Agent for poly(adp-riboso) polymerase inhibition
FIELD: medicine, pharmaceutics.
SUBSTANCE: what is presented is an agent for poly(ADP-riboso)polymerase inhibition. The agent represents 7-methylguanine(2-amino-7-methyl-1H-purin-6(7H)-one)- a purine derivative of formula (I) The agent has shown the efficacy higher than that in 7-methyl-xanthine and is non-toxic for the human body.
EFFECT: agent can be used in treating conditions caused by necrotic cell death: stroke, myocardial ischemia, diabetes and complications thereof, shock, neurotrauma, arthritis, colitis, allergic encephalomyelitis and other inflammations.
1 dwg, 2 ex
The invention relates to biochemistry and molecular biology, particularly to a tool for inhibition of the enzyme poly(ADP-ribose)polymerase (PARP) of the person.
PARP is a eukaryotic enzyme regulation of DNA repair. After the activation of PARP in the binding to break the DNA chain is automaticaly and other modification of nuclear proteins by joining ADP-ribose) with further increase of the polymer, which in turn serves as a signal for activation of cellular repair systems. Members of the family of PARP, first of all isoforms of PARP-1 are promising therapeutic target in Oncology, because the functioning of the repair system causes the resistance of cancer cells to chemo - and radiotherapy. Selective interventions aimed at the inhibition of PARP may be used as an accompanying treatment [Jagtap, P., and Szabo, .Poly(ADP-ribose) polymerase and therapeutic effects of its inhibitors. (2005) Nat. Rev. Drug Discov., 4, 421-440]. In addition to the treatment of cancer, PARP inhibitors may also be used in the treatment of pathophysiological conditions caused necrotic cell death, such as stroke, myocardial ischemia, diabetes and its complications, shock, multiple trauma, arthritis, colitis, allergic encephalomyelitis and other forms of inflammation [Virag, L., and Szabo, .therapeutic potential of poly(ADP-ribose) polymerase inhbitors. (2002) Pharmacol. Rev., 54, 375-429].
Many compounds inhibit the activity of PARP in vitro and in vivo in millimolar-micromolar range [Banasik, M., and Ueda, K. Inhibitors and activators of ADP-ribosylation reactions. (1994) Mol. Cell. Biochem., 138, 185-197; Milam, C.M., and Cleaver, J.E. Inhibitors of poly(adenosine diphosphate-ribose) synthesis: effect on other metabolic processes. (1984) Science 223, 589-591]. However, the known inhibitors are either under active and specific for therapeutic use, or not reviewed pharmacokinetics, pharmacodynamics and toxicity. Thus, at the moment, is still relevant to the development of a wide range of active compounds.
Closest to the claimed means for inhibiting PARP, the prototype, is a natural compound, a metabolite of caffeine - 7-methylxanthines [Geraets, L., Moonen, H.J., Wouters, E.F., Bast, A., and Hageman, G.J. Caffeine metabolites are inhibitors of the nuclear enzyme poly(ADP-ribose)polymerase-l at physiological concentrations. (2006) Biochem. PharmacoL, 72, 902-910]. The disadvantages of the prototype is low inhibitory activity against PARP (IC50172 μm in the case of PARP-1).
An object of the invention is the creation of a more effective inhibitor of PARP-based natural purines. The technical result is to reduce the value of the IC50(the concentration of inhibitor at which the enzyme activity is reduced by 50%) when using the created inhibitor compared to the prototype.
Set t the economic problem is solved by that as a means for inhibiting PARP is suggested to use the purine derivative of formula (I), representing a 7-methylguanine (2 - amino - 7 - methyl - 1H - purine - 6(7H)-one).
The proposed connection will get described in the literature method [Jones, J.W., and Robins, R.K. Purine Nucleosides. III. Methylation Studies of Certain Naturally Occurring Purine Nucleosides. (1963) J. Am. Chem. Soc., 85, 1963], which consists in the methylation of the guanosine dimethylsulfate with subsequent hydrolysis of N-glycosidic bonds. The structure and purity of the obtained compounds were confirmed by the data of NMR spectroscopy. Below are examples of implementation of the proposed technical solution.
The invention is illustrated by figure 1, which presents a graph of the dependence of the reaction rate of poly(ADP-ribosyl)financing from the concentration of inhibitor, demonstrating the inhibitory activity of 7-methylguanine against PARP in Example 1.
