Therapeutic application of yessotoxins as inhibitors of human tumour cell growth
SUBSTANCE: invention concerns biochemistry and medicine. There is offered therapeutic application of yessotoxins as inhibitors of human tumour cell growth. The mechanism of action of yessotoxin (YTX) is associated with activation of cell phosphodiesterases and respectively with decreasing the content of cyclic adenosine monophosphate in cytosol. This cytotoxic effect of YTX with respect to tumour cells can be applied as a strategy to develop preparation effective in treating tumour processes.
EFFECT: inhibition of human hepatocellular carcinoma cell growth following introduction of YTX.
3 cl, 1 dwg, 1 tbl
The present invention relates to therapeutic use of exotoxins as a cytotoxic agent to tumor cells because of their ability to activate cellular phosphodiesterase.
Exotoxin, referred to in this description of YTX and its natural analogues represent a polycyclic ethers produced by dinoflagellates species Protoceratium reticulatum and Lingolodinium polyedrum, and originally they were isolated from the digestive system Patinopecten yessoensis (Murata, M., Kumagai, M. et al., 1987, Tetrahedron Letters, 28, 5869-5872). Its molecule represented in the drawing, is formed eleven rings with ether groups and unsaturated side chain, which has associated with it various radicals. This drawing shows some of YTX analogues, although there are more than 50 natural analogues derivatives.
YTX is a lipophilic compound that is not toxic when administered orally (Aune, T., Sorby, R. et al., 2002, Toxicon, 40, 77-82); however, it causes death after intraperitoneal injection (Tubaro, A., Sosa, S. et al., 2003, Toxicon, 41, 783-92), although this requires a very high dose.
YTX and its analogues have a mechanism of action that differs from the mechanism of action of another toxin. Initially, they were classified in the group of toxins that cause diarrhea, as they often find together; however, they differ in that they are not the mod who try diarrhea, and also not affect the cellular phosphatase, representing the cellular target of the toxins that cause diarrhea. Their mechanism of action relates to other enzymes; in this regard, it was described that YTX reduces the levels of cyclic adenosine monophosphate (camp) in the cytosol, because it increases the activity of cellular phosphodiesterase by calcinating mechanism (Alfonso, A., de la Rosa, L.A. et al., 2003, Biochem. Pharmacol., 65, 193-208). In addition, YTX increases the levels of calcium in the cytosol via the stimulation of its revenues through the channel localized in the cell membrane (De la Rosa, LA., Alfonso, A. et al., 2001, Biochem. Pharmacol., 61, 827-833; De la Rosa, LA, Alfonso, A. et al., 2001, Cell Signal, 13, 711-716). The effect of RBCs was used to develop sensitive methods of detecting the presence of these toxins in contaminated shellfish that have been recently published (Alfonso, A., Vieytes, M.R. et al., 2004, Analytical Biochem., 326, 93-99; Pazos, M.J., Alfonso, A. et al., 2004, Analytical Biochem., 335, 112-118). There are eleven families of RBCs, which are very important from a pharmacological point of view, because their modulation involved in the treatment of diseases, such as asthma, rheumatoid arthritis and cancer (Houslay, M.D. and Adams, D.R., 2003, Biochem. J. 370,1-18).
YTX induces apoptosis, programmed cell death in human neuroblastoma cell and cancer cells human cervical line (HeLa) because AK is ivali caspase (Leira, F., Alvarez, .et al., 2001, Toxicology in vitro, 15, 277-283; Malaguti, C., Ciminello, P. et al., 2002, Toxicol in Vitro, 16, 357-363). In addition, this toxin has a cytotoxic effect on cells of the hepatic cell cancer (HEP-G2) cells and HeLa229; therefore, a priori valid application as anticancer drugs.
Biochemical path of camp due to the levels of this second messenger, and activation taking place against a protein kinase involved in cell proliferation. Inhibition of protein kinases And gives antitumor activity (Wang, H., Cai, Q. et al., 1999, Proc Natl Acad Sci USA, 96, 13989-94), although it was also described that the resistance to anticancer drugs such as cisplatin, is associated with the inactivation of this protein (Cvijic, M.E., Yang, W.L et al., 1998, Pharmacol Ther, 78, 115-28). In addition, the levels of camp in turn are associated with cytotoxicity and resistance to drugs (Mann, S.C., Andrews, R.A., et al., 1991, Int J Cancer, 48, 866-72; von Knethen, A., Lotero, A. et al., 1998, Oncogene, 17, 387-94). In other words, the biochemical path camp plays an important and complex role in the regulation of cell growth. For this reason, description of the natural or synthetic molecules that affect phosphodiesterase, and methods of study of the activity of these enzymes, which can be used in protocols EPS (high throughput screening), is a very useful tool for the discovery of new therapies. In this sense, OPI is the W inhibitory effect of YTX on the growth of tumor cells indicates the pharmacological importance of these molecules for their potential therapeutic applications. In addition, some authors emphasize that YTX
due to their low toxicity should not be considered a toxin, but rather a natural product with different pharmacological applications.
