Methods and compositions for treating cancer

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a kit for lung cancer cell sensitisation to cisplatin. The declared kit comprises a first composition containing a therapeutically effective amount of sodium metaarsenite, and a second composition containing a therapeutically effective amount of cisplatin. Also, the invention refers to using the therapeutically effective amount of sodium metaarsenite for lung cancer cell sensitisation in a patient treated with cisplatin.

EFFECT: invention provides increasing the therapeutic effectiveness with a reduced risk of side effects.

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The scope of the invention

The present invention relates, in General, to the combined treatment, exhibiting synergistic inhibition of growth and/or proliferation of cancer. In particular, the invention relates to kits, compositions and methods, including combination therapy, in which metaarsenite sodium or of arsenic trioxide and the second cytotoxic agent that inhibits the telomeres, such as cisplatin or Texan, used for the treatment of cancer, including solid tumors and leukemia.

Prior art

Chemotherapy, systemic introduction antineoplastics funds that go throughout the body by the blood circulation system, for many years it was widely used in the treatment of a wide range of cancer types.

Currently, there are many antineoplastics funds, which are successfully used in the treatment of cancer. However, the search continues for more effective and less toxic means.

For example, the treatment of patients with cancer, using antineoplastics funds, representing the coordination complexes of platinum, such as CIS-diaminedichloroplatinum (II) (cisplatin) in the last decade has increased significantly. Cisplatin is antineoplastics tool, which turned out to be applicable in the treatment of many malignant novobrdo any, including testicular cancer, ovarian cancer, bladder cancer, head and neck, and some types of lung cancer. In particular, it was shown that cisplatin is particularly effective in treating cancer cells that have long telomeres. Cisplatin is regarded as a Pro-drug and when activated, it interacts with the nucleophilic sites in DNA, creating mainly purine-purine interchain crosslinking. Such genotoxic stress activates the transmission signal, which in most cells results in the cessation of DNA synthesis and programmed cell death. Unfortunately, the initial success of chemotherapy with cisplatin is often brief, because in many cases, relapse of cancer. The effectiveness of chemotherapy drugs based on platinum limited by several factors, including dangerous side effects, limited solubility and congenital or acquired resistance. Therefore, new drugs for the treatment of patients with cancer.

Consider that as cisplatin, an anticancer tool adriamycin and taxanes, such as paclitaxel, larotaxel, ertxel, tesetaxel and docetaxel, are associated with telomeres or in conflict with telomerase. Such anti-cancer drugs are usually used to treat bladder cancer, prostate jelly is s, lung, breast, ovarian and other solid tumors and leukemias. However, as with cisplatin, their effectiveness is often limited by external factors.

The use of arsenic compounds as therapeutic agents is currently experiencing a revival, especially in the field of Oncology. Studies have shown that certain arsenic compounds are effective against malignant tumors, such as acute promyelocytic leukemia (APL) (arsenic trioxide) or urogenital cancer (metaarsenite sodium). Cm. Shen et al. Blood 1997; 89:3354-3360; Soignet SL et al. N.Engl. J. Med. 1998; 339:1341-1348; WO2006121280 A1. In the US clinical studies on the use of arsenic trioxide in the treatment of patients with APL and investigated the mechanism(s) of action of various arsenic compounds in the possibility of rational use of inorganic arsenic. Cm. W.C. Chou et al. J.Clin.Invest.2001; 108:1541-1547; Senior K. Drug Discovery Today 2002; 7:156-157.

In these clinical studies, it was reported that the trioxide of arsenic exerts its anticancer effects through activation of apoptosis through the induction of reactive oxygen species and by the destruction of the PML-RARa crosslinked protein (Chou et al). Later its effectiveness was associated with the inhibition of transcription subunit of reverse transcriptase gene of human telomerase (hTERT) and subsequent induction of shortening of telomeres and chromosomal instability (Chou et al. and Senior, above).

Similarly studies have shown that metaarsenite sodium inactivates the transcription of the hTERT gene and capable of shortened telomeres in human cancer cells, showing that he is a poison to telomeres. However, metaarsenite sodium is the most effective in the treatment of cancer with short telomeres.

Therefore, there remains a need for an improved method and compositions for treatment of cancer, including solid tumors, leukemia and cancer.

The INVENTION

Effective cancer treatment and/or prevention of metastasis is achieved by introducing metaarsenite sodium (NaAsO2) or arsenic trioxide in combination with cisplatin, adriamycin and/or taxonom, such as docetaxel, larotaxel, ertxel, tesetaxel or paclitaxel. The present invention relates to compositions, kits and methods (e.g., combination therapy), including metaarsenite sodium and/or arsenic trioxide and cisplatin, adriamycin or taxon, such as paclitaxel, larotaxel, ertxel, tesetaxel or docetaxel, or a combination of both. Compositions, kits and methods of the present invention can be used for prevention, intervention and/or treatment of neoplastic diseases, are disclosed in the present description.

In one aspect of the invention provides a method for having ecene solid tumors, leukemia or metastases in a patient, comprising the administration to a patient a therapeutic amount of arsenic compounds selected from metaarsenite sodium and arsenic trioxide, and a therapeutic amount of cisplatin. In one embodiment of the invention a compound of arsenic is metaarsenite sodium, which can be administered orally, whereas cisplatin is administered via infusion. In other embodiments the invention, the cancer being treated is a cancer of the lung or breast cancer or ovarian cancer.

In certain embodiments of the invention metaarsenite sodium and/or arsenic trioxide is administered in therapeutically effective amounts to a patient who receives anticancer treatment with cisplatin, adriamycin, paclitaxel, docetaxel, or a combination of both.

In another aspect of the invention provides a kit containing multiple therapeutically effective doses of metaarsenite sodium and/or arsenic trioxide and cisplatin, adriamycin and/or taxane, for example, larotaxel, ertxel, tesetaxel, docetaxel or paclitaxel. In one embodiment of the invention set includes dosage forms for oral administration of metaarsenite sodium and parenteral composition of cisplatin and/or taxane, such as larotaxel, aratake is, tesetaxel, paclitaxel or docetaxel. In another embodiment, the invention metaarsenite sodium and/or arsenic trioxide and cisplatin, adriamycin, larotaxel, ertxel, tesetaxel, docetaxel and/or paclitaxel prepared for administration by infusion.

In another aspect of the invention provides compositions that include a therapeutically effective amount of metaarsenite sodium or of arsenic trioxide in a mixture with a therapeutically effective amount of cisplatin.

You must understand that the foregoing General description and the subsequent detailed description are representative only and explanatory and do not limit the invention as claimed.

BRIEF DESCRIPTION of DRAWINGS

Figa is a graph showing the growth curve for the sole means of cisplatin (diamonds) and introduce at the same time the combination of cisplatin with metaarsenite sodium (squares) cells A; the results obtained from studies of cell proliferation MTT.

