Means affecting blood pressure

 

(57) Abstract:

The invention can be used in pharmacy and medicine for the production of drugs that affect blood pressure. The claimed preparation containing as active substance S-alkalization formula

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where Alk is a branched or unbranched1-C4-alkyl, and x-anion fosforsoderzhashchie acid. The invention expands the range of tools hypertensive action. A new tool is devoid of unwanted side effects, inherent agonists exhibiting the same effect. 2 C.p. f-crystals, 14 tab., 14 Il.

The invention relates to the field meet vital human needs, namely to new medicines, which can find application in the chemical-pharmaceutical and medical industry, particularly to phosphate derivative Saturnia, including new chemical compounds that affect blood pressure, which possess vasoconstrictor tool used in cases of chronic and acute hypotension (bleeding, trauma, shock, poisoning), including especially in emergency medical care.

Medical practitioner who-adrenergic receptors, or by direct action on the smooth muscles of the vascular wall. Most often used adrenoceptor agonists, such as epinephrine, norepinephrine, mezaton, methoxsalen, ephedrine, fetanol and others, and preparations of polypeptide nature, such as glucagon, antiotensin, octapussy etc.

On pharmacological properties, the closest analogue to the proposed connection is a known drug mezaton (M. D. Mashkovsky. Drugs, ed. 12-e, M, Medicine, 1993, part I, page 303).

Mezaton represents a 1-(m oksifenil)-2-methylaminoethanol hydrochloride. It selectively stimulates1-adrenergic receptors, causes narrowing of arterioles and increased systolic and diastolic blood pressure (with possible reflex bradycardia). Mezaton virtually no cardiotonic action. Unlike adrenaline and noradrenaline mezaton is not a catecholamine (it contains only one hydroxyl group in the aromatic nucleus) and little affected by the action of the enzyme catechol-O-methyltransferase, and therefore more racks have a lasting effect. Antihypotensive action mezatona usually lasts about 20 minutes after a single intravenous videka regulation of the function of adrenergic receptors, M, Medicine, 1988, page 8).

Adrenoceptor agonist, including mezaton, have some common disadvantages, so they increase the consumption of oxygen by the tissues, causing metabolic acidosis can cause arrhythmia (especially during General anesthesia), have a stimulating effect on the Central nervous system (O. M. Avakian, Pharmacological regulation of the function of adrenergic receptors, M, Medicine, 1988, page 8, Century, kulinskaya, A. N. Kovalevsky, Bull.the experimental.Biol.med., 1984, page 9, "Dual control of catecholamine oxygen consumption by mice"). They are characterized by the occurrence of secondary hypotension. The agonists are not correct arterial hypotension caused by blockers, in conditions of metabolic acidosis have only a weak antihypotensive effect (C. Kortanje, V. I. Mathy, R. Chartdorp, Haunyn-Gohinedeleg is Arh. Pharmacol., v.330, N3, p. 187-192 (1985), "Influence respiratory acidosis or alkalosis on pressor responses imediated by and alfa-adrenoreceptors in pithed normotensive rats", I. M. Autkunson, S. I. Dusting, V. I. Rand, Aust.J.Exp.Biol.Med., v.50, p.847-859 (1972), "Acidosis induced by catecholamines in acidosis").

Preparations of polypeptide structure and most agonists have a short duration of action and to achieve prolonged effect they are administered in the form of perfusion (I. M. Autkunson, S. I. Dusting, V. I. Rand, Aust. J. Exp.Biol.Med., v.50, p.847-859 (1972), "Acidosis indu is written by the interaction of thiourea with trialkylphosphine or dialkylphosphate when heated in an organic solvent, however, the resulting compounds is attributed to the structure of the phosphate N-allylthiourea (J. B. Parker, T. D. Smith, J. Chem.So., 1961, RV 442-445, "The reaction of thiourea with dialkyl phosphites and trialkyl phosphates"). After the structure has been correctly installed as phosphate or phosphonate S-alkalization) (P. G. Geraschenko, Y. D. silber, G. P. Pospechova and others, Radiobiology, so-8, pages 582-587 (1968), "Radioprotective effect of salts of S-alkyl substituted derivatives estimacion at their separate and combined study") and confirmed by physico-chemical methods of analysis (L. I. mizrah, V., Yakovlev, E. M. yuhno and others, Joh, T. 41, page 2654-2658 (1971), "Some of phosphate derivatives Saturnia"), however, a detailed method of obtaining them is still not described.

