Composition and utilization of et743 for malignant tumor treatment

FIELD: medicine, oncology.

SUBSTANCE: invention relates to method for malignant tumor treatment (including cancer, sarcoma, melanocytoma) in human by ectasceine ET743 intravenous infusion in dose of 500-1650 mug/m2 of surface are; to similar treatment by combination of ET743 with antiemetic agent; as well as to relative composite preparation. Method of present invention provides clinical amelioration in subject suffering from progressive or metastasing cancer and improves treatment effectiveness of diseases being progressed after known chemotherapy.

EFFECT: new effective method for cancer treatment; drug with good acceptability.

31 cl, 3 ex, 1 tbl

 

The present invention relates to the treatment of malignant tumors.

Background of invention

Malignant tumors include a group of malignant neoplasms that can be divided into two categories: carcinoma, covering the majority of cases seen in the clinic, and other less common types of malignant tumors, including leukemias, lymphomas, tumors of the Central nervous system and sarcoma. Carcinomas originate from epithelial tissues, whereas sarcomas develop from connective tissue and structures, originating from the mesoderm tissues. Sarcoma can affect, for example, muscle or bone and are found in the bones, bladder, kidney, liver, lung, parotid glands or spleen.

Malignant tumors are invasive and tend to metastasize to new places. They are distributed directly into the surrounding tissue and can also be spread through the lymphatic and circulatory system. There are many methods of treatment of malignant tumors, including surgery and radiation for localized disease, and use of drugs. However, the effectiveness of available treatments is limited for many types of malignant tumors, and need new, ulucan the e form of treatment, with clinical benefits. This is especially true for patients with advanced and/or metastatic stage of the disease. This also applies to patients with recurrent progressive disease after previously held specifically to a specific therapy, for which the further application of the same therapy is largely ineffective, due to the acquisition of resistance or limitation of therapy because of associated toxicity.

Chemotherapy plays an important role in the treatment of malignant tumors, because its use is required in the treatment of advanced malignant tumors with distant metastases, and it is often useful to reduce the tumor before surgery, and developed many anti-cancer drugs based on different modes of action.

Ecteinascidin (ecteinascidins) are alkaloids of marine origin and some of them are in vitro have shown significant antitumor activity. Some ecteinascidin previously described in the patent and scientific literature.

For example, in U.S. patent No. 5089273 described new substances extracted from tropical marine bespozvonochnykh, Ecteinascidia turbinata, and designated here as ecteinascidins 729, 743, 745, A and 770. These compounds are used in quality is ve antibacterial and/or anticancer agents for mammals.

In U.S. patent No. 5256663 described pharmaceutical compositions comprising substances extracted from tropical marine bespozvonochnykh, Ecteinascidia turbinata, and designated here as ecteinascidin, and the use of such compositions as antibacterial, antiviral and/or anticancer agents for mammals.

In U.S. patent No. 5478932 described ecteinascidin isolated from the Caribbean lander Ecteinascidia turbinata, which provide in vivo protection against lymphoma xenografts R, B16 melanoma, sarcoma ovarian M, carcinoma of the lung Lewis (Lewis), human lung carcinoma LX-1 human breast carcinoma MX-1.

In U.S. patent No. 5654426 describes several ecteinascidins isolated from the Caribbean lander Ecteinascidia turbinata, which provides in vivo protection against xenografts lymph R, B16 melanoma, sarcoma ovarian M, carcinoma of the lung Lewis (Lewis), human lung carcinoma LX-1 human breast carcinoma MX-1.

In U.S. patent No. 5721362 described method of synthesis for the preparation of compounds of ecteinascidins and related structures.

