The remedy for the prevention and treatment of infectious diseases and correction of pathological conditions of the living body
(57) Abstract:The invention relates to medicine. Agent for the prevention, treatment and elimination of consequences of viral, bacterial, cancer, liver diseases, gastrointestinal tract, urinary system, immune system, wounds, burns, stress, used in medicine and veterinary medicine, contains a pyrophosphate polyprenol General formula: H-[-CH2-C(CH3)= CH-CH2-]a-X, where X is the anion pyrophosphoric acid, and not less than 7. The proposed tool is more active because it has a multifunctional activity at the cellular level. 5 table. The invention relates to a means for prevention, treatment and elimination of consequences of viral, bacterial, cancer, liver diseases, gastrointestinal tract, urinary system, immune system, wounds, burns, stress, used in medicine and veterinary medicine.Known antiviral agent, in the form of monophosphate of polyprenol General formula H-[-CH2- (CH3)= SN-SN2-]and-X (polyprenylated), where a is the number of isoprene units, X is the anion of phosphoric acid (RU, patent 2005475 And 61 To 31/21, 1991). Using known which of the proposed use of biologically active substances is to improve the efficiency of its antiviral action.This technical result is achieved by using pyrophosphate polyprenol [1, 2] the General formula H-[-CH2- (CH3)= SN-SN2-]and-X, where X is the anion pyrophosphoric acid, and not less than 7, as a means for the prevention and treatment of infectious diseases and correction of pathological conditions of the living organism.The proposed biologically active substance has a multifunctional activity at the cellular level and at the level of the organism as a whole.At the cellular level it is embedded in the cell membrane, increasing their conductivity, normalizes and stimulates the biosynthesis of glycoproteins on the cell surface, normalizes the reproduction of cells, intercellular and, as a consequence, interstitial interaction.In the body as a whole - normalizes the functioning of the immune system, promotes tissue regeneration, improves the functioning of individual organs, enhances hematopoietic function.Describes the properties of the proposed biologically active substances allow it to be used for prevention, treatment and elimination of consequences of viral, bacterial, cancer, diseases of pecanpie funds can be illustrated by the following examples.Example 1. Antiviral activity of pyrophosphate polyprenol.The experiments were conducted on mice SV infected intranasally with influenza virus type A (H1N1) strain WSN in a dose of 5 LD50.Simultaneously with the virus once introduced monophosphate of polyprenol or pyrophosphate polyprenol (solution of 0.4% at a dose of 5 μg per mouse).The average life expectancy of animals, which were injected monophosphate of polyprenol, was 6.6 days, the animals, which were introduced pyrophosphate polyprenol - 8.1 days.The example indicates that more effective action pyrophosphate polyprenol compared with monophosphates of polyprenol.Example 2. Preventive protective effect of pyrophosphate polyprenol in mice treated with endotoxin of gram-negative bacteria.In the experiment white mice weighing 20 g Animal-1 day before injection of endotoxin injected intraperitoneally pyrophosphate of polyprenol at the rate of 100 mg per 1 kg of body weight. Then the animals injected intraperitoneally 7 mg of glycolipid chemotype Re obtained from Salmonella Minnesota R595 by extraction with chloroform, and methanol. The death of animals into account within 3 days. Each group should have at least 20 belly is anything from the deaths of 6 of the 20 animals. Differences between groups significant at p<0,01.Tests conducted on 3 volunteers with dysbiosis. Volunteers were orally administered 3 ml of a 0.4% solution of pyrophosphate polyprenol morning and evening for 3 days and 1 time on the fourth laziness. Before the first admission and 6 hours after the last dose of the analysis of blood and feces. In the blood determine the content of IgG-antibodies to endotoxin of gram-negative bacteria (glycolipid of chemotype Re), the total number of leukocytes and leukocyte numbers, svyazyvaysya endotoxin in the bloodstream or are able to bind endotoxin in vitro (blood smears). The antibody is determined using enzyme-linked immunosorbent assay (ELISA) using protein a labeled with horseradish peroxidase. As an indicator of the standards used pooled blood sera of 40 healthy volunteers. Leukocytes, bound endotoxin in vivo were detected using ELISA in blood smears using antibodies to Re-glycolipid, labeled with horseradish peroxidase. For the detection of leukocytes, are able to bind endotoxin in vitro, the strokes first treated with a Re-glycolipid, and then conjugate is sevov on various nutrient media. Research results are reflected in table 1.After povtornogo drug recovery has been observed in all the studied indices to normal.Example 4. Correction of pathological conditions. Correction stressinducing immunodeficiency