The literature describes that the phosphorus-containing derivatives of S-alkalization have a pronounced radioprotective action (P. G. Geraschenko, Y. D. silber, G. P. Pospechova and others . Radiobiology, so-8, pages 582-587 (1968), "Radioprotective effect of salts of S-alkyl substituted derivatives estimacion at their separate and combined study; N. A. Ismagilov, Y. C. Gilev, L. I. East and others . Abstracts of the 2nd all-Union conference on the pharmacology of radioprotective drugs, M , 1972, pages 129-133, "Modification of radiation mortality through, Radioprotective efficacy at the cellular level of phosphate derivatives isothiourea"; T. Y. Luchenok, L. M. Rigidula, Y. C. Zavialov, etc.. Pharmacology and toxicology, T. 39, pages 191-198 (1972), "Radioprotective properties of some phosphorus-containing derivatives isothiourea"; J. A. goloshchapova, Radiation exposure, recovery, and chemical protection. Sverdlovsk, 1978, pages 71-75, "Toxicity and radioprotective properties of some phosphorus-containing derivatives isothiourea"; J. A. goloshchapova, T. N. Turikova, L. I. East, Radiobiology, T. 21, pp. 521-525 (1981), "Experimental validation of the use of certain derivatives Saturnia as radioprotective compounds") and studied some Toxicological characteristics.

The task of the invention is to find substances, including new compounds with hypertensive activity and deprived of these disadvantages agonists.

The problem is solved by the use of phosphorus-containing derivatives of S-alkalization, including new not described in the literature, the General formula

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where Alk is a branched or unbranched alkyl, and X-anion fosforsoderzhashchie acid, kajaste just by alkylation of the corresponding thiourea phosphate derivatives, occasionally used in the exchange reaction of salts.

As can be seen from the following data on the biological study (Fig. 1-10, PL.1) phosphorus-containing derivatives of S-alkalization have expressed, as a rule, fast and long-lasting impact on blood pressure.

Notable new chemical compounds:

dimethylphosphate S-methylisothiourea,

metaphosphate S-isopropyltoluene,

isobutylphenyl S-isobutylthiazole.

It is useful to emphasize that metaphosphate S-isopropyltoluene, significantly increasing blood pressure do not affect the frequency of respiratory movements.

The most studied in detail diethylphosphate S-utilization, the effect of which is presented in the table. 2-5 and Fig. 11-14.

Diethylphosphate S-utilisation compared with agonists (for example, mezatonom) 2-3 times (table. 2-5, Fig. 11-13). The proposed connection will not have a negative impact on acid-base balance (PL. 6, 7), does not cause secondary hypotension (Fig. 11-13), has a specific activity under-blockers (table. 3), practically does not reduce the effectiveness in terms of metabolic and action diethylphosphate S-utilisation indicators of systemic hemodynamics change as follows: increases peripheral vascular resistance, increased stroke volume and Central blood volume, increases the work of the left ventricle (table. 4).

With the brutal conditions (traumatic, hemorrhagic) intramuscular administration of diethylphosphate S-utilisation possible to assist prehospital (PL. 4), which cannot be achieved in medicines currently in use.

It is recommended to use diethylphosphate S-utilisation as a medicinal substance to increase blood pressure in acute arterial hypotension caused by surgery, trauma, poisoning, shock, hemorrhage, epidural anesthesia overdose ganglioblokatorov (PL. 5), alpha blockers (table. 3), neuroleptics, anesthetics and other conditions, when the agonists are contraindicated or ineffective (table. 6, 7).

Interestingly, the influence of diethylphosphate S-utilisation stronger in the case of hypotensive animals than for normotonic (Fig. 12, 13).

All these data show that the proposed connections are different tools that can be used to increase blood pressure.

The use of the compounds in medical practice creates new possibilities in the treatment of acute and possibly chronic arterial hypotensia, and in cases of emergency and ambulance.

Phosphorus-containing derivatives of S-alkalization can be applied in handy for this particular case the dosage form. Most often, it is proposed to use drugs in the form of tablets, ampoules for intramuscular or intravenous injection, but you can use other dosage forms, such as candles. In emergency conditions, it is recommended to introduce drugs intravenously or intramuscularly in the form of a 1-10% aqueous solution in a dose of 0.1-20 mg/kg of body weight, usually 0.2 to 5 mg/kg

Phosphorus-containing derivatives of S-alkalization are of low toxicity (LD50equals 100-1000 mg/kg).

Relative contraindications are: arterial hypertension, pheochromocytoma, pregnancy. Caution should be prescribed to elderly.

In case of overdose of the drug is recommended intravenous antagoniste not limit the claims of the applicant.

Synthesis of phosphorus-containing derivatives of S-alkalization.

Diethylphosphate S-utilization.

In the flask is charged with 36,6 g (0,201 M) of triethyl phosphate and 15.2 g (0.2 M) pre-shredded thiocarbamide. The reaction mass with stirring is heated to 132-135oC and maintained at this temperature until complete dissolution of thiocarbamide (about 3-5 minutes). While continuing the stirring, the heating stop and allow the mixture to cool spontaneously. Upon reaching the reaction mixture temperature 50-60oFrom it poured 40 ml of acetone. With further increasing temperature begins crystallization of the product which fails under stirring at room temperature for 3 hours. The crystals are filtered, washed with 10 ml of acetone and dried to constant weight. Allot of 26.6 g of diethylphosphate S-utilisation raw, which is recrystallized from acetone. Get to 24.6 g (47,7% of theoretical) of diethylphosphate S-utilisation with so pl. 144-146oWith data from the literature so pl. 145o(J. B. Parker, 1961), the basic substance content 99.6%.