Lighting further assumptions can be found in: Corey, E.J., SOC., 1996, 118, pp.9202-9203; Rinehart, et al., Journal of National Products, 1990, "Bioactive Compounds from Aquatic and Terrestrial Sources, vol.53, pp.771-792; Rinehart et al., Pure and Appl.Chem., 1990, "Biologically active natural products", vol.62, pp.1277-1280; Rinehart et al, J.Org.Chem., 1990, "Ecteinascidins 729, 743, 745, A, V and 770: Potent Antitumour Agents from the Caribbean Tunicate Ecteinascidia turbinata", vol.55, pp.4512-4515; Wright et al., J.Org.Chem., 1990, "Antitumour Tetrahydroisoquinoline Alkaloids from the Colonial Ascidian Ecteinascidia turbinata", vol.55, pp.4508-4512; Sakai et al., Proc.Natl.Acad.Sci.USA, 1992, "Additional antitumour ecteinascidins from a caribbean tunicate: Crystal structures and activities in vivo" vol.89, 11456-11460; Science 1994, "Chemical Prospectors Scour the Seas for Promising Drugs", vol.266, pp.1324; Koenig, K.E., "Asymmetric Synthesis", ed. Morrison, Academic Press, Inc., Orlando, FL, vol.5, 1985, p.71; Barton, et al., J.Chem.Soc.Perkin Trans., 1, 1982, "Synthesis and Properties of a Series of Sterically Hindered Guanidine Bases", pp.2085; Fukuyama et al., J.A.Chem.Soc., 1982, "Stereocontrolled Total Synthesis of (+)-Saframycin B", vol.104, pp.4957; Fukuyama et al., SoC., 1990, "Total Synthesis of (+)-Saframycin A, vol.112, p.3712; Saito, et al., J.Org.Chem., 1989, "Synthesis of Saframycins. Preparation of a Key Tricyclic Lactam Intermediate to Saframycin A, vol.54, 5391; Still, et al., J.Org.Chem., 1978, "Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution", vol.43, p.2923; Kofron, W.G.; Baclawski, L.M., J.Org.Chem., 1976, vol.41, 1879; Guan et al., J.Biomol.Struc.& Dynam., vol.10, pp.793-817 (1993); Shamma et al., "Carbon-13 NMR Shift Assignments of Amines and Alkaloids: p.206 (1979); Lown et al., Biochemistry, 21, 419-428 (1982); Zmijewski et al., Chem.Biol.Interactions, 52, 361-375 (1985); Ito, CRC CRIT.Rev.Anal.Chem., 17, 65-143 (1986); Rinehart et al., "Topics in Pharmaceutical Sciences 1989", pp.613-626, D.D.Breimer, D.J.A.Cromwelin, K.K.Midha, Eds., Amsterdam Medical Press B.V., Noordwijk, The Netherlands (1989); Rinehart et al., "Biological Mass Spectrometry", 233-258 eds. Burlingame et al., Elsevier, Amsterdam (1990); Guan et al., Jour.Biomolec.Struct.& Dynam., vol.10, pp.793-817 (1993); Nakagawa et al., J.Amer.Chem.Soc., 111: 2721-2722 (1989); Lichter et al., "Food and Drugs from the Sea Proceedings" (1972), Marine Technology Society, Washington, D.C. 1973, 117-127; Sakai et al., J.Amer.Chem.Soc., 1996, 118, 9017; Garcia-Rocha et al., Brit. J. Cancer, 1996, 73: 875-883; Pommier et al., Biochemistry, 1996, 35:13303-13309.

In particular, we discovered that ecteinascidin 743 when tested in animal models also has a promising effect, as, for example, when evaluating his actions against xenografts of breast cancer, non-small cell lung cancer, melanoma and malignant tumors of the ovary.

Article on the antitumor activity in vitro of new means of marine origin, ecteinascidin-743 (ET-743, NSC-648766) against human tumors isolated from patients (Annales of Oncology, 9: 981-987, 1998) is a typical message about the study in vivo. On the basis of their data, the authors conclude that continuous or prolonged exposure may lead to increased activity. Article related to the observed in vitro according mielotoksichnosti and cytotoxicity of ecteinascidin 743 (ET-743) from schemes, published on pages 989-993 the same number of the specified log, it is concluded that prolonged exposure may represent the best scheme introduction.

The invention

A method of treating patients AT, leading to clinical improvement.

For carrying out the invention

Thus, the present invention relates to a method of treating any mammal, especially human, affected by a malignant tumor, which includes the introduction of Paragon the mu to the subject a therapeutically effective amount AT or pharmaceutical compositions based on it.

The present invention also relates to pharmaceutical compositions which contain as the active ingredient AT, as well as to methods for their preparation.

Examples of pharmaceutical compositions include liquid (solutions, suspensions and emulsions) suitable for intravenous administration, the composition and they may contain the compound as such or in combination with any carrier or other pharmacologically active compounds.

Introduction compounds or compositions of the present invention is carried out by intravenous infusion. Preferably, the infusion periods were up to 72 hours, more preferably from 2 to 24 hours, or most preferably about 3 hours, or about 24 hours. Especially suitable are brief periods of infusion, which allow for treatment without the patient remained in the hospital overnight. However, if you want, infusion can last about 24 hours or even longer. Infusion can be carried out at intervals of, for example, from 1 to 6 weeks. Further guidance is given in the text below.

The correct dosage of a substance may vary depending on the specific composition, the route of administration and the specific place of the patient and the tumor that is being treated. You should also take into account such factors as age, body weight, sex, diet, BP is introducing me, the rate of excretion, condition of life of the patient, a combination of drugs, the sensitivity and the severity of the disease. The introduction can be performed continuously or periodically within the maximum tolerated dose.

