Medicinal agent for arresting syndrome of systemic inflammatory response

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a medicinal agent used in arresting syndrome of systemic inflammatory response. Agent comprises, mg: diphosphopyridine nucleotide, 0.3-100 and inosine, 40.0-1200. Proposed medicinal agent can comprise additionally inhibitor of angiotensin-converting enzyme, mainly, lisinopril, 2.5-100 and cardiac glycoside, mainly, digoxin, 0.07-0.3. The new medicinal agent possesses the capacity for arresting syndrome of systemic inflammatory response being independently of etiology of its rise, and allows obtaining the expressed and stable curative effect for short times.

EFFECT: improved and valuable properties of medicinal agent.

5 cl, 4 tbl, 4 ex

 

The invention relates to medicine and can be used in cardiology, Nephrology, cardiovascular surgery, pulmonology, surgery, anestesiologia and intensive care, gynecology, endocrinology.

There are many common symptoms related to diseases such as sepsis, peritonitis, pancreatic necrosis, ileus, burn disease, prolonged compression syndrome, hemorrhagic, traumatic shock, decompensated diabetes mellitus, tumors, and many others, have served as the basis for combining them into a single complex simptomokomplex. It includes General weakness, lethargy, muscle and joint pain, increased blood pressure, headache and dizziness, sleep disturbances and other signs of encephalopathy, and even coma, pale and yellowing of the skin, nausea, vomiting, dryness of mucous membranes, sweating, loss of appetite, tachycardia, impaired Central and peripheral hemodynamics. The emergence of these symptoms in various combinations, such as tachycardia, tachypnea, hyperthermia (clinical triad on Ipocurve, Intonaciei), were classified as a syndrome of endogenous intoxication or, as previously adopted in the foreign literature, the syndrome systemic (generalized) (systemic inflammatory response syndrome - SIRS) inflammatory response (SIRS) [9, 13, 22, 33].

CER is or syndrome of endogenous intoxication is the most common in clinical practice, which can cause such various pathological processes such as tissue destruction and severe tissue hypoxia, chronic poisoning [13, 29, 33]. RSIS is observed in the most various etiological and pathogenetic not identical conditions. SWOT is an essential and defining part of the shock of any etiology, septic process, burns and traumatic diseases, including closed craniocerebral and operative trauma [10]; uremia; diseases of the bronchopulmonary system [13]; oncological processes, as well as surgical diseases accompanying pancreatic necrosis and acute pancreatitis, peritonitis[9, 13, 30, 40].

A detailed study of clinical and laboratory findings revealed the presence of the syndrome and significantly more favorably occurring disorders, where RSIS does not pose a threat, but significantly affects the quality of life of patients with uncomplicated myocardial infarction and coronary heart disease[1, 2, 8, 12, 27, 32-33], atherosclerosis, hypertensive heart disease, complicated by chronic heart failure regardless of etiology[2, 5, 12, 21], in paediatric practice [4], deforming osteoarthrosis [13], preeclampsia [20, 35], burn disease [15].

In the early development of RSIS toxins and metabolites enter the blood, lymph, interstitial fluid and spread Auda of the pathological focus (inflammation). If the protective system of the body is able to neutralize these substances, clinical symptoms may not occur, although any pathological condition associated with the accumulation in tissues and biological fluids products normal or perverted metabolism or kletochnogo response, there is a latent or transient RSIS [30]. When decompensation of protective and regulatory systems and excretion, detoxification (microsomal oxidation, conjugation), mononuclear-macrophage begins the accumulation of endogenous toxins in the body - the stage of accumulation of the products of primary affect. At this stage, the accumulation of toxic products occurs in organs and tissues locally, in primary pathological lesion giperergicakie inflammatory reaction.

It is now established that the development of endotoxinemia as one of the three key elements of SIRS is diagnosed in patients with a variety of hidden and/or chronic diseases [2, 13, 22, 41-42]. Moreover, the use of antibiotics often enhances the effects of endotoxemia. This is a great role for application operating on the bacterial wall of antibiotics, in particular, antibiotics, beta-lactam series [38, 42], which by binding to so-called penitsillinsvyazyvayuschy proteins on the surface of gram(-)bacteria cause endotoxinemia. Moreover, between the severity of endotoxemia and antimicrobial efficacy of antibiotics there is a direct relationship [50]. Obviously, mild variants antibioticsonline endotoxinemia more often. In this regard, simultaneous with antibiotic use tools that eliminate the effects of endotoxemia and thereby impeding the development of RSIS, is a necessary condition for ensuring the rapid detoxification of endotoxin in the body. In 1999 C.J.Wiedermann et al. for the first time showed a sharp increase in the incidence of atherosclerosis in people with chronic or recurrent infections if they have endotoxinemia above 50 PG/ml [59]. It is interesting to note that Smoking was found to be a risk factor only in people with severe endotoxemia.

Mechanisms RSIS various origins similar: among sources of intoxication focuses on the inflammatory foci of destruction, chemisorbant tissues, areas of natural vegetation microflora in the body, accelerating the development processes of apoptosis and necrotic changes [29, 30, 33]. Despite the similarity in pathogenesis, RSIS each nosological form has certain specific features.

Criteria for determining the degree of endogenous intoxication are pronounced degree violated what I hemodynamics, functions of the Central nervous system, the presence of respiratory failure, decreased urine output, refractory to therapy, signs of multiple organ failure, severe nonspecific stress response of the body, failure of two or more functional systems, universal destruction of all organs and tissues of the body, aggressive mediators critical state with a temporary predominance of symptoms of one or other organ failure - pulmonary, cardiac, renal [13, 16, 36]. As follows from the above mechanisms for the development of RSIS, they are based on numerous "vicious circles"are autocatalytically and contributes to the development of clinical signs of endotoxemia in patients. Although the exact mechanism and the sequence of events in the formation of dysfunction of the organs is still not defined, the result of excessive COURSE is the development of endothelial dysfunction. One of the main endogenous mediators of inflammation and probably one of the most versatile agents involved in the implementation of the syndrome EI, activation of apoptosis, is a tumor necrosis factor produced by macrophages and endothelial cells [2, 39]. The manifestation of which can be the development of pulmonary hypertension [5, 33], renal and myocardial insufficiency [4].

The idea of atherosclerosis, ka is micropersuasion granulomatous inflammation with impaired lipid metabolism and increased in far-advanced stages of blood clots allows you to select "atherogenic" targets/effects of endotoxin, including damage to the endothelium, the induction of the formation of foam and froth-like cells from macrophages, thrombogenic effects, etc. In this regard, when expressed forms of RSIS in the tool, aimed at relief of endotoxinemia and the formation of adhesion molecules must include components to address endotoxinemia[4, 19, 27, 32, 34, 39].