Found, %: C 32.57, H 7.43, N 10.75, P 11.87, S 12.47. C7H19N2O4PS. Calculated, %: 32.56, H 7.36, N 10.85, P 12.01, S 12.40.

Thin-layer hromiak:chloroform: propan-2-ol (3:1:2) Rf=0,44.

Isopropylphenyl S-isopropyltoluene.

A mixture of 13.7 g (0,082 M) diisopropylamide and 6.2 g (0,082 M) thiourea is heated in a three-neck flask, equipped with stirrer and reflux with potassium chloride tube, to a temperature of 135oC. When this occurs, the dissolution of thiourea and forms a homogeneous mass. Heating at this temperature continued for another 60-75 minutes before the red light of the reaction mass. Then cool the mixture to 40-50oAnd while the mixer pour 50 ml of acetone. After 30 min raw filtered off and receive a 10 g (50.8 per cent). After recrystallization from a mixture of acetone - ethanol (2:1) to obtain 6.0 g of isopropylthio S-isopropyltoluene with so pl. 169-171oWith data from the literature so pl. 164o(C. C. Orel, B. A., Vovsi, Joh, T. 39, pp. 1259-1260 (1969). To the question about the interaction of dialkylphosphites with thiourea).

Metaphosphate S-utilization.

A mixture of 8.65 g (0.05 M) of diethylphosphate and 3.8 g (0.05 M) well powdered thiourea is heated with stirring, raising the temperature to 145oC for 1.5 hours, then maintained at this temperature for 10 minutes, cooled, poured a mixture of ethanol - acetone (3:2) and leave overnight. Pound wasp is the S-utilisation with so pl. 224-225oC.

Found, %: C 19.57, H 4.90, P 16.73, S 17.32. C7H19N2O4PS. Calculated, %: C 19.55, H 4.90, P 16.85, S 17.40.

This same substance get in another way:

A mixture of 4.25 g of timetophoto and 3.0 g of thiourea with stirring is heated for 1.5 hours to 145oC, kept at this temperature for 10 minutes, cooled and treated as above. Receive 5.0 g (69%) of metaphosphate S-utilisation with so pl. p.223-224,5oC.

Other compounds are obtained analogously:

metaltastic S-methylisothiourea with the release of 73%, so pl. 119-120oWith data from the literature so pl. 120oWith (in. A. Orlovsky, 1969),

dimethylphosphate S-methylisothiourea with the release of 54%,

ethylphosphate S-utilisation exit 62%, so pl. 109-110oWith data from the literature so pl. 112oWith (in. A. Orlovsky, 1969),

prophylactic S-propositione with the release of 40%, so pl. 99-100oWith data from the literature so pl. 102oWith (in. A. Orlovsky, 1969),

metaphosphate S-isopropyltoluene exit 21%, so pl. 257-259oWITH,

dibutyltin S-butylstyrene with 38%, so pl. 96-98oWith data from the literature so pl. 98oWith (in. A. Orlovsky, 1969),

isobutylphenyl S-isobutylthiazole with the release of 43%, so pl. 162-164oC.

Strain absorption in thePO1195-1207 cm-1,CN1680-1695 cm-1,NH1568-1590 cm-1and UV spectra with a characteristic wavelength absorptionmax=201-203 nm and 223-225 nm.

Biological study of phosphorus-containing derivatives of S-alkalization.

In this section the results of the primary pharmacological evaluation of phosphorus-containing derivatives of S-alkalization. The experiments were conducted on 52 anesthetized (teminal sodium, 45 mg/kg, intraperitoneally) cats of both sexes weighing between 2.8 to 4.2 kg Blood pressure was recorded using a mercury manometer and ECG in the second standard lead. Simultaneously recorded respiratory rate. Evaluated the severity of the hypertensive effect (in percentage to the baseline systolic blood pressure (SBP), the duration of observation was 1-3 hours, ECG was calculated heart rate (HR). The results are shown in Fig. 1-10 and table. 1.

Metaltastic S-methylisothiourea raises blood pressure by 20%. Hypersensivity effect lasts for 1 hour, the compound does not affect the heart rate (Fig. 1).

Dimethylphosphate S-methylisothiourea is one of the most active coeliadinae increases the frequency of respiratory movements (NPV) (Fig. 2).

Metaphosphate S-utilisation raises blood pressure by 25 mm RT. Art. that is about 15% from baseline. Hypertension affects NPV (Fig. 3).

Ethylphosphate S-utilisation raises blood pressure by 15%. Duration is 1.5 hours, the compound causes bradycardia, but does not affect the NPV (Fig. 4).

Diethylphosphate S-utilisation is one of the most active compounds. In the studied dose increases GARDEN by 40%, increases the NPV (Fig. 5).

Prophylactic S-propositione raises blood pressure by 24%. Hypertensive effect lasts for 1 hour, the compound causes mild tachycardia, but no effect on NPV (Fig. 6).

Metaphosphate S-isopropyltoluene slowly increasing the GARDEN, the maximum effect is observed only after 15 min, but the effect persists for more than 2 hours. Does not affect the NPV (Fig. 7).