A deeper explanation of the families of toxins, specific characteristics of YTX and mechanism of their action is given in the description of the main applications and divisional applications relating to the present invention.
In the proposed invention describes the use of YTX as an inhibitor of cell growth in accordance with their ability to activate cellular phosphodiesterase.
Application: APPLICATION activates phosphodiesterase YTX and compounds as inhibitors of proliferation of tumor cells
Inhibition of growth of tumor cells is an indicator of antitumor activity, is widely used to describe the antitumor properties of new drugs. Discovered that YTX is cytotoxic for cells of the hepatic cell carcinoma of the person, and, in addition, it was described that this toxin induces apoptosis in neuroblastoma cells (Leira, F., Alvarez, S. et al., 2001, Toxicology in vitro, 15, 277-283), all these data indicate that YTX is valid for use as anticancer drugs. The effectiveness of YTX as cytotoxic drugs to tumor cells and hepatic cell carcinoma opredelyayuschee in the present application. Inhibition of cell growth can be determined in accordance with the various protocols described in the literature. One of these protocols described below, in which the response is determined quantitatively in cell lines HEP-G2 by crystal violet staining and subsequent acetylation.
The EMBODIMENT of the INVENTION
(a) Cells HEP-G2 plated on microtiter plate at a density of 10,000 cells per well. Cells incubated for 24 hours with growth medium at 37°C and 5% CO2.
b) Add various concentrations of YTX and incubated for 48 hours at 37°C and 5% CO2.
C) Add 10 ál of 11%glutaraldehyde for fixation of cells and incubated for 15 minutes. They are washed 3-4 times with distilled water.
g) Add 0.1%solution of crystal violet and the plate is shaken for 15 minutes.
d) the Dye is removed by rinsing with distilled water, and then dried.
e) Add 10%acetic acid and stirring is maintained for 15 minutes.
W) Absorption read on the spectrophotometer at 595 nanometers.
C) using this Protocol, it was found that 10 μm YTX induce inhibition of cell growth by approximately 82+/-1%.
Results induction of growth inhibition of cells
|The concentration of YTX (M)||% inhibition of cell growth||SEM|
1. Alfonso, A., de la Rosa, L.A., Vieytes, .R., Yasumoto, T. and Botana, L.. (2003). "Yessotoxin a novel phycotoxin, activates phosphodiesterase activity. Effect of yessotoxin on cAMP levels in human lymphocytes." Biochem. Pharmacol. 65: 193-208.
2. Alfonso, A., Vieytes, M.R., Yasumoto, T. and Botana, L.M. (2004). "A rapid fluorescent microplate method to detect yessotoxins based on their capacity to activate phosphodiesterases." Analytical Biochem. 326: 3-99.
3. Aune, T., Sorby, R., Yasumoto, T., Ramstad, H. and Landsverk, T. (2002). "Comparison of oral and intraperitoneal toxicity of yessotoxin towards mice." Toxicon 40(1): 77-82.
4. Cvijic, M.E., Yang, W.L. and Chin, K.V. (1998). "Cisplatin resistance in cyclic AMP-dependent protein kinase mutants." Pharmacol Ther 78(2): 115-28.
5. De la Rosa, L.A., Alfonso, A., Vilarino, N., Vieytes, M.R. and Botana, L.M. (2001). "Modulation of cytosolic calcium levels of human lymphocytes by yessotoxin, a novel marine phycotoxin." Biochem. Pharmacol. 61(7): 827-833.
6. De la Rosa, L.A., Alfonso, A., Vilarino, N., Vieytes, M.R., Yasumoto, T. and Botana, L.M. (2001). "Maitotoxin-induced calcium entry in human lymphocytes - Modulation by yessotoxin, Ca2+ channel blockers and kinases." Cell Signal 13(10): 711-716.