Tissue dysoxia serves as the basis for the formation of anomalous mechanism of extraction of oxygen to peripheral tissues. This happens due to the lack of desaturation entering the capillary hemoglobin. Systemic release of cytokines, catecholamines, angiotensin II, prostaglandins promotes the formation of tissue shunt with reduced perfusion [33].

Because RSIS or the syndrome of endogenous intoxication is closely related to fluid overload, it occurs in severe arterial hypertension, accompanied by conditions associated with myocardial dysfunction, renal failure [1, 22, 54]. Restoration of fluid balance, in turn, suppresses the progression of the COURSE. However, despite the fact that the COURSE is one of the main components of inflammatory-destructive pathological process in the body, on the date a clinical investigation of the manifestations and stages of the syndrome is extremely insufficient, and rational ways and means pharmacologist who worked correction practically does not exist.

During cardiac operations, the development of RSIS in addition to operating the injury caused by the transition to artificial circulation, a large contact of blood with non-biological surfaces, stay blood in non-physiological conditions, ischemia and reperfusion after removing the clamp from the aorta, the change in body temperature, the release of endotoxins. These pathological conditions can cause RSIS all patients of varying severity, which is characterized by the activation of complement due to the release of histamine, platelet aggregation and leukocyte count, increased capillary permeability and pulmonary vasoconstriction. If the protective system of the body can not cope with the inflammatory response, these mediators will inevitably lead to the development of complications, the development of postoperative respiratory failure, neurologic disorders, and disorders of the blood coagulation system, and finally multiple organ failure.

For the treatment of syndrome of endogenous intoxication use two approaches - detoxication therapy and detoxification [24, 26]. Detoxification therapy is aimed at the intensification and optimization of physiological systems responsible for the elimination of toxins. Detoxification is the removal of toxic factors stress these systems (efferent detoxification). E. ferentina detoxification (plasmapheresis, the plasma sorption, limfosorbtsiya, etc) justified in severe advanced toxicosis in the phase of multiple organ failure due to decompensation natural detoxification mechanisms. However, she always carries a high risk of complications, which include DIC, the effect Bartrina, hemorrhagic syndrome and other current detoxification therapy safer, but less effective. The basic principles of its implementation are increased perfusion of the tissues with the aim of creating conditions for the diffusion of toxic factors from the affected cells, tissues and organs in the overall flow, gemodilucia, accompanied by a decrease in the concentration of toxins in the blood plasma, forcing diuresis, resulting in toxins and metabolites are excreted from the body. Nemalovajno is also the normalization of the functional state of hepatocytes, which are essential in detoxification of metabolic transformations, struggle with metabolic acidosis, the recovery of energy metabolism. Until recently, components of detoxification treatment were solutions of crystalloids (electrolytes, glucose) and a colloidal solution of a synthetic polymer polyvinylpyrrolidone (neogemodez, mm 8000±2000). Today, however, it is shown that the use of these drugs leads to serious Oslo the changes, due to the toxic effect of large fractions of the polymer cell RES [26]. In the closest used combination therapy COURSE, based on the use of ultrafiltration to remove excess fluid from the blood, improving circulation, reducing brain damage, in particular with the use of sorbitol and resorbable. Based on the rapid excretion of the major mediators of inflammation. However, this may lead to the simultaneous removal of protective molecules, such as protective cytokines increased levels of TNF (tumor necrosis factor).

Thus, a known drug used in the treatment of RSIS, complicating the course of various diseases do not provide effective methods of influence on its own protective detoxifying systems of the body. As a result, even in acute myocardial infarction, cardiopulmonary failure after cardiac operations there is a further progression of the severity of SIRS [1-2], which significantly worsens the clinical picture of the disease and the effectiveness of pharmacological effects.

The objective of the invention is the creation of highly effective tools in a short time to get pronounced and persistent effect, having the ability to arrest the COURSE regardless of etiology its buildings permanently, it is incurred.

The essence of the invention is that the drug for the treatment of RSIS or syndrome of endogenous intoxication is characterized by the fact that it contains inosine (a purine) and diphosphopyridine (nicotine-meddelandenycklar) under the following proportions of ingredients, mg:

Diphosphopyridine0.3 to 100
Inosine40-1200

With the development of RSIS on the background of the ischemic kidney, heart, hypertension, catecholamine stress medication further comprises an inhibitor of angiotensin converting enzyme with direct biological activity in the following ratio of components, mg:

The angiotensin-converting enzyme inhibitor2.5 to 100 mg
Diphosphopyridine0.3 to 100
Inosine40-1200

As an inhibitor of angiotensin converting enzyme with direct biological activity mainly contains lisinopril.

In the case of the development of RSIS on the background of severe heart failure drug further comprises a cardiac glycoside in the following ratio of components, mg:

Cardiac glycosideof 0.07 to 0.3
Diphosphopyridine0.3 to 100
Inosine40-1200

As a cardiac glycoside mainly contains digoxin or its derivatives, beta-acetyldigoxin and beta-methyldigoxin.

The use of the invention allows to obtain the following technical result:

to increase the effectiveness of the treatment COURSE or syndrome of endogenous intoxication,

- to develop the best measures to prevent the development of SIRS,

to achieve fast positive changes reverse the development of RSIS and thereby significantly reduce the risk of complications in patients with acute myocardial infarction after cardiac surgery, particularly in the use of cardiopulmonary bypass, the risk of developing chronic cardiac, cardiopulmonary insufficiency, and cerebrovascular insufficiency in various diseases of the heart ischemic kidney diseases and inflammatory diseases,

- to develop rational tactics surgery, including cardiac surgery patients in the early postoperative period, the tactics of prevention of infectious-inflammatory complications and prevention of the syndrome of endogenous intoxication, which will create conditions to significantly reduce the possible risk of complications during cardiac surgery on the one hand, and will significantly reduce the cost of cardiac and neurosurgical operations, on the other,

- reduce dosage, increase efficiency and reduce the time of use of antibiotics in infectious inflammatory diseases, sepsis, pancreatitis and others,

- to enhance the protective system of the body, to remove or facilitate removal from the body of mediators that cause complications or even lead to the development of multiple organ failure,

to maintain homeostasis, the liver is a target organ for cytokines and other mediators.

Received therapeutic effect is persistent, as is achieved by the simultaneous and balanced impact on the various links and protective forces and detoxifying systems of the body. therapeutic effect of the developed tools is achieved by cupping complex cascade Ableton molecular changes, restore the balance between the intimate mechanisms of regulation of homeostasis of the organism in various diseases.

The technical result is achieved exclusively through the synergistic action of ingredients developed in medicine, a balanced exposure to all three-level COURSE: groove toxins, tissue hypoxia and failure of protective is osmogenesia own detoxifying systems of the body.