For the induction of stress, experimental mice were kept in conditions of limited movements (muscle deprivation). Within 10 days, the mice were placed one each in plastic chambers 8,54,02,0 cm to 7 hours each day. Control mice were kept in standard cages for 10 individuals (the size of a standard cell 421411 cm). On the 10th day stress experimental and control animals were injected with the test antigen-sheep red blood cells, after which the animals were kept under normal conditions  . To determine the level of stress used local hemolysis in gel  . The mice were injected intraperitoneally a sheep erythrocytes (EB) 5108in the order of 0.5 mil To 5 days after immunization in mice took spleen and obtained a suspension of erythrocytes. Test cells (106in 0.1 ml) were introduced into the molten agarose (0.7 percent), with swietlicki 20%-tion sheep red blood cells, after which the resulting mixture was layered on the surface of plastic cups is 1 ml of complement Guinea pigs, and incubated additionally for 1 h at 37oWith, then the complement decanted and count the zones of hemolysis. The calculation of the number of antibody productive cells (ATOC) produced 1 million viable splenocytes.Investigated the following groups of mice (10 animals per group):
1. Control - treated EB (5%) intraperitoneally in 0.5 ml.2. Subjected to stress - receiving unit on the 7th day stress.3. Mouse, in which 1-day stress was introduced pyrophosphate polyprenol, and on the 7th day DL.The results presented in table 2, show that the stress-induced hypokinesia, induces in mice a significant suppression of the primary immune response unit (204 up to 70 atok 1 million splenocytes). A single injection of the drug increases the number of ATOC to normal, completely preventing the development of stressinducing immunodeficiency.Example 5. Correction of pathological conditions. The study of the production of interferon.The experiments were conducted on mice SW, surviving after infection with influenza virus type A (H1N1) strain WSN.The mice SW (weight of mice 12-14 g) was injected intraperitoneally pyrophosphate of polyprenol. After 24 h in the experimental and control the Intesa interferon in the serum. 2. The level of interferon synthesis induced by Newcastle disease virus (virus-induced interferon, VBN, 108TCD50/02 ml). 3. The level of interferon synthesis induced by staphylococcal enterotoxin A (mitogen-induced interferon, sea, 1 μg/ml). The interferon titration is carried out in cell cultures of L-929. As a test virus use 100 TCD50virus encephalomyocarditis mice. Per unit of interferon take the last dilution of the sample, providing 50% protection of the cells in complete destruction of the monolayer in the control.In the experiment used the following groups of mice: 1) control (C), 2) control treated with pyrophosphate polyprenol (CPR), 3) control of the survivors of a viral infection (KB), 4) the survivors of a viral infection and treated with pyrophosphate polyprenol (WFP).Set (PL. 3) that the pyrophosphate polyprenol restores the rate of interferon status of mice surviving after viral infection, while not affecting the interferon status of mice without interferon deficiency.Example 6. Correction of pathological conditions. The profile of cytokine mRNA.Used cell line MG-63 (osteogen the th livestock (cattle). When the cells of a solid monolayer growth medium was changed for a supportive and experienced the culture was treated with pyrophosphate polyprenol. After 2, 24 and 48 h the cells were removed with trypsin solution and versene, washed with saline and perform the allocation of total RNA (used sets for selecting RNA Rneasy Total RNA System - Qiagen, Santa Clarita, CA) followed by cDNA synthesis using oligo dT primers and AMV-reverse transcriptase (New England Biolabs, Bedford, MA). cDNA