Connection AT and compositions of the present invention can be used with other drugs to provide a combination therapy. Other medicines can also be part of the same composition, or be provided as a separate composition for administration at the same time or at another time. The other drug is not particularly limited, and suitable candidates are:

a) medicines with antimitoticheskoy effects, especially those that are directed at elements of the cytoskeleton, including modulators of microtubules, as medicines group taxane (such as Taxol, paclitaxel, Taxotere, docetaxel), podophyllotoxin or Vinca alkaloids (vincristine, vinblastine);

b) medicinal antimetabolites such as 5-fluorouracil, cytarabine, gemcitabine, purine analogues, such as pentostatin, methotrexate);

c) alkylating agents or nitrogen mustards (such as derivative nitrosoanatabine, cyclophosphamide or ifosfamide);

d) medicines directionally acting on DNA, such as ant is AllInOne drugs adriamycin, doxorubicin, pharmorubicin or epirubicin;

e) drugs, directionally acting on topoisomerases such as etoposide;

f) hormones and agonists or antagonists hormones, such as estrogens, antiestrogens (tamoxifen and related compounds) and androgens, flutamide, leiprorelina, goserelin, cyproteron or octreotide;

(g) drugs, directionally acting on signal transduction in tumor cells, including those derived antibodies like Herceptin (herceptin);

h) alkylating drugs such as drug platinum-based (cisplatin, carboplatin, oxaliplatin, paraplatin) and derivatives nitrosomonas;

i) drugs, potentially suppressing metastasis of tumors, such as inhibitors of matrix metalloproteinases;

(j) gene therapy and antisense agents;

k) the antibody therapy;

1) other bioactive compounds of marine origin, especially didemnin, such as aplidine (aplidin);

m) analogues of steroids, in particular dexamethasone;

n) anti-inflammatory drugs, including non-steroidal drugs (such as acetaminophen or ibuprofen) or steroids and their derivatives, in particular dexamethasone; and

o) antiemetic drugs, including NT-3 inhibitors (such as gramie the Ron and ondansetron) and steroids and their derivatives, in particular dexamethasone.

The present invention also relates to compounds of the invention for use in a method of treatment and to the use of compounds in the formulation of the composition for the treatment of malignant tumors.

In clinical trials with ET was observed response of patients, demonstrating the applicability of the method of treatment.

Clinical studies phase I and pharmacokinetic analysis demonstrated that ET-743 is positive therapeutic window with manageable toxicity within the dosage required to achieve clinical efficacy in the treatment of patients with malignant tumors.

The method comprises the administration of a medicinal product by intravenous infusion for 72 h or less at the level of the recommended dose (RD) in combination with other therapeutic means or without it.

ET-743 is supplied and stored as a sterile lyophilized product, including ET-743 and a filler in the form of a formulation suitable for therapeutic applications, in particular in the form of a formulation containing mannitol and phosphate salt, increased the buffer to the appropriate pH.

The preferred preparative form, characterized by an increased stability at high temperature storage is that it is which is obtained from 1000 ml of 0.9% sodium chloride or other suitable solvent for infusion, 250 g ET-743 with 250 mg of mannitol, 34 mg monosubstituted potassium phosphate and phosphoric acid to bring the pH to a value in the range from 4.00 to 6.00, with a preferred pH value equal 4,80. Product lyophilizer and stored until use at cold, at a temperature from +4°-20°C, protected from light.

Preparation reconstituirea solution is carried out in aseptic conditions by adding distilled water in an amount of 5 ml per 250 g ET-743 and intermittent shaking to dissolve the solids.

Preparation of infusion solution also carried out in aseptic conditions selection of reconstituirea solution corresponding to the dosage calculated for each patient, and slow injection of the desired amount reconstituirea solution bag or bottle dropper for infusion, containing from 100 to 1000 ml of 0.9% sodium chloride, after which all the contents homogenized slow hand shaking. Infusion solution of ET-743 should be administered intravenously as soon as possible within 48 hours after preparation. The preferred materials for containers and tubes droppers are PVC and polyethylene, as well as transparent glass.

The introduction of a cycle; the preferred way of intravenous infusion of ET-743 administered to patients during the course the e first week of each cycle, during the remaining cycle time patients are able to recover. The preferred duration of each cycle is 3 or 4 weeks; if necessary, can be assigned to multiple cycles. The drug can also be given in every first day of each cycle. Delay dose and/or dose reduction, and correction schemes are carried out, if necessary, depending on the tolerability of the individual patient treatment; in particular, a lower dose is recommended for patients with elevated compared with normal concentrations of serum liver transaminases or alkaline phosphatase, or bilirubin.