The technical result is achieved due to the fact that the tool has been developed with high pharmacological activity and low toxicity, for the first time allows pathogenetically based treatment of RSIS, to stop the processes associated with the growing pool of toxic substances, products of proteolysis in the body in various diseases. This is the first time will help to stop damage to the vascular endothelium, increased permeability of the vascular wall, disorders of platelet and plasma hemostasis, in particular in ischemic heart disease, atherosclerosis and heart failure, the development of respiratory failure, renal failure, neurological disorders, and disorders of the blood coagulation system.

For the first time managed to get the effect of a short COURSE in various diseases by synergistic action of ingredients for which the previously described influence on various processes associated with RSIS, but in clinical practice they are not applied.

Purine nucleotides, adenosine and its primary metabolite inosine (inosine is a natural purine formed by splitting the short-lived adenosine) are low molecular weight compounds and participate in a wide range of intracellular biochemical processes. Ino is in works as a precursor of DNA and RNA. Moreover, inosine plays an important role as a signaling molecule [57]. Although small quantities of adenosine and inosine are present in the extracellular space, the defeat of the cells during metabolic stress conditions, such as ischemia and intoxication, there is a significant increase in the extracellular concentration of these compounds [48]. In 1995 Konvay E, Zolin PN. [13] first formulated the mechanism of purine metabolism disturbance as a typical pathological process that leads to energy deficit, accumulation of nucleosides and nitrogen bases, increased involvement gipoksantina in ksantinoksidazu reaction, which produced reactive oxygen species that damage the membrane structure [46]. It turned out that extracellular adenosine and adenosine A2A(purine) receptors play an important role in the transfer of anti-inflammatory signal, and are sensitive to the inflammatory lesions [48]. Activation of A3 receptors has additional anti-inflammatory effect [45, 46]. Unlike adenosine, inosine, which is inaktivirovannye the product of cleavage of adenosine, also binds to the adenosine receptors and initiates a series of intracellular signaling mechanisms [48, 53], including, increased uric acid, inhibition of poly(ADP-ribose)n is Limeray (inhibition of accelerated cell death by type of apoptosis), the neuroprotective effect through the formation of ribose 1-phosphate, increased regulation of GAP-43 in neurons [43, 45]. Inosine activates cellular processes and not through a receptor mechanism and, moreover, the modulatory action of the adenosine is likely due to its transformation into inosine. And finally, inosine has a strong regulatory effect on the immune system, is anti-inflammatory agent in macrophages and lymphocytes [43, 45]. In 2000, data were obtained that inosine dulls mediaready the macrophage inflammatory response to endotoxin in vivo [48]. The suppression of inosine inflammatory response in ischemia-reperfusion injury in heart and brain can significantly improve the safety of intracellular homeostasis and arrest necrotic changes [45, 57].

Thus, inosine, natural purine, is non-toxic to humans even at a dose of 10 g/kg / day and has anti-ischemic and anti-inflammatory action, therapeutic efficacy which should be revised in the aspect of the received data about the intimate mechanism of action. It is shown that inosine reduces RSIS, the lesions, the severity of cellular desoxyn, dysfunction of blood vessels, which leads to improved survival in septic shock [48] and for edema endotoxinemia [45, 46].

Diphosphopyridine acid (nicotinamide adenine dinucleotide) has catalytic activity, as containing heterocyclic base - nicotine, and forms the prosthetic group of enzymes [33]. Various diseases (hypoxic condition of the liver, heart, brain), myocardial infarction, myocarditis, anoxia, acute cardiovascular failure hemodynamic type, rheumatic process with circulatory failure, diabetes, and others), intoxication with alcohol, carbon tetrachloride, dichloroethane, gelatina, some antibiotics and other pathological conditions cause significant disruption to the system ABOVE, which may affect many processes in the body, in the regulation involving OVER-dependent coenzymes [39]. Moreover, it is shown that the large density of NAD-dependent enzymes in the cells of the immune system may underlie the increase under the influence of exogenous NAD tolerance of the immune system to inflammation [39]. The application for this purpose nicotinamide is not effective, because the conversion of nicotinamide in NAD requires two molecules of ATP, pronounced deficit which is typical for all of the above pathological conditions, and the application of the ABOVE with the purpose of eliminating the effects of intoxication in medicine was not applied.

One component of the development of RSIS, as mentioned above, is decontamination with the public detoxifying systems of the body, which include first of all the antioxidant defense system and lysosomal system. In conditions of heart failure compensatory activation of the sympathoadrenal system and the damaging action of catecholamines on the heart muscle is one of the main reasons for the defeat of membrane structures of cells, in particular membranes of lysosomes, resulting in the release into sarcoplasm proteoliticheskie enzymes [9]. It is shown that therapeutic doses strofantina and other cardiac glycosides containing cyclopentanoperhydrophenanthrene the core, have a direct effect on the lysosomal apparatus [16]. The reason for the stabilization of lysosomal membranes under the influence of therapeutic doses of cardiac glycosides may be due to their direct effect on the activity of hydrolytic enzymes in the myocardium (β-glucosidase and cathepsin D), and inherent ability to block SH-groups of thiol enzymes, and in this case we are talking not only about the inhibiting effect of glycoside of cardio-tonic membrane Na+,K+-ATPase [47], but also about possible vnutrirezonatornoi blockade of SH-groups of hydrolytic enzymes [51]. Thus, the inclusion of a tool has been developed cardiac glycosides in heart and cardio-respiratory failure due to not only the x direct inotropic effect on the myocardium, but direct action on one of the key components of the syndrome of endogenous intoxication of any etiology - activation or increasing adaptive capacity own detoxifying systems of the body.

Violation of the metabolism and the accumulation of products perverted metabolism during the COURSE leads to the activation of processes of lipid peroxidation (LPO), disruption of the homeostasis of blood rheology and microcirculation. Suffers function of cell membranes, intracellular respiratory enzymes. The mechanism of the damaging effects of excessive activation of free-radical processes at the cellular level is one of the main reasons for the heavy flow of RSIS.

Used in the formula proportion of ingredients included in the product, reflect the result of numerous reliable experimental observations, which showed that beyond presents contents of components reduces the synergistic effect of the ingredients and, as a consequence, therapeutic efficacy of the drug.

The developed tool is proposed for release in glass or plastic vials or ampoules containing a clear liquid or lyophilized white powder (in the latter case, it is possible to complete the solvent), or in the form of enteric-soluble and sublingual that the notches white, when following ingredients in 1 vial-ampoule, a tablet or capsule.