was used as template in the reaction RT-PCR with pairs of primers for the following cytokines - IFN-, IFN-, IL-lb, IL-2, IL-4, IL-6, IL-10, TNF- (Yamamura et al. , 1991; Gelder et al. , 1995; Lin et al. , 1998). Reaction conditions - 94oWith 2 min; 35 cycles at 94o1 min - 55o2 min - 72oWith 2 min; 72o5 min --> SHUT-OFF. The reaction product was detected by electrophoresis in 3% agarose gel.It has been shown that in cells MG-63 pyrophosphate polyprenol induced biosynthesis of mRNA for IL-1 and IL-2. Induction was clearly observed at 24 h after treatment; the reaction product was not detected after 2 h after treatment; trace amounts of PCR product was detected after 48 h after treatment. It should be noted that in cells MG-63 constitutive were presented mRNA for IFN - and TNF-.Prima is adenilatcyclase (2-5A synthetase), while in complex with dsRNA, polimerizuet ATP in oligoadenylate that activate ribonuclease, RNase L. system Activation of the enzymes of the 2-5A synthetase/RNase L leads to increased decay of mRNA in the cell and, as consequence, to decrease in the rate of cell reproduction, suppression of viral infection and others Used transplantable line of human cells J-96, obtained from the blood of men, patient subacute monocytic leukemia, and transplantable line of mouse fibroblasts L-929. Cells were cultured in medium 199 with 10% serum of cattle embryo. On the 2nd day of cultivation when the cells of an incomplete monolayer growth medium was replaced with supports (with 2% serum of cattle embryo) and were treated with pyrophosphate polyprenol. After 24 h the cells were removed from the glass with a solution of Versene, besieged by centrifugation at 2000g for 5 min, suspended in the buffer and frozen at -70oC. After thawing cells was appropriate processing and determination of the activity of 2-5A synthetase according to A. N. Narovlya et al. (1988). Activity of 2-5A synthetase was expressed in moles AMR included in the dimer 2-5A for 14 h incubation per 1 mg protein in the cell lysate. As can be seen from table 4, when processing cells J-96 and L is I, exceeding its original 5.7 times for cell culture J-96 and 2.9 times for the culture of cells L-929.Example 8. Correction of pathological conditions. Effect on camp-dependent protein kinase.Used transplantable line of human cells J-96, obtained from the blood of men, patient subacute monocytic leukemia. Cells were cultured in medium 199 with 10% serum of cattle embryo. On the 2nd day of cultivation when the cells of an incomplete monolayer growth medium was replaced with supports (with 2% serum of cattle embryo) and were treated with pyrophosphate polyprenol. After 24 h the cells were removed from the glass with a solution of Versene, besieged by centrifugation at 2000g for 5 min, suspended in the buffer and frozen at -70oC. After thawing cells was appropriate processing and determination of the activity of camp-dependent protein kinase according to A. N. Narovlya et al. (1988). The activity of protein kinase expressed in pulses per 1 min per 1 mg of protein in the cell lysate.Presented in the table 5 data allow us to compare the activity of this enzyme in cell culture J-96 with and without treatment with pyrophosphate polyprenol. It is shown that the activity of camp-dependent is iterator
1. Rip J. W. et al. , Distribution, metabolism and function of dolichol and polyprenols. //Prog. Lipid Res. - 1985. - v. 24. - 6. -p. 269-309.2. Shibaev V. N. , Danilov L. L. New developments in the synthesis of phosphopolyprenols and their glycosyl esters. // Biochem. Cell. Biol. - 1992. - v, 70. - 6. - R. 429-437. The use of pyrophosphate polyprenol General formula
where X is the anion pyrophosphoric acid,
a - not less than 7,
as a means for the prevention and treatment of infectious diseases and correction of pathological conditions of the body.
< / BR>showing hepatoprotective and anti-HIV activity
SUBSTANCE: invention proposes applying bis-phosphonic acids (bis-phosphonates) for the embolic treatment of angiogenesis and corresponding methods for prophylaxis or treatment of angiogenesis by embolization. Invention provides suppression of growth, invasion or metastasis of tumors, treatment of angiogenesis in myocardium ischemia, rheumatic arthritis, osteoarthritis by embolization of newly formed vessels in intra-arterial route of administration of bis-phosphonate (for example, pamidronic acid or zoledronate).
