Pharmaceutical biphosphonate application

FIELD: medicine.

SUBSTANCE: method involves applying biphosphonates for producing preparations and treating osteoblastic (osteosclerotic) metastases connected with prostate cancer.

EFFECT: enhanced effectiveness in inhibiting abnormal osteoblast proliferation.

5 cl, 3 tbl

 

The present invention relates to bisphosphonates, in particular to a new use of bisphosphonates for pharmaceutical purposes.

Bisphosphonates are widely used to suppress osteoclastic activity in a variety of both benign and malignant diseases that cause inappropriate or excessive bone resorption. These analogues of pyrophosphates not only reduce the occurrence of phenomena associated with changes in the bones of the skeleton, but also bring clinical benefits to patients and improve survival. Bisphosphonates can prevent bone resorption in vivo; therapeutic efficacy of bisphosphonates has been demonstrated in the treatment of osteoporosis, impaired bone formation, Paget's disease, tumor-induced hypercalcemia (TIH) and, as was recently shown, in the treatment of bone metastases (BM) and multiple myeloma (MM) (see review Fleisch H. 1997. Bisphosphonates clinical. In the book "Bisphosphonates in Bone Disease. From the Laboratory to the Patient." Publishing house: The Parthenon Publishing Group, new York/London, pp. 68-163).

The mechanisms by which bisphosphonates inhibit bone resorption, is not yet fully clear, and seem to vary depending on the studied bisphosphonates. It has been shown that bisphosphonates bind strongly to hydroxyapatite crystals of bone, reduce the bending of the bone and resorption, reduce the levels of hydroxyproline is or alkaline phosphatase in the blood and, in addition, they inhibit the formation, recovery, activation and activity of osteoclasts.

Multiple myeloma is a malignant disease of plasma cells, characterized by proliferation and accumulation of malignant plasma cells in the bone marrow. The main clinical consequences are associated with lysis of bone injuries, accompanied by pathological fractures and bone pain. These injuries are the result of excessive bone resorption, often leading to hypercalcemia. Bisphosphonates used for long-term treatment of multiple myeloma in combination with conventional chemotherapy. Recently it was shown that bisphosphonates, such as clodronate and pamidronate can reduce the occurrence of phenomena associated with changes in the bones of the skeleton, such as, for example, associated with lysis of bone injuries and pathological fractures, and can facilitate associated with this pain in the bones and to improve the quality of life of patients (Laktinen, etc.. Lancet 1992, 340,1049-1052; McCloskey and others, B.J. HaemotoL, 1998, 100, 317-325, and Berenson, etc., N. Eng. J. Med. 1996, vol 334, No. 8, 488-493). About similar effects were reported in the case of patients with breast cancer were treated with bisphosphonates (Hortobagyi G.N. and others, "Effectiveness of pamidronate in reducing skeletal complications in patients with breast cancer and in patients with lytic the ski bone metastases", Protocol 19 Aredia group for the study of breast cancer, New England Journal of Medicine 1996; 335:1785-91; Kanis J.A., and others, "Lowering clodronate frequency of skeletal metastases in women with breast cancer". Bone, 1996; 19: 663-7).

Thus, bisphosphonates are effective inhibitors osteoclastic bone resorption and demonstrate therapeutic efficacy in the treatment of hypercalcemia in malignant disease, when treatment is associated with lysis of bone diseases caused by multiple myeloma and for the treatment of mixed lytic and plasticheskih bone metastases caused by breast cancer. However, other malignancies, such as prostate cancer, are accompanied by skeletal metastases, which by their nature are predominantly osteopaticheskii (osteosclerotic) and it remains unclear whether they respond similarly metastases of these last malignant diseases for treatment with bisphosphonates.