FIGU is a graph showing the effect of the combined index (CI) (Fa = fractional effect) for the combination of metaarsenite sodium and cisplatin in cells A.

Figs is a graph showing the effect of the combined index (CI) (Fa = fractional effect) for the combination of metaarsenite sodium and cisplatin in cells N. CI<1 demonstrates blue is Gia. With=1 is additive;>1 is antagonistic.

DETAILED description of the INVENTION

The set, composition or method (e.g. combination therapy) according to the invention leads to a synergistic anticancer effect for maximum therapeutic benefits and may improve the tolerability of therapy with reduced risk of side effects, which often result from the use of higher doses or more prolonged monotherapy (i.e. treat each connection separately). Therefore, compositions, kits and methods according to the invention may allow use of lower doses of each compound (for example, lower doses of arsenic compounds or cisplatin) with reduced side effects each connection (e.g., reduction of side effects of arsenic compounds or medicinal preparations for the treatment of cancer, such as cisplatin). Suboptimal dosing can provide a higher margin of safety and can also reduce the cost of the medicinal product(s)necessary to achieve prevention and treatment. Synergistic treatment using a combination of compound(s) of arsenic and cisplatin, adriamycin, docetaxel and/or paclitaxel or other taxane may also provide increased convenience and can lead to Lu is our adherence to treatment. The advantages of combination therapy may additionally include higher stability against decomposition and metabolism, a longer duration of action and/or greater duration or efficiency especially in low doses.

In certain aspects the invention relates to a set, in particular set, which includes pharmaceutical compositions containing metaarsenite sodium and/or arsenic trioxide and cisplatin or other cytotoxic anticancer agents such as adriamycin, docetaxel or paclitaxel, and combinations of cytotoxic anticancer means, optionally in combination with pharmaceutically acceptable carriers, excipients or carriers.

Current methods of cancer treatment include administration to a mammal in need of such treatment, an effective amount of the compound(s) of arsenic in combination with cisplatin or other cytotoxic anti-cancer agent that inhibits or affects telomeres, such as Texan. The connection of arsenic, or a combination of arsenic compounds can be administered either before or after, or simultaneously with the introduction of cisplatin or other cytotoxic anti-cancer tool. For example, the daily dosage of the arsenic compounds can be entered within one to ten Nam is th and subsequent treatment of the cytotoxic agent(s) from one to ten days or longer, if you want to. Alternatively, the cytotoxic agent(a) may be given before connection(s) of arsenic. Also, the compound(I) of arsenic, and the cytotoxic agent(a) you can enter the patient simultaneously, though not necessarily at the same time. The treatment regimen can easily be installed by the attending physician based on factors such as dosages of each of the induction medications, type and stage of cancer, patient and kind.

When the connection arsenic is metaarsenite sodium, it can be entered in any form, for example, orally, by infusion, rectal, IPR etc. When the trioxide of arsenic include in treatment, it can be administered by infusion in some embodiments of the invention, but can be used by any acceptable route of administration. Similarly cisplatin or other cytotoxic anti-cancer agent, for example, taxon, usually administered by infusion, but you can enter through any appropriate means known in the technical field.

The invention provides improved methods and products for treating patients with cancer or at risk of developing cancer or metastasis of the primary tumor. The invention is based, in part, on the discovery that when metaarsenite sodium (NaAsO2) and/or arsenic trioxide IP is result in combination with cisplatin or other cytotoxic anti-cancer, inhibiting telomeres, such as adriamycin or taxon, such as docetaxel and/or paclitaxel see some unexpected and superior results that indicate synergy between arsenic-containing and not containing arsenic anti-cancer agents. For example, the effectiveness of combination therapy significantly improves patients, cancer patients whose tumors have longer telomeres compared with any anticancer funds separately. Also the toxicity of combination therapy can be significantly reduced in patients, cancer patients, compared with the use of any of the anticancer funds separately.

The invention also encompasses the use of an inhibitor of telomerase, other than cisplatin, in combination with or metaarsenite sodium or arsenic trioxide. For example, stipulate that the combination of one of these arsenic compounds with adriamycin and/or taxonom, such as docetaxel or paclitaxel, which is known that they are synergistic with other inhibitors of telomerase or peptides that bind telomeres, or small molecules that block and inhibit the restoration of telomeres, can be used in the kits, compositions and methods according to the invention. Specialist equipment can easily determine the dosage, composition and scheme of injection of the same is of telomerase inhibitors on the basis of their known use in combination with other anticancer drugs or use as a single anti-cancer drug.

In accordance with the present invention the combination of the compound(s) of arsenic and cisplatin and/or other cytotoxic anticancer means, for example, adriamycin, taxane, for example, docetaxel and/or paclitaxel, promotes the effective treatment of cancers that cannot be successfully treated with any drug separately. For example, it is known that cisplatin is an effective treatment for some types of lung cancer, especially those with long telomeres, whereas metaarsenite sodium is more effective in treating cancer with short telomeres, for example, prostate cancer. However, the combination of cisplatin and metaarsenite sodium is unexpectedly significantly more effective in the treatment of tumor cells with long telomeres, i.e. certain types of lung cancer than cisplatin separately. Accordingly, the present invention provides compositions and methods for the synergistic treatment of many solid tumors and/or cancerous diseases or conditions, including, but not limited to, the following: carcinoma, including that of the bladder (including well-differentiated and metastatic bladder cancer), breast, cervix, colon (including colorectal cancer), kidney, liver, lung (including small cell and namacalathus the first lung cancer and lung adenocarcinoma), ovary, prostate, testes, genitourinary tract, lymphatic system, rectum, larynx, pancreas (including exocrine carcinoma of the pancreas, esophagus, stomach, gall bladder, cervix, thyroid and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid Rostock, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, b-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, histiocytoma lymphoma and Burkitt's lymphoma; hematopoietic tumors of myeloid Rostock, including acute and chronic myelogenous leukemia, myelodysplastic syndrome, myeloid leukemia, and promyelocytic leukemia; tumors of the Central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and swannery; tumors of mesenchymal origin, including fibrosarcoma, liposarcoma, rhabdomyosarcoma, and osteosarcoma; and other tumors, including melanoma, xeroderma pigmentosum, keratoakantoma, seminoma, thyroid follicular cancer cancer and teratocarcinoma.

In certain embodiments of the invention cisplatin, adriamycin and/or taxon, such as larotaxel, ertxel, tesetaxel, docetaxel and/or paclitaxel, administered during the treatment of the patient, which under argueta treatment metaarsenite sodium and/or arsenic trioxide. In certain embodiments of the invention, the patient undergoing such treatment has lung cancer or breast cancer or ovarian cancer. In other embodiments of the invention cisplatin is administered in the treatment of a patient who receives treatment by metaarsenite sodium.