7. Houslay, M.D. and Adams, D.R. (2003). "PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desentization and compartmentalization." Biochem j 370: 1-18.
8. Leira, F., Alvarez, C., Vieites, J.M., Vieytes, M.R. and Botana, L.M. (2001). "Okadaic acid and yessotoxin induce caspase-3 mediated apoptosis in neuroblastoma cells. Characterization of distinct apoptotic changes induced by these phycotoxins in the BE(2)-M17 cell line by means of new fluorimetric microplate assays." Toxicology in vitro 15: 277-283.
9. Malaguti, C., Ciminello, P., Fattorusso, E. and Rossini, G.P. (2002). "Caspase activation and death induced by yessotoxin in HeLa cells." Toxicol in Vitro 16(4): 357-363.
10. Mann, S.., Andrews, P.A. and Howell, S.B. (1991). "Modulation of cis-diamminedichloroplatinum(ll) accumulation and sensitivity by forskolin and 3-isobutyl-1-methylxanthine in sensitive and resistant human ovarian carcinoma cells." Int J Cancer 48(6): 866-72.
11. Murata, M., Kumagai, M., Lee, J.S. and Yasumoto, T. (1987). "Isolation and structure of Yessotoxin, a novel polyether compound implicated in diarrhetic shellfish poisoning." Tetrahedron Letters 28: 5869-5872.
12. Pazos, M.J., Alfonso, A., Vieytes, M.R., Yasumoto, T., Vieites, J.M. and Botana, L.M. (2004). "Resonant mirror biosensor detection method based on yessotoxin-phosphodiesterase interactions." Analytical Biochem. 335: 112-118.
13. Tubaro, A., Sosa, S., Carbonatto, M., Altinier, G., Vita, F., Melato, M., Saake, M. and Yasumoto, T. (2003). "Oral and intraperitoneal acute toxicity studies of yessotoxin and homoyessotoxins in mice." Toxicon 41(7): 783-92.
14. von Knethen, A., Lotero, A. and Brune, B. (1998). "Etoposide and cisplatin induced apoptosis in activated RAW 264.7 macrophages is attenuated by cAMP-induced gene expression." Oncogene 17(3): 387-94.
15. Wang, H., Cai, Q., Zeng, X., Yu, D., Agrawal, S. and Zhang, R. (1999). "Antitumor activity and pharmacokinetics of a mixed-backbone antisense oligonucleotide targeted to the RIalpha subunit of protein kinase A after oral administration." Proc NatI Acad Sci USA 96(24): 13989-94.
1. The use of exotoxins (YTXs) as activators of RBCs against tumor cells with altered activity of phosphodiesterase.
2. The use of exotoxins (YTXs) according to claim 1 for modulating the viability and growth of tumor cells.
3. The use of exotoxins (YTXs) according to claim 1 in the manufacture of compositions for the treatment of tumors involving the modulation of phosphodiesterase.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to application of transcript modifying agents to prevent the genetic grading of malignant cells required to resist cell damage and their survival in chemotherapy or radiotherapy. There is applied a pharmaceutical composition containing hydralazine and valproic acid or its salt, e.g. magnesium valproate, in a pharmaceutically acceptable carrier to assist in cancer treatment along with chemotherapy or radiotherapy.
EFFECT: invention provides synergetic effect in cancer treatment by conventional therapeutic agents.
5 cl, 5 ex, 9 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to drugs and concerns a pharmaceutical composition for percutaneous delivery of 4-hydroxy-tamoxsifen which contains 4-hydroxy-tamoxifen in an alcohol water solution where amount of spirit is 35-99.9 wt % of the composition weight, and about 45%-55%, about 46%-54%, about 47%-53%, about 48%-52%, about 49%-51% or about 50% of said 4-hydroxy-tamoxifen is found as an isomer Z and remained amount of said 4-hydroxy-tamoxifen is in the form of isomer E. There is also disclosed method for preparing a pharmaceutical composition for percutaneous delivery of 4-hydroxy-tamoxifen.
EFFECT: preparation of the pharmaceutical composition which contains an equilibrium ratio of isomers E and Z of 4-hydroxy-tamoxifen.
13 cl, 9 dwg, 4 tbl, 6 ex
SUBSTANCE: present invention relates to four defined crystalline polymorphous forms of the monohydrate of a compound A having the following chemical composition:
Compound A. These four polymorphous forms, denoted here as forms I, II, III and IV, exhibit CXC chemokine receptor ligand activity.
