Method for preserving myocardium accompanying transplantation

FIELD: medicine.

SUBSTANCE: preserving the myocardium in transplantation involves perfusion and storage of the isolated heart with using a Custodiol solution at a temperature of 2-4°C. The heart tissue culture into the donor precedes a 10-12-hour infusion of Levosimendan 10 mcg/kg of body weight, while the perfusion and storage of the isolated organ is ensured by adding Levosimendan into the Custodiol solution at 10 mcg of the preparation per 1 litre of the solution. The surgical stage of the heart transplantation after the recipient's aorta de-clamping and the blood flow recovery is followed by introducing Levosimendan 12.5 mg into the continuing bypass circuit and infusing it for 1 hour.

EFFECT: invention aims at preventing the ischemic and re-perfusion myocardial injuries, providing the adequate function of the donor's heart in the recipient's body.

2 ex

 

The invention relates to medicine, namely to transplantation, and is intended to prevent ischemic and reperfusion injury of the myocardium, providing proper function of the donor heart in the body of the recipient.

One of the urgent problems of transplantation is to develop ways to maintain the viability of the stopped heart and restore his full contractile function after preservation. Dysfunction heart transplant in 50% of cases occur for reasons of inadequate preparation of donor diagnosed with brain death before the donor site, bad anti-ischemic protection of the donor heart preservation and transplantation, as well as insufficient medical support recipient in the postoperative period.

At the same time, it is known that the restoration of blood flow through the ischemic myocardium leads to the development of "reperfusion syndrome", characterized by the distribution of the affected area of the myocardium in the form of a "contracture" necrosis, accumulation of acute heart failure, complex rhythm disorders, which often ends in sudden cardiac death.

One of the ways of dealing with ischemic damage of isolated organs in transplantation is their preservation using different perfusia the solutions and the cooling of the graft to a temperature of 2°C-10°C. However, due to the intensity of metabolic processes in the myocardium and power consumption reductions to date there is no "perfect" cardioplegic solution that provides long-term preservation of the myocardium and its simultaneous protection against reperfusion damage.

There is a method of preservation of donor organs, which extracorporal perfusion of the transplant is carried out after the withdrawal within 2 hours of perfusion with a solution consisting of 25% solution "Custodial", not less than 20% of perftoran, at least 1.5 million ME streptokinase, not less than 50,000 IU of heparin, at least 300 mg of prednisolone (U.S. Pat. 2423931 Grew. Federation: IPC A61B 17/00, A61K 31/02 A61K 33/14, A61P 41/0. The method of restoring the viability of the ischemia damaged donor organs [Text] / S. F. Bagnenko, O. N. Reznik, A. E. Skvortsov; applicant and patentee of the State institution "St. Petersburg scientific research Institute of emergency medical aid to them. And. And. Janelidze (RU). No. 2009136319/14; Appl. 30.09.09; publ. 20.07.11, Bulletin No. 20). Perfusion of donor organs is carried out in normothermy conditions with a gradual decrease in the temperature of the perfusion solution to 5°C-12°C.

The disadvantages of the method are that the presence of thrombolytics (in this case, streptokinase) in the composition of the perfusion solution is impossible when performing cardiac surgery is with artificial circulation. At the same time, the addition of the composition perftoran does not provide pre/myocardial postconditioning, but only improves oxigenada properties of the perfusion solution. In addition, the use of the present methods continuous perfusion circuit for a donor organ is still very problematic.

There is a method of preservation of the heart for transplantation, in which the laundering authority within 10 minutes of cardioplegic solution containing sodium pyruvate, inorganic salts and albumin, while the solution temperature is from 30°C to 37°C, and for preservation of the heart in the resulting solution was further added ethanol, and the temperature of the perfusion solution is reduced to 2°C-10°C (U.S. Pat. 5,075,210 USA: IPC A01N 001/02 Preservation of the heart for transplantation [Text] / Wikman-Coffelt; Joan (Davis, CA); the applicant and the holder of The Regents of The University of California (Oakland, CA). No. 07/455,580; Appl. 21.12.89, publ. 24.12.91).