The present invention additionally provides compositions, kits and methods for the treatment of many solid tumors and leukemias, including, but not limited to, tumors listed in table 1.

Table 1
FibrosarcomaColon cancerAdenocarcinoma
MyxosarcomaColorectal cancerCarcinoma of the sweat glands
LiposarcomaKidney cancerCarcinoma of the sebaceous glands
ChondrosarcomaPancreatic cancerPapillary carcinoma
Osteogenic sarcomaBone cancerPapillary
adenocarcinoma
ChordomaBreast cancerCystadenocarcinoma
AngiosarcomaOvarian cancerPapillary
adenocarcinoma
Ehotelier.comProstate cancerCystadenocarcinoma
LymphangiosarcomaCancer of the esophagusMedullary carcinoma
LymphangiosarcomaStomach cancerBronchogenic carcinoma
SinoviomaOral cancerCancer renal cell
MesotheliomaCancer of the nasal cavityhepatoma
Tumor abnormal EwingCancer of the pharynxCarcinoma of the gallbladder
duct
LeiomyosarcomaSquamous cell carcinomaHoriokartsinoma
RhabdomyosarcomaBasal cell of carcino is and Seminoma
Embryonal carcinomaLung cancerCraniopharyngioma
Wilms tumorEpithelial carcinomaEpendymoma
Cervical cancergliomaPinealoma
Cancer of the uterusGlioblastoma, multiformeHemangioblastoma
Testicular cancerAstrocytomaAcoustic neuroma
Small cell carcinoma of lungMedulloblastomaoligodendroglioma
Carcinoma of the bladderSkin cancerMeningioma
retinoblastomaMelanomaBronchogenic carcinoma
Medullary carcinomaNeuroblastoma

In certain embodiments of the implementation of the present invention to provide the supports of the composition, kits and methods for the treatment of lung cancer. Most types of lung cancer are expressed chromosomal anomalies and the overexpression of certain oncogenes. Lung cancer can be histologically sub-classified into squamous cell carcinoma, small cell carcinoma, adenocarcinoma, both carcinoma (non-small cell lung carcinoma), carcinoid tumor, mesothelioma, and other

In certain embodiments the invention, kits and compositions may optionally include other therapeutic agent suitable for treatment of a particular cancer or tumor. For example, kits, compositions and methods can include one or more optional therapeutic agent, such as immunotherapy, vaccines, cancer, biological response modifiers (e.g., cytokines and hematopoietic growth factors) or hormonal therapy (e.g., adrenocorticosteroid, androgens, anti-androgens, estrogens, anti-estrogens, progestins, aromatase inhibitors, agonists of gonadotropin-releasing hormone, somatostatin analogues and the like.

In yet another embodiment of the invention an optional therapeutic agent is a hormone, such as, when necessary, therapy with estrogens, such as diethylstilbestrol and ethinyl estradiol, therapy anti-estrogen, for example, t is maxifoam, therapy progestins, such as medroxyprogesterone and megestrol acetate, an androgen blockade, for example anti-androgens such as flutamide, adrenocorticosteroid, including adrenal steroids, treatment with synthetic glucocorticoids, such as prednisone, methylprednisone and dexamethasone, androgens, for example, fluoxymesterone, synthetic analogs of testosterone, aromatase inhibitors, for example, aminoglutethimide, agonists of gonadotropin-releasing hormone, for example, leuprolide, somatostatin analogues, such as octreotide. In certain embodiments of the invention the method further includes the introduction of the patient with interferon-α.

As used in the present description, the term "pharmaceutical composition" refers, or to mixtures or combinations of arsenic compounds selected from arsenic trioxide, metaarsenite sodium, and combinations thereof, and cisplatin, adriamycin, docetaxel, paclitaxel, or a combination or each of the selected compounds separately. The pharmaceutical composition may include other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients.

As used in this description, "treating" or "treatment" refers to the introduction of two or more funds (i.e., arsenic compounds, or is soedineniya arsenic and cisplatin, of adriamycin, docetaxel, paclitaxel, or combinations thereof, or other cytotoxic anticancer funds) to the patient, a cancer patient, or having the risk of cancer or metastasis. "Inhibition of growth of tumor cells" refers to inhibiting the growth of tumor cells present in the patient. Such treatment may also lead to regression of tumor growth, i.e. the reduction in the size of measurable tumors. In some embodiments of the invention, such treatment leads to complete regression of the tumor.

The term "prevention" includes or preventing development of clinically overt neoplasia completely, or prevention of the development of preclinical explicit stage of neoplasia in patients with risk, for example, metastasis. Also intended for inclusion in the present description, the prevention of the development of malignant cells or stopping or reversing the progression dislocating cells or malignant cells. This includes prophylactic treatment of the patient with the risk of developing neoplasia.

As used in the present description, the term "synergistic result" or "synergy" refers to a therapeutic effect against certain cancers, so the introduction of a combination of a compound of arsenic and cisplatin or other cytotoxic agent according to the invention give results which you which is significantly better than the best efficiency obtained for any one tool in cancer treatment.

As used in this description of the "introduction" or "enter" or "application" refers to the issuance, use or view the patient two or more funds (for example, metaarsenite sodium and/or arsenic trioxide and cisplatin, adriamycin and/or taxane, for example, paclitaxel or docetaxel). The introduction may be carried out using any of several methods known in the art. For example, "introduction", as used in the present description, refers to the introduction by infusion (intravenous (I/V)), parenteral and/or oral administration. Under "parenteral" refers to intravenous, subcutaneous and intramuscular administration. In using the subject invention metaarsenite sodium, for example, can be administered simultaneously with, for example, cisplatin, or compounds may be administered sequentially in any order. Understand that the exact preferred method and order of introduction will vary according to, among other things, the specific composition used arsenic compounds; the specific composition used another cytotoxic anticancer means (for example, cisplatin, adriamycin and/or taxane); certain Podwale what's the treatment of cancer cells and a particular host organism, receiving treatment. The method and order of introduction of the compound(s) of arsenic and other anti-cancer drug(s) in a certain group of States can be determined by the expert in the field of technology using conventional techniques and in the light of the information specified in the present description.

The compound(I) of arsenic according to the present invention and cisplatin, adriamycin, docetaxel, paclitaxel and/or other cytotoxic anti-cancer agent can be administered as part of combination therapy or joint therapy. Hence "combination therapy" (or "co-therapy") includes the introduction of the compound(s) of arsenic and cisplatin or other cytotoxic anticancer means according to the invention as part of a specific treatment regimen intended to provide the beneficial effect from the co to the synergistic action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic joint action resulting from a combination of therapeutic agents. The introduction of these therapeutic agents in combination typically is carried out for a certain period of time (usually minutes, hours, days or weeks depending on the selected combination). "Combination therapy" is not usually the purpose is to embracing the introduction of two or more of these therapeutic agents as part of a separate scheme monotherapy that randomly and arbitrarily leads to the combinations of the present invention. "Combination therapy" is intended to cover the introduction of such therapeutic agents sequentially or simultaneously, thus, when each therapeutic agent is administered in a different time period, as well as the introduction of such therapeutics or at least two of these therapeutic agents almost simultaneously.

