynamics with a maximum at 14 days (4.58 points). Figure 3, position C, shows the morphological equivalent of enteric failure, corresponding to 5 points. Staining with hematoxylin and eosin, magnification 40x. In experimental group 3, the severity of enteral insufficiency did not increase from 3 to 14 days of observation; on days 7 and 14 was significantly lower than in control group 3. Figure 4, position D, shows the intestinal wall in experimental group 3, morphological severity of enteric failure corresponds to 2 points. The data obtained are shown in Table 3 (mean ± error of the mean).

The data obtained indicate that the proposed method allows for the treatment of enteric insufficiency.

Thus, the claimed method allows for the treatment of enteral insufficiency with a single administration of the drug - the p38 MAP kinase blocker, which, in comparison with the known methods, simplifies the treatment method, reduces its trauma, the risk of organ trauma and the laboriousness of its implementation.

The proposed method is not difficult to implement and can be used in medicine, veterinary medicine and biology.

Claims (6)

1. A method for the treatment of enteral insufficiency in inflammatory and traumatic injuries of the peritoneum, including intracavitary administration of the drug, characterized in that the blocker p38 MAP kinase is administered. 2. The method according to claim 1, characterized in that SB203580 is used as the p38 MAP kinase blocker. 3. The method according to claim 1, characterized in that SB239063 is used as the p38 MAP kinase blocker. 4. The method according to claim 1, wherein VX-745 is used as the p38 MAP kinase blocker. 5. The method according to claim 1, characterized in that the p38 MAPK kinase blocker is injected into the serous cavity once in the form of a sterile solution at a concentration of 2-10 μg / ml. 6. The method according to claim 1, characterized in that the p38 MAPK kinase blocker is administered into the serous cavity with a pharmaceutically acceptable carrier and / or excipient.

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