The drug is applied to patients with different nosologies, pathogenetic mechanisms of development which includes the development of RSIS depending on the severity of the disease. Single dose of medicinal product contains an active principle, the mass ratio of ingredients which does not exceed the following limits:

Diphosphopyridine0.3 to 100
Inosine40-1200

The dose depending on the severity of the disease varies from a single dose up to 4 times per day (every 6 hours).

In severe forms of RSIS, especially developed on the background of renal ischemia, ischemic heart disease, arterial hypertension, catecholamine stress, drug use in injection or pill form, the active principle which further comprises an inhibitor of angiotensin converting enzyme mass ratio of ingredients which do not go beyond the following limits, mg:

The angiotensin-converting enzyme inhibitor2.5 to 100 mg
Diphosphopyridine0.3 to 100
Inosine 40-1200

In severe forms of RSIS, developed on the background of severe heart failure, the drug is used in injection or pill form, the active principle which additionally contains a cardiac glycoside, a mass ratio of ingredients which do not go beyond the following limits, mg:

Cardiac glycosideof 0.07 to 0.3
Diphosphopyridine0.3 to 100
Inosine40-1200

therapeutic effectiveness of developed drugs established in experiments on 112 white rats, 72 rabbits of the chinchilla breed and purebred dogs. The severity of SEI was assessed by the increase in plasma and erythrocyte content of molecules of average weight [21], the sorption capacity of red blood cells [30]. Determination of histamine and serotonin fluorimetric method, alanine and aspartataminotranferase (Alt and AST) using sets of "Bio-La-Test" "Lachema (Czech Republic).

Example 1. In the experiment the materials used in the study of different types of biological action (hepatotoxic, teratogenic, General toxic, etc) when exposed to chemicals, organic (various toxins, endotoxins, and so on) and inorganic (salts thee is elih metals, in particular coming from the drinking water, sulphur dioxide). The combined action of the drug is considered one of the most difficult models gepatoksicskih, General toxic lesions that plays with the introduction of carbon tetrachloride.

In clinical toxicology, poisoning by carbon tetrachloride (CCl4we meet quite often, patients with this pathology are up to 60% of all liver Toxicological patients. Hepatoxicity destruction under the influence of caregories carbon is accompanied by progression of necrotic changes and steatosis. Intravenous infusion of tools developed at a dose of 101 mg/kg suppresses the development gepatoksicskih destruction caused CCl4, galactosamine, acetaminophen, holidaycity diet and other cholestatic lesions.

Experiments carried out on 28 white rats-males, weighing 180-220 g, contained in vivarium on a standard diet. Acute exposure to carbon tetrachloride reproduced by daily subcutaneous injection of 1 ml/kg CCl4dissolved in an equal volume of olive oil for 6 days. Animal experimental and control groups were aftanaziva pairs at the same time under geksenalovy anesthesia on day 10 of treatment. 7 was a group of normal animals.

Introduced rats by carbon tetrachloride accumulates in endo is plazmaticheskoi reticulum of hepatocytes and is associated with a hydrophobic stretch of apparment cytochrome P450, and with the heme iron. The formed free radicals and electrophilic intermediates damage the cell membranes of hepatocytes, causing severe violations of the liver, leading to the deaths of 18% of the animals. Under the influence of inosine mortality is reduced to 16%, while in developed combination (101 mg/kg) - up to 6%.

Activation in rats with CCl4-hepatitis processes of free radical oxidation of membrane phospholipids entails the development of syndromes cytolysis (increase in serum rats the content of the transaminases ALT and ACT 131 and 200 times, respectively, and alkaline phosphatase 3.4 times) and cholestasis (increase in total bilirubin 2.5 and free - 4.1 times). High activity in plasma ACT correlates with decreased activity of glutathione peroxidase (r 0,73, p<0,001). In the cytosol of hepatocytes poisoned animals significantly reduced the activity of glutathione peroxidase and glutathione reductase, catalyzing phase II detoxification of xenobiotics and participating in antipersonnel protection.

Intraperitoneal administration of patented medicines in a dose of 101 mg/kg weight of the animal (100 mg inosine + 1 mg diphosphopyridine) twice a day, reduces cholestasis that is logged to reduce the content of total and direct bilirubin in 2 times and 1.5 times, respectively, relative to the control group. Intraperitoneal in the introduction of patented medicines in a dose of 40.3 mg/kg weight of the animal (40 mg inosine + 0,3 mg diphosphopyridine) twice a day, reduces cholestasis, what is logged to reduce the content of total and direct bilirubin 1.76 times and 1.39 times, respectively, relative to the control group.

In the cytosol of hepatocytes developed tool helps to increase ATP levels and increases the content of cytochrome P450and cytochrome b5microsomal fraction, while under the influence only of inosine substantial increase in the level of cytochromes in the respiratory chain of mitochondria is not observed. On a more pronounced ability developed combination to stop the cytolysis of hepatocytes shows a stronger decrease of transaminase activity and content of alkaline phosphatase in serum, and increased activity of enzymes I and II biotransformation (glutationtransferase and glutathione reductase) in 1.6 and 2 times, respectively (whereas in the case of monotherapy inosine 1.4 and 1.35 times). The effect persists with increasing doses of the combined funds to 1250 mg/kg weight of the animal. therapeutic effect of large doses not significant different from the pharmacological activity of small doses, but it is especially important not shown any signs of toxicity, which is of great importance in the clinic.

Thus, it was established that under the influence of cetarehhloristam carbon causes damage to cellular energetics, membranes and item intracellular detoxification. Developed a combined tool is able to revive hepatocyte"damaged by exposure to extreme factors.

This mechanism underlies heavily under the influence of the combined funds RSIS characteristic of toxic lesions (table 1).

Table 1.

The change in optical density of plasma and erythrocytes as an integrated indicator RSIS in defeat.
ExtenzeNormaToxic damage, duration, days
61224
Plasma λ=282 nm0,23±0,040,29±0,040,78±0,12*#x0,85±0,08#x
Erythrocytes, λ=258 nm0,56±0,051,23±0,15***1,63±0,18***#0,47±0,05x
Inosine 100 mg/kg per day
Plasma λ=282 nm0,23±0,040.27±0,04**0,58±0,08*#0,67±0,08#x
Erythrocytes, λ=258 nm 0,5B±0,050,93±0,11*1,05±0,18*#x0,87±0,07#x
The drug of 40.3 mg/kg per day

(Inosine 40 mg + diphosphopyridine 0.3 mg)
Plasma λ=282 nm0,23±0,040,25±0,040,38±0,040,35±0,06
Erythrocytes, λ=258 nm0,56±0,051,09±0,04*0,78±0,080,51±0,05
Inosine 1200 mg/kg / day
Plasma λ=282 nm0,23±0,040,32±0,040,56±0,04*0,65±0,08*
Erythrocytes, λ=258 nm0,56±0,050,87±0,15*0,81±0,08*0,45±0,05*
Drug 1250 mg/kg of body weight per day

(Inosine 1200 mg + diphosphopyridine 50 mg)
Plasma λ=282 nm0,23±0,040,25±0,040,37±0,050,29±0,08
Erythrocytes, λ=258 nm0,5B±0,050,73±0,110,71± 0,100,49±0,05
Drug 1250 mg/kg of body weight per day

(Inosine 100 mg + diphosphopyridine 1 mg + lisinopril 2.5 mg)
Plasma λ=282 nm0,23±0,040,25±0,040,32±0,050,31±0,06
Erythrocytes, λ=258 nm0,56±0,050,73±0,110,89±0,060,63±0,05

Note: comparison of differences average:*- normal#- 2 hour, 12 hour, 24 - X.

