Liposomal composition containing selegiline, its preparation, pharmaceutical composition having mao - inhibitory activity
(57) Abstract:The present invention provides a liposomal composition comprising as active ingredient (-)-N-(dimethyl-N-(2-Propylenediamine) (selegiline) and/or salts thereof. This composition contains 0.1 to 40% by weight selegilina and/or its salts, from 2 to 40% by weight of lipids, preferably phospholipids, from 0 to 10% by weight of cholesterol, from 0 to 20% by weight of the alcohol, from 0 to 25% by weight of glycol, from 0 to 3 % by weight of an antioxidant, from 0 to 3% by weight preservere agent, from 0 to 2% by weight of an agent affecting the viscosity, from 0 to 50% by weight of the cyclodextrin or cyclodextrin derivative and from 30 to 90% by weight of water. This invention provides a process for the preparation of liposomal compositions containing selegiline and/or its salts. In accordance with this invention, the liposomal composition may be introduced in the treatment of Alzheimer's disease, Parkinson's disease, depression, paralysis, movement disorder, or myelitis. The resulting composition is more effective. 3 S. and 14 C.p. f-crystals, 9 Il., table 1. The invention relates to liposomal compositions containing as the active ingredient selegiline (-)-(N - dimethyl-N-(2-propylpentyl) and/or its salt. Further, the invention relates"ptx2">Currently, in the area known a huge number liposomal compositions and processes for their manufacture.Such compositions are, for example, "system drug delivery" (DDS), as described by G. Gregoriadis et al. (Receptor-mediated targeting of drugs, Plenum Press, New York, 243-266, 1980). They contain the active ingredient, similar to the encapsulated position in one or more lamellar membrane lipid containing, for example, in liposomes. On a good adsorption and Bioecology active ingredient(s) may affect, among other things, the composition and method of preparation of liposomes so that they can deliver the active ingredient in a specific area. In liposomal compositions the active ingredient is surrounded by one or more lipid plates, which also serve as a carrier of the active ingredient.Multiplatinum lipid carriers (MLV) were first prepared and described by Bangham et al. (J. Mol. Biol. 13, 238-252, 1965). When the biologically active substance encapsulated in small, single-disk, lipid carriers, water-soluble substances can be encapsulated with a low efficiency because of the small volume of water enclosed in a small single-disk lipid vesicles and methods for example by injection of ethanol [S. Batzri and E. D. Korn: Biochem. Biophys. Acta. 298: 1015-1019, (1973)] or ether [D. Deamer and A. D. Bangham: Biochem. Biophys. Acta 443, 629-634, (1976)] so that the solution of lipids in an organic solvent was injected quickly into the buffer solution and, thus, a single-disk liposomes were formed spontaneously. The method is fast and widely used, but results in diluted liposomal drugs and poor encapsulation efficiency.A single-disk liposomes can also be formed so-called detergent-resolves system [H. G. Neither and A. Zumbuehl: Liposome Technology, edited by G. Gregoriadis, CRC Press Inc., Boca Raton, Florida, Vol. 1, Part 7, pages 79-107, (1984)], where the lipids and other substances are dissolved together with a detergent and then a detergent eliminated by dialysis.Packing in a single-disk liposomal capsule is carried out in accordance with the description of U.S. Patent N 4,234,871 (Papahadjopoulos) by the so-called technology of evaporation on reversed phase (REV) and in accordance with the specification of U.S. Patent N 4,016,100 (Suzuki) by freeze-drying the water-lipid dispersions of lipids and biologically active substances.In the published description of the Patent N WO 93/20934 revealed the drug stabilzers preparing the above liposomal compositions of the variance of the lipid and the aqueous phase is carried out in contact reactions to inert solid material, in most cases, the glass beads [description to the U.S. Patent N 4,485,054].In accordance with the description of U.S. Patent N 4,761,288 that is specifically made here in the links, multiphase system serves to improve the adsorption of biologically active substances having poor solubility in water, which contain the active ingredient in the form of a highly-saturated solution, in solid form and encapsulated in a single-disk lipid vesicles. Vesicles, solution and solid form biologically active compounds dispersively in hydrocolloid gel. Hydrocolloid gel is prepared using the method of preparation multiplatinum lipid vesicles described in U.S. Patent No. 4.485.054, specially made here in the links. Thus, can be prepared liposomal