Application of binuclear sulphur-nitrosyl complex of anion type iron as vasodepressor medication
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to application of binuclear sulphur-nitrosyl complex of anion type iron of formula Na2[Fe2(S2O3)2(NO)4]·4H2O as vasodepressor means for obtaining medication for treatment of ischemic diseases.
EFFECT: invention ensures extension of arsenal of cardiotropic medications with improved activity spectrum based on said iron complex, which is non-toxic water-soluble NO donor.
2 cl, 4 dwg, 5 tbl
The invention relates to a binuclear sulfur-nitrosyl complexes of iron anionic type - new NO donors with vasodilatory properties and may be used as anti-hypertensive drugs for the treatment of cardiovascular diseases.
NO, as has been known for over 20 years, involved in various physiological and pathophysiological processes in mammals [1) J.A.McCleverty, Chem. Rev., 2004, 104, 403; 2) ..Ford, L.E.Laverman, Coord. Chem. Rev., 2005, 249, 391; 3) N.M. Crawford, J. of Experimental Botany, 2006, 57, 471; 4) R.Butler and I.L.Megson, Chem. Rev., 2002, 102, 1155; 5) L.J.Ignarro (Ed.), Nitric Oxide: Biology and Pathobiology, Academic Press, San Diego, 2000; 6) D.A.Wink, Y.Vodovotz, J.Laval, F.Laval, M.W.Dewhirst, J.B. Mitchell, Carcinogenesis, 1998, 19, 711; 7) A.Butler, R.Nicholoson (Eds.), Life, Death and Nitric Oxide, The Royal Society of Chemistry, Cambridge, 2003; 8) P.C.Ford, J. Bourassa, S.Kudo and K.Miranda, Coord. Chem. Rev., 1998, 171, 185]. The obtained data about the diverse biological activity of the radical of the mediator and its reactions with biological substrates in the cells used in the design of effective drugs - NO-donors. To change the interstitial level of NO use connection or generating the radical, or effectively binding.
The recent research in the field of molecular cardiology established the Central role of nitric oxide (NO) in the regulation of vascular tone and myocardial metabolism [S.P. Jones, Bolli R. The ubiquitous role of nitric oxide in cardioprotection. J Mol Cell Cardiol 2006; 40(1): 16-23]. Wiesn is but that lack of education NO leads to the development of endothelial dysfunction, which, in turn, causes an increase in tone of the coronary vessels, and increases the aggregation and adhesion ability of platelets. In ischemic and reperfusion injury of the heart, it contributes to the development of the syndrome of "no reflow", leading to the progressive deterioration of blood flow and ultimately the death of cardiomyocytes [B.I. Jugdutt Nitric oxide and cardioprotection during ischemia-reperfusion. Heart Fail Rev 2002; 7(4): 391-405]. The most common drugs in disorders of the cardiovascular system are organic nitrates and nitroprusside [Vggrai, Nbeglaryan. Exogenous nitric oxide donors (chemical aspect) // proceedings of the Academy of Sciences. A series of chemical, 2002, No. 8, str-1313]. However, these drugs have a number of disadvantages and side effects of: i) nitrate tolerance and cyanide poisoning, ii) the need for additional activation (thermo-, photo - or enzymatic), which limits the possibility of their use in the clinic. In this regard, the urgent task is to develop promising new NO-donors, which include binuclear nitrosyl iron complexes with sulfur-containing ligands, which were first isolated in crystalline form in IPCP RAS in 2004-2008 [Nasunin, Smolderin. "Functional mo who ate nitrosyl [Fe-S] proteins", WPI. An. Ser. chem. 2004 (11) 2326-2345; Nasanen, Smolderin, Tunia, Nigrosine, Gavrilov, Umoja, Vmmachinename, Nsabagasani. "Synthesis, structure and solid-phase transformations of nitrosyl iron complex Na2[Fe2(S2O3)2(NO)4]·4H2O", Coordination Chemistry, 2005, 31, 301-306]. Synthesized in IPCP RAS nitrosyl [2Fe-2S] complexes are analogues of the active sites is not heme nitrosyl [2Fe-2S] proteins and represent a hybrid molecule containing two farmacognosia fragment: sulfur containing ligands of natural origin (penicillamine, structural analogy of natural sulfonates and others) and NO group. So, it is established that the vasodilatation of the coronary vessels under action of solutions managernew of dinitrosyl iron complexes with cysteine and restored glutathione (dncg) accompanied by a decrease in the duration of arrhythmias during occlusion of the coronary artery and reliable by reducing the damage of cell membranes in the risk zone during subsequent reperfusion. These effects are due to the antioxidant properties dncg and combined with the best recovery of aerobic metabolism in ischemic cardiomyocytes. As a rule, dnce get metastability aqueous solutions or in the form of freeze-dried composites of these RA the solutions with water-soluble polymers [A.F. Vanin, Lozinsky V.I., kapelko VI Polymer composition to obtain a stabilized form of dinitrosyl iron complex and the method of obtaining this form of complex Patent RU 2291880 C1], which limits their widespread use in applications associated with uncontrollability of the original part.