Sequential or substantially simultaneous introduction of each of therapeutic agents can be achieved by any appropriate means, including, but not limited to, oral route, intravenous route, the direct absorption through mucous membranes, and combinations thereof. A therapeutic agent can be entered the same way or in different ways. For example, the first therapeutic agent is selected combinations can be administered by intravenous injection, for example, cisplatin or arsenic trioxide, while another therapeutic agent, for example, metaarsenite sodium can be administered orally. Alternatively, for example, both or all of therapeutic agent can be administered by intravenous injection or infusion. The sequence in which the injected therapeutic agent is not critical.

"Combination therapy" also can embrace the centuries the Denia therapeutics, as described above, in further combination with other biologically active ingredients (such as, but not limited to, various antineoplastics funds) and non-drug therapies (such as, but not limited to, surgical or treatment by irradiation). When combined therapy further includes radiation therapy, radiation therapy can be performed at any appropriate time, while useful effect is achieved as a result of joint action by the combination of therapeutic agents and radiation therapy. For example, in appropriate cases, a useful effect is still achieved when radiation therapy temporarily cease with the introduction of therapeutic agents, possibly for days or even weeks.

The term "therapeutically effective" is intended to indicate the quantity of each product, which achieves the purpose of reducing tumor size or burden of malignant or neoplastic disease and frequency of malignant diseases in the treatment of each tool itself, while avoiding adverse side effects typically associated with alternative treatment. "Therapeutic effect" or "therapeutically effective amount" is also intended to indicate the desired number of anticancer means, in combination or composition with one or more of the other anticancer agent to relieve to some extent one or more symptoms of neoplastic disease, including, but not limited to: 1) reduce the number of cancer cells; 2) reduction in tumor size; 3) inhibition (i.e. slowing to some extent or stop) infiltration of cancer cells into peripheral organs; 3) inhibition (i.e. slowing to some extent, or stop) of tumor metastasis; 4) inhibition, to some extent, of tumor growth; 5) the investment or reducing to some extent one or more symptoms associated with the disease; and/or 6) the relief or reduction of side effects associated with the introduction of cancer cells.

The invention provides a pharmaceutical composition, kit and method for the treatment method of combination therapy or prophylaxis and inhibit the growth of solid tumors, leukemias and metastasis, which includes the introduction of metaarsenite sodium and/or arsenic trioxide with cisplatin, adriamycin, docetaxel, paclitaxel and/or other cytotoxic anti-cancer agent in effective amounts to a patient in need of treatment. In certain embodiments implementing the invention provides a pharmaceutical composition, kit and method that includes a combination therapy to treat lung cancer or preventing metastasis of lung cancer in other places and organs of the patient.

The invention that the same provides the set, including metaarsenite sodium and/or arsenic trioxide and cisplatin, adriamycin, docetaxel, paclitaxel and/or other cytotoxic anti-cancer agent together in a composition or in separate compositions for combination therapy in accordance with the invention. The set can be a package which includes a container or containers that contain the compound(I) arsenic and cisplatin, adriamycin, docetaxel, paclitaxel and/or other cytotoxic anti-cancer agent, and also contains instructions for the introduction of the composition(s) to the patient. In particular, the kit may include instructions for simultaneous, separate or sequential use. The set may contain a single dosage form, or it may contain a separate dosage forms, i.e. one for each input a therapeutic agent. In one embodiment, the invention includes a fixed ratio of doses of the compound(s) of arsenic and cisplatin or other cytotoxic anti-cancer tool. The kit can also contain multiple doses of each anticancer means, or combined or compiled separately.

The kit may further include other materials desirable from a commercial and consumer point of view, including, without limitation, buffers, diluents, entry, needles, syringes, and annotation with instructions for performing any of the methods described in the present description (for example, methods of treating diseases described in the present description). The medicinal product or composition set according to the invention can include any of the combinations or compositions described in the present description.

In aspects of the invention set can be applied to any of the methods described in the present description, including, without limitation, the treatment of a patient suffering from or having a risk of developing cancer, a solid tumor or lung cancer.

Composition

The active ingredients according to the invention are pharmaceutical preparations (for example, together in a composition or separately for use in combination therapy) for the introduction of a mammal for the treatment of cancer.

For oral administration, the pharmaceutical preparation may be in liquid form, for example, solutions, syrups or suspensions, or may be presented in the form of a medicinal product for restore before using water or other suitable media. Such liquid preparations can be obtained by conventional means with pharmaceutically acceptable additives such as suspendresume means (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying cf is DSTV (for example, lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid). The pharmaceutical compositions may take the form of, for example, tablets or capsules, obtained by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hypromellose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrant (for example, potato starch or glycolate starch sodium) or moisturizing agent (e.g. sodium lauryl sulphate). Tablets may be coated using methods well known in the field of engineering.

Preparations for oral administration can be suitably designed to provide controlled release of active compounds. For oral administration the compositions may take the form of tablets or lozenges made in the usual way.

For administration by inhalation, the compounds for use in accordance with the present invention is usually administered in the form of aerosol sprays pressurized packs or a nebulizer with the use of a suitable propellant, for example, DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the unit dosage form can be determined by providing a valve to deliver a measured quantity. Can be obtained in capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator containing a powder mix of the compound and a suitable powder base such as lactose or starch.

A therapeutic agent can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Such compositions are sterile. Compositions for injection may be presented in unit dosage form, e.g., in ampoules or in mnogochasovykh containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous carriers can contain prescription drugs, such as suspendida, stabilizing and/or dispersing the funds. Alternatively, the active ingredient may be in powder form for recovery before applying a suitable vehicle, e.g. sterile pyrogen-free water.

The connection can also be formulated in rectal is omposite, such as suppositories or retention enemas, e.g. containing conventional bases for suppositories, such as cocoa butter or other glycerides.

In addition to the compositions described previously, the connection can also be made in the form of a drug depot. Such compositions with long-lasting effects can be introduced by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Therefore, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, in the form of an emulsion in the applicable oils) or ionoobmennymi resins, or as sparingly soluble derivatives, for example, in the form of moderate soluble salts. Liposomes and emulsions are well known examples of bases for shipping or carriers for hydrophilic drugs.