The study showed that the effect of the developed tools is not merely the sum of its constituent ingredients is expressed positive synergy of ingredients in their ability to arrest the development of RSIS (sum of effects of individual ingredients in the same doses the effect is almost twice less pronounced than in established medicinal product). By the severity of the effect at the optimum ratio of ingredients in established medicinal product, irrespective of its form, strength of the effect is not significantly changed. Faster dynamics of therapeutic effect of cupping COURSE is achieved when the drug of the angiotensin-converting enzyme inhibitor lisinopril (table 1), as well as captopril or enalapril.

Example 2. As a model of the development of RSIS used the model of polymicrobial sepsis induced by legirovaniem cecum at its basis and its dual perforation. Animals of the control group were injected intraperitoneally with saline, animals 1-3 comparison group was introduced inosine at the dose of 100, 200 and 1000 mg/kg one hour before the operation and its combination with antibiotics, gentamicin at a dose of 10 mg/kg and clindamycin at a dose of 300 mg/kg after 6, 12 hours after surgery and 4-6 of the main group is a combination drug I, containing the inosine - 100 mg/kg of body weight, diphosphopyridine - 1 mg/kg dose of 101 mg/kg, 202 mg/g and 1010 mg/kg rat an hour before, and in combination with antibiotics, gentamicin and clindamycin in the same doses at 6 and 12 hours after surgery (table 2). In the second case, the treatment began 24 hours after surgery and lekarstvennoe means additionally contain cardiac glycoside digoxin (table 3).

It is shown that 24 hours after playback of sepsis, the number of colonies formed under aerobic conditions at 37°With, in the liver decreased from 9.9±to 2.5·108SFUs to 6.9±1,3·108, 6,75±1,55·108, 6,7±1,9·108with the introduction of inosine at the dose of 100, 200 and 1000 mg/kg in the face of antibiotics and to 5.8+1,3·108(p<0.05), 5,6±1,5·108(p<0.05), 5,6±1,4·108(p<0.05) in the introduction the AI combined drug at a dose of 101 (100 mg/kg of inosine and 1 mg/kg diphosphopyridine), 202 (100 mg/kg of inosine and 1 mg/kg diphosphopyridine) and 1250 (1200 mg/kg inosine and 50 mg/kg of diphosphopyridine) mg/kg weight of the animal on the face of antibiotics, respectively.

The data obtained indicate that the potentiation of antibiotics developed in combination, and this action is more pronounced than the combination with antibiotics only inosine.

After 2 h after surgery in the spectrogram, the plasma tends to increase the peak optical density at the wavelength (λ) 282 nm, increases the maximum extinction of erythrocytes in λ=258 nm 2.9, and the total index of toxicity in 3 times - exit-sized molecules from the source of aggression and their sorption on glycocalix or inside red blood cells. After 12 h, along with the increase of the peak optical density of erythrocytes at 1.7 times, there is an increase in the extinction of the plasma 1.8 times (plasma becomes rich biochemical substrates of endogenous intoxication, substance catabolic origin, products of peroxidation of structures, collapse of the cells and so on). To 24 h of development in sepsis there is a significant increase in the average molecule in the plasma and in erythrocytes. The extinction of the plasma exceeds the norm 5.9, and erythrocytes in 3.9 times (table 2).

Table 2.

The change in optical is lotnosti plasma and erythrocytes, as an integrated indicator of SIRS with sepsis
ExtenzeNormaSepsis, duration, h
61224
Plasma λ=282 nm0,23±0,040,25±0,040,78±0,12*#x0,85±0,08#x
Erythrocytes, λ=258 nm0,56±0,051,23±0,15***1,63±0,18***#0,47±0,05x
Inosine 100 mg/kg in the face of antibiotics
Plasma λ=282 nm0,23±0,040,17±0,04**0,58±0,08*#0,55±0,05#x
Erythrocytes, λ=258 nm0,56±0,050,98±0,03*1,13+0,11*#x0,52±0,02#x
Drug 101 mg/kg per day (inosine 100 mg + diphosphopyridine 1 mg) on a background of antibiotics
Plasma λ=282 nm0,23±0,040,15±0,030,42±0,04* 0,80±0,03##
Erythrocytes, λ=258 nm0,56±0,050,73±0,080,91±0,06***0,77±0,06##
Inosine 1000 mg/kg per day on a background of antibiotics
Plasma λ=282 nm0,23±0,040,25±0,040,38±0,04*0,85±0,08##
Erythrocytes, λ=258 nm0,56±0,051,23±0,15*1,31±0,08*0,47±0,05##x
Drug 1250 mg/kg per day (inosine 1200 mg + diphosphopyridine 50 mg) per day on a background of antibiotics
Plasma λ=282 nm0,23±0,040,49±0,050,48±0,04*0,29±0,04###xxx
Erythrocytes, λ=258 nm0,56±0,050,83±0,15*0,77±0,06*0,69±0,05##xx
Drug 1250 mg/kg per day (inosine 100 mg + diphosphopyridine 1 mg + beta acetyldigoxin 0.01 mg) per day on the background of antibi the ticks
Plasma λ=282 nm0,23±0,040,19±0,030,18±0,03*0,29±0,04###xxx
Erythrocytes, λ=258 nm0,56±0,050,83±0,15*0,67±0,06*0,69±0,05##xx
Note: comparison of differences average:*- normal#- 2 hour,xwith 12-hour, 24-H.