Isopropylphenyl S-isopropyltoluene is one of the most promising substances, which increases the GARDEN almost 30%, the maximum effect was achieved at 2 min after injection and persists for more than 2 hours. Observed transient bradycardia, the compound does not affect the NPV (Fig. 8).

Dibutyltin Sfig. 9).

Isobutylphenyl S-isobutylthiazole has a moderate hypertensive effect for 2 hours, increasing the heart rate and the NPV (Fig. 10).

The following are the main results of the experiments confirm the possibility of applying diethylphosphate S-utilization specified in the description fields.

Experiments to study the effects of diethylphosphate S-utilisation on indicators of systemic hemodynamics held on 8 anesthetized cats weighing 2-4 kg For anesthesia was applied urethane (intraperitoneally in the form of a 30% solution at the rate of 1-1 .2 g/kg). In order to identify the period of maximum effectiveness and duration of action of the drug the main parameters of the systemic circulation was determined prior to its injection (baseline) and at 2, 15, 30 and 60-second minutes after the introduction of diethylphosphate S-utilisation at a dose of 5 mg/kg

Systemic hemodynamics were assessed by the following indicators: the values of blood pressure (BP), heart rate (HR), minute volume of blood (IOC), stroke volume of the heart (CO), total peripheral vascular resistance (SVR), the work of the left ventricle (Ali).

The results of the experiments showed that a single intravenous diethylphosphate S-utilisation at a dose of 5 mg/kg causes a rapid and pronounced increase in blood pressure. Already on the 2nd min after drug administration the HELL was 141% compared to the baseline level and remained at a high level for a long time. At the 60th min BP levels were decreased compared to the established on the 30th min, but still exceeded (11%) of the original value. The difference of the quantities characterizing the AD during the hours were substantial and statistically significant. The severity and duration of elevated BP depended mainly on increasing the CSO and to a lesser extent (on the 2nd min of drug action) from ascending the IOC (PL. 2).

In the Yu and remained high throughout the observation period. In the 60th minute it surpassed the original value of 58%. Therefore, the overall tone of the vascular resistance after administration of the drug was increased (table. 2). The IOC at 2 min after injection of the drug increased by 7%, and on the 15th and 30th min decreased by 11 and 22%, respectively. Such changes IOC was determined by the nature of the change under the influence of drug - CSC, the size of the venous return of blood to heart and as a consequence FROM the heart. The increase Ali was transient, so on the 2nd and 15th min after injection of the substance exceeded the original value of 89% and 22%, and on the 30th min returned to the original level. The results obtained indicate that the hypertensive effect that occurs when a single intravenous diethylphosphate S-utilisation and continued for long periods of time (up to 1 hour), depends mainly on increasing the CSO and to a lesser extent (mostly in the initial period of drug action) from ascending the IOC.

It is known that almost agonists do not inhibit hypotension caused by blockers. It was interesting to study the effect of diethylphosphate S-utilisation hypotension caused by introduction of the famous1-blocker - prazosin (years of selective places the actions of adversuten significantly reduced peripheral resistance of blood vessels, consequently, the level of HELL. After the introduction of adversuten already at the 5th min, blood pressure is reduced by 51 mm RT. Art., against this background, the introduction of diethylphosphate S-utilizationa already on the 2nd min increases the HELL is 29 mm RT. Art. On the 15th and 30th min level of HELL was 11.8 and 9.4% higher than the 5th min since the introduction of adversuten. Statistically significant changes in heart rate and respiratory rate were not observed (except in the 60th min since the introduction of diethylphosphate S-utilization when there was bradycardia). Based on the above we can conclude that diethylphosphate S-utilisation increases HELL and on the background of the action1-adrenoblokatorov though shorter than without their destination.

As an experimental model of hemorrhagic shock, approximates the current to severe clinical forms, selected acute blood loss (3.2% of animal body weight) that is 45-47% of the circulating blood volume within 3-5 minutes in order To detect the maximum efficiency and duration of drug action the main parameters of the systemic circulation was determined to blood loss, 30 minutes after blood-letting, and at 2, 10, 30 and 60 min after nutrientsa of 8 fixed to the machine animals blood loss was caused by a drop in blood pressure with 140,03,9 to 65,04,1 mm RT. Art. which constituted 46% of the original level, heart rate at the 30th min from the beginning of blood loss increased by 18%. The IOC has declined from 102,84,5 to 44,05,2 ml/minkg, i.e. 57% compared to the original.

The reduction of blood pressure at the 30th min of the onset of acute blood loss was caused mainly by reducing the IOC, which depends, in turn, from the reduction in stroke volume (up 36%) and Central blood volume. Thus, posthemorrhagic hypovolemia leads to a decrease of the IOC, which cannot be compensated by an increase in SVR and increase of heart.

Calculations Ali indicate the reduction in 6 times.