The pharmaceutical preparations can, if necessary, to be presented in a pack or the metering device, which may contain one or more unit dosage forms containing the active ingredient. The package may, for example, comprise metal or plastic foil, such as a blister pack. Packaging or dispensing device may be accompanied by instructions for administration.

Route of administration

Specialist in engineering understands that the content of AK the active ingredients in the pharmaceutical preparations of the present invention can vary widely depending on many factors, such as the desired dosage and used pharmaceutically acceptable carrier. For injection dosage of arsenic compounds is usually in the range from about 0.1 mg/kg to about 100 mg/kg, in certain embodiments of the invention from about 1.0 to about 50 MC/kg, in other embodiments of the invention from about 2.5 to about 25 mg/kg and in other embodiments of the invention from about 3 to about 15 mg/kg

In some embodiments of the invention the pharmaceutical composition according to the invention containing cisplatin may contain cisplatin in an amount of from about 0.1 mg/ml to about 500 mg/ml, or from about 1 mg/ml to about 50 mg/ml, and in other embodiments of the invention from about 1-5 mg/ml Mannitol and/or sodium chloride may be included in amounts customary for drugs cisplatin. The physiological pH of the injectable drugs or drug combinations infusion set by including buffer means, as is known in the technical field.

When other cytotoxic anticancer tools are used instead of cisplatin, the number determined on the basis of properties of the used tools. For example, adriamycin, you can enter in a dose of 60 mg/m2entered as a continuous infusion through a Central venous catheter or, for example, as 15 or 25 day of courso the ADM with an average dose of about 3.8 mg/m 2(2,2-4,5 mg/m2)entered with programmable portable pump. Similarly docetaxel or paclitaxel (or other taxon) can be given in the form of high-dose chemotherapeutic drugs, for example, 250 mg/m2once every three weeks, once in two weeks or in low doses, less than 100 mg/m2on a weekly basis, for example. In some cases taxon, e.g., docetaxel or paclitaxel can be given slowly over a 24-hour infusion. Specialist in the field of technology can determine the appropriate dose of anti-cancer remedies and the delivery time depending on several factors, including the relative health of the patient and the type and stage of cancer, as well as other drugs, administered in combination therapy.

Appropriate pharmaceutically acceptable carriers and diluents for use in the pharmaceutical preparations according to the invention are well known to the specialist in the field of machinery for the preparation of compounds in pharmaceutical compositions. The pharmaceutical preparations according to the invention are in a form suitable for parenteral administration may be formulated for intravenous infusion or injection in a variety of ways, well known to the expert in the field of technology with pharmaceutically acceptable carriers. In the definition is the R versions of the invention, such pharmaceutical preparations are in the form of a lyophilized mixture of the active ingredients in a single dosage form, derived by conventional methods, which can be restored at the time of introduction of water or other suitable infusion fluid.

For the treatment of breast cancer and many other forms of solid tumors, as well as in the treatment of leukemia and lung cancer arsenic compounds according to the invention is generally administered systemically in pharmaceutical compositions containing such excipients or inert components which are well known in the technical field related to cancer chemotherapy. In particular, if the connection of arsenic according to the invention should be administered systemically, it may be made in the form of powder, pills, tablets or the like or in the form of a syrup or elixir suitable for oral administration. For intravenous or intraperitoneal introduction arsenic compounds receive in the form of a solution or suspension capable of introduction through injections. In certain cases, can be used to prepare such compounds in the form of injections. In certain such cases, it may be applied to make such connections in the form of suppositories, or in the form of compositions with prolonged release for placement under the skin or intramuscular injection.

The connection of arsenic according to the invention is administered in the form of chemotherapeutic agents in combination with cisplatin in the applicable therapeutic doses is, which varies from state to state, and which in certain circumstances may vary depending on the severity of the condition being treated, and patients receiving treatment. Accordingly, will not continually be used by a single dose, and will require modification depending on the properties of the tumor or malignancy being treated. Such doses can be obtained through routine experimentation. For the treatment of solid tumors and leukemias, especially breast cancer and acute myeloid leukemia suggest that arsenic compounds according to the invention is introduced into, for example, 1-8 weeks the patient who needs it, at a dose that is effective to stop, slow growth or spread of the tumor or stop the proliferation of leukemia cells. In certain embodiments of the invention a compound of arsenic is metaarsenite sodium, which should be administered orally in a daily dose, which in some embodiments of the invention is in the range from approximately 0.0001 ág / day to 100 mg/kg per day; or in the range from 0.05 mg/kg to 50 mg/kg per day; or in other embodiments of the invention in the range from 1 mg to 25 mg per day; and in other embodiments of the invention in diapazonom 2 to 20 mg/kg per day or 2.5 to 10 mg/kg in day. However, the dose may be skorrigirovanna in the direction of increase or decrease to match the need of any particular patient.

Cisplatin, or another component of cytotoxic anticancer means of combination therapy can be entered in accordance with the invention in the same manner, as is well known in clinical practice. For example, slow intravenous diffusion is a method of choice for cisplatin. To ensure diuresis during cisplatin inclusion of mannitol, glucose/saline solution is preferred carrier. The Protocol may also include prehydration patient by administration of dextrose/saline before administration of cisplatin, adriamycin, docetaxel and/or paclitaxel. In some embodiments of the invention, the dosage of cisplatin with the introduction with the connection of arsenic in accordance with the invention, is a single dose of about 3 to about 100 mg/m2cisplatin and in certain embodiments of the invention is introduced into the end of the course one-five consecutive days of treatment with compound of arsenic. In other embodiments of the invention, the dose of cisplatin is about 20 mg/m2or more than once in three or four weeks. Alternatively, the patient can be administered a therapeutically relevant to the respective number of other cytotoxic agents, for example, adriamycin, docetaxel and/or paclitaxel. Infusion of cisplatin, adriamycin, docetaxel and/or paclitaxel or other cytotoxic funds can be given one to two times per week and weekly repeat the treatment several times, if there are no contraindications due to renal toxicity, neurotoxicity, or other side effects.

For parenteral administration of arsenic trioxide commonly used therapy is from 0.0001 to 100 mg/kg per day for five consecutive days or 0.001-50 mg/ml, and in other embodiments of the invention, from 0.01 to 20 mg/kg for five consecutive days. In some embodiments of the invention the dosage of arsenic trioxide for use in combination with cisplatin is from about 0.1 to 5.0 mg/kg per day. Specialist in the field of technology can determine the appropriate amount and rate of injection of arsenic trioxide and to adjust the treatment Protocol accordingly.