compositions in which the active ingredient is present in higher concentrations than could be expected on the basis of their water and/or laboratoriosi.In the description of the U.S. Patent N 4,937,078 disclosed liposomal compositions locally applied active ingredients of anesthetics and analgesics. It was found that locally applied active ingredients are more effective in the liposomal enkapsuliran is prohibited, as described in the descriptions to the U.S. Patent N 4,485,054 and N 4,761,288.Preparation of liposomal compositions were aimed primarily at increasing the absorbent capacity and the local concentration and/or the planned absorption of active ingredients that have poor solubility in water.Our invention relates to the preparation of liposomal compositions of selegilina or its salts, which are soluble in water and solvents (1 g/3 ml water, 1 g/5 ml in chloroform or 1 g/3 ml in ethanol), then, for oral, parenteral or local application, arbitrarily in percutaneous, controlled release compositions.Selegiline is a known pharmaceutical composition, widely sold under the name Jumex, Deprenyl, Eldepryl or L-Deprenyl, being very effective, for example, in the treatment of tuberculosis or immune modulation [A. Dow: The Deprenyl Story, Toronto: Stoddart (1990); Inhibitors of Monoamine Oxidase B, edited by I. Szelenyi, Birkhauser Verlag, Basel-Boston - Berlin, 237-358 (1993)] . One of its most important effects is the antidepressant and psychostimulatory and MAO-inhibitory effect (monoamine oxidase), more precisely their selective MAO-B inhibitory effect. There are several processes for their prigotovlennymi Parkinson's.Liposomal composition in accordance with the present invention contains preferably from 0.1 to 40% by weight of selagine (-)-[N--dimethyl-N-(2-propylpentyl) or its salt, from 2 to 40% by weight of lipids, preferably phospholipids, from 0 to 10% by weight of cholesterol, from 0 to 20% by weight of the alcohol, from 0 to 25% by weight of glycol, from 0 to 3% by weight of an antioxidant, from 0 to 3% by weight preservere agent, from 0 to 2% by weight of an agent affecting the viscosity, from 0 to 50% by weight of the cyclodextrin or cyclodextrin derivative and from 30 to 90% by weight of water.Liposomal composition in accordance with the present invention contains preferably from 0.1 to 20, most preferably from 0.1 to 10% by weight selegilina and/or its salts and at least 10% by weight in the number of single and/or multiplatinum lipid vesicles and in the remaining amount needed to 100% by weight, in the free state and/or as a saturated solution. Liposomal composition in accordance with the invention contains as a lipid, preferably a phospholipid, preferably phosphatidyl choline and/or lysophosphatidyl-choline or phosphatidyl serine or phosphatidyl ethanolamine or phosphatidyl Inositol; as an alcohol, preferably ethanol or Santa preferably tocopherol or BHA (botellita-xenical); as preservere agent preferably germaben (International Specialy Product, Vienna, Austria); as agent for affecting the viscosity, preferably a hydrocarbon or a derivative of cellulose, preferably carbonol (Carbomer, Goodrich, Cleveland); and as a cyclodextrin and/or cyclodextrin derivative, preferably, or a cyclodextrin, a water-soluble polymer cyclodextrin, methylated, gidrauxilirovanne or succinylcholine derivative of cyclodextrin or any mixture.Compositions in accordance with the invention may contain liposomal composition, if desired, together with widely used filling, diluting or auxiliary agents. The composition may be introduced preferably by the oral, parenteral or percutaneous manner. When the percutaneous preparation of the composition of the liposomal composition may be applied to the bearing surface, preferably on a foil, film or plastic.Liposomal compositions can be prepared as disclosed in the descriptions to U.S. Patent No. 4,485,054 and 4,761,288, the organic solvent is evaporated from the mixture of organic solvent containing laboratoriya components containing at least Otechestva mixture of organic solvent, preferably a mixture of chloroform and methanol.Liposomal compositions in accordance with the invention can preferably be used for the treatment of Alzheimer's disease, Parkinson's disease, depression, paralysis, movement disorders or myelitis.Liposomal composition contains the active ingredient in a multiphase, single and/or multiplatinum the vesicles, in the free state and in its saturated solution, for example, is a multiphase liposomal delivery system of drugs. Thus obtained liposomal system is stable and can be easily diluted with water. Its rheological conditions may vary from the diluted liquid to gelatinous state.From a pharmacological