Antitumor agent for local treatment of malignant tumors

 

(57) Abstract:

The invention relates to medicine, namely to Oncology, and in particular to compositions used for treatment of malignant tumors. The purpose of the invention is improving the efficiency of anticancer chemotherapy. To achieve the goal in a water-oil emulsion containing thiotepa, enter into certain relations of biological antioxidants (retinol-acetate and tocopherol-acetate), which provides additional prolongation of action of medicinal substance and increases lymphotropism. table 1.

The invention relates to medicine, namely to Oncology, the compositions used to enhance the effectiveness of neoadjuvant chemotherapy of malignant tumors of various localizations, as well as for palliative treatment of inoperable patients.

The efficiency of modern anticancer drugs in the majority of malignant tumors is still not high enough (N. Blokhin. N. Perevozchikova N. And. 1984). This is largely due to the lack of selectivity of action of cytotoxic drugs to tumor cells. In addition, cytostatics necessary in large doses has textsa resistant systemic application of existing drugs. Drug pathomorphosis of 3-4 degree of damage observed in only 9% of all cases (Frank, A. and others 1989).

A promising direction of research aimed at improving the effectiveness of drug therapy is the search for agents that can increase the effectiveness of chemotherapy. One possible modulators of chemotherapy can be bioethically (BAO), the biological mechanism of action of which is to offset the competitive free-radical and enzymatic oxidation. Found an increased level of antioxidant activity of lipids in a number of experimental tumors in the period of maximum rate of growth (Zhuravlev, L. I., 1968).

The introduction of BAO in the form of a thin emulsions, contributing to more complete absorption, increases their efficiency in the experiment. Evaluation of therapeutic action BAO in the experiment using the transformation coefficient gives a value of about 1.6 to 1.9 ( Bobmassoco E. and others 1976). Installed, one hundred under combined action of BAO and chemical carcinogens increases the duration of the latent period and reduced the percentage of tumours (A. I. Zhuravlev and others, 1958, 1959). However, the question about the possibility of using BAO when l is as anticancer drugs after intratumoral injection of cytotoxic agents in emulsion forms. The increase in the median survival in the experiment with the introduction of the emulsions was 200% against 146% in the case of using an aqueous solution of cytostatic (T. Kato, 1990, Kami, 1990). This composition was used as a prototype.

Disadvantages of the proposed structure are:

the instability of the emulsion resulting from the use of sesame oil, due to its high specific weight and viscosity of the emulsion is unstable, with a life expectancy of only 6-8 hours, followed by complete separation of the emulsion, which makes it unsuitable for injection;

a quick release of the cytostatic agent from the area of the tumor and the possibility of complications (principally, bleeding) with the introduction of the emulsion into the tumor.

Moreover, there was no development of effective forms of emulsions for chemotherapy (depending on the physico-chemical properties of the individual ingredients).

Was unstudied question about the possibility of increasing the effectiveness of anticancer drugs when they emulsions BAO. Studies were only experimental. Data was not available for clinical testing of composition.

Previously oxidants used only separately with chemotherapy drugs, which significantly reduces the efficiency chemotherapeutical target molecules (DNA, RNA, enzymes) in cancer cells.

The purpose of the invention increase the efficiency of anticancer chemotherapy. The goal is achieved by introducing a part of the preparation of water-in-oil emulsion is immobilized cytostatic and biochemically. The choice thiotepa as an antitumor agent was due to its high efficiency in the treatment of malignant tumors of different localization (breast cancer, ovarian cancer and others). As the oil phase used sunflower oil. BAO (vitamin a, vitamin E) was added to the emulsion in the form of oil solutions. Emulsions were prepared in an ultrasonic disintegrator in three modes for 60 s each. For stability of the emulsion were added 0.5 ml of surfactant TWEEN-20.

The composition was opprobious of Moscow in them. P. A. Gertsen in the experiment on the model carcinoma PC-1.

Experiments conducted on rats male Wistar original weight 200-220, Perepevku tumor was performed subcutaneously in the region of the anterior abdominal wall by the introduction of 0.4 mg 25% suspension of tumor tissue in 0.9% sodium chloride solution. On the 14th day after tumor inoculation the animals were divided into seven groups of 10 rats each;

1. Introduced parathas is the same dose of the drug. The emulsion contained about 7. including sunflower oil with BAO.

3. Introduced in the same way and to the same dose of the emulsion in which the oil phase used sesame oil (about 3.h.).

4. Introduced in the same way and in the same dose emulsion containing 7,0 about. including sesame oil.

5. Introduced papathanasio in the same dose aqueous solution thiotepa.

6. Introduced intravenous solution containing 10 mg thiotepa.

7. The control group (perebivka tumor).

Data on dynamics of tumors in animals of different groups are presented in the table.