EFFECT: invention relates to a pharmaceutical composition based on said compounds, to use thereof for treating different diseases and to methods for synthesising the said polymorphous forms.
58 cl, 2 tbl, 4 dwg
SUBSTANCE: invention relates to new crystalline modifications of N-α-(2,4,6-triisopropylphenylsulphonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonyl piperazide and/or its salts. Such crystalline modifications have high stability particularly at low hygroscopicity compared to known amorphous forms of the compound.
EFFECT: invention relates to a method of obtaining such new crystalline modifications, to pharmaceutical compositions containing these new crystalline modifications and their use as an anti-tumour agent.
26 cl, 7 tbl, 13 ex, 20 dwg
SUBSTANCE: invention refers to medicine, namely to oncology and can be used for treatment of pulmonary cancer. Essence of invention lies in the fact that before initiation of treatment an extracorporeal ray treatment of 300 ml of patient's blood in red diapason range with λ=0.67 mcm in continuous-wave mode during 3 minutes at maximum radiant power 17 mlW, radiation level w=3.06 J/cm2 is conducted. Then irradiated blood is incubated with cytostatic in therapeutic dose during 40 minutes at T=37°C, whereafter the irradiated blood with cytostatic is inserted to patient intravenously by drop infusion. During course of treatment three or four such procedures are conducted at three days interval, in total one or two courses of treatment at three weeks interval are conducted.
EFFECT: use of this invention enables to transfer patients with tumors of stage three or four into resectable condition by means of stimulating involution and regress of neoplastic deposits from lymphonodus at neoadjuvant therapy delivery of photo- modified autoblood.
SUBSTANCE: group of invention concerns medicine, namely to oncology and can be used in prostate cancer treatment. The methods of the invention imply administration of a composition containing therapeutically effective quantities of supercritical extracts of rosemary, curcuma, marjoram and ginger, as well as therapeutically effective quantities of water-alcoholic extracts of holy basil, ginger, curcuma, Scutellaria baicalensis, rosemary, green tea, Polygonum cuspidatum, Coptis chinensis Franchet and barberries.
EFFECT: inhibition of prostate cancer cell growth due to the effect of COX-2 composition without any significant side-effects.
36 cl, 1 tbl, 5 dwg, 4 ex
SUBSTANCE: invention relates to a method for regiospecific synthesis of rapamycin 42-ester derivatives of formula , where R is ketal isopropylidene substituted with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid, linear or branched C1-C10 alkyl, which possibly contains a halogen, C2-C8 alkenyl, or phenyl, where the said method involves acylation of 42-hydroxyrapamycin with an acyl donor in the presence of lipase. The invention also relates to regiospecific preparation of rapamycin 42-ester from ketal isopropylidene substituted with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid in the presence of lipase.
EFFECT: increased output of the product under mild conditions.
13 cl, 12 ex
SUBSTANCE: invention relates to novel condensed heterocylic protein kinase modulators of formula I where L1 and L2 independently denote a bond, and R1 and R2 denote a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aryl, as well as to pharmaceutical compositions containing such compounds, and methods of using the compounds to prepare medicine for diseases mediated by protein kinase activity.
EFFECT: increased effectiveness of using the compounds.
24 cl, 20 tbl, 24 ex
SUBSTANCE: invention relates to novel compounds selected from compounds of formulae Ia, lb and Ic, which have protein kinase activity on kinase selected from CDKs, Aurora, Jak2. Rock, CAMKI, FLT3, Tie2, TrkB, FGFR3 and KDR, abnormal activity of which is observed in pathological conditions such as nonmalignant and malignant proliferative diseases. In compounds of formulae , and : n equals 0 or 1, R1 is selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted CpC6alkyl and halogen-substituted C1-C6alkoxy, R2 is selected from a group comprising phenyl, 6-member heteroaryl containing 1-2 nitrogen atoms in the heteroaryl ring as heteroatoms, and phenyl(C0-C4)alkyl, where the said phenyl and heteroaryl in R2 are optionally substituted with 1-3 radicals independently selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy, -S(O)0-2R5, -COOR5 and -NR5C(O)R6, where R5 is selected from C1-C6alkyl, and R6 is selected from phenyl, where the said phenyl in R6 is optionally substituted with 1-3 radicals independently selected from a group comprising C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxy, X is selected from CR7 and N, where R7 is selected from hydrogen or C1-C6alkyl.