Recommended dose (RD) represents the highest dose that can be administered safely to patients with obtaining portable, manageable and reversible toxicity, according to the General criteria of toxicity (Common Toxicity Criteria)established by the National Cancer Institute (USA), for the manifestation of any of limiting the dose species toxicity (dose limiting toxicities = DLT) not more than 2 of 6 patients. Manual therapy of malignant tumors often recommend the introduction of chemotherapeutic agents in the highest safe dose at which toxicity is managed in order to achieve maximum effectiveness (DeVita, V.T. Jr., Hellman, S. and Rosenberg, S.A., Cancer: Principles and Practice of Oncology, 3rded., 989, Lipincott, Philadelphia).

DLT for ET-743 according to this method of treatment as defined clinical research, are myelosuppression and malaise. These studies have established the recommended dose level of 1500 micrograms per m2the surface of the body for 24-hour infusion or 1650 micrograms per m2the body surface for a 3-hour infusion. Dose of 1,800 micrograms per m2the surface of the body or above has resulted in too large proportion of the patients showed DLT and thus it was determined that these doses are too toxic for safe injection.

Despite the fact that in the case of malignant tumors in the mammary gland response reported in June 1998, was observed at the dose level equal to 1800 micrograms/m2this level was considered unsafe at any speed infusion, because 2 of the 4 patients had a strong toxic reactions, limiting the dose. Another case, which was reported earlier, is the response of a patient suffering from melanoma, after a 1-hour infusion, and this method does not allow to reach the level recommended dose without limiting the dose thrombocytopenia and fatigue.

ET-743 can be safely administered at the dose level equal to the recommended dose (RD), or below.

In particular, intravenous infusion for 24 h at the level of doses is from 500 to 1500 micrograms per m 2the surface of the body, preferably from 1000 to 1500 micrograms per m2the surface of the body, and is the last EP for this scheme introduction as shown in the examples in clinical trials.

In particular, appropriately carry out intravenous infusion for 3 h with a dose of from 500 to 1650 micrograms per m2the surface of the body, preferably from 1000 to 1650 micrograms per m2the surface of the body, and is the last EP for this scheme, as shown in clinical trials.

Another form of treatment includes intravenous infusion for 72 h at RD for this circuit is equal to 1050 micrograms per m2the surface of the body.

An alternative procedure is intravenous infusion for 5 consecutive days, 24 hours per day, when the RD for this circuit is equal to 1650 micrograms per m2the surface of the body.

When ET-743 is used in combination with other therapeutic means, the dosage of all funds may need to be adjusted.

Earlier biological reactions associated with the introduction of ET-743, observed only in animal models and in vitro models; which are known to be quite incorrect to use for predicting the response of patients-people or patients in experimental conditions, as in the case of models it is impossible to assess the efficacy and safety of STRs is both the treatment (or used dosage was toxic dose significantly exceeding the recommended dose or not proper schemes).

In clinical trials of the method of the present invention when using the RD were achieved relevant characteristics of blood plasma, and, more importantly, objectively measured responses showed evidence of clinical benefit to patients.

Determine the response of the patient was borrowed from the General criteria of toxicity (Common Toxicity Criteria) WHO, and responses were evaluated following the standard of medical practice in this field.

Objective responses were obtained in patients with advanced and/or metastatic cancer, unresponsive to previous treatment, which included soft tissue sarcoma, bone and gastrointestinal stromal sarcoma, breast cancer and melanoma. An obvious activity using different suboptimal schemes introduction, observed also in cases of progressive melanoma of the eye and mesothelioma, and the presence of the responses with positive clinical signs of ovarian cancer suggests that the method according to the present invention is also applicable to the treatment of these diseases.

In the private version of the treatment used in this method were identified response in cancer patients with advanced and/or metal shirouma form of the disease, characterized by disease progression after existing treatment using known methods of treatment.

Therefore, the preferred method according to this invention includes the identification of patients with malignant tumors who had undergone cancer treatment, especially in patients subjected to chemotherapy, and the treatment of their ET-743.

In the private version of the treatment in this way were also identified response in patients with soft tissue sarcoma, bone, and gastrointestinal stromal sarcoma. In the private version of the treatment in this way were identified response in patients with soft tissue sarcoma. In the private version of the treatment in this way were also identified response in patients with bone sarcoma. In the private version of the treatment in this way were also identified response in patients with gastrointestinal stromal sarcoma. In the private version of the treatment in this way were identified response in patients with breast cancer.

The table shows the response observed when using this treatment method.

Further, the invention is illustrated by the following examples, which relate to clinical trials in humans.

EXAMPLE 1.