Thus, 24-72 h characterized by severe toxaemia, correlate with the manifestation of clinical signs of SIRS, the accumulation of toxic products in the blood plasma is and the products of proteolytic degradation necrotizing myocardium may hepatocytes, lesions formed elements, rapid excretion in the blood indicates an adequate activity of lysosomal enzymes (table 2). After 3 days the height of erythrocyte peak in the spectrogram becomes below the normal level of 18%. At the same time in the plasma content increases myofibrillar fraction of creatine phosphokinase (token destruction of myofibrils) and cytochrome C and R450(damage mitochondria of cardiomyocytes and hepatocytes), documenting the persistence of necrotic, dystrophic (mosaic) porazeni the heart muscle and liver, as well as inflammatory processes with a high content of serotonin and histamine. Similar results were obtained in conditions of reduced blood circulation in the skin flap and traditional defeat. The basis of the cardiac glycoside in combination with inosine and diphosphopyridine in patent medicine, aimed at the relief of RSIS, lies, apparently, the ability of drugs to inhibit the production of interleukin-6 and tumor necrosis factor - α. Previously A.Matsumura et al. (1997) have shown the ability of the cardiac glycoside, ouabain to suppress to some extent liposaccharide-induced lethality associated with the development of endotoxemia in mice, although the mechanism of this phenomenon remains unknown until the end.

Example 3. With the aim of playing the COURSE with hypertension normotensive rats operated under necrosum, opened the abdominal cavity was exposed area of the aorta and the radiating arteries of the kidneys and put titanium spiral ring constricting the lumen of the aorta to 2/3 of its diameter. Blood pressure was measured by using a sensor with a rubber cuff on the tail of the animal. The signal from the sensor was registered on Mingograph EMT-118, animals were subjected to attanasio 15, 20 and 35 days after surgery.

4,67±0,13
Table 3.

The change in optical density of plasma and erythrocytes as an integrated indicator RSIS in hypertension
IndexNormaRSIS in hypertension, the day
152035
Systolic pressure108±5152±7167±7207±10
The mass of the heart0,97±0,041,08±0,071,23±0,121,36±0,09
The relative weight of the heart, mg/g of body weight4,6±0,25,1±0,25,9±0,35,6±0,2
Plasma λ=282 nm0,23±0,040,25±0,040,38±0,04**0,85±0,08###xxx
Erythrocytes, λ=258 nm0,56±0,051,23±0,15*** 1,31±0,08***0,47±0,05##xx
Inosine 100 mg/kg per day
Systolic pressure108±5142±6*154±7*178±10*
The mass of the heart0,97±0,041,08±0,04*1,19±0,12*1,32±0,05*#
The relative weight of the heart, mg/g of body weight4,6±0,25,0±0,2*5,7±0,2*#5,6±0,1*#
Plasma λ=282 nm0,23±0,040,25±0,040,38±0,04"0,45±0,08
Erythrocytes, λ=258 nm0,56±0,050,61±0,150,63±0,080,77±0,05*
Drug 111 mg/kg per day (inosine 100 mg + diphosphopyridine 1 mg + lisinopril 10 mg),
Beats the static pressure 108±5112±7116±7121±6
The mass of the heart0,97±0,040,98±0,070,98±0,121,03±0,06
The relative weight of the heart, mg/g of body weight4,6±0,24,6±0,24,7±0,34,8±0,2
Plasma λ=282 nm0,23±0,040,25±0,040,27±0,040,25±0,08
Erythrocytes, λ=258 nm0,56±0,050,58±0,060,63±0,080,61±0,05
Lisinopril, 10 mg/kg per day
Systolic pressure108±5112±6137±7167±10*#x
The mass of the heart0,97±0,041,02±0,051,11±0,07 1,16±0,07
The relative weight of the heart, mg/g of body weight4,6±0,25,1±0,2*5,4±0,3*5,6±0,2*#
Plasma λ=282 nm0,23±0,040,56±0,040,57±0,04**0,65±0,08*#
Erythrocytes, λ=258 nm0,56±0,050,98±0,15*0,91±0,08*0,97±0,05*
Drug 1270 mg/kg per day (inosine 1200 mg + diphosphopyridine 50 mg + lisinopril 20 mg)
Systolic pressure108±5102±7107±7110±10
The mass of the heart0,97±0,041,00±0,071,01±0,121,02±0,02
The relative weight of the heart, mg/g of body weight4,6±0,24,65±0,154,7±0,2
Plasma λ=282 nm0,23±0,040,25±0,040,38±0,04*0,35±0,08
Erythrocytes, λ=258 nm0,56±0,050,63±0,100,51±0,08*0,47±0,05
Note: comparison of differences average:*- normal#- 15 days, x - 20 day.

Studies have shown that combined treatment based purines containing the controller is additionally ADP-ribosylate diphosphopyridine nucleotide and angiotensin-converting enzyme inhibitor, lisinopril allows to achieve a lasting reduction in blood pressure, nausea proliferation of cardiomyocytes, the development of hypertrophy of the myocardium and result in stopping the development of COURSE - there are no changes in the optical density of plasma and erythrocytes (does not change the level of average molecules). Moreover, the effect of the combination significantly superior effect as the optimal dose of inosine (purine)or an inhibitor of angiotensin-converting enzyme (lisinopril).

Example 4. As a model of the development of RSIS dominated by heavy series is echnol failure model is used toxico-allergic myocarditis.

After 2 h after resolution of injection staphyloccocal toxin in the spectrogram, the plasma tends to increase the peak optical density at the wavelength (λ) 282 nm, increases the maximum extinction of erythrocytes in λ=258 nm 2.2, and the total toxicity index 2.4 times - exit-sized molecules from the source of aggression and their sorption on glycocalix or inside red blood cells. After 12 h, along with the increase of the peak optical density of erythrocytes in 1.3 times, extinction of the plasma was increased 1.8-fold (plasma becomes rich biochemical substrates of endogenous intoxication, substance catabolic origin, products of peroxidation of structures, collapse of the cells and so on). Apparently, it is between 2-12 h toxic products accumulate mainly in the myocardium, as the target organ (inflammatory, as well as mosaic focal-dystrophic-necrotic lesion with secondary giperergicakie allergic reaction). To 24 h of development THERE is a significant increase in the average molecule in the plasma and in erythrocytes. The extinction of the plasma exceeds the rate of 3.9 and erythrocytes 2.9 times exceeding the norm (table 4).

Table 4.