In IPCP RAS binuclear sulfur-nitrosyl iron complexes isolated in crystalline form, and is firmly established that proton environments (water, physiological solutions) generate NO spontaneously without additional activation and form in solutions of dinitrosyl menagerie intermediates (dncg). Quantified NO donirovaniya synthesized compounds depending on the concentration used donor, temperature, pH of the medium under aerobic and anaerobic conditions by electrochemical method using the touch electrodes amiNO-700. Taken together, these results suggest the possibility of creating new original antihypertensive and anti-ischemic drugs based on binuclear nitrosyl iron complexes.
The present invention consists in expanding Arsenal of cardiotropic drugs and the creation of cardiotropic drugs with improved spectrum of activity-based non-toxic water-soluble donor NO: the complex is Na 2[Fe2(S2O3)2(NO)4]·4H2O (hereinafter drug TNCG).
The problem is solved by the use of anionic binuclear nitrosyl iron complexes complex Na2[Fe2(S2O3)2(NO)4]·4H2O as the original antihypertensive and anti-ischemic drugs.
The invention consists in the following. The inventors investigated the effect of the drug TNKZ aortic pressure in the isolated rat heart compared with clinical drug sodium Nitroprusside.
In experiments on isolated hearts of Wistar rats (average body weight and heart respectively 340 g and 1.7 g) studied the effect TNKZ aortic pressure (BP) in retrograde perfusion standard, saturated with Carbogen Krebs solution (RK) at t=37°C and constant coronary flow.
After anesthesia with urethane (1.25 mg/g body weight, b/W) and thoracotomy isolated hearts were placed in chilled Krebs solution at 30-40 seconds to stop contractions. Within 10-20 min heart was perfesional antegrade (at constant filling pressure of the left atrium 15 mm Hg and HELL 60 mm Hg) and determined the magnitude of spontaneous coronary flow (CF). After this went on perfusion with a constant volumetric rate of spontaneous CP (the average of 17 ml/min). Registered HELL, stabilization of which 60-65 mm Hg occurred in 5-10 min, which was the original background for the introduction of a test donor of NO.
In experiments with TNCI used the following initial concentrations: 0.01 (n=6), 0.10 (n=6), 1.00 (n=8), 5.00 (n=14) and 10.0 (n=6) microns. As in control experiments with NP, 1 ml TNKZ was injected into the aortic cannula within 2 seconds. Given KP corresponding average effective concentration TNKZ were: 0.006, 0.059, 0.587, 3.403 and 5.919 μm. As the comparison drug used sodium nitroprusside (NP). 1 ml of NP was injected into the aortic cannula within 2 C. the Initial concentration of NP were: 0.5 (n=11), 1.0 (n=8), 2.5 (n=10) and 5.0 (n=10) μm. Applicable concentration including KP was 0.31, 0.61, 1.50 and 3.03 μm. 12 control experiments in the aorta was introduced RK without NP. The action of RK and TM on blood pressure was observed within 15 min, TNCI and PA - 30 min after the injection of substances. Control the introduction into the aorta 1 ml of the Republic of Kazakhstan within 2" was accompanied by characteristic changes of AD are presented in figure 1 (the impact of the introduction of 1 ml of Krebs (RK) on changes in aortic pressure). At the beginning of the observation period (15" after the introduction of the RK) HELL grew on average by 29%, and in the next 15" fell on average by 13% from the original. In the future, HELL rather quickly recovered, and after 5-10 min the differences with the original value were defects in the faithful. It is obvious that by reason of changes in blood pressure in the control experiments was short giperwolemicescoy load of the coronary vessels, the so-called "hydrodynamic shock"occurred in all groups of experiments.