Analyzed test data for 24-hour intravenous infusion of ET-743 each is 3 or 4 weeks at a dose of 1500 mg/m 2.

The pharmacokinetics of ET-743 was monitored in all patients during the first cycle of therapy in order to assess the variability among patients and possible correlation with clinical activity or toxicity.

The totality of patients:

16 patients with progressive metastatic soft tissue sarcoma (CMT);

12 patients with soft tissue sarcoma without prior chemotherapy;

8 patients with progressive metastatic gastrointestinal stromal tumor (GISO).

The observed safety/options toxicity:

Treatment was associated with good tolerability.

Vomiting, essentially, were stopped by the use of dexamethasone as prophylactic antiemetic.

Myelosuppression.

Temporary/asymptomatic increase of transaminases.

The fatigue.

These data revealed no significant differences compared with the early phase I.

Efficiency:

- 6 out of 10 evaluate patients with CMT, previously not exposed to chemotherapeutic treatment, has demonstrated stable disease or mild response after 2 cycles of therapy,

- 4 out of 12 patients with CMT who had previously undergone chemotherapy treatment, has demonstrated stable disease or slabovia the military response after 2 cycles of therapy,

- preliminary evidence of activity was observed in cases of liposarcoma, leiomyosarcoma and synovial sarcoma.

EXAMPLE 2.

Analyzed test data of 20 patients with advanced/metastatic breast cancer who have been subjected to a previous treatment, with 24-hour intravenous infusion of ET-743 every 3 weeks at the dose level equal to 1500 g/m2.

Characteristics of the tested patients:

20 women,

all with the estimated disease, progressive in the beginning of the study;

age from 33 to 64 years (mean 50 years);

health status 0-1 (criteria ECOG);

the minimum number of affected organs: 2 (range 1-6);

foci:

subcutaneous12 (60%);
in the liver10 (50%);
bones9 (45%);
in lymph nodes6 (30%);
in the pleura and the lungs6 (30%).

The minimum number of prior chemotherapy courses 2 (1-6)

Patients previously exposed to treatment anticyclone20
Patients previously subjected to treatment taxonomy16
Patients that are resistant to anthracic the Inam and similarly to taxanes 5
Patients that are resistant only to similarly to taxanes2
Patients that are resistant only to anthracyclines3

Safety/options toxicity:

The total number of cycles introduction 56

the minimum number of cycles per patient 2 (range 1 to 8)

The number of observed variants toxicity 3 or 4 degrees per cycle:

Neutropenia25 (50%)
Thrombocytopenia4 (2%)
Reversible increase of transaminases34 (60%)
Asthenia (grade 2/3)13 (23%)

The data showed no significant differences compared with the early phase I.

Efficiency:

In 16 patients observed two cases of partial response (pleural-pulmonary lesions and lesions of the skin of the breast), which lasted for 3.5 months and over 2 months in patients with initial resistance to any of the drugs used in the previous treatment. Six patients achieved stabilization of disease (more than 2 months, 3 months, over 3 months, 4.5 months and over 6 months), including two with long-term illnesses when the marker SA 15-3A of this disease.

EXAMPLE 3.

Analyzed the data IP is itani 20 patients with progressive metastatic soft tissue sarcoma, subjected to prior treatment, with 24-hour intravenous infusion of ET-743 every 3 weeks at a dose equal to 1500 g/m2for all patients, except two.

Characteristics of the tested patients:

30 patients/22 women

35 with soft tissue sarcoma (CMT)

3 with osteosarcoma (OS)

1 Ewing sarcoma (XU)

22 patient to the beginning of the study was characterized by a deployed condition, and 56% in the previous regime had disease progression.

age from 16 to 71 years (average 45 years)

health 0 (0-2) (criteria ECOG)

The minimum number of prior chemotherapy 2 (1-7).

The majority of patients prior to chemotherapy treatment received anthracyclines and alkylating agents.

Safety/options toxicity:

The total number of cycles introduction 137

the minimum number of cycles per patient 2 (range 1-12)

The number of observed variants toxicity 3 or 4 degrees per cycle:

Neutropenia34%, 6.5%, from fever
Thrombocytopenia5%
Acute, reversible increase of transaminases44%
Asthenia (grade 2/3)13 (23%)

These data are not being identified the differences compared with the early phase I.

Efficiency:

Among the 34 patients:

observed 4 cases of partial response (11,7%), two of which were complete responses after surgery

observed 3 cases of weak responses, one of which became a full response after surgery,

11 cases, stabilization of the disease, most of which lasted for 3 months or longer.

Response was observed at various histological types, including 2 of the 3 cases of osteosarcoma, all foci, including visceral metastases, in the case of deployed and non-deployed diseases, and resistant to anthracyclines and sensitive to them tumors.