EFFECT: increased effectiveness of using the compounds.
7 cl, 3 dwg, 1 tbl, 3 ex
SUBSTANCE: invention relates to tetrahydropyridoindole derivatives of general formula , where R1, R2, R3 and R4 independently represent hydrogen; C1-C5alkyl, which can be optionally substituted and represents trifluoromethyl if C1-C5alkyl is substituted; C1-C3alkoxy or halogen, and R5 is C1-C6alkylcarbonyl, C1-C5alkylcarbamoyl, C1-C5alkoxycarbonyl, C2-C5alkenylcarbonyl, C3-C6cycloalkylcarbonyl, C3-C6cycloalkyl(C1-C3)alkylcarbonyl, C3-C6cycloalkylcarbamoyl, C3-C6cycloalkylthiocarbamoyl, phenylcarbonyl or phenyl(C1-C3)alkylcarbonyl, where the phenyl residue in these two groups contains one, two, three or four substitutes, independently selected from a group comprising C1-C4alkyl, C1-C3alkoxy, halogen, trifluoromethyl and trifluoromethoxy, monosubstituted with a C3-C6cycloalkyl group, or monosubstituted with a phenyl group which in turn is substituted with a C1-C3alkyl group; phenyl(C1-C3)alkoxycarbonyl, phenylcarbamoyl or phenylthiocarbamoyl (where these two groups are optionally independently monosubstituted with a C1-C5alkyl group or halogen atoms); phenyl(C1-C3)alkylcarbamoyl, phenyl(C1-C3)alkylthiocarbamoyl, biphenylcarbamoyl, naphthylcarbonyl, naphthyl(C1-C3)alkylcarbonyl or naphthylcarbamoyl (where the naphthyl residues in these three groups are optionally monosubstituted with substitutes independently selected from a group comprising C1-C3alkyl, C1-C3alkoxy and halogen); fluorenylcarbonyl, optionally substituted with an oxo group, fluorenyl(C1-C3)alkoxycarbonyl; or 5-9-member heteroarylcarbonyl groups containing one or two heteroatoms, independently selected from a group comprising oxygen, nitrogen and sulphur, where the said groups can be substituted with one or two groups independently selected from C1-C3alkyl and halogen, provided that if R1, R2, R3, R4 are hydrogen, R5 is not ethoxycarbonyl or tert-butoxycarbonyl, or salt thereof. The invention also relates to a pharmaceutical composition based on the compound of formula I and to use of the compound in preparing a medicinal agent.
EFFECT: obtaining novel tetrahydropyridoindole derivatives which have CRTH2 receptor antagonistic activity.
14 cl, 14 tbl, 171 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to cosmetology, more specifically to application of a flavonoid compound chosen from isoxantogumole (4',7-dihydroxy-5-methoxy-8-prenylflavanone), 8-prenylnaringenin (4',5,7-trihydroxy-8-prenylflavanone), pinocembrin (5,7-dihydroxyflavanone), pinostrobin (5-hydroxy-7-methoxyflavanone), sacuranetin (5,4'-dihydroxy-7-methoxyflavanone) and their mixtures for making a composition for activation of cannabinoid receptors in skin.
EFFECT: invention provides fast easing of scalp itching in people suffering from dandruff.
8 cl, 6 ex, 2 tbl
SUBSTANCE: invention relates to novel substituted cycloalkene derivatives of formula (I) in which X and Y are a group, in which X and Y together with a carbon atom on ring B to which they are bonded form a ring A, X and Y together represent a ring B substitute, or each of X and Y is a hydrogen atom.
EFFECT: invention relates to a medicinal agent based on the said compounds, which has inhibitory effect on intracellular signal transduction or cell activation induced by an endotoxin.
21 cl, 3 tbl, 191 ex
SUBSTANCE: treating of lipidosis and body-weight reduction in the patients with cardiovascular diseases is ensured by diet therapy based on the lacto-vegetarian diet. It involves introduction of proteins in daily amount of 67-79 g, including animal 48-57%, fats in daily amount of 32-49 g, including animal 40-52%, carbohydrates in daily amount of 240-257 g, cholesterol in daily amount of 40-268 mg, cellulose in daily amount of 18-20 g, dietary fibers in daily amount of 150 mg, potassium (K) in daily amount of 4567-6433 mg, magnesium (Mg) in daily amount of 535-693 mg, vitamin E in daily amount of 44-53 mg, arginine in daily amount of 3.9-5.2 g, dehydrated powdered maral meat in daily amount of 1200 mg, microcrystalline cellulose in daily amount of 900 mg. Duration of the diet therapy course is 33 days.