Effect of sodium nitroprusside.
The results presented in table 1 and figure 2 (changes in blood pressure under the effect of the introduction of 1 ml of 0.5, 1.0, 2.5 and 5.0 μm of sodium nitroprusside), showed that the introduction of solutions of NP with current concentrations of 0.31, 0.61 and 1.5 μm causes changes in blood pressure, similar control as in control experiments, the greatest drop in blood pressure (observed through 30" after the introduction of the NP) was preceded by a transient increase and then a gradual recovery of HELL. In General, the dynamics of blood pressure did not differ from the control, except for the expression "hydrodynamic shock, which was significantly less compared with the control. When increasing the current concentration of NP to 3.03 µm initial rise HELL was even less, and restore the HELL was slowed down, so that by 15' is still below the original value. Therefore, the effective concentration of NP 3.03 μm was used as a control for comparison with other substances.
Table 2 presents the results of introducing solutions TNKZ with the current concentration in the range from 6 nm to 6 μm. It is shown that significant differences with minimum source to what centrala 0.01 μm appear when using a 1 μm solution TNCI, in the future, with increasing concentration TNKZ to 10 μm, the differences become more pronounced. Figure 3 (impact of the introduction of 1 ml of 1.0, 5.0 and 10.0 μm TNKZ HELL) presents the evolution of the restoration HELL within 30' after the introduction of the aorta 1 ml TNKZ with initial concentrations of 1, 5 and 10 μm (effective concentration 0.587, 3.403 and 5.919 μm, respectively). It is shown that by increasing the concentration of the substance decreases the severity of the initial rise HELL, increases the degree of fall AD 30 on average from 27% to 35% of the original, increasing the deficit recovery HELL to 30' from 0 to 13%.
Comparing the effectiveness of TMS and TNCG.
In table 3 presents the results obtained by the action of the HELL of equal (or approximately equal) existing concentrations of substances: NP (3.03 μm) and TNCG (3.40 μm). It is shown that when using equal current concentrations of the most effective dilatation is TNKZ: the maximum degree of the fall the HELL over 30" after the introduction of the 30 per cent from the source (vs 19% in NP), and the deficit recovery HELL to 15' was 10% (NP - 6%).
|Effect of sodium nitroprusside on HELL (%)|
|Time after injection||RK||Nitroprusside, mcm|
|a - P<0,05 vs 0,5|
|b - P<0,05 vs l,0|
|c - P<0,05 vs 2,5|
|d - P<0,05 vs all|
|Action TNKZ to HELL (%)|
|Time after injection||TNCI, mcm|
|a - P<0,05 0,01 vs|
|b - P<0,05 vs 0,10|
|c - P<0,05 vs 1,00|
|d - P<0,05 vs all|
|The effect of ~3 µm NP, PA and TNKZ to HELL (%)|
|Time after injection||NP||TNKZ|
|a - P<0.05 vs NP|
|b - P<0,05 vs PA|
Thus, the results indicate that TNCI reduces HELL when bolus injected into the aorta isolated rat heart, perfusing at a constant coronary flow. Vasodilatory efficacy studied donor NO near existing concentrations (about 3 μm) decreases in a series TNKZ>nitroprusside.
The inventors also examined the effect of the drug TNKZ on coronary, contractile and pump function in the isolated rat heart.