1. A method of treating cancer in humans, including intravenous ecteinascidin ET in dosage from 500 to 1650 mg/m2.

2. The method according to claim 1, in which IT is injected in a dosage of 1000 to 1500 mg/m2.

3. The method according to claim 1, in which IT introduced in cycles of intravenous infusion at intervals of from 1 to 6 weeks.

4. The method according to claim 1, in which IT introduced over time infusion up to 72 hours

5. The method according to claim 1, in which IT introduced over time infusion from 2 to 24 hours

6. The method according to claim 1, in which IT introduced over time infusion of about 3 hours

7. The method according to claim 1, in kotoroy introduced over time infusion of about 24 hours

8. The method according to claim 1, in which ET is in one week intervals.

9. The method according to claim 3, in which patients are allow to recover for the remainder of the cycle.

10. The method according to claim 3, in which the cycle is 3 or 4 weeks.

11. The method according to claim 1, wherein the malignant tumor is a melanoma, leiomyosarcoma, stromal sarcoma of the colon, stromal sarcoma of the stomach, osteosarcoma, liposarcoma, breast cancer, ovarian cancer, mesothelioma or ocular melanoma.

12. The method according to claim 1, wherein the malignant tumor is a metastatic tumor.

13. The method according to claim 1, in which a malignant tumor in humans was previously subjected to treatment with chemotherapy.

14. The method according to claim 1, wherein the treatment includes combination therapy.

15. The method according to 14, in which combination therapy includes the introduction of an antiemetic.

16. The method according to item 15, in which combination therapy consists of the administration of dexamethasone.

17. The method of treatment of malignant tumors in humans, including combination therapy, including the introduction AT and prophylactic antiemetic.

18. The method according to 17, in which antiemetic drug is dexamethasone.

19. The method according to 17, in which antiemetic drug is part of the same medicine the aqueous media such as ET.

20. The method according to 17, in which antiemetic drug is introduced in the form of a separate drug to IT.

21. The method according to claim 20, in which individual drug is administered simultaneously with IT.

22. The method according to claim 20, in which individual drug is not injected simultaneously with IT.

23. The method according to any of PP-22, where the patient has progressive and/or metastatic, previously subjected to the treatment of malignant tumors.

24. The method according to any of PP-23, in which the patient has a malignant tumor resistant or resistant to other treatment methods.

25. The method according to any of PP-24, in which the malignant tumor is a sarcoma.

26. The method according A.25, in which the malignant tumor is a sarcoma of soft tissues.

27. The method according A.25, in which the malignant tumor is a sarcoma of bone.

28. The method according to any of PP-24, in which the malignant tumor is breast cancer.

29. Pharmaceutical preparative form, including ET and prophylactic antiemetic drug.

30. A method of treating a malignant tumor in humans, involving the introduction of a dose AT from 1000 to 1500 g/m2by intravenous infusion over a 24-hour period, carried out by multiple cycles of 3 or 4 n is Delhi every moreover, the administration of a medicinal product is carried out once on the first day of each cycle.

31. A method of treating a malignant tumor in humans, involving the introduction of a dose AT from 1000 to 1650 mg/m2by intravenous infusion over a 24-hour period, carried out by multiple cycles of 3 or 4 weeks each, with the introduction of medicines is carried out once on the first day of each cycle.



 

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12 cl, 5 tbl, 6 dwg, 10 ex

FIELD: chemical-pharmaceutical industry, medicine, pharmacy.

SUBSTANCE: invention relates to a spontaneously dispersing composition comprising N-benzoylstaurosporin, a hydrophilic component, a lipophilic component and a surface-active substance taken in the definite ratio of components. Also, invention relates to a method for treatment of the patient needing administration of N-benzoylstautosporin as a component of the spontaneously dispersing composition. The composition possesses the enhanced level of biological availability or diminished variability of the biological availability levels and effectiveness.

EFFECT: improved and valuable properties of composition.

13 cl, 3 dwg, 2 tbl, 5 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new heteroaryl derivatives, in particular, derivatives of quinoline of he general formula (I): wherein R, R1, R2 and R3 are similar or different and mean independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl, halogen atom, aryl-(C1-C8)-alkoxy-group, aryl. Except for, R and R1 or R2 and R3 can form six-membered aromatic ring condensed with quinoline residue; X means oxygen atom; p, Q mean in each case -CH2-; X means nitrogen atom; n = 2; m = 0; R4 means phenyl or pyridyl. Also, invention relates to their pharmaceutically acceptable salts, in particular, acid-additive salts. Compounds are useful as antitumor agents. Also, invention describes a method for preparing compounds and medicinal agent based on thereof.