EXAMPLE 1:

In vitro studies with cisplatin and metaarsenite sodium

And cisplatin, and metaarsenite sodium can cause damage to the telomeres. Therefore, the combination of these two anticancer means tested to determine are two medicinal properties synergy in vitro in two cell the lines of non-small cell lung cancer. Chose H460 (4kb, IC50, IC50=10 μm) and A549 (6kb,IC50=13 μm), as they have relatively short telomeres and are part of a panel of 60 cell lines of the National Cancer Institute (NCI). IC50 concentration for cisplatin and KML001 was determined by MTT analysis and widely accepted methodology median effect Chou and Talalay (Advances in Enzyme Regulation (1984); 22:27-55, is included in its entirety in the present description) based fixed IC50 ratios used to determine synergy, additivity or antagonism (figa-1C).

Cell culture and MTT analysis

Cells were grown in standard conditions (5% CO2/37°C/humidified atmosphere) in the recommended environment, such as RMPI 1640, Iscove's or DMEM (Invitrogen) and grown routine. For analysis of cell proliferation MTT exponentially grown cells were collected and seeded in 96-well plates (2000/cell). To assess the potential of inhibiting the growth of pharmaceuticals investigational medicinal product was added in concentrations ranging from 1 nm to 100 μm. To determine cell growth at the time of adding drugs (d0), which allows to calculate the exact number of destroyed cells, one of the 96-well plates were treated immediately after addition of the drug. The rest were incubated for 5 days before adding 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylethane is impromed (MTT), and conversion of the purple formazan living cells was measured using the counter tablets SynergyHT (550 nm) and software CS (BioTEK). Formazan was dissolved with DMSO. Growth curves were created in MS Excel and determined the concentration inhibiting growth by 50 and 100%, and the total dead cells. The results are presented on figa-C and tables 2-4.

A and N have IC50 for cisplatin 1.5 and 1 μm, respectively, but are relatively insensitive to metaarsenite sodium, although cells N that have shorter telomeres (4 kb), have a lower IC50 than cells A with relatively long telomeres (6 kb, figa). When two drug combined, received a very significant synergies for most levels of effects (FIGU, table 2-4). Combined indexes CI) of the cell is lower than 1 were found for level of effective dose (ED) 50, 75 and 90% (table 2), reducing, for example, the IC50 of cisplatin from 1.5 μm to 0.45 μm in cells A (Piga). Therefore, KML001 able to sensitize cell lines of lung cancer to this drug called cisplatin.

Table 2
The value of the combined index
Cell lineCI ED 50CI ED 75CI ED 90
A0,860,750,68
N0,330,160,09

Table 3
Index values separate funds: the cells N
mcmMetaarsenite sodiumCisplatinMetaarsenite
sodium-cisplatin
IC501010,7
IC75201,71
IC90302,51,5

Table 4
Index values separate funds: the cells A
mcmMetaarsenite sodiumCisplatinMetaarsenite
sodium-cisplatin
IC50131,50,457
IC75 1920,7
IC901741,1

Other embodiments of the invention will be obvious to a person skilled in engineering from consideration of the description and implementation of the invention described in the present description.

1. Set for sensitization of lung cancer cells to this drug called cisplatin, comprising a first composition comprising a therapeutically effective amount of metaarsenite sodium, and a second composition comprising a therapeutically effective amount of cisplatin.

2. The kit according to claim 1, where the first composition is formulated for oral administration.

3. The kit according to claim 1, where the cancer cells are cells of non-small cell lung cancer.

4. The kit according to claim 1, where the chromosomes lung cancer cells have long telomeres.

5. The kit according to claim 1, where cell lung cancer are adenocarcinoma cell.

6. The use of a therapeutically effective amount of metaarsenite sodium for sensitization of cells of lung cancer patients during treatment with cisplatin.

7. The use according to claim 6, where the patient has non-small cell lung cancer.

8. The use according to claim 6, where the chromosomes lung cancer cells have long telomeres.

9. The use according to claim 6, where the lung cancer cells are cells of the adenocarcinoma.

10. The use according to claim 6, where a therapeutically effective amount of metaarsenite sodium is in the range from 1 mg to 25 mg per day.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: a combination for treating a proliferative disease containing (a) the phosphoinositide3-kinase inhibitor 5-(2,6-dimorpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethylpyridin-2-ylamine (compound B) or a pharmaceutically acceptable salt thereof and (b) a compound that modulates the Ras/Raf/Mek pathaway specified in a group consisting of (i) a compound that modulates Raf kinase activity that is Raf265, SB590885, XL281 or PLX4032; (ii) a compound that modulates Mek kinase activity that is PD325901, PD-181461, ARRY142886/AZD6244, ARRY-509, XL518, JTP-74057, AS-701255, AS-701173, AZD8330, ARRY162, ARRY300, RDEA436, E6201, RO4987655/R-7167, GSK1120212 or AS703026, wherein the active ingredients in each case present in a free form or as a pharmaceutically acceptable salt or a hydrate thereof, and used simultaneously, separately or sequentially, a respective pharmaceutical composition or a combination drug, and a method of treating a proliferative disease in a homoithermic animal, principally a human.

EFFECT: what is shown is a synergism of the antineoplastic action of the declared combinations.

11 cl, 6 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a compound CL168 of general structural formula I where R is oxygen. The invention also relates to a method of producing a compound of formula I and use of the compound of formula I to produce a medicinal agent for preventing or treating tumorous and immunological diseases.

EFFECT: compound of formula I for producing a medicinal agent for preventing or treating tumorous and immunological diseases.

4 cl, 11 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound - N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulphonamide of formula A and/or a pharmaceutically acceptable salt thereof, having KDR and/or FGFR1 inhibitor properties. The compounds can be used to treat disorders associated with KDR mediated angiogenesis, such as cancer and age-related macular degeneration, or various cancerous diseases which respond to FGFR1 inhibition. Compound (A) corresponds to the structural formula (A) given below.

EFFECT: invention relates to crystalline forms I and II of said compound A and methods for production thereof, pharmaceutical compositions and a method of treatment.

38 cl, 8 dwg, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, oncology, therapy of patients suffering lung cancer and having contraindications to the surgical management. There are prescribed autohemochemotherapy (AHCT) that is administering chemopreparations incubated with autoblood, and radiation therapy (RT). Pre-therapeutic blood prolactin and progesterone are measured, and before the beginning of the AHCT, the patient starts taking bromocriptine 2.5 mg once a day with food; besides, oxyprogesterone capronate 1 ml is administered intramuscularly twice a week every 3 days. That is followed by the AHCT course consisting of 1-3 administrations of autoblood CP, and if observing a complete tumour resorption, the surgical management to the extent of pneumoectomy is supposed to follow, while a partial resorption observed two weeks after the last auroblood CP administered, implies the RT: at first 2 Gy twice a day every 4-5 hours starting from 5 days a week to achieve a basic dose of 28 Gy. That is followed by a 2-week pause, then 4 Gy daily, 3 radiation fractions a week, 6 fractions in total, up to a total radiation dose of 52 Gy for the whole RT course. Throughout the treatment, the patient keeps taking bromocriptine and oxyprogesterone capronate with controlling the blood prolactin and progesterone values: as compared to the pre-therapeutic values, prolactin is expected to fall to the end of the treatments, while progesterone - to rise.