Example 1. The study of the influence of 7-methylguanine on the activity of PARP-1
Recombinant protein PARP-1 person (EC 126.96.36.199) was obtained by the literature method [Sukhanov M.V., Khodyreva S.N., Lavrik, I. Poly(ADP-ribose)polymerase 1 inhibits DNA synthesis preemptive chain, catalyzed by DNA polymerase R. (2004) Biochemistry, 69, 686-698]. Reaction of poly(ADP-ribosyl)investments carried out under the following conditions: 50 mm Tris-HCl, pH 8.0, 20 mm MgCl2, 150 mm NaCl, 7 mm β, activated DNA (2 PU280/ml, the degree of activation 25%), 0.6 mm [3H]NAD+(isotope dilution 1:500), temperature 37°C. the Reaction was started by addition of PARP-1 to a final concentration of 200 nm and was stopped after 60 seconds, causing the reaction mixture to paper filters (Whatman-1), soaked in 5%trichloroacetic acid. The filters were washed 4 times in 5%THU, then in 90%ethanol (to remove THU) and air-dried. The amount of radioactive label incorporated into acid-insoluble product, were recorded on a scintillation counter QuantaSmart. The determination of the number of radioactively-labeled product was carried out on the initial part of the dependence of the reaction rate from time to time. Activity 7-methylguanine as an inhibitor of PARP-1 was evaluated in the reaction autopole(ADP-ribosyl)investing in the concentration of NAD+equal to 0.6 mm. The concentration of the inhibitor was varied in the range from 1 to 100 μm. The reaction and detection of the products were performed as described above. Figure 1 shows a typical curve of the dependence of the reaction rate autopole(ADP-ribosyl)investments (in arbitrary units proportional to the number of decays in radioactively-labeled product per minute) on the concentration of 7-methylguanine. The value of the IC50for 7 - methylguanine was 30 μm.
Example 2. The study of the influence of 7-methylguanine on the activity of PARP-2
Measurement of inhibitory actively the tee 7-methylguanine against PARP-2 was performed, as described in Example 1. The concentration of the inhibitor was varied in the range from 1 to 100 μm. The value of the IC50for 7-methylguanine was 50 μm.
Thus, 7-methylguanine shows inhibitory activity against PARP-1 - the most important from a therapeutic point of view of the representative of the family of PARP. The value of the IC50(the concentration of inhibitor at which the enzyme activity is reduced by 50%) in the case of PARP-1 is 30 μm, which is 6 times less than for the prototype. In addition, 7-methylguanine inhibits PARP-2 is most similar to PARP-1 isoforms. It should be noted that 7-methylguanine is a metabolite of nucleic acids and is found in biological fluids [Chao, M.R., Wang, C.J., Yang, H.H., Chang, L.W., and Hu, C.W. Rapid and sensitive quantification of urinary N7-methylguanine by isotope-dilution liquid chromatography/electrospray ionization tandem mass spectrometry with on-line solid-phase extraction. (2005) Rapid Commun. Mass Spectrom., 19, 2427-2432], and, therefore, should not have a toxic effect. The proposed connection, 7-methylguanine, can be used to create medicines applicable in clinical medicine, because it is a more effective inhibitor of PARP, than the prototype, and, as a natural metabolite that is not toxic to the human body.
Means for inhibition of the enzyme poly(ADP-ribose)polymerase person representing a purine derivative of formula (I
SUBSTANCE: composition is proposed which comprises stem cells of human amniotic fluid with the phenotype CD73+/CD90+/CD105+/CK19+, nutrient medium, erythropoietin, epidermal growth factor, and collagen taken in an effective amount.
EFFECT: invention enables to increase the proliferative potential and viability of the cells, while simultaneously providing cytoprotective effect on the cells of the transplant and stimulation of migration and proliferation of patient's own cells, and also to reduce significantly the concentration of injectable cells and to activate vascularisation and regeneration at the defect site and can be used in therapy for elimination of congenital and acquired defects of soft tissue arising as the result of injuries, after removal of tumors, congenital diseases, age-related changes or other damages.
2 tbl, 4 ex
SUBSTANCE: invention represents a pharmacological geroprotective composition, which includes a polyphenol component, vitamins and microelements, humic acids, containing polyphenol components, vitamin C, vitamin A, iron (II) chloride and selenium (IV) dioxide, with the composition components being in a specified ratio in wt %.
EFFECT: increased life expectancy and retardation of tumour development.
2 cl, 3 dwg, 2 tbl, 4 ex
SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).
EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.