EFFECT: improved preparing method, valuable medicinal properties of compounds and agent.

11 cl, 2 tbl, 13 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: medicine.

SUBSTANCE: one should perform the following stages: a) removal of contaminants out of plant; b) plant's reducing; c) treatment of reduced plant with laser radiation; d) suspending the mixture obtained at stage c) in water; e) maceration of suspension obtained at stage d) and f) separation of liquid developed. Composition should be obtained due to this technique. It should be applied at treating hepatitis C as an aqueous extract. It should be applied as aqueous extract as immunostimulant. Pharmaceutical preparation includes aqueous extract as an active constituent.

EFFECT: increased biological activity of the product.

43 cl, 16 ex, 1 tbl

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating malignant tumors of mammary gland in case no tumor penetration into thoracic fasciae. The method suggested includes autohemochemotherapy. Moreover, on the 1st d of therapy it is necessary to sample 30 ml blood out of patient's peripheral vein into the 1st vial to combine its content with 500 mg 5-fluorouracil and 600 mg cyclophosphan; then one should sample 20 ml blood into the 2nd vial to combine its content with 40 mg doxorubicin; both vials should be incubated at 37-37.5 C for 20-30 min, afterwards its necessary to inject the mixtures out of both vials under the tumor and along its circumference. On the 8th d of therapy one should repeat impact procedures at the same dosages of anti-tumor preparations and at the same order. The innovation suggested enables to develop the largest concentration of anti-tumor preparations in lesion focus, divide into fragments, decrease tumor's size and its inflammatory component and border it against surrounding tissues for performing radical surgical treatment.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with applying fulvestrant as a curative preparation of the third line in treating patients with resistant cancer of mammary gland after failed application of tamoxifen and aromatase inhibitor. The innovation shows positive therapeutic result in 41% cases.

EFFECT: higher sensitivity to fulvestrant.

5 cl, 1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: method suggested should be implemented due to conserving velvet antlers after cutting, purification and reducing up to particles' size of not more than 7x7 mm to be then applied into vacuum drying drum-type chamber to create there discharging of 0.95-1.0 atm. It is necessary to supply water at 50-60 C into heat casing of drying chamber, treatment process lasts for 14-18 h at oscillating rotation of drying chamber at frequency being 10 rot./min, moreover, the product should not be heated above 37 C, at achieving the moisture of product preparing being 3-5% one should rotate drying chamber at frequency of not less than 50 rot./min and reducing should be fulfilled with grinding metal bodies as either spheroidal or cylindrical form which are present in drying chamber up to dispersity of not more than 0.1 mcm to be then packed airproof for better storage. The innovation is oriented to increase bioavailability and bioactivity of powder obtained due to decreasing the temperature for conserving velvet antlers up to 37 C.

EFFECT: higher efficiency.

1 tbl

FIELD: pharmaceutics.

SUBSTANCE: the suggested powder consists of crystals of one component amiphostin, the length of crystalline granule corresponds to 300-700 mcm at the content of 1-3 molecule of crystalline water. In method for obtaining amiphostin powder for injections one should apply the process of vacuum drying. The innovation provides resistance of the product obtained, the crystals obtained have got moderate length and acceptable mobility without any reduction.

EFFECT: higher efficiency of application.

6 cl, 5 dwg, 13 ex, 3 tbl

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a new pharmaceutical preparation comprising active substance and chitosan derivative that present in nanosol in an isoionic state. Pharmaceutical preparation is prepared by the following manner: the chitosan derivative is taken to provide isoionic state at the definite level of pH value or equilibrating charges of active substance and a carrier in the preparation. An aqueous sol is prepared from chitosan derivative that contains an active substance. The pH level is regulated to provide an isoionic state at possible precipitation of colloidal particles or nanoparticles of active substance, and prepared sol is dried. Pharmaceutical preparation elicits the enhanced bioavailability, releases active substance rapidly and stable in storage.

EFFECT: improved and valuable properties of pharmaceutical preparation.

8 cl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to an antiviral medicinal preparation. The preparation comprises ribavirin, phosphatidylcholine, cholesterol, α-tocopherol, sucrose, sodium chloride and represents lyophylizate in isotonic solution. Invention provides preparing the liposomal ribavirin eliciting high biological and therapeutic effectiveness with low toxicity.

EFFECT: improved, enhanced and valuable medicinal properties of preparation.

3 cl, 2 tbl

FIELD: gastroenterology.

SUBSTANCE: eradication of infection Heliobacter pylory in stomach comprises oral administration of corresponding drugs in powdered form mixed with orange juice. In particular, mixture of colloidal bismuth subcitrate (De-nol), Nifuratel (Macmirror), and Amoxycyllin (Flemoxin solutab) are used. Administration is performed on an empty stomach at least 30-40 min before the food intake. Patient then lies at least 30 min on the both sides alternatively.