EFFECT: method provides suppression of cholesterol biosynthesis and intensification of excretion thereof that reduces the atherogenic index, reduces manifestations of oxidative stress, with reduced risk of realisation of the modified factors of a cardiovascular pathology.
SUBSTANCE: described are spirocyclic derivatives of cyclohexane of general formula . Values of radicals are given in the formula of invention. The compounds have affinity to the ORL1 receptor and can be used for treating abstinence syndrome (withdrawal syndrome) and pain. Also described is a medicinal agent and use of formula (I) compounds for preparing respective medicinal agents.
EFFECT: increased effectiveness of using the compounds.
13 cl, 17 ex, 1 dwg
SUBSTANCE: invention relates to use of benzopyranones of formula II
for making a pharmaceutical preparation for treating and/or preventing pathological conditions related to oxidative stress and/or inflammatory response. The invention also relates to a potassium salt 6,8-bis-(sulfoxy)-7-hydroxy-2H-1-benzopyran-2-one.
EFFECT: benzopyranones with antioxidative properties, useful for preventing and treating pathological conditions associated with oxidative stress and inflammatory response.
7 cl, 2 tbl, 2 dwg, 5 ex
SUBSTANCE: invention refers to new compounds that are lipoxin A4 analogues of general formula (I) and (II) where R1, R2, R3, R4 and R5 have values specified above. The inventions also refers to specific compounds of formula 1 and 11, to pharmaceutical compositions based thereon and to methods of treating inflammatory and autoimmune diseases in a human, and also treating inflammation of pulmonary or respiratory tracts in a human.
EFFECT: higher clinical effectiveness.
40 cl, 14 ex
SUBSTANCE: invention refers to pharmaceutical industry, particularly to a wound healing agent. The wound healing gel balm containing dihydroquercetin, medicinal glycerine, linseed or cedar oil, aqueous chitosan gel taken in a certain ratio of components.
EFFECT: wound healing and antiinflammatory gel balm.
SUBSTANCE: invention refers to pharmaceutical industry, particularly to a drug with antiviral activity with respect to viruses of influenza types A and B. Application of dihydroquercetin and/or its calcium salts as a drug with antiviral activity with respect to viruses of influenza types A and B.
EFFECT: drug shows improves antiviral activity with respect to viruses of influenza types A and B.
4 cl, 6 dwg, 3 tbl, 5 ex
SUBSTANCE: pharmaceutical unit dosage form for treatment or prevention of cardiovascular episodes contains therapeutic amount of: antagonist of β-adrenergic receptor, diuretic or both; an agent lowering cholesterol level; an inhibitor of renin-angiotensin system; and aspirin. The pharmaceutical unit dosage form can be made in a two-layered tableted form. The first layer thereof contains simvastatin and aspirin, the second layer contains athenolol and lisinopril, or the second layer contains hydrichlorothiazide and lisinopril.
EFFECT: according to the invention pharmaceutical unit dosage form combines a number of drugs for oral intake once a day that improves compliance by the patient with prescribed regimen due to elimination of inconveniences related to intake of several doses of drugs during the day, and reduces probability of missing the dose.
24 cl, 5 ex
SUBSTANCE: invention refers to chemical-pharmaceutical industry and medicine, namely to pharmaceutical compositions for the oral medical products applied in the integrated treatment of menopause osteoporosis in women. There is offered pharmaceutical composition which contains one or more active substances mainly with different therapeutic modalities providing intensified osteogenesis or decreased bone resorption, an element-vitamin complex containing elements in the form of physiologically acceptable compounds, providing intensified bone formations and decreased bone resorption, and the vitamins intensifying therapeutic action of the active substances and ensuring intensified bone formation and decreased resorption, and an excipient in the form of one substance or mixed substances which is monoexcipient or one component of the excipient.
EFFECT: higher effectiveness of the composition.
6 cl, 13 tbl, 8 ex
FIELD: organic synthesis.
SUBSTANCE: invention provides compounds of general formula I:
, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.
EFFECT: increased choice of cysteine protease inhibitors.
34 cl, 1 tbl, 13 ex