37 cl, 6 dwg, 12 tbl, 186 ex
SUBSTANCE: halogen-containing hydrocarbonate chloride sodium, alkaline, boron high-magnesium, iodine and fluorine natural mineral water 'Lazarevskaya Tselebnaya' No. 84-E of the Volokonskoye deposite in Sochi is taken according to the following procedure: 30-35 minutes before meals in small sips, six times a day daily in a dose of 200-250 ml at t°=(23-24)°C, for 45 days every 2-3 days with taking the above natural halogen-containing mineral water in the same volumes for the following 45 days. The therapeutic course makes 3 years.
EFFECT: method enables improving the health status in the individuals subject to the hazardous effect of radionuclides taken with water or food.
2 cl, 6 tbl, 3 ex
SUBSTANCE: food ration is added with multi-component natural concentrated food products (NCFP) with high concentrations of biologically active substances (BAS) of herbal (HNCFP) and (or) protein-herbal (PHNCFP) raw material, for the purpose of nutritional support of sportsmen doing various sports, their individual physiological requirements; that results in recovering a set of characteristics of physiological functions and qualities determining a degree of activity of morphofunctional body systems, activities of daily living and professional performance, with providing preventing donozological and pathological conditions, achieving high sport scores. The above food products can be presented by NCFP Antitox and NCFP SportAtiv-2.
EFFECT: invention provides easier exercise tolerance and recovery thereafter, improving health in sportsmen.
SUBSTANCE: method involves preliminary intraperitoneal single administration of 5% aqueous alloxan in a dose of 15 mg/kg of body weight into a rat's body on an empty stomach. That is followed by administering afobazol under conditions of oxidative stress after observing the rat's blood glucose gain at least twice. Afobazol is administered subcutaneously in a dose of 10 mg/kg of body weight once a day for 30 days with underlying administration of L-arginine in a dose of 10 mg/kg of body weight or with underlying NG-nitroarginine methyl ester (L-NAME)-inhibitor of NOS-3 enzyme in a dose of 25 mg/kg of animal's weight.
EFFECT: method enables correcting the oxidative stress and NO-producing endothelial dysfunction accompanying vascular complications of diabetes mellitus.
1 dwg, 6 tbl, 1 ex
SUBSTANCE: invention refers to medicine, namely to rehabilitation medicine and concerns prevention of meteopathic reactions. That is ensured by administering an adaptogene agent presented by a phytococktail containing mixed 70% tinctures of eleuterococcus, common licorice and rhodiola rosea in the ratio of 2:1:1. The cocktail is introduced in a dose of 10-15 drops for two weeks once a day, taking into account an individual's chronotype. That is followed by a magnetic-infrared-laser exposure covering the acupuncture points Tr(X)5 - Wai Guan, E(III)36 - Zuo San Li, Tr(X)15 - Tian Liao and MC(IX)5 - Jian Shi through an applicator wetted in the phytococktail containing 70% alcoholates of rhodiola rosea, common licorice, yellow starwort and spiny eleuterococcus in the ratio of 2:2:1:1, in a combination with an aromatherapy with Atlas cedar oil.
EFFECT: integrated exposure in the developed mode provides higher non-specific body resistance to meteorological factors.
2 ex, 3 tbl, 8 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: there are presented: using a compound of formula (1) or its salt for preparing a drug for increasing HIF-1α stabilisation in a cell, as well as for preparing a drug enhancing the immune response in an individual, for preventive management of a wound to avoid an infection, for treatment of the microbial infection, for improvement of efficacy of a vaccine for management of the wound in the individual. What is presented is a pharmaceutical composition containing the above HIF-1α prolyl hydroxylase inhibitor and one or more additives. What is shown is achieving the declared applications by using the new compound of formula (1) with the HIF-1α prolyl hydroxylase (HIFPH2 (EGLN1)) inhibitor. It makes it applicable for treating HIF-1 alpha activity related diseases, conditions and/or syndromes.
EFFECT: preparing the drug for increasing HIF-1α stabilisation in a cell.
26 cl, 20 dwg, 8 tbl, 13 ex
SUBSTANCE: what is used is a 20% alcoholic tincture (1:10) of medicinal herbs in the following weight proportions: Rhaponticum carthamoides roots and rhizomes - 2, tormentil roots - 1, peppermint leaves - 3. A mouthwash is prescribed before a dentist's appointment for 3-4 days 3 times a day, as well as 10-15 minutes before an impression manipulation.