Action TNCI, the most effective vasodilator in coronary, contractile and pump function was studied in experiments on isolated hearts of rats male Wistar (body weight 360 g weight heart of 1.6 g). After anesthesia with urethane (1.25 mg/g,/b) and thoracotomy isolated heart was placed in chilled Krebs solution (RK) 3-40 sec to a complete stop contractions. Within 10-15 min heart retrograde was perfesional standard RK (37°C, pH=7.4), saturated with Carbogen (95% O2+5% CO2), at a constant perfusion pressure (PD) 60 mm Hg After removal of blood from the coronary vessels and cavities of the heart into the left atrium was entered cannula and heart were perfesional antegrade at a constant filling pressure of the left atrium 15 mm Hg and the resistance to outflow (aortic pressure) 60 mm Hg
The pressure in the aorta and the left ventricle was recorded using a strain gauge sensors P 50, monitor SP 1405 and Registrar SP 2010, Gould Statham. The intensity contractile function SF (investment and construction) was the product of frequency of heart rate (HR) at pressure, RD (the difference between systolic and minimum diastolic pressure, DD). Pump function characterized minute volume (MO - the amount of coronary flow (cf) aortic volume). Coronary function (KF) was assessed by coronary resistance (KC - aortic pressure, referred to KP).
Stabilization function has lasted 15-20 minutes, then registered source parameters and stopped the outflow of the solution from the aorta (distal to the aortic camera) for 15 minutes While the ROK continued to arrive in LV antegrade, however, the perfusion solution, flowing from LV, fell in coronary vessels in full (because the outflow of the peri what the series was blocked). The solution TNKZ was injected into the aortic cannula of an infusion pump at a rate of 1 ml/min for 5 min (6 to 10 min occlusion of the aorta). The effective concentration TNCI and NP was 3.7·10-5M with an average KP 18+2 ml/min Made 8 experiments with TNCI and NP. In the control (n=7) was administered standard RK without NP and TNCG. After infusion of NP or TNKZ heart was perfesional RK for 5 min, after which he resumed antegrade perfusion with normal outflow of perfusion solution from the aorta, which lasted 15 minutes, the Statistical processing of the results using t-student test.
The beginning of the occlusion of the aorta was accompanied by an increase KP and AP to 136% and 111%, respectively. While the COP was reduced by 20%, investment and construction 18% (due to the decrease of RD), while heart rate remained stable, and DD increased by 7 mm Hg (table 4).
During the control infusion RK, KP and AP decreased below baseline values, and the COP, on the contrary, increased to 121%. Infusion of NP and TNCG significantly differed from the control, followed by an increase in CP and lower values of KS, which, apparently, was due to the dilatation of the coronary vessels. If the control on the background of reduced KP continued decline in SF, the infusion of NP and especially TNKZ provided higher values of SF in terms of occlusion. When infusion TNKZ indicators SF is slightly different is the n from the beginning of the occlusion, while the decline in the supervision and with the introduction of the NP was more pronounced (table 4).
When laundering (after infusions) rapid alignment of indicators of coronary and contractile function in the control and experiments with NP. At the same time in experiments with TNCI beneficial effect after infusion was maintained, which was reflected in higher performance SF (table 4).
In table 5 shows the values of coronary contractile and pump function after 15 min after cessation of occlusion of the aorta. You can see that the restoration of function in experiments with NP better than the control, but especially is successful after infusion TNCI (figure 4).
|Function occlusion of the aorta and infusion RK, TM and TNCG (in % from the original values)|
|The ORIGINAL VALUES||OCCLUSION of the AORTA|
|5 min||5 min||5 min|
|63±6 mm Hg||NP||104±2A*||93±1ab|
|3.58±0.04 mm Hg/ml||NP||91±4A*||124±6ab|
|101±1 mm Hg||NP||83±3A*||70±3ab|
|-4±1 mm Hg||NP||6±1a||9±1ab*|
|104±1 mm Hg||NP||74±4A*||58±3ab*|
|Frequency of contractions of the heart||RK||100±1||80±2A||76±2ab|
|307±2 /min||NP||91±2A *||79+2ab|
|The intensity SF||RK||82±2||50±4A||39±3ab|
|33038±524 mm Hg/min||NP||68±5a*||47±4ab*|
|* - edit the deposits in absolute values|
|a - P<0,05 vs early occlusion|
|b - P<0,05 vs infusion|
|* - P<0,05 vs RK|
|** - P<0,05 vs PK NP|
|Restoration of function after occlusion of the aorta (in % from the original values) and infusion RK, TM and TNCG|
|The ORIGINAL VALUES||REPERFUSION, 15 min|
|63±6 mm Hg|
|3.58±0.04 mm Hg/ml|
|101±1 mm Hg|
|Diastolic pressure *||5±1||3±1a||-1±1ab|
|-4±1 mm Hg|
|104±1 mm Hg|
|Frequency of contractions of the heart||85±2||89±2a||95±2ab|
|The intensity SF||61±4||69±4A||86±5ab|
|33038±524 mm Hg/min||is the|
|- changes in absolute values|
|a - P<0,05 vs RK|
|b - P<0,05 vs NP|
Thus, the results show that TNCI is expressed prolonged dilatation of the coronary vessels. Perhaps it is the improvement of coronary function provides a more efficient recovery of contractile and pump function in the isolated rat heart after 15 min of occlusion of the aorta in comparison with nitroprusside. Figure 6 shows the effect of 5-min infusion 3.7·10-5M of sodium nitroprusside (NP) and TNCG on recovery of coronary flow (KP), the contractile function (SF) and measure the pumping function of minute volume (ml) after occlusion of the aorta.