point of view, we aimed to prepare a liposomal composition containing selegiline, which are systems of drug delivery with controlled their release and, thus, are able to enter the exact dose during percutaneous treatment even in dose mode "once a week". Method of administration and dose depend, among other things, from the disease (Alzheimer's disease, Parkinson's disease, depression, paralysis, movement disorder or myelitis), its severity, the overall condition of the patient, etc.Farmakologicheskaya from 300 to 350 g (line Charless-River, SPF: specific non-pathogenic) by local treatment groups, consisting of three animals, randomly selected as test animals.The second phase of experiments was conducted on pigs weighing from 20 to 22 kg, by treatment of the three animals a single dose of one of the formulas.Animals were kept separately in cages, on a bed of wood chips at an average temperature of 23oC, with the same food and drink.As the test compositions were used products in accordance with Examples 1, 2, 3, and 6.Liposomal preparations of Deprenyl were applied on bespoleznoy back (Guinea pigs) or neck skin (pig) on the surface 1.5x1.5 and 3x3 cm2accordingly, and after drying for a few minutes fixed Tegaderm (produced ZM, USA). The control pigs were introduced selegiline-tablets orally once a day.During the evaluation measured the MAO-a inhibition in the blood, brain, liver and intestines, then the concentration of active ingredient in the blood. The accumulation of the active ingredient and its metabolites in different organs of pigs (blood, brain, heart, liver, kidneys, lungs and spleen) were studied after administration of lipo the blood samples for determination of serum concentrations before treatment and then 6, 24, 48, 72, 96, 120, 144 and 168 hours after injection. Was measured quantity selegilina and its metabolites, then MAO-a activity of platelets.Clamps Tagederm were removed after 6 hours and remaining adsorbed amount selegilina was measured in ethanol extract. After the experiment was also measured MAO-a activity in isolated brain, liver and intestines of slaughtered animals. When determining the enzyme activity of MAO-A and MAO-B was also investigated selectivity of inhibition of the enzyme.The combined concentration of Deprenyl and its metabolites were measured in blood and isolated brain, lung, spleen, liver, heart, stomach, small and large intestines and kidneys of slaughtered animals as well as on the skin surface, where were the liposomal treatment. At certain intervals, blood samples were taken from the angle of the palpebral fissure Guinea pigs and from the large neck veins pigs.After the seventeenth day of the Guinea pigs were killed and instantly took blood samples from the heart. In the case of pigs blood samples were taken before driving, as described above.Selected organs and tissues properaly and homogenized in a 4-fold volume of physiological solution chlorine samples were received, as described above for blood samples.The radioactivity of the organs is determined by counting pulses in the liquid phase, these data give the total number of measured Deprenyl and its metabolites.The amount of the drug remaining on parafilm and Tegaderm also determine the radioactive method.Specific radioactivity determined from an aliquot of samples of the original preparations of liposomes that were used to calculate values related to organs and tissues.MAO activity in the brain was determined by the method of Wurtman and Axelrod [Biochem. Pharmacol. 12, 1414-1419 (1963)] and the protein content in homogenizate was determined by the method of Lowry et al. [J. Biol. Chem. 193, 265-275 (1951)] .MAO-a activity of platelets was investigated by the method of Willberg and Orlando [Med. Biol. 54, 137-144 (1976)].The concentration selegilina and its metabolites such as amphetamine, methamphetamine and desmethyl-selegiline was determined by gas chromatography.Biological drugs, the results are explained on the following figures.Figures 1 and 2 show the data of metabolites selegilina, such as methamphetamine, in the blood after a single percutaneous attachment selegiline-liposomal composition.Doses of the Yu liposomal composition of small vesicles, the distribution in accordance with Example 6, absorption and metabolism occur quickly.Basically multiplatinum liposomes lower distribution level because of the larger size particles (Examples 1 to 3) and produce slow lagging behind the level of blood components with a low number of platelets provide a relatively high blood levels within 72 hours and multiplicata composition provides primaryemail blood level even after 168 hours (Figure 2).In the case of the same compositions can also be stated that the