EFFECT: method provides reducing intensity a gag reflex accompanying dental manipulations.
SUBSTANCE: what is presented is a method for stimulating the post-traumatic spinal cord regeneration consisting in a single-stage transplantation of human umbilical cord blood mononuclear cells pre-transduced with recombinant adenovirus with a cloned gene of glial derived neurotrophic factor (gdnf), in the damage area.
EFFECT: using the invention enables providing a better outcome of the post-traumatic spinal cord regeneration, reduced length of staying in hospital of patients suffering from a spinal cord injury and improving the patients' quality of life.
SUBSTANCE: corneal deepithelialisation and 0.1% riboflavin saturation is followed by applying a soft contact lens at least 100 mcm thick without an UV filter. The cornea is exposed to ultraviolet rays at wavelength 365-375 nm for 30 minutes.
EFFECT: method enables enhancement and eliminates the damaging action of ultraviolet on the corneal endothelium by increasing total thickness of the cornea.
3 cl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to the chemical-pharmaceutical industry and represents a compound having a structure according to formula I:
compositions containing the compounds of the above formula applicable to stimulate neurogenesis and/or inhibition of neuron degeneration.
EFFECT: invention may be used in treating diseases and conditions characterised by neuron loss and lower neurogenesis, including Alzheimer's disease, stroke, traumatic brain injury, traumatic nerve injury and depression.
8 cl, 2 tbl, 2 ex, 1 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions relates to methods of obtaining a lyophilised preparation of tetrodotoxin and to a tetrodotoxin preparation for relief of the drug withdrawal in case of addiction to opiates. The method of obtaining the lyophilised preparation of tetrodoxin includes the following stages: 0.1-20 mcg/dose of tetrodotoxin is dissolved with 0.1% solution of citric acid to regulate pH within the range of 3.5-4.5 in injection water and filtered to remove pyrogen; separately dissolved are: a stabiliser - dextran or trehalose - and a filling agent, representing an isotonic solution of sodium chloride or mannit in injection water. After that, 0.1% solution of citric acid is added to regulate pH within 3.5-4.5, then, activated carbon is added with keeping at a temperature of 60°C and mixing for more than 30 minutes, filtering to remove pyrogen and cooling to room temperature. After homogeneous mixing of the obtained solutions and realisation of ultrafiltration, lyophilic drying is carried out. Lyophilic drying consists in preliminary freezing, drying under vacuum at reduced temperature, drying under vacuum at increased temperature, with each drying being performed at a certain temperature for the specified time period. After that, filling with inert gas is performed with control of water content at 3% level, with further sealing. Another version includes addition of additional solution of lidocaine chloride to the solution of tetrodotoxin and citric acid at the first stage. Also disclosed is the tetrodotoxin preparation for relief of the drug withdrawal in case of addiction to opiates, obtained by the said method, which is characterised by the weight ratio tetrodotoxin:filling agent:stabiliser, equal to 1:(150-3000):(50-6000).
EFFECT: claimed group of inventions ensures obtaining the stable tetrodotoxin solution with accurate dosage, which is used for introduction into the human organism.
25 cl, 9 tbl, 14 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry and represents an agent consisting of theobromine and a non-opiate antitussive agent representing an NMDA antagonist in the form of a combination preparation for treating cough.
EFFECT: invention provides a synergetic effect on cough suppression and improved clinical effectiveness in cough treatment.
20 cl, 1 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to antimicrobial compositions and methods for using them, and aims at the preoperative skin processing and disinfection, wound care, and as a disinfectant for sterilisation of surgical instruments. An antimicrobial composition contains at least approximately 30 wt % or more of C1-C6 alcohol, approximately 1.5 wt % to 15 wt % of citric acid, approximately 0.01 wt % to 1 wt % of paraben, and approximately 0.01 wt % to 0.2 wt % of a redox compound. The antimicrobial composition has pH from approximately 3 to approximately 7. The other aspects present an applicator that comprises an absorbent material and an absorbed antimicrobial composition, or an adsorbent material and a handle comprising an amount of the antimicrobial composition.
EFFECT: using the group of inventions provides effective and fast elimination of microorganisms particularly found on the skin surface, thereby providing the antimicrobial effect stable for a long period of time after use.