Thus, the research results point to the ability of the drug TNKZ effectively influence vascular tone. Vasodilatation effect of the NO donor is clearly manifested on the model of the isolated perfusing rat heart dose-dependent decrease in aortic pressure: on this model the most vasodilatation efficiency found in TNKZ. The present invention expands the Arsenal of cardiotropic drugs and allows you to create cardiotropic drugs with improved spectrum of activity-based Neto is water-soluble or toxic donor NO: Na 2[Fe2(S2O3)2(NO)4]·4H2O.
The present invention allows the use of oniony binuclear nitrosyl complex of iron formula Na2[Fe2(S2O3)2(NO)4]·4H2O as the original antihypertensive and anti-ischemic drugs with improved spectrum of activity.
1. The use of binuclear sulfur-nitrosyl iron complex of the anionic type formula Na2[Fe2(S2O3)2(NO)4]·4H2O as vasodilatory drugs.
2. The use of binuclear sulfur-nitrosyl iron complex of the anionic type formula Na2[Fe2(S2O3)2(NO)4]·4H2O to obtain drugs for the treatment of ischemic diseases.
SUBSTANCE: modelling a myocardial infraction is followed by intravenous introduction of the immune corrector tamerite 3 mg/kg in an animal every days for seven days. The histological results of the myocardial tissue presented after the first, third and seventh days show the sufficiency and efficacy of the therapy.
EFFECT: effective therapy of the acute myocardial infraction ensured by reducing the intensity of an acute inflammatory reaction, providing faster granulation tissue formation.
SUBSTANCE: modelling a myocardial infraction is followed in a rat is followed by intravenous introduction of the immune corrector tamerite 3 mg/kg. The preparation is injected daily for seven days. The histological results of the myocardial tissue presented after the first, third and seventh days show the sufficiency and efficacy of the therapy.
EFFECT: effective therapy of the acute myocardial infraction with high possibility of cure ensured by reduced manifestations of systemic inflammation response syndrome, faster granulation tissue formation and necrotic zone replacement by cicatricial tissue.
SUBSTANCE: invention refers to medicine, namely to purulent surgery, and can be used for treating patients with critical ischemia of lower extremities. For this purpose, standard medical therapy is additionally combined with single-step wound layered infiltration of soft tissues by Perftoran at 3 cm from wound edges in dose 10-15 ml if the wound is localised on a feet, and 40-50 ml if the wound is localised on a leg or a hip every second day in amount 8-10 procedures.
EFFECT: method allows reducing length of treatment and managing pain syndrome, accelerating wound cleansing and healing in higher intensity of repair processes ensured by constant maximally effective active Perftoran concentration in the wound zone.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns creation of a pharmaceutical composition with a wide spectrum of pharmacological activity, namely exhibiting antihypoxic, neuroprotective and antiamnestic activity, and also showing an ergogenic nature. The declared pharmaceutical composition contains semax and choline. The outcome of experiments proves that the offered pharmaceutical composition containing semax and choline, mutually intensifies an effect of each of them.
EFFECT: composition can find application in creation of the new drug preparations exhibiting neuroprotective activity in a combination with antihypoxic and antiamnestic activity and the ergogenic nature and used for treatment of various pathologies of the central nervous system.