You can see that on the 28th day of the experiment, the size of tumors in animals of groups 1 and 2 was significantly lower than in animals 4-7 groups. At all subsequent periods of the experiment, the tumor size in group 1 were significantly lower than all the others. The size of the tumors in the groups of animals that received emulsion form with BAO, was significantly different from groups where were injected emulsion without BAO.

In clinical conditions, the method was carried out as follows: used oil-water emulsion containing thiotepa 60 mg retinol acetate in oil 25000 IU 1.0 ml of tocopherol acetate in oil of 0.01-1.0 ml, sunflower oil 1.0 ml of the Face for 3 minutes Then the emulsion was placed in a sterile vial and injected once perfumowana.

A specific example. Patient Nechayev, C. N. 48 years old, and a/b BA-284, housed in the Department of General Oncology, NIOI them P. A. Gertsen with 11.02 on 3.03.92,

Clinical diagnosis: cancer of the right mammary gland II A stage, TNAME. From the anamnesis: in the summer of 1989 produced puncture the seal in the right breast. The histological conclusion cyst. 07.91, a new seal value in the "pea", which subsequently increased by approximately 4 times. Turned of Moscow in them. P. A. Herzen. To enroll in upper-outer quadrant is palpated tumor size of 4 x 4 cm, mobile. The patient was discussed at the clinical conference. Given the presence of adverse prognostic factors rapid tumor growth, family history (mother died of cancer)4.02.92, perfumowana introduced 60 mg thiotepa in emulsion form by the method described above. Complications were observed. 20.02.92 were radical surgery resection of the right breast. The postoperative period was uneventful. Histology: E 52328-46, ductal cancer, drug disease variability in different parts of the tumor expressed in Ratnapura. In l/metastases were not detected. The patient was re-discussed at the clinical conference office, she underwent a course of radiation therapy. The patient continues to be monitored in the clinic of Moscow them. P. A. Herzen.

Thus, the introduction of cytostatic thiotepa in emulsion form of biological antioxidants (tocopherol and retinol) significantly increased the efficiency by increasing prolongation and lymphotropism anticancer drug.

Antitumor agent for local treatment of malignant tumors, including thiotepa, characterized in that it additionally contains retinol acetate, tocopherol acetate, components of the water-in-oil emulsion of sunflower oil, tween-20 and water in the following ratios of components in a single dose:

The thiotepa 60 mg

Retinol acetate in oil 25000 IU in 1 ml

Tocopherol acetate 0.01 to 1 ml

Sunflower oil 1 ml

Tween-20, 0.5 ml

Water for injection 7 million

 

Same patents:

The invention relates to new biologically active compound, specifically to the dichloride 2-[5-(2-methylpyridyl]ethyl, bis{2-[5-(2 - methylpyridine)] ethyl}of phosphoryla (I) of the formula I

MeCCHMeCH2CHP=0

possessing antibacterial activity

-diphenylphosphinoethyl, n-2-hydroxy(2-nitroxy)-3,5 - dibromopropylether showing neurotropic activity" target="_blank">

The invention relates to new chemical compounds, namely, N-substituted the hydrazones: N-definiltey - ylacetic, N-2-hydroxy-(I) and N-2-nitroxy (II)-3,5-dibromoindigotin formula

(C6H5)CHNHN=CHwhere X=HE(I), ONa(II) showing neurotropic activity

-diphenylphosphinoethyl, n-diphenylphosphinyl-(2 - hydroxy-3,5-dibromo)phenylmercapturic showing neurotropic activity, and method thereof" target="_blank">

The invention relates to new chemical compounds, namely, bis-phosphorylated N-, N-substituted semicarbazide-N-diphenylphosphinite - Thiel, N-diphenylphosphinyl, (2-hydroxy-3,5-dibromo)phenylmercapturic formula I

(C6H5)Nshowing neurotropic activity

The invention relates to medicine, namely to endocrinology, and can be used for the treatment of autoimmune thyroiditis
Radioprotector // 2049469
The invention relates to experimental biology and medicine and can be used to protect living organisms, when exposed to ionizing radiation

The invention relates to medicine, Pediatrics infectious diseases in children, and may be embedded in children's medical institutions

Antiviral agent // 2038083
The invention relates to medicine and veterinary medicine, in particular to antiviral agents, and can be used to treat AIDS, viral hepatitis and encephalitis

FIELD: medicine, ophthalmology.