33 cl, 12 dwg, 2 tbl, 6 ex
SUBSTANCE: invention refers to medicine, particularly to dentistry and concerns preparing an oral care agent. For this purpose, a kit comprising an optically transparent composition containing a photosensitising dye, and a light-emitting device emitting light at a wave length and over a period of time sufficient to activate the photosensitising dye is presented. The above dye is specified in a group consisting of chlorophyllin sodium copper salt, tartrazin (FD&C yellow No.5), riboflavin-5'-monophosphate sodium salt, Allura Red AC (FD&C red No.40), new coccine (CI 16255, edible red 7), chromotrope FB (CI 14720, edible red 3), indigo carmine, erioglaucine disodium salt (FD&C blue No.1), fast green FCF (FD&C green No.3), lissamine green B, naphthol green or acid green, cochineal, carmoisine azorubin, amaranth, brilliant scarlet 4R, complexes of copper and chrolophyl, brilliant black BN (PN), chocolate brown HT, β-carotin, bixin, lycopene, betanin, Erythrosin B sodium salt and mixtures thereof. The optically transparent oral care composition contains a negligible amount of titanium dioxide and 3% or less of silicone dioxide.
EFFECT: invention provides effective treatment and/or prevention of conditions caused by microorganisms by creating strong antibacterial activity with non-toxicity and safety of the used dyes.
16 cl, 3 ex, 14 tbl
SUBSTANCE: invention refers to medicine, namely to infectious diseases and immunology, and may be used for treating the patients with influenza and other influenza-like illnesses complicated with pneumonia. That is ensured by prescribing an antibacterial therapy and administering cytokine presented by interleukin-1β subcutaneously in a dose of 0.5…1.0 mcg, and then cytoflavin immediately after cytokine intravenously drop-by-drop in a dose of 5…10 ml once a day for four days.
EFFECT: method enables reducing the length of the clinical manifestations of influenza and influenza-like illnesses complicated with pneumonia, and forming protective immunity ensured by lowering the concentration of the anti-inflammatory cytokines and increasing blood serum circulating interferons with reducing side effects.
1 dwg, 7 tbl, 5 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to purine compounds of the formula (I):
wherein R1 is specified in a group containing H, halogen and C1-C6alkyl, R2 is specified in a group containing H, CN, an optionally substituted C1-C12alkyl, an optionally substituted C3-C12cycloalkyl, an optionally substituted C2-C12heterocycloalkyl, an optionally substituted C6-C18aryl, an optionally substituted C1-C12alkyloxy, COR8, COOH, COOR8, CONR8R9 and acyl; if R2 represents the optionally substituted C6-C18aryl, the above optional substitute is specified in F and CH3; if R2 represents the optionally substituted C1-C12alkyl, the above optional substitute is specified in CH3, OCH3 and O-C(CH3)3; if R2 represents the optionally substituted C3-C12cycloalkyl, the above optional substitute represents CH3; if R2 represents the optionally substituted C2-C12heterocycloalkyl, the above optional substitute is specified in a group consisting of COOC(CH3)3, CO(CH2)2CH3, COPh and CO(5-methylthiophen-2-yl), each R3 and R4 is independently specified in a group containing H, C1-C6alkyl and OR8, R6 is specified in a group containing H, OH, OR8, CH2OH, NH2 and NR8R9, or R8 and R9 if taken together with atoms attached thereto form a cyclic group, each R8 and R9 is independently specified in a group containing H and C1-C12alkyl; each R2 independently represents C1-C6alkyl, q represents an integer specified in a group containing 0 and 1, X represents a group of formula (CR10 2)m, each R10 is independently specified in a group containing H and C1-C6 alkyl, m represents an integer specified in a group containing 0, 1, 2 and 3, C2-C12heterocycloalkyl contains at least one heteroatom specified in a group containing O, N and S, in at least one ring; each ring is 3- to 10-merous, or their pharmaceutically acceptable salts or N-oxides.
EFFECT: compounds may be effective as agents for a number of proliferative diseases or disorders, including tumours and malignant growth, as well as other PI3K and/or mTOR kinase related disorders or diseases.