composition, providing rapid absorption, has produced stable MAO-inhibition, while the slow adsorption leads to relatively quickly regenerating inhibition in the blood (Figures 3 and 4). Similar data were obtained in the measurements in the brain (Figures 5 and 6).Similar blood levels were measured in radioactive tests on Guinea pigs (unmodified selegiline and its metabolites together) (Figure 7). In the case of liposomes with slow adsorption significant level could be measured in the bodies, despite the fact that the blood level is reduced by 168 hours, and in the brain, being important because of the effect, and in the liver, plays an important role in McKinney ingredient later. The intestine contains a relatively small quantity of the substance, thus supporting the data on inhibition and loss of MAO-A inhibition (Figure 5). Figure 9 (table) compares the levels obtained in organs with a number of substances accumulated in the skin. Well it can be seen that, although significant, above 10 ng/g, values that are above the known data of human posmertnyh data could be measured in the organs (dashed line in the Figure), there are significant reserves in the skin, which can ensure the delivery of the active ingredient over a long period of time. Different doses from 10 to 140 mg, yield significantly higher difference in the blood (about 100 times higher) than in the brain (just 2 to 3 times higher) (cf. Figures 7 and 8).Research confirms the following benefits liposomal compositions that contain selegiline.The active ingredient avoids the gastrointestinal tract, leading thus to a significant decrease in the inhibition of concentrated there MAO-A enzyme, plays an important role in the metabolism of tiramina, as it is not in contact with the active ingredient.Being introduced to any other ways of introducing, in addition to will araliberal vena portae and thus, the first path of metabolism. Thus, this provides a higher selegilina reduced level of metabolite, "MAO-a inhibition is reduced. Less is possible that the effect of "cheese". Higher doses can be used without any side effects and thus can be extended for use as an antidepressant. Metabolites are stimulating and cause insomnia, low level means a decrease in side effects.When percutaneous introduction the skin keeps the amount of active ingredient required for continuous adsorption, by not limiting its function.The absorption of liposomal compositions (depending on composition) is from about 1 to 20 minutes, after which any needless clamping and floor (dressing, Tegaderm), the composition cannot be washed away, thus, does not prevent the washing, removing it may not be a source of fear even when dementia. When changing composition (composition or particle size) can be achieved optimal delay (1 day, 1 week, a few weeks). When the change of attitude is encapsulated and free ingredient can be achieved stable ratio ingredienten explains the following unlimited examples.Examples 1 to 6
Preparation of liposomal compositions Deprenyl
20 g of Phospholipon 90-G (unsaturated phospholipid) and 10 g of the hydrochloride selegilina dissolved in a round-bottom flask in 20 ml of a mixture of 2:1 chloroform with methanol at a temperature of 40oC. To the solution was added 100 g of small glass peas. The solvent is evaporated in vacuum in the rotavapor, and during this procedure, on the wall of the glass bulb and the surface of the glass dots formed thin film. There is added 70 g of a mixture of 1:3 ethanol and water, heated to 40oC. the flask Contents are well mixed and then stirred at medium speed, 200 revolutions/minute for 30 minutes at 35oC. Glass pea filtered over a Buchner funnel without filter paper. The filtrate is left for one hour at ambient temperature for forming liposomal system. The formation of liposomes is confirmed by the study on the optical microscope. Total weight of this liposomal product (CH-L-1) is equal to 100 gLiposomal structure is confirmed by microscopic examination and by measuring the size distribution of the particles.Example 2
The liposomal composition selegilina prepared as described in Examples what about the liposomal structure prove microscopic examination and measurement of the size distribution of the particles.Example 3
The process takes place as described in Example 1 with the difference that the phospholipid in an amount of less than 1 g, and cholesterol in the amount of 1 g was dissolved in a mixture of an organic solvent. The resulting product is called (CH-L-3).Example 4
The process takes place as described in Example 1 with the difference that used 20 g selegilina and 30 g of the phospholipid. Microscopic examination and measurement of the size distribution of the particles 118 g of the product proved that the product is a liposomal composition.Example 5