At 2 min after injection of isotonic indicators of systemic hemodynamics differed little from those at the 30th min of the onset of acute blood loss, but on the 10th and 30th min after administration of 1 ml of isotonic sodium chloride indicators of systemic hemodynamics progressively worsened. So, at 30 min after injection solution BP was decreased by 13% compared to 30 min from the beginning of the bloodletting. CIOs decreased by 7%, and the IOC and decreased by 11% and 8% respectively, ALG decreased by half, and SVR increased by 8%. Further tx2">

A single intravenous diethylphosphate S-utilisation at a dose of 5 mg/kg in hemorrhagic shock quickly and markedly increases AD. So, at 2 min after injection of medicinal substances HELL increased by 88% (compared to the 30th min after blood loss) and this effect persisted throughout the observation period. At 2 min after injection of diethylphosphate S-utilizationa significant decrease in heart rate, which can be explained as a reflex influence upon the heart as a result of sharp increase in blood pressure. Diethylphosphate S-utilisation has a biphasic effect on the IOC. Originally IOC increased by 19%, followed by its reduction on the 30th and 60th min after administration of the drug. However, it should be noted that in the control group with the introduction of 1 ml of isotonic at the 30th and 60th min revealed a similar decrease of the IOC. WITH significantly increased only 2 min after injection of the drug. Ali significantly increased in the 2nd and 10th minutes SVR significantly increased during the whole observation time.

Analyzing the change of indicators of systemic hemodynamics under the influence of diethylphosphate S-utilisation, it can be concluded that the substance increases the blood pressure in the initial replication is typestate S-utilisation on the background of arterial hypotension, caused by a known ganglioblokatora - Hexham. Geksony was administered once intravenously at a dose of 10 mg/kg Stimulation of the sciatic and vagal nerves were conducted by electronelectron EM-1 over threshold rectangular pulse current duration of 1 sec, the duration of the irritation of 10 sec and a frequency of 20 pulses/sec (peripheral segment of the vagus nerve) and 300 pulses/sec (the Central end of the sciatic nerve). The results are shown in table 5. After 2 min after injection of hexane HELL decreased by 46%. The introduction of diethylphosphate S-utilizationa already on the 2nd min increases AD 61 mm RT. Art. and reliable increase in the HELL is maintained throughout the period of observation. Heart rate was changed in the direction of bradycardia, but these changes are not statistically significant. Respiratory rate was not changed. Ganglioblokiruyuschimi properties with the introduction of diethylphosphate S-utilisation completely preserved, as evidenced by the absence of changes in the level of HELL when re (2, 15, 30 and 60 min) stimulation of the peripheral segment of the vagus and the Central end of the sciatic nerve.

We can conclude that diethylphosphate S-utilizationa quickly restores the level of HELL after hypotension caused g is of diethylphosphate S-utilisation at a dose of 5 mg/kg on the basic parameters of acid-base status (KHS) and the gas composition of the blood in case of hemorrhagic shock in experiments on cats, anesthetized by intraperitoneal injection of etamine sodium (Nembutal) in the dose of 40 mg/kg Blood loss caused by bleeding from the common carotid artery in the amount of 3.2% of the weight of the animal, which is approximately 45-47% of circulating blood volume. Phlebotomy was performed within 3-5 min. voltage values of oxygen and carbon dioxide in arterial blood (PAO2The Paco2) and mixed venous blood. NSS and pH was investigated by micromethods of Astrup. Hemoglobin (HB) was determined zianokobalaminom method. Gas composition of the blood and the pH is adjusted in accordance with the body temperature of the animal. The content of bicarbonate ions [HCO3-] performance shift buffer bases (BE) was calculated using the line of Severinghaus. To simplify the calculations were carried out on a computer model GM-1403-02 on the previously compiled program in the Fortran. Indicators KHS and gas composition of blood was examined in the initial state, on the 30th min after the beginning of acute blood loss, as well as on the 2nd, 10th, 30th and 60th minutes after administration of drugs. The substance was administered once intravenously at the 30th min after blood-letting.

Control group (n=8). Cats were administered 1 ml of isotonic repotery at the 30th min after the bloodletting changes KHS arterial blood has been mixed, in 5 out of 7 cats were observed metabolic and respiratory acidosis, and in two metabolic acidosis with compensated respiratory alkalosis. the pH of arterial blood decreased on average with 7,3130,015 in original condition to 7,2840,033 to the 30th min from the beginning of the blood loss. On the 40th and 60th minutes after the bloodletting was noted further reduction of RNA to 7,2420,056 and 7,1520,072 respectively. A more pronounced decrease in pH was observed from venous blood. So, at 7 cats from 8 to 30th min after blood loss pH was decreased, while one did not undergo significant changes. was significantly decreased with 7,2840,011 in original condition to 7,1840,028, 7,1270,049 and 7,0810,049 respectively on the 30th, 40th and 60th minutes after phlebotomy (p<0,05).3-] was 14.6% lower than the control.

The shortage of buffer bases was significantly increased to the 30th, 40th and 60th minutes after acute blood loss, respectively, 55%, 99% and 130% compared to baseline (P<0,01). Thus, in the early stages after acute massive blood loss according to our results, the most common form of violation KHS is metabolic acidosis. This is consistent with literature data.