The disadvantage of this method is that the effect of cardioplegic solution aimed at maintaining homeostasis of the body and its antioxidant protection, due to the inactivation of the electrophysiological mechanisms in the myocardium, while the cardioprotective action of a solution slightly and is manifested only indirectly.

Closest to the claimed is a method of graft preservation of the myocardium based on perfusion and preservation of the heart of the solution, terrasim peptide inhibitor of protein kinase C (U.S. Pat. 2440131 Grew. Federation: IPC A61K 38/04 A61K 9/08. Method of conservation bodies [Text] / YOUNG Lyndon; applicant and patentee PHILADELPHIA COLLEGE OF OSTEOPATHIC MEDICINE (US). No. 2008127753/15; Appl. 11.12.06; publ. 20.01.10, Bulletin No. 2). The proposed solution is designed not only for storage but also for reperfusion when resuming circulation in the body of the recipient after ischemia. However, the advantages of the proposed method is described only when the duration of myocardial ischemia less than 80 minutes, which is often insufficient for transporting and transplanting the organ, thus supporting the effectiveness of perfusion solution are conducting a study of hemodynamic parameters, in particular the level of diastolic pressure of the left ventricle (LVDP), which is a marker of myocardial ischemia. Another drawback is that the drug exerts a positive inotropic effect only in the presence of polymorphonuclear leukocytes (PMN). The proposed structure does not allow to use it for preconditioning of donor organ prior to explantation.

The technical result of the proposed invention is to reduce anoxic damage to the donor myocardium, increase "vesisenaho" time interval between explantation and transplantation of the heart, increasing the efficiency of the recovery and amicucci damaged myocardium.

The technical result is achieved due to the fact that advanced complex of intensive therapy aimed at the preservation of the donor heart, perform pre - and postconditioning using sensitizer calcium - " levosimendan". To do this, before explantation of the heart donors for 10-12 hours enter " levosimendan " in a dose of 10 µg/kg body weight; the next stage of conservation in the solution perfusion solution add " levosimendan " at the rate of 10 g/1 l of solution. After transplantation, at the time of recovery of blood flow in the body of the recipient conduct simultaneous infusion of 12.5 mg of " levosimendan " in a path parallel artificial blood circulation, which leads to rapid recovery of contractile function of the myocardium with minimal ischemic damage by reducing intracellular receipt of ions of calcium in cardiomyocytes.

"Levosimendan " is neglecting tool with a positive inotropic effect, the increase in contractility is due to the higher sensitivity of myofilaments to calcium without increasing its intracellular concentration. The contractile apparatus of cardiomyocytes sensititivy only in systole; diastole, when the concentration of calcium decreases, " levosimendan " dissociates with cardiac troponin C, and p is ocess relaxation of the myocardium is not disturbed. Moreover, increased inotropic function is not accompanied by substantial growth needs of cardiomyocytes in the oxygen.

Another positive effect of " levosimendan " - the ability to open potassium channels in smooth muscles of the vascular wall, mainly ATP-dependent. The result is coronary and peripheral vasodilation, which provides anti-ischemic effect and the number of positive hemodynamic effects.

Special attention deserves the cardioprotective potential of " levosimendan", based on its ability to activate mitochondrial ATP-dependent potassium channels of cardiomyocytes. In the norm K+ATP channels are closed and opens only in response to metabolic stress. Activation of these channels is one of the most important moments in adaptation to hypoxia, preventing peroxide-induced death of cardiomyocytes at the time of acute ischemia (Papp Z., Csapo K, Pollesello, P. Pharmacological mechanisms contributing to the clinical efficacy of levosimendan. Cardiovasc Drug Rev 2005 Spring; 23 (1):71-98).

The method is as follows: during preconditioning of donor in complex activities, providing hemodynamic stability, hold the infusion of " levosimendan " in a dose of 10 mg/kg of body weight of the donor, lasting 10-12 hours. After explantation isolated heart perfusely is kept in a solution of Custodiol with the addition of " levosimendan " at the rate of 10 g/1 l of solution, in this case, the temperature of the solution and the isolated body is reduced to 2°C-4°C. After complete surgical stage heart transplant, while removing the clamp on the aorta of the recipient and restore blood flow in the path of the ongoing parallel artificial blood type 12.5 mg of " levosimendan " and carry out its perfusion within 1 hour.