EFFECT: method provides improving the conservative therapeutic effect in the patients of the given group: downsizing the tumour and lymph nodes until the primary tumour regresses completely by 30%, and the patients change to the resectable state; improving the patient's quality of life.

2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to experimental studies in oncology and may be used for assessing the anti-tumour action of metal nanoparticles (NP). An iron nanoparticle suspension 1.25 mg/kg is introduced into grafted Pliss lymphosarcoma intratumourally. That is followed by the paratumoural introduction of methotrexate 0.2 mg/kg. The tumour is locally heated to temperature 42-43°C using an electromagnetic UHF emission at frequency 12.7 MHz for 10 minutes. The therapy requires 5 such sessions in total every 48 hours. That is followed by calculating an effectiveness index, a complete regression percentage and Pliss lymphosarcoma growth inhibition percentage.

EFFECT: method intensifies the antitumor effect of the thermal chemotherapy without increasing body toxicity.

2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology and radiology, and can find application in treating the patients suffering cerebral malignancies. The method for determining the indications for a radiation therapy in the patients by prediction of the effectiveness including blood sampling, gamma-irradiation of a portion of this sample in vitro, incubation of the irradiated and non-irradiated portions of the blood samples, staining of the DNA components of both blood portions with a DNA-specific fluorescent dye, leukocyte count in the irradiated portion of the blood sample, leukocyte count in the non-irradiated blood sample, staining of all DNA containing blood components, determination of DIi that is the DNA amount in all the DNA containing blood components at one leukocyte of the irradiated portion of the sample and DIn that is the DNA amount in all the DNA containing blood components at one leukocyte of the irradiated portion of the blood sample, calculation of DIn/DIi. Blood is sampled additionally, added with an aqueous solution containing ferrous iron ions in the concentration of 50-75 mg/l in the amount of 8-14% of the blood sample amount. The additional blood sample is then incubated for 15-30 minutes that is followed by gamma irradiation of a portion of the additional blood sample. Then the irradiated and non-irradiated portions of the additional blood sample are incubated for 2.5-3.5 hours with leukocyte counting in the irradiated and non-irradiated portions of the additional blood sample, staining of the all DNA containing components of the portions of the additional blood sample and determination of DIi add that is the DNA amount in all the DNA containing components of the additional blood sample at one leukocyte of the irradiated portion of the blood sample and DIn add that is the DNA amount in all the DNA containing components of the additional blood sample at one leukocyte of the non-irradiated portion of the blood sample. Then, the relation DIn add/DIi add is calculated, and if observing DIn add/DIi add> DIn/DIi being 20-35% and DIn/DIi>1, the radiation therapy is considered to be indicated.

EFFECT: invention provides higher effectiveness of the method used for determining the indications for the radiation therapy in the patients suffering glioblastomas.

2 ex

Anti-axl antibodies // 2506276

FIELD: chemistry.

SUBSTANCE: present invention relates to immunology. Disclosed are monoclonal antibodies which bind to the extracellular domain of receptor tyrosine kinase AXL and which at least partially inhibit AXL activity, as well as antigen-binding fragments. Also provided is an isolated nucleic acid molecule, a host cell and a method of producing a monoclonal antibody and an antigen-binding fragment thereof, as well as use of the monoclonal antibody or antigen-binding fragment thereof to produce a drug, pharmaceutical compositions, a method of diagnosing and a method of preventing or treating a condition associated with expression, overexpression and/or hyperactivity of AXL.

EFFECT: invention can be used in therapy and diagnosis of diseases associated with AXL.

23 cl, 20 dwg, 24 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to molecular pharmacology and particularly to a peptide which is an interleukin-15 (IL-15) sequence derivative which is optimised for inhibiting biological activity of said compound. The invention shows that when bound with an alpha subunit of the receptor (IL-15Rα) the peptide inhibits T cell proliferation induced by IL-15, tumour necrosis factor α (TNFα) induction caused by IL-15, and expression of IL-8 and IL-6 caused by IL-15Rα. The invention also relates to use of the peptide in treating pathologies where anomalous expression of IL-15 or IL-15Rα is associated with the course of a disease such as rheumatoid arthritis (AR) and prostate cancer.

EFFECT: obtaining an interleukin-15 (IL-15) sequence derivative which is optimised for inhibiting biological activity of said compound.

18 cl, 6 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I, including stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof: where Z1 is CR1; Z2 is CR2; Z3 is CR3 or N; Z4 is CR4 or N; where (i) X1 is N and X2 is S or (iv) X1 is S and X2 is CR7; R1, R2, R3, R4 and R7 are independently selected from H, F, Cl, Br, I, -CN, -CH2OR10, -(C1-C12 alkylene)NR10R11, -(C1-C12 alkylene)NR12C(=O)R10, -CO2R10, -C(=O)N(R10)OR11, -NR10R11, -C(=O)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10C(=O)OR11, -C(=O)NR10(C1-C12 alkylene)NR10C(=O)R11, -C(=O)NR10(C1-C12 alkylene)R11, -C(=O)NR10(C1-C12 alkylene)R10, -C(=NR10)NR10R11, -NR12C(=O)R10, -NR12C(=O)OR11, -NR12C(-O)NR10R11, -NR12C(=O)(C1-C12 alkylene)NR10R11, NR12(C=O)C1-C12 alkylene)NR11(C=O)R12, -C≡CR10, C1-C20 heteroaryl, said heteroaryl being an unsaturated carbocyclic residue containing 5-6 ring atoms, where 1-4 ring atoms are nitrogen atoms, and phenyl, where the heteroaryl and phenyl are optionally substituted with one or two groups selected from -CH2OH, -(CH2)2OH, -CH2CO2H, -CN, -CH2NH2, -(CH2)2N(CH3)2, -CH3, -CO2H, -CH2CO2CH3, -NH2 and -S(O)2CH3; A is selected from -C(=O)NR5R6, -C(=S)NR5R6, phenyl and C1-C20 heteroaryl, said heteroaryl being an unsaturated carbocyclic residue containing 5-10 ring atoms, 1-4 of which are heteroatoms selected from nitrogen, oxygen or sulphur, C1-C20 heteroaryl and phenyl are optionally substituted with one or three groups independently selected from C1-C12 alkyl, -(C1-C12 alkylene)NR10R11, -CH3, oxo, -CO2CH3, -NH2, 1-methylpiperid-4-yl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, benzoimidazolyl, benzyl and phenyl, where the alkyl, benzoimidazolyl and phenyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CF3, -CH2OH, -CH3, -C(=O)NHCH3, -NH2, -OH, -OCH3, -CH2OCH3, -C(=O)N(CH3)2, -N(CH3)2, -C(CH3)2OH, -CH(CH3)2, -CH2(1H-1,2,4-triazol-5-yl) and C(=O)4-methylpiperazin-1-yl; R5 is selected from C1-C12 alkyl, optionally substituted with one group independently selected -NH2, -NHCOCH3 and -OH; R6 is selected from pyridinyl and phenyl, each optionally substituted with one or two groups independently selected from F, Cl, Br, I, -CN, -CF3, -C(=O)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10R11 and -C(=O)NR10R11; R10, R11 and R12 are independently selected from H, C1-C12 alkyl, C1-C12 alkylene-phenyl, cyclopentyl, pyridinyl and imidazolyl, where C1-C12 alkyl, cyclopentyl are optionally substituted with one or two groups independently selected from -CH2OH, -N(CH3)2, -NHCOCH3, -OH and -S(O)2CH3; or R10 and R11 together with a nitrogen atom to which they are bonded form a C5-C6 heterocyclic ring containing one or two heteroatoms selected from nitrogen and oxygen, or pyrazolyl, optionally substituted with one or two groups independently selected -CH3, -NH2, -N(CH3)2; -OH and oxo. The invention also relates to a pharmaceutical composition having PI3K inhibiting activity based on said compounds.