EFFECT: valuable medicinal properties of medicine agents.
10 cl, 3 dwg, 7 ex
SUBSTANCE: method involves applying intracoronary phosphocreatine introduction into infarction-responsible artery when carrying out coronary angioplasty. Phosphocreatine solution is injected after reperfusing the infarction-responsible artery at constant volume rate of 0.1-4 ml/s with introduced phosphocreatine dose being equal to 0.5-4 g.
EFFECT: reduced myocardium necrosis zone; prevented cardiac insufficiency and cardiac rhythm disorders.
SUBSTANCE: disclosed are combine product and kits useful in treatment for solid tumor by application of ZD6126 compound having formula in combination with platinum antitumor drug (e.g. cysplatine) and/or taxane. Treatment methods may include ionizing radiation. In was discovered that certain doses of abovementioned combined substances according to method of present invention have synergic action on solid tumors (as well as on angiogenesis neoplasm).
EFFECT: new method for solid tumor treatment.
12 cl, 5 tbl, 9 dwg
SUBSTANCE: the present innovation deals with applying a vasculodestroying agent or its pharmaceutically acceptable salt to be introduced for a warm-blooded animal as divided dosages to obtain anti-tumor effect. In particular, a vasculodestroying agent is being ZD6126, AC-7700, combrestatin A4 phosphate or their pharmaceutically acceptable salts. Moreover, total daily dosage of vasculodestroying agent is divided into two or more equal or unequal parts, and interval of time between introduction of every part corresponds to above 0 to about 6 h. The innovation enables to obtain greater anti-tumor effect against the one obtained at introducing the same total dosage of vasculodestroying agent as a single dosage.
EFFECT: higher efficiency of therapy.
18 cl, 2 dwg
FIELD: organic chemistry, medicine, oncology.
SUBSTANCE: invention relates to organic amine salts, amino acid salts and combrestatin A-4 phosphate amino acid ester salts. Invention describes compound of the general formula (I):
wherein one of substitute -OR1 or -OR represents -O-QH+ and another one represents hydroxyl or -O-QH+; Q represents (A) optionally substituted aliphatic organic amine comprising at least one nitrogen atom that in common with proton forms quaternary ammonium cation QH+; (B) amino acid comprising at least two nitrogen atoms wherein one of nitrogen atoms in common with proton forms quaternary ammonium cation QH+; (C) amino acid comprising one or some nitrogen atoms wherein one of nitrogen atoms in common with proton forms quaternary ammonium cation QH+ and wherein, except for, all carboxyl groups of amino acids are in ester form. Also, invention describes pharmaceutical compositions used in modulation of tumor or metastasis proliferation and growth of benign vascular proliferative disorders, using compound of the formula (I) and a method for synthesis of compound of the formula (I). Invention provides preparing new combrestatin A-4 salts showing useful physicochemical properties that enhance solubility of combrestatin A-4.
EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.
27 cl, 13 dwg, 5 ex
FIELD: medicine, virology, biochemistry.
SUBSTANCE: invention relates to a method for treatment or prophylaxis of infections caused by a related virus in animal, such as SIV, FIV or AIDS, and to using some inhibitors of cyclooxygenase isoform-2 (COX-2) by this designation. Preferable COX-2 inhibitors are L-745337, rofecoxibe, NS398, SC58125, etodolac, meloxicam, celecoxib, DuP-697, DFU, tricyclic MF, valdecoxib, paraoxib-sodium, etoricoxib or nimesulide relating to nonsteroid anti-inflammatory drugs. They improve immune functions of T-cells, reduce or eliminate the immunodeficient state.
EFFECT: improved method of prophylaxis, valuable medicinal properties of drugs.
24 cl, 18 dwg, 6 tbl, 7 ex
FIELD: medicine, chemical-pharmaceutical industry, pharmacy.