SUBSTANCE: one should apply an autohemocomponent preparation being supernatant liquid of patient's autoblood at increased serotonin content obtained due to irreversible thrombocytic aggregation due to the impact of 0.5 mg ATP per 1.0 ml plasma followed by a 30-min-long centrifuging at the rate of 1000, 2000 and 3000 rot./min for 20, 7 and 3 min, correspondingly. In case of no exudative phenomena on patient's eye bottom the obtained preparation should introduced at the quantity of 7-10 ml once in 48 h for 1 mo (totally, 15 injections). In case of exudative-hemorrhagic phenomena it should be introduced parabulbarly at the volume of 0.5 ml and parenterally - 7.0-10.0 ml once in 48 h for 1 mo per 15 injections, correspondingly. The preparation enables to improve visual functions due to decreased tissue hypoxia and normalization of microcirculation in visual analyzer.

EFFECT: higher efficiency of therapy.

2 cl, 7 dwg, 2 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: one should apply an autohemocomponent preparation being supernatant liquid of patient's autoblood at increased serotonin content obtained due to irreversible thrombocytic aggregation due to simultaneous impact of 0.5 mg ATP per 1.0 ml plasma followed by a 30-min-long centrifuging at the rate of 1000, 2000 and 3000 rot./min for 20, 7 and 3 min, correspondingly. Preparation should introduced parabulbarly at the volume of 0.5-1.0 ml, parenterally - 7.0-10.0 ml once daily at 20 injections for 1 mo. The method enables to increase visual functions due to normalization of functional activity of photoreceptors and neurons of internal layer in retinal peripheral departments.

EFFECT: higher efficiency of therapy.

1 cl, 2 ex

FIELD: coordination compounds synthesis.

SUBSTANCE: invention provides complex comprising calcium and [[(4R)-4[bis[carboxy.kappa.O)methyl]amino-.kappa.N]-6,9-bis[carboxy-.kappa.O)methyl]-1-[(4,4-diphenylcyclohexyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecane-11-ylic acid-.kappa.N6,.kappa.N9,-kappa.011]-oxydato(6-)]-,6H, (MS-325) or its salt with physiologically acceptable cation in each case containing essentially no Gf-MS-325. Also described are pharmaceutical agent based on compounds according to claim 1 and a method for preparing galena composition, complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent reducing effect produced by heavy metals as well as complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent suitable for NMR diagnostics and/or diagnostic radiology, a method for amplifying patient's image in NMR tomography based on compounds according to claim 1 and above defined complex or its salt with physiologically acceptable cation in each case containing essentially no visualizing metal chelates and MS-325.

EFFECT: increased assortment of complexes with useful medicine-destination properties.

14 cl, 4 dwg, 30 ex

FIELD: experimental medicine.

SUBSTANCE: on should introduce solution into fracture area at the following ratio of ingredients, g/l: 1-hydroxyethylidenediphosphonic acid 1.80 - 2.06, water-free calcium chloride 1.44 - 2.22, gadolinium (III) nitrate hexahydrate 0.30 - 0.40, dysprosium (III) chloride hexahydrate 0.038 - 0.076, moreover, solution's pH corresponds to 7.3 - 7.8. The present innovation enables to shorten the process of bony tissue regeneration in the site of its lesion or defect and, also, shorten the period for restoring normal physiological function of traumatized bone.

EFFECT: higher efficiency of regeneration.

22 ex, 1 tbl

FIELD: experimental medicine.

SUBSTANCE: on should introduce solution into fracture area at the following ratio of ingredients, g/l: 1-hydroxyethylidenediphosphonic acid 1.80 - 2.06, water-free calcium chloride 1.44 - 2.22, gadolinium (III) nitrate hexahydrate 0.30 - 0.40, dysprosium (III) chloride hexahydrate 0.038 - 0.076, moreover, solution's pH corresponds to 7.3 - 7.8. The present innovation enables to shorten the process of bony tissue regeneration in the site of its lesion or defect and, also, shorten the period for restoring normal physiological function of traumatized bone.