12 tbl, 4 dwg
SUBSTANCE: invention refers to a therapeutic and diagnostic agent used in treatment or diagnostics of a cerebral disease caused by a mitochondrial dysfunction, or in a method for prevention within a surgical intervention and an intravascular surgery, and also to a diagnostic technique for cerebral diseases. The therapeutic agent contains an iron compound and δ-aminolevulinic acid or its salt by formula R2R1NCH2COCH2CH2COR3 (1) where each R1 and R2 independently represents hydrogen atom, and R3 represents a hydroxyl group or C1-24 alkoxy group. The diagnostic agent contains 8-aminolevulinic acid or its salt by formula specified above. The diagnostic technique for the cerebral disease caused by mitochondrial dysfunction, involves a stage of introduction of the specified diagnostic agent followed by a stage of exposure of a diagnosed brain region to light, capable to excite protoporphyrin IX, accompanied by emission of red light, and a stage of diagnostics of the involved brain by the detected emission of red light.
EFFECT: higher diagnostic efficiency.
7 cl, 4 dwg, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to medicine, in particular, to pharmacy. As medical substance composition contains therapeutically effective quantity of trimetazidine dihydrochloride, as prolonging agent - interpolymer complex of polyacrylic acid and polyethylenglucol. As additional substances composition includes: bibasic calcium phosphate, monocrystalline cellulose, basic calcium carbonate, group of sliding substances - stearic acid and/or its salts. Composition can be made in form of pills, covered with coating, contains optimal quantity of additional substances, makes it possible to sufficiently release medical substance and ensures its high bio-availability.
EFFECT: obtaining prolonged pharmaceutical composition, which has antianginal action.
16 cl, 6 tbl, 6 ex, 2 dwg
SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.
EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.
11 cl, 38 ex, 3 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: claimed invention relates to field of pharmaceutics and medicine and pharmaceutical composition for treatment of reperfusion disorders, which contains inert auxiliary substances and as active component compounds of general formula I-Iva.
EFFECT: obtaining pharmaceutical composition for treatment of reperfusion disorders.
SUBSTANCE: invention relates to novel flavonoid compounds of formula 1 where R1-R5 assume values given in the description. The invention also relates to a pharmaceutical composition based on said compounds and a treatment and prevention method. Such compounds and corresponding pharmaceutically acceptable derivatives and/or salts are used in pharmaceutical, veterinary and nutraceutical fields.
EFFECT: compounds and compositions have antioxidant properties and are especially effective in treating ischemic and reperfusion injury.
39 cl, 19 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine, and concerns an injection dosage form for treating an acute ischemic stroke and a craniocereberal injury characterised by the fact that as an active ingredient, it contains a therapeutically effective amount of heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro, and at least one substance chosen from a group of antioxidants.
EFFECT: invention provides high neuroprotective effect in acute severe CNS affections associating various models of the stroke and the craniocereberal injury, as well as high stability and prolonged use.
12 cl, 13 ex, 2 dwg, 5 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: there are offered compounds for injections in local lipopexia regions, containing a prolonged selective beta-2-adrenergic receptor agonist selected from salmeterol, formoterol, their salts and their solvates; a compound for decreasing fatty tissue desensitisation to the beta-adrenergic receptor agonist (or a compound for decreasing target tissue desensitisation to the beta-adrenergic receptor agonist - a version); and a liquid carrier, a related method of local treatment of lipopexia regions (versions), a method of decreasing fatty tissue. It is shown that combined use of the ingredients surpasses an effect (e.g., waist size) as compared with intake of only one of them.
EFFECT: development of the method of decreasing fatty tissue.
30 cl, 1 dwg
SUBSTANCE: invention relates to medicine, namely to endocrinology, and deals with treatment of patients with neuropathic and neuroischemic forms of "diabetic foot" syndrome. For this purpose at the first stage on both extremities injection of 0.25% Novocain is made in dose 50.0 ml into fascial compartment of common paroneal nerve in distal direction to upper musculo-peroneal canal. After 1-2 days as the second stage injections of 0.125% Novocain solution in amount 50.0 ml are repeated in turns into each extremity with interval 3-5 days, course containing 5-6 injections.
EFFECT: elaborated doses and mode of Novocain introduction provide possibility to preserve foot due to stopping purulent inflammation with absence of side effects.