On the 30th min after acute blood loss has decreased PaCO2and a slight increase which led to an increase in the arteriovenous gradient RNO2in comparison with the initial level. It is quite clear that the observed dynamics in acute blood loss reduction gradient significantly worsened conditions of gas exchange in lungs and tissues and led to a sharp increase in metabolic and respiratory acidosis. The degree of oxygenation of arterial blood in the control group is quite high, whereas RHO2venous blood when this was significantly reduced.

The group with the introduction of diethylphosphate S-utilizationa (n=6). The drug was administered in the dose of 5 mg/kg

From table 6 it follows that diethylphosphate S-is increasing the pH of arterial blood with 7,2300,015 at the 30th min after blood-letting to 7,2520,018 and 7,3100,064 respectively on the 10th and 30th minutes after injection diethylphosphate S-utilization.

Similarly, changes in pH were observed and changes in deficit buffer bases that on the 10th and 30th minutes after administration of a drug significantly decreased respectively by 20% and 18% compared to the values observed at the 30th min of shock (table. 6). The average amount of bicarbonate ions in the arterial blood at the 10th and 30th min after injection of diethylphosphate S-utilisation increased respectively by 5% and 16% compared with baseline values (table. 6).

The same change was observed from the side of the main indicators of acid-base status of the mixed venous blood, however, these changes were not statistically significant.

Partial carbon dioxide tension arterial and venous blood compared to the 30th min after the bloodletting fell on the 10th and 30th minutes after injection diethylphosphate S-utilisation. So, on the 10th min, it decreased by 9% (table. 6, PL. 7). Partyonline pressure of oxygen in arterial and venous blood under the action of diethylphosphate S-utilisation changed in different ways: in the arterial blood it had a tendency to increase, and in the venous to decline, however, these variations were not statistically significant.

It can also be assumed that diethylphosphate S-utilization affects the performance KHS blood by releasing the body from the end products of metabolism: in particular, lactic acid due to more active inclusion in cycles Measles and Krebs, while maintaining synchronism in the oxidation and phosphorylation.

In the next series of experiments we studied the effect of diethylphosphate S-utilisation on the cardiovascular system of dogs. HELL was measured in two ways: recorded at the tail artery using the piezosensor on the device for measuring the pressure of the firm Ugo Bazile or in the femoral artery using a catheter, pre-filled heparin. Electrocardiogram was recorded in three standard leads on mingograph-82.

In Fig. 11 presents data on the selection of the optimal dose of the drug by intravenous route of administration. Ditillo Christiania all applied doses has expressed hypertensive reaction. The optimal dose is apparently dose of 5-10 mg/kg On the electrocardiogram in the study of all the above-mentioned doses of the drug are no lesions were found. Marked only the development of a bradycardia reaction, which develops from the first minutes after injection, reaching on average 25-30% of the original level. The maximum value of this reaction is observed in 30-40 min after the start of the experiment and stored until the 60th min of observation.

Particularly noteworthy is the fact that the severity of hypertensive reactions in dogs with low blood pressure (hypotension) is significantly higher than in dogs with high baseline blood pressure (hypertension). For this reason, further study was carried out separately for normotonic and hypotensive.

In Fig. 12 and 13 shows the parameters of blood pressure during the injection of different doses of diethylphosphate S-utilisation. As can be seen from the drawings, it is confirmed that hypertensive reaction in dogs with low blood pressure stronger and longer, and the optimal dose of diethylphosphate S-utilisation with intravenous method of administration is 5-10 mg/kg

In Fig. 14 shows the parameters of blood pressure in experiments on sobaki the effect of increasing the HELL is stored, and the time of action of the drug increases substantially.

In experiments on mice F1(C57BlxCBA), we estimate the functional state of the organism for biochemical tests with the introduction of diethylphosphate S-utilisation with intravenous method of administration in a dose of 500 mg/kg once and at a dose of 100 mg/kg in chronic experiment for 30 days in a row. In the acute experiment, blood was taken after 30, 60, and 75 min after drug administration. In the chronic experiment, the blood was examined daily after 1 hour after drug administration. Study periods 1, 7, 14 and 21 days after administration of the drug. Assessed the state of the protein, lipid and carbohydrate metabolism, which determined the concentration of total protein, total cholesterol and glucose in the serum of mice according to standard techniques. Total protein was determined by biuret method, total cholesterol - method ILike, glucose - oxidase method.

Blood from mice was received after a quick decapetala studied material selected at the same time in the same season.

Blood to obtain serum was collected in centrifuge tubes were placed in a thermostat at 30-40 min, the resulting clot was fortified with a needle, then put in In. The resulting serum without signs of hemolysis were collected in a clean tube. All quantitative indicators of the biochemical characteristics of blood were obtained using a spectrophotometer SF-26. Previously constructed calibration curves for the determination of total protein and total cholesterol. The data are summarized in tables 8 and 9.

In the study found that after the introduction of diethylphosphate S-utilisation at a dose of 500 mg/kg observed significant increase of concentration of total protein, cholesterol and glucose after 30 min, which tend to normalize.