The process takes place as described in Example 2, but using 30 g selegilina, 40 g of phospholipid and 40 ml of a mixture of chloroform and methanol.Received 135 g of the product and proved that he is a liposomal composition by microscopic examination and measurement of the size distribution of the particles.Example 6
The process takes place as described in Example 1 with the difference that used 16 g of Phospholipon 90-N, 4 g of cholesterol, 10 g of the hydrochloride selegilina, 50 g of distilled water and 5 g of propylene glycol and the sweep was carried out at the speed of 250 revolutions per minute.It is proved that the obtained product (CH-L-10) is a liposomal composition by microscopy the products, obtained in accordance with Examples 1 through 5.Figure 1: mean levels of methamphetamine (SD, n=3) in the plasma of pigs after oral or percutaneous treatment of (-) Deprenyl (CHL - 10).Figure 2: mean levels of methamphetamine (SD, n=3) in the plasma of pigs after percutaneous treatment liposomal composition comprising (-) Deprenyl.Figure 3: MAO-B inhibition of platelets after percutaneous introduction of liposomal composition (CHL-10) and oral administration of conventional tablets.Figure 4: MAO-B inhibition in platelets 168 hours after percutaneous introduction multiplatinum liposomal composition.Figure 5: MAO-a inhibition in the brain, liver and small intestine 168 after percutaneous introduction of liposomal composition CHL-2.Figure 6: MAO-a inhibition in brain and liver 168 hours after percutaneous introduction of liposomal compositions.Figure 7: concentrations of serum, calculated from the radioactivity (uncharged substance and metabolite) after percutaneous injection of different doses of the composition CHL-2.Figure 8: the Concentration of radioactive substances (selegiline+metabolites) 168 hours after percutaneous introduction of the composition CHL-2.Figure 9: the Radioactivity of various organ is 1. Liposomal composition, characterized by a content of active ingredient (-)-(N--dimethyl-N-(2-propionylthiocholine)(selegilina) and/or its salts.2. Liposomal composition on p. 1, characterized in that it contains, wt%:
Selegiline and/or its salt is 0.1 - 40
Lipids - 2 - 40
Water - 30 - 90
3. Liposomal composition on p. 2, characterized in that it contains as lipids phospholipids.4. Liposomal composition on p. 2 or 3, characterized in that it additionally contains up to 10 wt.% of cholesterol.5. Liposomal composition according to any one of paragraphs.2 to 4, characterized in that it further comprises up to 20 wt.% spirit.6. Liposomal composition according to any one of paragraphs.2 to 5, characterized in that it further comprises up to 25 wt.% glycol.7. Liposomal composition on p. 1, characterized in that it contains 0.1 to 20 wt.% selegilina and/or its salts.8. Liposomal composition on p. 7, characterized in that it contains 0.1 to 10 wt.% selegilina and/or its salts.9. Liposomal composition on p. 5, characterized in that as the alcohol it contains ethanol or isopropanol.10. Liposomal component is l-choline, and/or phosphatidyl serine or phosphatidyl ethanolamine or phosphatidyl Inositol.11. Liposomal composition on p. 6, characterized in that as the glycol contains propylene glycol or polyethylene glycol.12. Pharmaceutical composition having MAO-inhibitory activity, characterized in that it includes a liposomal composition under item 1 or 2, and the usual filling, dilution and other auxiliary agents.13. The pharmaceutical composition according to p. 12, characterized in that it contains at least 10 wt.% of the total number selegilina and/or salts thereof, enclosed in one or multiplatinum vesicles, and the remaining amount selegilina in solution or in solid form.14. The pharmaceutical composition according to p. 12, characterized in that it is intended for oral or parenteral or percutaneous injection.15. The method of preparation of liposomal compositions containing selegiline and/or its salts, characterized by evaporating the organic solvent from the organic solution mixture laboratoriya components containing at least one lipid and selegiline, and then combining the obtained residue with whether as an organic solvent a mixture of chloroform and methanol.17. Composition according to any one of paragraphs.1, 2, 12, characterized by the use of it for the treatment of Alzheimer's disease, Parkinson's disease, depression, paralysis, movement disorders, or myelitis.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes compound of the formula (I):
as a free form or salt wherein Ar means group of the formula (II):
wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.