SUBSTANCE: endothelial dysfunction correction is ensured by simulating endothelial dysfunction by the intraperitoneal introduction to laboratory male rats Wistar of N-nitro-L-arginine methyl ether 25 mg/kg daily for 7 days. A development degree of endothelial dysfunction is estimated by the relation of endothelium-independent and endothelium-dependent vasodilation indicators. The endothelial dysfunction correction is ensured by the intragastric introduction of trimetazidine 6 mg/kg and the intraperitoneal introduction of L-arginine 200 mg/kg.
EFFECT: method provides activation of the L-NAME-induced endothelial dysfunction correction ensured by the introduction of a specific combination of the pharmacological preparations promoting the improvement of endothelial vasorelaxation properties.
2 tbl, 1 ex
SUBSTANCE: invention relates to N-alkylamides of formula I
, where A is selected from such groups as -CH2-CH2-, -CH2-CH2-CH2- and -Y-CH2-CH2-, where Y is selected from O, S and NR11 and Y is bonded to a Het group; Het denotes a 5-member or 6-member monocyclic aromatic group which contains one or two identical or different heterocyclic ring elements selected from N, NR13 and S, and which can be substituted with one or more identical or different substitutes R5; X denotes a single bond; R1 and R2 together with a N-CO group which contains them, form a 4-10-member monocyclic or bicyclic saturated or unsaturated ring which, besides a nitrogen ring atom which is part of the N-CO group, can contain one or two additional heterocyclic ring elements selected from N, NR12, O and S, which can be identical or different, provided that two ring elements from O and S cannot be in neighbouring positions in the ring, where the ring, formed by R1 and R2 and the N-CO group containing them, can be substituted with one or more identical or different substitutes R8; R3 is selected from phenyl, naphthalinyl and heteroaryl, which all can be substituted with one or more identical or different substitutes selected from a halogen atom, (C1-C4)alkyl, (C1-C4)alkyloxy group, which can be substituted with one or more fluorine atoms, (C1-C4)alkylamino, di((C1-C4)alkyl)amino, ((C1-C4)alkyl)-CONH-, CONH2, CN, CF3, H2NSO2- and (C1-C4)alkyl-SO2-; R5 is selected from a halogen atom and (C1-C4)alkyl; R8 is selected from a halogen atom, (C1-C4)alkyl and an oxo-group; R11 denotes a hydrogen atom; R12 is selected from a hydrogen atom and (C1-C4)alkyl; R13 is selected from a hydrogen atom and (C1-C4)alkyl; heteraryl is a 5-member or 6-member monocyclic aromatic group which contains one, two or three identical or different heterocyclic ring elements selected from N, NR13, O and S; in any of its stereoisomeric forms or mixture of stereoisomeric forms in any ratio, or its physiologically acceptable salt; provided that the -N(R2)-CO-R1 group cannot be an unsubstituted 2-oxopyrrolidin-1-yl group or unsubstituted 2-oxoimidazolin-1-yl group if the -N(R2)-CO-R1 group simultaneously denotes a group of formula
in which the bond through which the group is bonded to group A, is denoted by a line starting from position 2 of the pyridine ring, and in which R90 is selected from imidazol-1-yl, isoxazol-5-yl, isothiazol-5-yl, 1,2,4-thiazol-1-yl, pyrazin-2-yl and pyrazol-3-yl, which can all be substituted with (C1-C4)alkyl and which can be substituted in the pyridine ring with at most four substitutes selected from (C1-C4)alkyl and a halogen atom; and provided that the -N(R2)-CO-R1 cannot be a 1,3-dioxoisoindol-2-yl group of formula
in which the bond through which the group is bonded to group A is denoted by a line beginning from the nitrogen atom. The invention also relates to a method of producing said compounds, a pharmaceutical composition for stimulating endothelia NO synthase, as well as to use thereof in preparing a medicinal agent.
EFFECT: novel compounds which can be used in conditions where high expression of the said enzyme, high content of NO or normalisation of low content of NO is desired are obtained and described.
18 cl, 87 ex, 1 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to derivatives of 4-aminocarbonylpyrimidine of formula (I).