Due to the fact that the liver is included in all biochemical processes in the body, and is the site of the formation of protein components of the blood, it can be assumed that diethylphosphate S-utilisation at a dose of 500 mg/kg has an effect on the functional state of the liver. Elevated levels of total protein possibly involved a violation of regulatory processes of protein synthesis blood, liver, as well as damage to the parenchyma.

Thus, it is possible to conclude that the introduction of diethylphosphate S-utilisation at a dose of 500 mg/kg leads to a change of indices of protein, lipidemia functional abilities. These changes go beyond the physiological adaptive responses and lead to changes that lie on the verge of pathology, however, these changes are not accompanied by long-term changes in functional status, changes are reversible.

In the chronic experiment shows that a dose of 100 mg/kg of diethylphosphate S-utilization fluctuations of the studied parameters are within the limits of physiological fluctuations and do not cause the observed changes of biochemical parameters.

In experiments on dogs was assessed functional state of the organism for biochemical tests with the introduction of diethylphosphate S-utilisation in the form of a 10% solution for injection intravenous dose of 10 mg/kg daily at the same time of day for 3 consecutive days. The blood was examined daily after 1 hour after administration of the drug for 3 days and after the introduction of 4, 5 and 10 day. Assessed the state of the protein, lipid and carbohydrate metabolism, which determined the concentration of total protein, albumin, globulin, total cholesterol and glucose in the serum of dogs according to standard techniques. Total protein was determined by biuret method, total cholesterol - is after the drug had undulation with a tendency to fall on the 4th and 5th day, also wavy changed the level of albumin and globulin, total cholesterol and glucose were minor fluctuations, not beyond the fluctuations inherent to healthy dogs.

Thus, on the basis of a study of General toxic action and biochemical parameters during the daily three-day experiment intravenous drug in the dose of 10 mg/kg as a 10% solution can be concluded that the drug, in addition to specific anticipo-tensing effect no significant effect on the health of the dogs revealed no signs of intoxication or any significant deviations of the studied indices in comparison with the original data, not marked sensitivity of the individual animals by intravenous injection of the drug.

The results of pathological examination of the internal organs of experimental animals (mice, dogs), subjected to single and repeated impacts of diethylphosphate S-utilisation in srednesemennyh and sublethal doses, it was found that the drug in conditions of experiments causes early observations moderately expressed signs of disorders of the nogo and venous channel mainly in the liver, the myocardium, lungs, spleen and, to a lesser extent, in the kidneys. Circulatory disorders is reversible and usually normal in 7 to 10 days after discontinuation rate effects of the drug. Any expressed inflammatory, degenerative or necrobiotic changes of internal organs in all experiments was not observed. In some cases there is evidence of compensatory-adaptive reactions of the liver (the proliferation of Kupffer cells, hyperchromia cytoplasm and nuclei of hepatocytes).

1. Tool, affecting blood pressure, containing as active substance fosforsoderzhashchie derived S-alkalization General formula

< / BR>
where Alk is a branched or unbranched1-C4- alkyl;

x-anion fosforsoderzhashchie acid.

2. Means under item 1 for the treatment of emergency conditions in the form of liquid solutions containing 1-10% of the active substance.

3. Means under item 1 for the treatment of hypotonic conditions in the form of a solid dosage form when the dosage of active ingredient is 0.1-20 mg/kg

 

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FIELD: veterinary science.

SUBSTANCE: the present innovation deals with preparations and method for treating parasitosis in animals. The suggested curative-fodder additive contains, weight%: univerm 0.5-1.0; albendasol 0.05-0.1; fodder filler as concentrated feedstuffs and water - the rest. Water should be introduced into the additive to achieve 25-30% moisture of the mixture. While carrying out antiparasitic treatments animals should be fed with an antiparasitic preparation in its granulated preparative form in the dosages of 1.5-7.0 g/kg body weight, once for 3 d. Application of the present innovation enables to increase therapeutic efficiency and widen action range of antiparasitic treatments in animals.

EFFECT: higher efficiency.

3 cl, 6 ex, 5 tbl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): their pharmaceutically acceptable salts or solvates, or stereoisomers possessing properties of agonists of β2-adrenoreceptors, to pharmaceutical composition based on thereof, using the claimed compounds in manufacturing a medicinal agent, and to a method for modulation of β2-adrenergic receptors. In the formula (I) each among R1-R5 is chosen independently from group comprising hydrogen atom, (C1-C4)-alkyl and Ra wherein alkyl is substituted optionally with substituted chosen from Rb; or R4 and R5 are combined to form group of the formula: -NRdC(=O)C(Rd)=C(Rd)-; R6, R7 and R8 represent hydrogen atom; R9 represents (C1-C4)-alkyl; R10 represents hydrogen atom or (C1-C4)-alkyl; each among R11, R12 and R13 is chosen independently from group including hydrogen atom, (C1-C4)-alkyl, vinyl, cyclohexyl, phenyl, halogen atom, -CO2Rd, -ORd, -S(O)mRd, -N(NRdRe)Rd or -S(O)2NRdRe, 5-6-membered monocyclic heteroaryl comprising 1 or 2 heteroatoms chosen from nitrogen (N), sulfur (S) atoms, 9-membered bicyclic heteroaryl comprising N as a heteroatom and 5-membered heterocycle comprising N as a heteroatom; or R11 and R12 in common with atoms to which they are bound form 6- or 7-membered heterocyclic ring comprising oxygen (O) atom as a heteroatom and wherein for R11-R13 each phenyl or heteroaryl is substituted optionally with 1 or 2 substitutes chosen independently from Rc, and each heterocyclyl is substituted optionally with 1 or 2 substitutes chosen from Rb and Rc; alkyl is substituted optionally with substitute chosen from Rb, and vinyl is substituted optionally with substitute chosen from Rm; w = 0, 1, 2, 3 or 4. Values Ra, Rb, Rc, Rd, Rm and m are given in the invention claim.