EFFECT: higher efficiency of regeneration.

22 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: the present innovation includes polychemotherapy and radiation therapy. Moreover, polychemotherapy should be carried out by the following scheme: on the 1st and the 8th d of the first and the third courses it is necessary to introduce doxorubicin, cyclophosphan, vincristine, and since the 1st to the 14th d - procarbazine and prednisolone; moreover, on the 1st and the 8th d of the second and the fourth courses one should introduce doxorubicin, bleomycin, vinblastine, dacarbazine. The method enables to decrease the quantity of late therapeutic complications, improves the results of relapse-free, total tumor-specific survival rate and decreases the number of polychemotherapeutic cycles.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: veterinary science, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to the development of veterinary agent used for treatment of animals with arachnidism. Agent for treatment of arachnidism comprises 11.6% of Trichlorfon (Dipterex) alcoholic-oily solution and sea-buckthorn oil in the following ratio of component, ml per 100 mk of preparation: 11.6% of Trichlorfon (Dipterex) alcoholic-oily solution, 4.3-25.8, and sea-buckthorn oil, 74.2-95.7. The preparation shows improved permeability and prolonged positive topical effect and its toxicity is lower as compared with the known preparation of the same designation.

EFFECT: improved and valuable veterinary properties of preparation.

FIELD: organophosphorus compounds, medicine.

SUBSTANCE: invention relates to new biologically active phosphonate compounds. Invention describes phosphonate compound of the formula:

wherein R1 and R'1 represent independently hydrogen atom (-H) substituted possibly with -O-(C1-C24)-alkyl, -O-(C1-C24)-alkenyl, -O-(C1-C24)-acyl, -S-(C1-C24)-alkyl, -S-(C1-C24)-alkenyl or -S-(C1-C24)-acyl wherein at least one among R and R'1 doesn't represent -H and wherein indicated alkenyl or acyl comprise from 1 to 6 double bonds; R2 and R'2 represent independently -H substituted possibly with -O-(C1-C7)-alkyl, -O-(C1-C7)-alkenyl, -S-(C1-C7)-alkyl, -S-(C1-C7)-alkenyl, -O-(C1-C7)-acyl, -S-(C1-C7)-acyl, -N-(C1-C7)-acyl, -NH-(C1-C7)-alkyl, -N-((C1-C7)alkyl)2, oxo-group, halogen atom, -NH2, -OH or -SH; R3 represents phosphonate derivative of nucleoside or biphosphonate; X represents compound of the formula:

L represents a valence bond or a bifunctional binding molecule of the formula: -J-(CR2)t-G- wherein t is a whole number from 1 to 24; J and G represent independently -O-, -S-, -C(O)O- or -NH-; R represents -H, unsubstituted or substituted alkyl or alkenyl; m means a whole number from 0 to 6; n = 0 or 1. Also, invention describes pharmaceutical compositions comprising phosphonate compounds, method for treatment of osteoporosis in mammal, method for increasing mineral osseous density, method for prophylaxis of apoptosis of osteoblasts and osteocytes in mammal, method for treatment of viral infection in mammal, method for treatment of growing neoplasm in mammal and method for proliferation of cells. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of phosphonate compounds.

17 cl, 2 dwg, 7 tbl, 21 ex

FIELD: chemistry of organophosphorus compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (1) showing affinity to one or more GABAB receptors and their pharmaceutically acceptable salts, solvates and stereoisomers but with exception for racemate of (3-amino-2-hydroxypropyl)-phosphinic acid. Invention provides increasing the therapeutic index value.

EFFECT: improved and valuable properties of compounds.

14 cl, 1 tbl, 21 ex

FIELD: medicine.

SUBSTANCE: invention proposes applying bis-phosphonic acids (bis-phosphonates) for the embolic treatment of angiogenesis and corresponding methods for prophylaxis or treatment of angiogenesis by embolization. Invention provides suppression of growth, invasion or metastasis of tumors, treatment of angiogenesis in myocardium ischemia, rheumatic arthritis, osteoarthritis by embolization of newly formed vessels in intra-arterial route of administration of bis-phosphonate (for example, pamidronic acid or zoledronate).

EFFECT: valuable medicinal properties of medicine agents.

10 cl, 3 dwg, 7 ex

Up!