EFFECT: suppressed water-repellent property of near-wall layer of stomach mucus and slowed down evacuation of liquid from stomach thereby ensuring fast diffusion of therapeutical substances into infect persisting zone and, therefore, direct bactericidal effect on Heliobacter pylory.

4 cl

FIELD: medicine, antibiotics.

SUBSTANCE: invention relates to cephalosporin antibiotic - cefuroximaxetil that is used in treatment of bacterial infections. Invention proposes a new form of cefuroximaxetil not forming gel in contact with an aqueous solution. New form represents a solid solution of cefuroximaxetil in polymer and/or solid dispersion on adsorbent. New form of cefuroximaxetil can be used for preparing a granulate that can be used in oral pharmaceutical compositions as tablets or powder. Exclusion of gel-formation allows improving solubility of cefuroximaxetil that results to enhancing absorption of cefuroximaxetil in digestive tract.

EFFECT: improved pharmaceutical properties of combinations.

23 cl, 3 dwg, 8 tbl, 19 ex

FIELD: medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to carvedilol-containing pharmaceutical composition that is used for treatment and/or prophylaxis of hypertension, cardiac insufficiency or stenocardia. The composition comprises carvedilol or its pharmaceutically acceptable salt and one or some adjuvants. Carvedilol is distributed in adjuvants as a molecular dispersion. Adjuvants are not surface-active substance and/or non-ionogenic surface-active substance. The concentration of adjuvants exceeds 5 wt.-%. Also, invention describes a method for preparing the composition and pharmaceutically acceptable solid formulation for oral administration. Compositions of the present invention provide the enhancing solubility of carvedilol and level of its absorption in lower regions of intestine.

EFFECT: improved and valuable pharmaceutical properties of composition.

17 cl, 9 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a composition eliciting an antibacterial effect. Composition comprises hydrophilic conglomerate of immunoglobulins consortium adsorbed with polyethylene glycol 4000-6000 and a special additive taken among the following substances: glycine, glucose, maltose, sodium chloride taken in the definite ratio of components. Invention provides sufficient desorption of biologically active substances in resuspending the composition eliciting an antibacterial effect and comprising consortium of immunoglobulins.

EFFECT: valuable medicinal properties of composition.

5 ex

FIELD: medicine, pharmaceutical industry and technology, pharmacy.

SUBSTANCE: invention relates to a composition eliciting an antiviral effect. The composition comprises hydrophilic conglomerate of immunoglobulins consortium adsorbed with polyethylene glycol 4000-6000, recombinant interferon-α2 and a special additive taken among the following substances: glycine, glucose, maltose, sodium chloride taken in the definite ratio of components. Invention provides elevating solubility of composition eliciting an antiviral effect and enhanced release of biologically active substances to solution.

EFFECT: valuable medicinal properties of composition.

5 ex

FIELD: medicine, pharmacology, biochemistry, pharmacy.

SUBSTANCE: invention relates to preparations reducing blood cholesterol level. Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin and their derivatives and analogs known as inhibitors of HMG-CoA-reductase are used as anti-hypercholesterolemic agents. Above mentioned active substances can be destabilized as result of effect of environment and their destruction can be accelerated in interaction with other pharmaceutical agents, such as excipients, binding agents, lubricating agents, substances promoting to slipping and disintegrating agents. Therefore, pharmaceutical components and a method for preparing a pharmaceutical preparation must be taken thoroughly to avoid above said undesirable interactions and reactions. Invention relates to inhibitor of HMG-CoA-reductase that stabilized by formation of a homogenous composition with buffer substance or an alkalinizing substance. This homogenous composition is used as an active substance in pharmaceutical preparation used for treatment of hypercholesterolemia and hyperlipidemia. Invention enhances the enhancement of stability and homogeneity of the preparation.

EFFECT: improved and valuable pharmaceutical properties of composition.

23 cl, 2 tbl, 3 dwg, 11 ex

FIELD: medicine, infectology.

SUBSTANCE: one should introduce rhoncoleukin in standard dosages and standard mode in combination with corbiculin for internal intake per 2 g once daily after meals, being pre-dissolved in 50 ml water, at 8-wk-long course. The present innovation enables to decrease the size of liver, favors regression of disease clinical manifestations in shorter period of time and normalization of detoxicational, protein-synthetic, pigment functions of liver and prolonged remission of the disease mentioned due to corbiculin and rhoncoleukin synergism.

EFFECT: higher efficiency of therapy.

3 dwg, 2 ex, 3 tbl

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