EFFECT: improved method for modulation, valuable medicinal properties of compounds and pharmaceutical composition.

22 cl, 225 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new phenethanolamine derivatives having selective stimulant action at β2-adrenoreceptors and can be used for the treatment of respiratory diseases. In formula (I) m is an integer from 2 to 8, n is an integer from 3 to 11 with the proviso that the sum total of m and n is from 5 to 19, R1 represents SOR6 or SO2R6, where R6 represents a C3-7cycloalkyl group or a C3-7cycloalkelene group, R2 and R3 are independently derived from hydrogen and C1-6alkyl, each of R4 and R5 represents hydrogen, Ar represents a group selected from (a) and (b) where R8 represents hydrogen, halogen, -(CH2)qOR11, -NR11C(O)R12 or -NR11SO2R12, and R7 represents hydrogen, or R8 represents -NR11C(O)R12 and forms with R7 5- or 6-membered heterocyclic ring, R9 represents -OR11, R10 represents hydrogen, each of R11 and R12 independently represents hydrogen or C1-4alky, q is zero or an integer from 1 to 4. The invention also relates to the methods of compounds production and their application in pharmaceuticals production.

EFFECT: production of the new phenethanolamine derivatives having a selective stimulant action can be used for the treatment of respiratory disease.

16 cl, 5 dwg, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-(methylsulphonylamino)phenyl analogues of general formula (I): in which A represents CONH; NHCO, NHC(=S)NH, NHC(=O)NH; R1-R4 independently represent at east one radical selected from the following group: hydrogen, halogen atom, cyanogroup, nitrogroup, lower alkoxygroup containing from 1 to 3 carbon atoms, carboxylic acid residue, alkyl ester group containing from 1 to 6 carbon atoms, benzylamide group, piperidino- morpholino- or piperazino-group; R5 and R6 independently represent at least one radical selected from the following group: hydrogen, linear or branched alkyl group containing from 1 to 6 carbon atoms, cycloalkyl group, containing from 1 to 6 carbon atoms and phenyl or benzyl group optionally substituted with at least one substituent selected from halogen atom and alkyl group, containing from 1 to 6 carbon atoms, on condition that both radicals R5 and R6 simultaneously do not represent hydrogen atom; B represents group selected from:

in which R7-R17 independently represent at least one radical selected from the following group: hydrogen, halogen atom and linear or branched alkyl group containing from 1 to 6 carbon atoms optionally substituted with more than one halogen atom, C represents group selected from alkyl, alkenyl and alkynyl group, containing from 1 to 5 carbon atoms which can include oxygen atom, m, n, p, q, r and s represents integer number from 0 to 3; symbol * and symbol (---) stand for chyral carbon atom and double bond or simple bond, respectively, and also to pharmaceutical compositions including said compounds. Said compounds can be used as vanilloid antagonists demonstrating analgetic activity, for prevention, alleviation or treatment of diseases connected with pain, or inflammatory diseases.

EFFECT: elaboration of compounds which can be used as vanilloid antagonists demonstrating analgetic activity, for prevention, alleviation or treatment of diseases connected with pain, or inflammatory diseases.

14 cl,1 tbl,152 ex

FIELD: medicine.

SUBSTANCE: invention refers to drugs and concerns a drug for prevention of a host reaction of a transplanted organ or cell, containing 2-amino-2-[4-(3-benzyl oxyphenylthio)-2-chlorophenyl]ethyl-1,3-propanediol in amount 0.01 mg to 100 mg a day, or its pharmaceutically acceptable salt or hydrate in combination with calcineurin inhibitor or mycophenolic acid. There is also disclosed a method for prevention of a host reaction of a transplanted organ or cell.

EFFECT: offered drug provides mutual intensification of efficiency of agents in its composition at smaller amounts, thereby reducing by-effects.

10 cl, 3 dwg, 4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to medicine, namely, to psychiatry, and deals with treatment of schizophrenia. For this purpose in addition to adequate psychotropic therapy introduced is anapherone in dose 2 pills 4 times per day after equal time intervals independently on food intake for 25-35 days. Such complex treatment, including introduction of anapherone immune-modulator in developed regime and doses, ensures positive dynamics in immunity system, as well as improvement of clinical indices, which are registered by PANSS, AIMS and CGI scales.

EFFECT: method ensures positive dynamics in immunity system, as well as improvement of clinical indices.

7 tbl, 1ex

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