EFFECT: improved preparing method, valuable medicinal properties of compounds.
13 cl, 3 tbl, 35 ex
FIELD: medicine, neurology.
SUBSTANCE: the present innovation describes arylalkylamines that specifically affect certain types of receptor-operated Ca2+-canals, their application and pharmaceutical compositions for treating neurological disorders or diseases.
EFFECT: higher efficiency.
55 cl, 29 ex, 11 tbl
FIELD: medicine, dermatology.
SUBSTANCE: invention proposes an anti-infectious preparation comprising the combination of active substances with topical and systemic antifungal agents and a water-insoluble film-forming agent. The systemic antifungal agent is taken among the group including intraconazole, terbinafine and fluconazole or their salts. The topical antifungal agent is taken among the group including ciclopirox, 6-(2,4,4-trimethylpentyl)-1-hydroxy-4-methyl-2(1H)-pyridone, amorolfine and butenafine or their salts. The preparation is used as lacquer for nails in therapy of onychomycosis. The lacquer preparation provides high concentration of systemic antifungal agents in nails after its topical applying. The significant advantage of the preparation involves short time in treatment of anychomycosis.
EFFECT: enhanced effectiveness and valuable medicinal properties of preparation.
6 cl, 6 ex
FIELD: medicine, gastroenterology, surgery, endoscopy.
SUBSTANCE: method involves injection of adrenaline hydrochloride 0.01% solution that is administrated in the amount 10 ml and injection is carried out from 4-6 points in the dose 1.6-2.5 ml per a point, and dalargin in the dose 1 mg diluted in 2 ml of physiological solution, and the preparation is injected from 4 points in the dose 0.5 ml per a point. These medicinal agents are administrated into submucosa periulcerogenic zone wherein the preparation "TakhoKomb" is used for application that is pressed to the bottom of ulcer defect for 2 min, not less. Invention promotes to diminish the amount of bleeding relapses in early post-hemorrhagic period due to the combined effect of "TakhoKomb", adrenaline and dalargin. Invention can be used in carrying out the endoscopic hemostasis in bleeding-complicated chronic gastroduodenal ulcers.
EFFECT: improved method for hemostasis.
FIELD: medicine, infectious diseases, psychotherapy.
SUBSTANCE: method involves antiviral therapy, immune correction with thymus hormones and interferon inductors. Since the first day the relapse symptom method involves prescription of antiox+ (1 capsule per a day) and detox+ (1 capsule, 2 times per a day) for 30 days, profluzak (20 mg, 3 times per a day for 5 days) and then in the dose 20 mg, 1 time per a day for 20 days. Derinate is prescribed topically as installation into urethra in the dose 3-5 ml or with tampon into vagina and with simultaneous prescription of microenemas in the dose 10-40 ml for 10 days. Since 10-14 day in exacerbation period in the proliferative stage of an antiherpetic immune response derinate is prescribed by intramuscular injections in the dose 5 ml, 1 time in a day, 10 injections in total number. Then since 6-th day of exacerbation and intake of profluzak psychotherapy seances are carried out. The first seance of rational psychotherapy involves explanation to a patient in available form mechanism of the disease, the necessity of prolonged treatment and motivation for treatment is enhanced by suggestion. The second psychotherapy seance involves neurolinguistic programming wherein a patient colorful and detailed description of desirable function when he imagines achievement of the desire result, and positive emotional and vegetative symptoms are notes and the conditional-reflect association is formed by tactile contact. Under psychotherapist control a patient imagines "part of person" responsible for achievement of the desire result the patient attention is accented for the desire result and arisen physiological responses are fixed by using tactile contact. Also, new behavior methods are proposed to take for a patient that are directed for achievement of the desire result - avoiding sexual contacts during exacerbation of genital herpes in one of partner and during every month hormonal cycles, avoiding stress situations, and in case of each stress situation significant for patient profluzak has to be intake in a single dose 40 mg, using a condom in sexual contact in the exacerbation period. Patient analyzes the proposed new behavior methods that help avoiding relapses, provide good state of health, promotes to recovery process of genitals recovery and selects at least three the most rationally available for him behavior methods. In the case of the positive response that is controlled by physiological symptoms the result is fixed by tactile contact. The third seance involves the suggestive psychotherapy directed for fixing the attained result. The suggestive therapy seance is carried out once per a week for 6 months. Method provides declining the treatment time, to reduce relapse frequency of genital herpes and to recover the emotional state of patient.