The change in optical density of plasma and erythrocytes, as the integral is tion rate RSIS in heart failure.
IndexNormaRSIS in heart failure, the day
1310
The maximum rate of filling of the left ventricle, mmHg/s1350±551052±771067±7899±98
The maximum rate of fall of pressure in the left ventricle, mmHg/s1650±1201008±97923±0,12836±79
Plasma λ=282 nm0,23±0,040,25±0,040,82±0,04**0,95±0,07#x
Erythrocytes, λ=258 nm0,56±0,051,23±0,15*1,61±0,09*0,43±0,04#x
Inosine 100 mg/kg per day
The maximum rate of filling of the left ventricle1350±551142±6*1054±7*1078±0,10*
The maximum rate of fall of pressure is of the left ventricle 1650±201,08±0,04*1,19±0,12*1,32±0,05*#
Plasma λ=282 nm0,23±0,040,25±0,040,38±0,04**0,45±0,08
Erythrocytes, λ=258 nm0,56±0,050,61±0,150,63±0,080,77±0,05*
Drug 101,25 mg/kg per day (inosine 100 mg + diphosphopyridine 1 mg + digoxin 0.25 mg)
The maximum rate of filling of the left ventricle1350±551112±871316±791521±96
The maximum rate of fall of pressure in the left ventricle1650±1201345±771498±1121494±106
Plasma λ=282 nm0,23±0,040,25±0,030,31±0,050,29±0,07
Erythrocytes, λ=258 nm0,56±0,05 0,59±0,060,60±0,060,50±0,05
Digoxin 0.25 mg/kg per day
The maximum rate of filling of the left ventricle1350±551172±1691297±671167±90*
The maximum rate of fall of pressure in the left ventricle1650±1201078±105*1101±87*1160±107*
Plasma λ=282 nm0,23±0,040,55±0,03*0,57±0,03*0,65±0,08*#
Erythrocytes, λ=258 nm0,56±0,050,90±0,15*0,89±0,07*0,90±0,05*
Drug 1252,5 mg/kg per day (inosine 1200 mg + diphosphopyridine 50 mg + digoxin 0.25 mg)
The maximum rate of filling of the left ventricle1350±551002±45*1007±71*1110±100*
Maxim is its rate of fall of pressure in the left ventricle 1650±1201390±89*1456±1201435±92
Plasma λ=282 nm0,23±0,040,25±0,040,28±0,040,25±0,08
Erythrocytes, λ=258 nm0,56±0,050,61±0,100,51±0,060,52±0,05
Note: comparison of differences average:*- normal#- 1-dayx- 10 days.

Thus, in all periods of application of the developed combined funds for the relief of RSIS in severe heart failure due to toxic-allergic myocarditis, much more pronounced than in the case of using only the inosine in the same doses and in combination. These changes on the day 3 joins relief on a background of application of the developed combined means of increasing the alkaline phosphatase activity and thymol turbidity tests, the elevated levels of transaminase and lactic acidosis, impaired activity not only aerobic, and anaerobic glycolysis. Thus, the application of the developed combined funds which allows the dynamics of the development of RSIS in severe heart failure, due to the toxic-allergic myocarditis, to prevent the development of insolvency systems homeostasis, often irreversible transition in the phase of decompensation with manifestations of the syndrome of multiple organ failure.

In addition, a combination of substantially inhibits the formation of cytotoxic phosphatidylcholine and normalizes changes in major classes of phospholipids, characteristic light, phosphatides-glycerides and lipid membranes of mitochondria of cardiomyocytes, and most importantly, inhibits giperandrogenii cytokines.

The results show that due to the influence on the metabolism, the key processes COURSE - groove toxins, tissue hypoxia and impaired functioning of protective systems of the body developed the tool is effective for edema RSIS and pulmonary heart disease.

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1. Drug, aimed at relief of the syndrome of systemic inflammatory response, characterized by the fact that it contains inosine and diphosphopyridine, in the following ratio of ingredients, mg:

Diphosphopyridine0.3 to 100
Inosine40,0-1200

2. The drug according to claim 1, characterized in that it further comprises an inhibitor of angiotensin-converting enzyme, in the following ratio of components, mg:

The angiotensin-converting enzyme inhibitorthe 2.5-100
Diphosphopyridine0.3 to 100
Inosine40-1200

3. The drug according to claim 2, characterized in that as an inhibitor of angiotensin-converting enzyme it mainly contains lisinopril.

4. L of the drug means according to any one of claims 1 to 3, characterized in that it additionally contains a cardiac glycoside in the amount of 0.07 to 0.3 mg.

5. The drug according to claim 4, characterized in that as a cardiac glycoside, it mainly contains digoxin.



 

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1 cl, 2 tbl, 1 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new derivatives of pyrrolopyrimidine of the formula (1) and their pharmaceutically acceptable salts possessing properties of selective inhibitor of specific cyclic guanosine 3',5'-monophosphate phosphodiesterase (specific cGMP PDE) (PDE V). In the formula (1) R1 represents hydrogen atom (H), (C1-C3)-alkyl substituted optionally with one or some fluorine atoms; R2 represents H, halogen atom, (C1-C6)-alkyl substituted optionally with hydroxyl group (-OH), (C1-C3)-alkoxy-group, (C3-C6)-cycloalkyl or one or some fluorine atoms, (C3-C6)-cycloalkyl; R3 represents (C1-C6)-alkyl substituted optionally with (C3-C6)-cycloalkyl or one or some fluorine atoms; R4 represents (C1-C6)-alkyl substituted optionally with one or some fluorine atoms; R5 represents -SO2NR6R, -NHSO2R8 or heterocyclyl such as tetrazolyl; each R6 and R7 represents independently H or (C1-C6)-alkyl substituted optionally with -CO2H or one or some fluorine atoms; or in common with nitrogen atom to which they are bound form monocylic ring, such as imidazole, pyrrolidine, piperidine, morpholine, piperazine and homopiperazine wherein indicated group is replaced optionally with R9 wherein R9 represents (C1-C6)-alkyl substituted optionally with one or some halogen atoms, hydroxyl group (OH), (C1-C3)-alkoxy-group that is replaced optionally with one or some fluorine atoms, -NR11R12, -C=NR13(NR14R15) or tetrazolyl group, 6-membered nitrogen-containing heteroaryl group; each R11 and R12 represents independently H or (C1-C4)-alkyl; R13represents H; each R14 and R15 represents independently H. Also, invention relates to intermediate compounds, methods for preparing compounds and pharmaceutical compositions. Proposed compounds can be used in treatment of impotency, sexual dysfunction in females, stable, nonstable and variant (Prinzmental) stenocardia and other diseases also.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

15 cl, 1 tbl, 250 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in treatment or prophylaxis of hypertension, heart diseases, vascular disorders and kidney diseases. The composition comprises compound of the formula (1) as antagonist of angiotensin II receptors and one or some diuretics. The composition shows enhanced effectiveness.

EFFECT: valuable medicinal properties of composition.

23 cl, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: first aid emergency kit has housing, medicinal aids disposed in order inside the housing and description of usage of first aid emergency kit provided with algorithm of taking of medicines and emergency actions (medicinal aids and description are disposed onto housing's walls). Set of medicinal aids has at max three single-use therapeutic dosages of at least two preparations which are characterized by cyto-protection mechanism of increase of survival of cells and tissues of brain but action of the mechanism is different for the preparations. Medicinal preparations composing the set are intended and provided for emergency self-aid and mutual aid at acute disorder of cerebral circulation of the blood. Preparation for decreasing arterial pressure and/or reducing giddiness, sickness and vomiting is introduced into the kit additionally.