SUBSTANCE: invention relates to creature of agents used in prophylaxis and treatment of diseases and pathological states associated with the locomotor system. Agent represents the complex preparation including the composition № 1 and № 2. The composition № 1 on hydrophobic base comprises the following active substances: phytocomponents of peppermint, common wormwood, mountain arnica, grape seeds, matricary, pine cones, pot-marigold, bur-marigold, sea-buckthorn oil, red pepper oil, red palm oil, mixture of essential oils of peppermint, lavender and clove in the ratio 1:1:1, bee venom, menthol, synthetic camphor and the following accessory substances: form-forming thickening agent - bee wax; preserving agent - propylparaben; emolents - cetiol CC, DC 345 and vaseline oil; antioxidant - kovi-ox. The composition № 2 on hydrophilic base comprises the following active substances: aqueous extracts of lilac flowers, mountain arnica, walnut peel; propocyanides of grape berries, propolis alcoholic extract, Kova-B-trox, and accessory substances: gel-forming agent - natrosol 250; moistening agents - propylene glycol and urea; chelating agent - disodium-EDTU; emolent - PLN phospholipids; preserving agents - methylparaben and caton CG; pH regulating component - triethanolamine and deionized water. Proposed agent possesses the expressed and prolonged curative effect that allows its using both for prophylaxis and treatment of different diseases and damages of structures in locomotor system and for improving skin state and adjacent tissues. Agent shows high therapeutic activity, namely its rapid and deep penetration into tissues, heating and relaxing effect, improving circulation in tissues and enlargement of blood vessels. Agent shows analgesic, anti-inflammatory, anti-edematous effect, accelerates reparative processes and improves tissue trophism. Agent shows the complex directivity on all mechanisms in base of diseases and pathological states of the locomotor system and their clinical symptoms and possesses the broad spectrum of pharmacological effect and both recovers the damaged functions of organ and shows the systemic effect on all body.
EFFECT: valuable medicinal properties of agent.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.
EFFECT: valuable medicinal properties of salts and drug.
14 cl, 1 tbl, 8 ex
SUBSTANCE: the present innovation refers to the compositions of water-soluble propophol promedicines composed upon water foundation being resistant at room temperature for prolonged period of time which include water-dissolved efficient quantity of propophol promedicine and efficient quantity of antioxidant acting as a stabilizing agent chosen out of monothioglycerol and EDTA that enables not to apply harmful co-solvents or surface-active substances for preparing the composition in question.
EFFECT: higher efficiency.
11 cl, 5 ex, 5 tbl
SUBSTANCE: compounds under the present invention are characterised by properties of aurora-kinase-A and/or aurora-kinase-B inhibitor. In general formula (I) : A represents 5-merous heteroaryl containing two nitrogen atoms; X represents NR14; m represents 0, 1, 2 or 3; Z represents the group chosen from -NR1R2, and 4-7-merous saturated ring connected by carbon atom containing nitrogen atom and substituted at nitrogen atom with C1-C4alkyl substituted by phosphonoxy; R1 represents C1-C6-alkyl substituted by phosphonoxy; R2 represents the group chosen from hydrogen, C1-C6-alkyl where C1-C6-alkyl is optionally substituted with 1, 2 or 3 halogen or C1-C4-alkoxy groups, or R2 represents the group chosen from C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4alkyl; or R1 and R2 together with nitrogen atom whereto attached form 4-7-merous saturated ring substituted at carbon or nitrogen atom by the group chosen from phosphonoxy and C1-C4-alkyl where C1-C4alkyl is substituted by phosphonoxy; R3 represents the group chosen from hydrogen, halogen, C1-C6-alkoxy; R4 represents phenyl substituted with 1-2 halogens; R5, R6, R7 and R14 represent hydrogen. In addition, the invention concerns the pharmaceutical composition containing therapeutically active amount of the compound under the invention, to application of the compound for preparation of a medical product applied in therapy of disease wherefore inhibition of one or more aurora-kinases is efficient, to method treatment, as well as production of the compounds under the invention.
EFFECT: high-yield end product.
26 cl, 5 tbl, 50 ex