EFFECT: improved treatment method.
2 cl, 3 tbl, 1 ex
FIELD: medicine, phthisiology, in particular chronotherapy of patients suffering from disseminated pulmonary tuberculosis with β2-agonists.
SUBSTANCE: two doses β2-agonists, namely salbutamol and fenoterol are administered at 11, 17 and 23 o'clock.
EFFECT: improvement of external respiration in early period; preventing severe blockages of bronchial tree; improvement of patient quality of life.
FIELD: medicine, narcology, biochemistry, pharmacy.
SUBSTANCE: invention proposes using the combination of dextromethorphan and the second medicine (quinidine, yohimbin, haloperdol, adjmaline, lobeline, pipamperon, fluoxetine, labetalol, chlorpromazine, domperidone, nortryptiline, quinine, oxyprenolol, propranolol, timolol, methaprolol, diphenhydramine, papaverine, mexiletine or their salts or isomers) for removing addiction to opiates, opioids or synthetic narcotics with exception cocaine and barbiturates (help in refusal in their using) or in case of chronic using antidepressant and corresponding treatment methods. The proposed combination of drugs reduces pain and relieves the withdrawal syndrome on the background of reducing morphine dose (antidepressant) up to the complete removing their intake.
EFFECT: enhanced effectiveness and valuable medicinal properties of medicine combinations.
54 cl, 2 ex
SUBSTANCE: invention relates to two-layered solid composition including a) the first layer of direct action containing effective antiallergic amount of desloratadine and at least one pharmaceutically acceptable carrier and b) the second layer of prolonged action containing effective amount of nasal anti-oedema agent and pharmaceutically acceptable carrier, wherein composition contains less than 2 % of desloratadine deterioration products. Composition is stable in administration of one or two times per day.
EFFECT: new composition for treatment and/or amelioration of prodromes or symptoms associated with common cold and allergic and/or phlogistic skin or pipe conditions.
28 cl, 1 dwg, 6 ex
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new derivatives of amidines possessing properties of inhibitors of phosphatases, and to a pharmaceutical composition comprising indicated compounds. Invention provides enhancing effectiveness of treatment.
EFFECT: valuable medicinal and biochemical properties of compounds.
4 cl, 1 dwg, 33 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to a combined medicinal preparation used in treatment of disturbance of thiol-disulfide status in kidney transplantation that comprises ambroxol as an effector of glutathione metabolism, α-lipoic acid and additives. Also, invention relates to using inhibitors of activity of angiotensin-converting enzyme - kaptopril, enalapril and ramipril or ambroxol along with α-lipoic acid for preparing a medicinal agent used in treatment of disturbance of thiol-disulfide status in kidney transplantation. Invention provides enhancing effectiveness of treatment.
EFFECT: valuable medicinal property of agent and its enhanced effectiveness.
14 cl, 7 dwg, 7 tbl, 6 ex
SUBSTANCE: method involves applying a composition comprising liposomes having gene structures encoding growth factors. The composition is administered for making injections into wound and impregnating materials for covering or closing wounds with the materials. Advanced bandage has coverage material and liposomes. Introducing liposome gene structures directly into wounds contributes to better healing results.
EFFECT: wide range of functional applications; enhanced treatment effectiveness and safety.
31 cl, 13 dwg, 4 tbl