EFFECT: invention is applicable as P2Y12 receptor antagonists for treatment and/or prevention of diseases or disease states of peripheral vessels, as well as vessels, supplying internal organs, vessels of liver and kidneys, in treatment and/or prevention of cardiovascular and cerebrovascular diseases and states, associated with aggregation of platelets, including thrombosis in humans and mammals.
26 cl, 500 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: declared invention refers to chemical-pharmaceutical industry, and concerns a composition for local application on a body part containing a vasodilative agent, e.g., glyceryl trinitrate as an active ingredient dissolved in a mixture of volatile and non-volatile solvents with different solvating behaviours with respect to the vasodilative agent, differing by the fact that the volatile solvent contains a mixture of water and C1-C5, alcohol, and the non-volatile solvent contains glycerine and an optional auxiliary solvent containing glycol, alcohol of maximum concentration 40 % of the composition weight. The volatile solvent is evaporated after applied on skin to maintain the saturation or unsaturation concentration of the active ingredient in a residue composition for a greater part of an absorption phase.
EFFECT: ensured maximum absorption with a low dose.
10 cl, 3 tbl, 2 dwg
SUBSTANCE: invention refers to medicine, namely to clinical pharmacology, and can be used for pharmacological correction of an adverse reactions on antihypertensive therapy observed in patients with bronchial asthma. That is ensured by calculation of a vegetative balance coefficient (VBC) by formula where SDNN is a standard deviation of a full RR indices array, Tp is total RR interval spectrum power. Am is mode amplitude, with SDNNref, Tpref, Amref indices. Before the therapy starts, SDNNi, Tpi, Ami indices are calculated. If with underlying calcium antagonist pharmacotherapy, VBC>1.01 standard units is observed, sympathetic hypertonus correction is enabled by the additional introduction of the preparation Kardosten, 2 tablets twice a day combined with a calcium antagonist preparation. Calculated VBC<1.0 standard units with underlying calcium antagonist pharmacotherapy does not require vegetative imbalance correction.
EFFECT: method provides well-timed decrease of high activity of sympathetic vegetative nervous system in treating arterial hypertension in the patients with bronchial asthma.
SUBSTANCE: from the onset of the disease, the conservative therapy of hypertensive intracerebral bleedings involves administration of simvastatine in a dose 20 mg a day within a month combined with the basic therapy.
EFFECT: method allows restoring vascular endothelium function in the patients with hypertensive intracerebral bleedings, having a positive effect on the clinical outcome without such by-effect of the preparation, as that involving the level of hepatic transaminases.
2 ex, 1 tbl
SUBSTANCE: invention refers to medical products and concerns a pharmaceutical combination including vinpocetine and betahistine or its pharmaceutically acceptable salt for prevention and treatment of cerebral circulatory depression, containing 5-10 mg of vinpocetine and 8-16 mg of betahistine or its pharmaceutically acceptable salt. Also there are disclosed compositions including said combination.
EFFECT: combinations under the invention exhibits synergetic action.
7 cl, 5 dwg, 16 tbl, 6 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: pharmaceutical composition on the basis of a Vinpocetine and Pyracetamum combination in the form of a solution for injections possessing cerebrovasodilating and nootropic activity and the method of its reception are offered. The solution contains 0.1-0.5 wt % of Vinpocetinum and 5-40 wt % of Pyracetamum and auxiliary substances.
EFFECT: maintenance of more expressed synergy at treatment of the diseases bound to acute or chronic insufficiency of a cerebral circulation in a combination to stability of the form.
12 cl, 4 ex, 3 tbl
SUBSTANCE: granular material contains (a) at least 50 wt %, in terms of the weight of granular material, of a solid water-insoluble inorganic mixed compound of layered double hydroxides of metals capable of binding phosphate, and which contains iron (III) and at least one of the following metals: magnesium, calcium, lanthanum or cerium; (b) 3-10 wt % chemically bound water in terms of the weight of granular material; (c) not more than 47 wt % filler in terms of the weight of granular material. The granular material is obtained via wet granulation. The disclosed granular material is meant for use in therapy for a condition or disease associated with unfavourable content of phosphate in the body.
EFFECT: invention enables to maintain physical integrity of granules and batches during storage, good phosphate binding after ingestion of the granules without their excessive breakdown in the mouth.
22 cl, 8 tbl