The method was successfully used in the clinic of anesthesiology and resuscitation Department of fsbi "research Institute of complex problems of cardiovascular diseases" WITH the RAMS with four orthotopic heart transplant in humans. After termination of CPB, all recipients fully restored contractile function of the myocardium, without the use of additional mechanical (intra-aortic balloon counterpulsation) or in vitro (membrane oxygenation) support methods in coronary blood flow.

Example 1

Patient P., 42 years of age, with a diagnosis of CHD; PEAKS (myocardial infarction 2008, 2011); PCI PNA and OA in 2008 occlusion in-stent OA; paroxysmal supraventricular tachycardia, paroxysmal ventricular tachycardia, implantation of a cardiac defibrillator, pulmonary hypertension (40%); CHF 2B, FC 3; PHI not more than 28%; ischemic myocardiopathy. Performed orthotopic heart transplantation in biatrial technique. For conditioning of donor (age 48) on the stages of establishing brain death is long with vazopressornye support norepinephrine 0.05 µg/kg/min to maintain the average AD held preconditioning of donor myocardium infusion of " levosimendan " 670 mg (10 mg/kg) for 14 hours. Perfusion of the graft with 4 liters of solution "Custodial" with the addition of 40 ág of " levosimendan". Total ischemia time of the graft 126 minutes Total time of cardiopulmonary bypass (IR) 192 minutes After the opening of the aortic parallel IR with a 50% performance (recovery of cardiac activity one defibrillation) is entered 12.5 mg of " levosimendan". The infusion of " levosimendan " was carried out for 1 hour with a gradual decrease in performance IR and restoration of adequate hemodynamic status of the recipient. With minimal inotropic support the adrenaline of 0.085 µg/kg/min - heart rate 110 / min (work EX), cardiac index of 3.6 l/min/m2AD average 97 mmHg, pulmonary artery pressure of 30 mmHg, in the study of clinical, laboratory and functional criteria for myocardial ischemia - level troponin I (TNI) is not more than 3.0 ng; brain natriuretic peptide (BNP) is not more than 1700 PG. In the future is not required increasing inotropic support and on the 11th day of the postoperative period, the patient was transferred from the hospital in satisfactory condition.

Example # 2

Patient R., 52 years, with a diagnosis of dilatational cardiomyopathy; complete left bundle branch block gissa; relative mitral and tricuspidal valves; HSN 2A; FC 4; pulmonary hypertension; PHI not more than 30% - held orthotopic the Kai heart transplant on biatrial technique. For conditioning of donor (54) on the stages of establishing brain death along with inotropic Pressor support of adrenaline to 0.1 mcg/kg/min held preconditioning of donor myocardium infusion of " levosimendan " 560 mg (10 mg/kg) for 10 hours. Perfusion of the graft 3 liters of custodiol with the addition of 10 µg/l solution of " levosimendan". Total ischemia time of the graft 212 minutes Total time of cardiopulmonary bypass 204 minutes After the opening of the aortic parallel IR with a 50% performance (self-recovery of cardiac activity) introduction to 12.5 mg of " levosimendan " in the path of the IR for 1 hour with a gradual decrease in performance and restoration of adequate hemodynamic status of the recipient with minimal inotropic support the adrenaline 0,065 mg/kg/min and dobutamine 5 mcg/kg/min, heart rate 110 / min (work EX), cardiac index of 3.2 l/min/m2AD average of 86 mmHg, pulmonary artery pressure 34 mmHg. In the future is not required increasing inotropic support, clinical, laboratory and functional criteria of myocardial ischemia were not recorded (TNI not more than 2.4 ng; BNP no more than 1340 PG), on the 8th day of the postoperative period transfer from the emergency Department and subsequent discharge from hospital in satisfactory condition.