EFFECT: obtaining novel compounds which can be used in medicine for treating cancer.

25 cl, 5 dwg, 2 tbl, 331 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel pyrimidine-substituted purine compound of formula (I) or pharmaceutically acceptable salt of said compound, which possess inhibiting action with respect to mTOR and P13 kinases and can be applied in cancer treatment. Formula (I) compound corresponds to structural formula Formula (I)

EFFECT: invention relates to pharmaceutical composition which contains therapeutically effective quantity of said compound and pharmaceutically acceptable diluents, auxiliary substance or carrier, to method of inhibition of proteinkinase, selected from mTOR or P13 kinase, and to method of treatment or prevention of state in mammal, associated with inhibition of mTOR and/or P13 kinase activity.

11 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to veterinary science and aims at treating a gastrointestinal pathology of non-infectious aethiology in calves. Acupuncture points are exposed to a remote therapeutic massage electrode No.1 of DiaDENS-PC apparatus in the 'Therapy' regimen with alternating frequencies of 77 Hz and 10 Hz on the acupuncture points located along the median sagittal line between the spinous processes of the thoracic spine, for 5 minutes, followed by introducing the medicine 'Liarsin' in a dose of 0.5 ml in the area of a biologically active point located between the spinous processes of the last thoracic and first lumbar vertebrae.

EFFECT: method has the high therapeutic efficacy and eliminates local allergic reactions, causes no anxiety in an animal.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents the use of sodium metaarsenite in preparing an oral dosage form of a pharmaceutical composition for inflammation treatment in a mammal.

EFFECT: use of sodium metaarsenite in preparing the oral dosage form of the pharmaceutical composition for inflammation treatment in a mammal.

6 cl, 7 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention relates to field of veterinary. Method consists in the following: applied is "EVL-Se-COMPOSITION" solution which is introduced into animals by group method with water one time per day in single dose 0.05 ml during 10 days, 5 days before weaning and 5 days after weaning.

EFFECT: application of claimed method makes it possible to realise prophylaxis of gastrointestinal diseases, increase average daily weight gain, does not cause side effects.

3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmacy, namely to creation of complexes for treatment of chronic fatigue syndrome (CFS). Four naturopathic complexes for CFS treatment contain herbal mixtures and homeopathic medications.

EFFECT: intake of naturopathic complexes ensures high therapeutic effect throughout the treatment without negative side effects and disease recurrences.

5 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed group of inventions relates to medicine, namely to oncology, and can be used for treatment of metastatic neoplastic disease. Claimed is treatment method which includes introduction of therapeutically efficient quantity of sodium meta-arsenite. Additionally introduction of other chemotherapeutical substance is carried out. Claimed is composition, containing sodium meta-arsenite. Claimed is set for inhibition of abnormal cell growth, which includes therapeutically efficient quantity of pharmaceutical composition, containing sodium meta-arsenite, and other chemotherapeutical substance.

EFFECT: group of inventions ensures possibility of metastatic neoplastic disease treatment with alternative compound with anticancer activity, as well as treatment safety.

2 tbl, 6 ex

FIELD: medicine, veterinary science.

SUBSTANCE: method involves application of EVL-Se COMPOSITION solution, which is introduced to animal inside orally by a group method with water (milk or imitation milk) once a day for 10 days in single dosage 1.0 ml per a head.

EFFECT: application of the method allows reducing disease incidence and recovery time, increasing average daily weight gains, ensures more rapid microflora formation and has no by-effects.

2 tbl, 3 ex

FIELD: agriculture.

SUBSTANCE: invention refers to the sphere of poultry keeping. Method includes application of preparation "EVL-Se COMPOSITION" solution, which is administered to chickens once by group method through unrestricted bottle-feeding with water once per day for 10-20 days in a single dose of 0.02 ml per head.

EFFECT: application of method makes it possible to reduce losses, to increase weight gains, to improve immune response in vaccinations.

4 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention belongs to veterinary. "ЭВЛ-Se КОМПОЗИЦИЯ" is administered to whole flock with free drinking in water once a day during 10 days in single dose 0.02 ml per capita.

EFFECT: method improves hens' insemination efficiency, hatchability and survival rate of poults.

2 tbl, 2 ex

FIELD: medicine, oncology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in treatment of solid tumors, for example, large intestine tumor, stomach tumor, breast tumor, ovary tumor, prostate tumor and kidney tumor, and these tumors are sensitive to effect of sodium meta-arsenite. Proposed composition comprises meta-arsenite (AsO2-) salt taken in the pharmaceutically effective dose and pharmaceutically acceptable accessory agent. Also, invention relates to using this composition in treatment of solid tumors in a patient, and to a method for treatment of solid tumor showing sensitivity to effect of sodium meta-arsenite. Invention provides enhancing effectiveness in treatment of solid tumors.

EFFECT: valuable medicinal property of pharmaceutical composition, enhanced effectiveness of treatment.

13 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, and namely to composition for prevention of iron deficiency anemia. Composition for prevention of iron deficiency anemia, which contains source of iron, source of copper, vitamins B1, B3, B6, B9, B12, ascorbic acid, extract from nettle leaves, extract from strawberry leaves, pantohematogen and auxiliary substances, with specified component ratio.

EFFECT: composition makes it possible to extend arsenal of methods for prevention of iron deficiency anemia and is effective.

4 cl, 3 ex

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