EFFECT: improved efficiency of self-aid and mutual aid.

17 cl, 2 dwg

FIELD: medicine.

SUBSTANCE: about 10 min before occlusion of carotid arteries into total carotid artery at the side of reconstruction it is necessary to introduce nicotinamide solution at 2.0 mg/kg body weight. The innovation provides cerebral protection against ischemic lesion in case of reconstructive operations upon carotid arteries under local anesthesia, at keeping patient's consciousness, in particular, in case of contraindications for total anesthesia and at necessity for verbal contact between a doctor and a patient under operation.

EFFECT: higher efficiency.

4 dwg, 1 ex, 1 tbl

FIELD: medicine, intensive therapy.

SUBSTANCE: it is necessary to apply 2 ml fentanyl, 2 ml tramadol, 1-2 ml droperidol into one syringe to be dissolved with physiological solution up to 10 ml. Solution should be injected at the rate of 1 ml per 6-10 sec intravenously. The innovation enables to completely interrupt pain syndrome, avoid its relapsing and, thus, decrease the frequency of therapeutic side effects that leads to favourable hemodynamic situation in this category of patients.

EFFECT: higher efficiency of therapy.

FIELD: medicine, cardiology.

SUBSTANCE: the present innovation deals with treating patients with ischemic cardiac disease at the background of type II diabetes. For this purpose, in case of stenocardia of functional class II and type II diabetes of average severity degree one should introduce enalapril at the dosage of 20 mg/d in combination with trental at the dosage of 400 mg/d, and at stenocardia of functional class III and type II diabetes of severe flow one should introduce enalapril at the dosage of 30 mg/d in combination with trental at the dosage of 400 mg/d. The innovation suggested normalizes monocytic-macrophageal link of immune system.

EFFECT: higher efficiency of correction.

2 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: method involves administering required dose of renin-angiotensin inhibitor Ramipryl or its salt combined with a hypotensive drug, means for reducing cholesterol content, diuretic or aspirin to patients showing no signs of left ventricle dysfunction or cardiac insufficiency.

EFFECT: prevented cardiovascular attacks, angina pectoris, diabetes manifestations.

18 cl, 5 tbl

FIELD: medicine.

SUBSTANCE: method involves administering Eucanol at a daily dose of 3-4 g and Ispradin at a daily dose of 1.2-1.3 mg twice a day. Eucanol is taken during a meal and Ispradin is taken 30-40 min before meals.

EFFECT: enhanced effectiveness of treatment; reduced drug consumption.

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutically acceptable salts of 2,4,6-trimethyl-2-hydroxypyridine with lower dicarboxylic acids of the general formulae (1-a-d): possessing an antioxidant activity wherein X means a simple bond (compound 1a), oxalate, C8H11NO x C2H2O4; X means -CH2 (compound 1b), malonate, C8H11NO x C3H4O4; X means -CH2-CH2 (compound 1c), succinate, C8H11NO x C4H6O4); X means the group -CH2CH(OH) (compound 1d), malate, C8H11NO x C4H6O5. Also, invention relates to a pharmaceutical composition of salt of the formula (1c) possessing geroprotecting and anti-ischemic activities, and to a method for preparing these salts.

EFFECT: improved preparing method, valuable medicinal properties of substances and pharmaceutical composition.

3 cl, 5 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: method involves additionally administering vitamins B6, B12 and folic acid to patients receiving anticoagulation therapy. Protein content is limited in daily food allowance to 0.8-1.1 g/kg of body weight and cysteine content is increased to 400-500 mg/day.

EFFECT: enhanced effectiveness of treatment; eliminated homocysteine link in pathogenesis.

FIELD: medicine.

SUBSTANCE: method involves administering Clonidine (Clophelinum). The drug is introduced intramuscularly, intravenously or as pills on the background of neurotropic therapy at a dose of 2.5-3.0 mcg/kg of body weight during the first hours of posttraumatic period within 7-10 days.

EFFECT: accelerated and simplified treatment course.

1 dwg, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 5-amidino-2-hydroxybenzenesulfonamide of the general formula (I): wherein R2 means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (A): wherein (A) means -COORA, -CONRBRC, 3-7-membered monocyclic heterocycloalkyl group comprising one or two heteroatom in ring chosen from atoms N, O, S that can comprise oxo-group and 5-6-membered monocyclic aromatic heterocyclic group comprising one-three heteroatoms in ring chosen from atoms N, O, S that can comprise oxo-group or lower alkyl wherein RA means hydrogen atom (H), 3-7-membered monocyclic aliphatic alkyl group, lower alkyl that can comprises a substitute chosen from the group (i) wherein (i) means -COORA1 wherein RA1 means hydrogen atom (H), -OCORA2 wherein RA2 means lower alkyl group, -OCOORA3 wherein RA3 means lower alkyl, -ORA4 wherein RA4 means hydrogen atom (H), lower alkyl -CONRA5RA6 wherein RA5 and RA6 mean independently hydrogen atom (H), lower alkyl, or -NRA5RA6 forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; wherein RB and RC mean independently hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (ii), or -NRBRC forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; (ii) means -COORB1 wherein RB1 means hydrogen atom (H), lower alkyl; T means oxygen atom (O), sulfonyl group; or TR1 means -SO2NRB3RC3 wherein RB3 and RC3 means independently hydrogen atom (H), lower alkyl; R2 means lower alkyl, phenyl that can comprise one-three substitutes chosen from the group (B) wherein (B) means halogen atom, -COORE, sulfamoyl, lower alkylsulfonyl wherein RE means lower alkyl; Q means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (D) wherein (D) means 5-6-membered monocyclic aromatic heterocyclic group that can comprise one-three heteroatom chosen from atoms N, O, S that can comprise a substitute chosen from the group (iv) wherein (iv) means oxo-group, lower alkyl; Z means hydrogen atom (H), hydroxyl group (OH), -COORN wherein RN means lower alkyl that can comprise a substitute chosen from the group (viii) wherein (viii) means -OCOR5 wherein RN5 means lower alkyl that can comprise -OCORN51 wherein RN51 means lower alkyl; or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit activated factor X in blood coagulation system that allows their using in pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds and compositions.

12 cl, 5 tbl

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to using the natural triterpenoid of the lupan order, namely betulin, as a capillary-restorative agent. It was found capillary-restorative properties of 1% alcoholic solution of betulin being without its toxic effect on organism. Betulin as 1% alcoholic solution decreases penetrability of mouse skin vessels by 2 times more effective as compared with the known capillary-restorative agent dihydroquercetin. The new agent can be used in treatment of many diseases.

EFFECT: valuable medicinal properties of agent.

2 tbl, 2 ex

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