How preservirovanii attack when transplan the purpose, including perfusion and storage of isolated hearts using solution Custodial at a temperature of 2-4°C, characterized in that prior to explantation of the heart donor for 10-12 hours spend infusion of " levosimendan " in a dose of 10 mg/kg of body weight, and for perfusion and storage of the isolated organ in a solution of Custodial add " levosimendan " at the rate of 10 micrograms of the drug per 1 liter of the solution; after performing the surgical stage heart transplant, while removing the clamp on the aorta of the recipient and restore blood flow in the path of the ongoing parallel artificial blood type 12.5 mg of " levosimendan " and carry out its infusion over 1 hour.



 

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32 cl, 111 ex

FIELD: biotechnology.

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2 cl, 6 dwg, 5 tbl

FIELD: medicine.

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6 cl, 2 ex, 3 tbl, 13 dwg

FIELD: medicine.

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2 ex

FIELD: biotechnologies.

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16 cl, 1 tbl, 29 ex

FIELD: biotechnologies.

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5 tbl, 319 ex

FIELD: medicine, pharmaceutics.

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2 cl, 1 tbl

FIELD: medicine, pharmaceutics.

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10 cl, 4 tbl, 2 ex

FIELD: medicine.

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2 ex

FIELD: chemistry.

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20 cl, 5 ex, 4 tbl, 7 ex

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41 cl, 2 tbl, 7 ex

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2 tbl, 1 ex

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9 cl, 1 tbl, 8 ex

FIELD: medicine, pharmaceutics.

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30 cl, 3 tbl, 23 ex

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2 tbl, 5 ex

FIELD: medicine, pharmaceutics.

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FIELD: chemistry.

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,

and

,

method of modulating CCR3 activity.

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18 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the chemical-pharmaceutical industry and deals with application of fullerene derivatives of the general formula 1

,

where in the general formula 1 fragment C2n stands for: fullerene carbon cage C60 (n=30), C70 (n=35); where in the general formula 1 "x" can take values from 4 to 12, and "y" from 0 to 16, where in the general formula 1 fragment A stands for a monovalent atom of fluorine or hydrogen; -oxygen atom (-O-), bound to the fullerene cage in a composition of an oxirane fragment; where in the general formula 1 NR1R2 is described by the following definitions: - amine residue, where R1 and R2 are hydrogen atoms or substituted with protonated (NH3+) or unprotonated (NH2) aminogroups or branched alkyl radicals (CmH2m+1; m=1-20); - residue of piperazine of the general formula Ic-1 , where R, R'1, R'2 R'3 and R'4 are hydrogen atoms or linear or branched alkyl (CmH2m+1 m=1-20) radicals, as antimicrobial preparations, as well as an antimicrobial composition, including fullerene derivatives.

EFFECT: invention can be used in biomedical research and in production of novel medications, intended for treatment and prevention of infectious diseases, as well as for creation of disinfection agents, intended for decontamination and sterilisation of media and surfaces contaminated with microorganisms.

2 cl, 4 ex, 2 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: composition contains recombinant interferon specified in a group: recombinant interferon alpha, recombinant interferon beta, recombinant interferon gamma, antibiotics, antiseptics, hypromellose and water in the following proportions, g per 1 ml of the composition: recombinant interferon, IU - 100-1,000,000; antibiotics, g - 0.00001-0.5; antiseptics, g - 0.00001-0.5; hypromellose, g - 0.00001-0.5; water - the rest up to 1 ml. The above composition can contain broad-spectrum antibiotics specified in a group: amoxicillin, ampicillin, oxacillin, methicillin, cephalexin in an amount of 0.00001-0.5 g per 1 ml of the composition. The composition contains antiseptics specified in a group: lysozyme, biclotymol, fusafungine, ambazon, benzyldimethyl-myristoylamino-propylammonium, co-trimoxazole, amylmetacresol, dichlorobenzyl alcohol, cetylpyridinium chloride, benzoxonium chloride in an amount of 0.00001-0.5 g per 1 ml of the composition.

EFFECT: invention enables providing higher therapeutic efficacy of the composition.

3 cl, 4 ex

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