31 cl, 3 tbl, 5 ex
SUBSTANCE: blood is examined for angiogenic factors, namely soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PIGF). An angiogenic factor (Ka) is calculated by formula: Ka=sFlt-1/PlGF×10. If Ka is 10 or less, the pregnant woman is stated to require no admission to hospital, no case follow-up; doctor's appointments are scheduled. If Ka falls within the range of 10 to 50, the pregnant woman is admitted to hospital, wherein foetal monitoring, Doppler monitoring are performed; an amniotic fluid index (AFI) is calculated; a therapy aiming at the uterine-placental blood flow improvement is prescribed for 10 days. The amount of infusion makes 400 ml a day. The prescribed preparations are Actovegin, Trental, Instenon, Carnitini chloridum. Control ultrasonography, Doppler monitoring, foetal monitoring, AFI and Ka measurements are performed 2 weeks later. The pregnant woman is discharged from hospital if observing no negative trends. If Ka falls within the range of 50 to 100, the pregnant woman is admitted to hospital, wherein foetal monitoring, Doppler monitoring are performed, and AFI is measured; a therapy aiming at the uterine-placental blood flow improvement is prescribed for 14 days The amount of infusion makes 800 ml a day. The prescribed preparations are Actovegin, Trental, Instenon, Carnitini chloridum. Control Doppler monitoring and foetal monitoring are performed every 3 days; 2 weeks later control Ka is measured. If the trend is positive, the pregnant woman may be discharged from hospital, while no positive trend requires another 2 weeks of the therapy. If Ka is 100 or more, but less than 150, the pregnant woman is admitted to hospital, wherein foetal monitoring, Doppler monitoring are performed, and AFI is measured; a therapy aiming at the uterine-placental blood flow improvement is prescribed for 14 days. The amount of infusion makes not less than 800 ml a day with the same preparations prescribed. Those are added with the preparations for homeostasis correction, including Fraxiparine, Fragmin, Clexane optionally. Control Doppler monitoring and foetal monitoring are daily. Hypamnion also requires measuring control AFI. If a gestational age is less than 34 weeks, respiratory distress syndrome (RDS) should be prevented by administering the preparation Dexon 24 mg according to the schedule: 6 mg every 12 hours 4 times. Control Ka is necessarily measured after 2 weeks of the treatment. If the trend is positive, the pregnant woman may be discharged from hospital, while no positive trend requires another 2 weeks of the therapy. If Ka is 150 or more, and the gestational age is more than 34 weeks, the therapeutic approach is the same, as for Ka being within 100 to 150, control Doppler monitoring, foetal monitoring are performed twice a day, as well as measuring AFI. If observing no foetal weight gain for 2 weeks of the therapy or the functional state of the foetus deteriorates, a Cesarean section is performed. If the gestational age is 34-36 weeks, the therapeutic approach and follow-up are the same as for the gestational age of 34 weeks, except for the prevention of foetal RDS. However, if observing the deterioration of a foetal movement pattern or the functional status of the foetus, a Cesarean section is performed according to the foetal monitoring and Doppler monitoring findings. If the gestational age is more than 36 weeks, and Ka is 150 or more, pre-mature delivery is applied.
EFFECT: optimal selection of the therapeutic approach ensured by determining the values reflecting the severity of the cardiovascular disorder directly in the uterine-placental complex and mother's and foetus's compensatory capacities.
SUBSTANCE: invention relates to novel compounds of formula I, having cell proliferation inhibitor properties. In formula I , Y1 and Y2 each independently denote N or C(R1), but Y1 and Y2 do not simultaneously denote N or do not simultaneously denote C(R1), where R1 is selected from a group consisting of a hydrogen atom, C1-6alkyl, where R1 is substituted with 0 or 1 substitutes RR1, selected from a group consisting of -ORa; where Ra is selected from a hydrogen atom; R2 is selected from a group consisting of a hydrogen atom, C1-6alkyl; R3 is a 6-7-member monocyclic or bridge heterocycloalkyl ring containing 2 heteroatoms, selected from N and O, where the group R3 is substituted with 0-3 substitutes RR3, selected from a group consisting of -Ri, Ri is selected from C1-6alkyl; A1, A2, A3 and A4 each denote C(H); and D denotes -NR4C(O)NR5R6, where R4 is selected from a group consisting of a hydrogen atom; R5 and R6 are each independently selected from a group consisting of a hydrogen atom, C1-6alkyl, C4-6heterocycloalkyl containing one oxygen heteroatom; and where R5 and R6 are further substituted with RD, where RD is selected from -S(O)2Rm, where Rm is selected from C1-6alkyl.
EFFECT: compounds can be used to produce medicine for treating cancer.
21 cl, 1 tbl, 21 ex
SUBSTANCE: invention provides topical blood circulation improving remedy containing simultaneously nitroglycerine and aminophylline. Remedy can be provided in the form of emulsion, gel, or ointment, which are administered 1-2 times a day.
EFFECT: strengthened blood circulation activation effect, which is prolonged to 24 hours.
5 cl, 9 ex