Recently it was reported that the use of bisphosphonates (clodronate, etidronate, alendronate and pamidronate) has a beneficial effect on bone pain in patients with metastatic prostate cancer (Nicola Adami, Cancer, 1997; 80: 1674-79). Recently it was also reported that bisphosphonates inhibit the adhesion of breast cancer cells and cancer cells prestat is through cancer with bone in vitro (Boissier and others, Cancer Res; 3890-3894, 1997) and, in addition, such pre-treatment of breast cancer cells and prostate cancer with bisphosphonates inhibited the invasion of tumor cells through direct effects on tumor cells. However, recently it was reported that in vitro treatment of cell lines prostate cancer by zoledronate acid significantly reduced the growth of cell lines (Brown and others, the Impact of zoledronate on cancer cells of the prostate gland, ASBMR, 2000; Lee et al. Treatment with bisphosphonates inhibits the growth of prostate cancer cells. Cancer Research, 2000/2001); at the same time did not find a significant reduction of tumor volume in the case of subcutaneous tumors caused by cell lines prostate cancer treated with zoledronate acid (Soju, etc.. Effects of zolendronic acid on prostate cancer in vitro and in vivo, Amer. Assoc. Cancer Res., presented in October 2000).

To date, however, there were no reports that any bisphosphonate showed clinical efficacy in the treatment of prostate cancer or bone metastases associated with prostate cancer. It was shown in a clinical study in a double-blind experience under the supervision placebo that zoledronicaa acid (ZOMETA®, Novartis Pharma) shows a statistically significant beneficial effect on CPA who to placebo in the treatment of bone metastases in patients with prostate cancer.

Accordingly, this invention provides a method of treating prostate cancer in patients in need of such treatment, which includes an introduction to the patient an effective amount of N-bisphosphonates.

The invention also provides the use of N-bisphosphonates for the preparation of drugs for the treatment of prostate cancer.

The method and the use according to the invention can be used for direct treatment of the prostate cancer. So, consider that N-bisphosphonates used in the present invention, can have a direct effect in vivo on the growth, proliferation or viability of prostate cancer cells, for example, as inhibitors of the growth or cell division of cancer of the prostate, or as promoters of death of prostate cancer cells (for example, as the activating apoptosis funds). The invention useful for the treatment of secondary effects from prostate cancer, including metastases, as metastases in soft tissue and bone metastases.

Essentially, in addition, believe that the invention can be applied more broadly to ensure osteopatichesky (osteosclerotic) metastases, in particular, osteopatichesky bone metastases, for example, osteoblastic the fir metastases, caused by prostate cancer and similar malignant diseases.

Thus, the invention also provides the use of N-bisphosphonates for the treatment of osteopatichesky metastases caused by malignant diseases or conditions in mammals.

In preferred embodiments implementing the invention provides:

(i) the use of N-bisphosphonates for the treatment of metastases due to prostate cancer;

(ii) a method of treatment of metastases due to prostate cancer, in a patient in need of such treatment, the method includes the introduction to the patient an effective amount of N-bisphosphonates and

(iii) the use of N-bisphosphonates in the preparation of medicines for the treatment of metastases due to prostate cancer.

The effectiveness of treatment with N-bisphosphonates osteopatichesky metastases or metastases of prostate cancer according to the invention can be demonstrated by monitoring the occurrence of events associated with changes in the bones of the skeleton (SRE)in patients subjected to treatment with N-bisphosphonates, and compare the obtained results with those for the group receiving placebo; for example, as further provided in the "clinical trials".

Phenomena associated with changes in the bones with elite (SRE), further defined in the "Description of clinical trials".

In a particularly preferred embodiment, the invention provides:

(i) the use of N-bisphosphonates to reduce the effects associated with changes in the bones of the skeleton due to metastatic prostate cancer;

(ii) a method of reducing effects associated with changes in the bones of the skeleton due to metastatic prostate cancer, in a patient with prostate cancer, the method which includes an introduction to the patient an effective amount of N-bisphosphonates, and

(iii) the use of N-bisphosphonates in the preparation of medicines to reduce the effects associated with changes in the bones of the skeleton due to metastatic prostate cancer.

In the present description, the terms "treatment" or "treat" refer to both prophylactic or preventive treatment and treatment of illness or disease modifying treatment, including treatment of patients at risk of developing metastasis or phenomena associated with changes in the bones of the skeleton, or patients with suspected progression of the disease, for example, prostate cancer, and patients who are sick or diagnosed as suffering from a disease or disease state such as cancer present is part of the gland.

For the purposes of the present description N-bisphosphonate means a compound, which in addition to typical hominalnoe bisphosphate component includes a nitrogen-containing side chain, for example, the compound of formula I,

where X is hydrogen, hydroxyl, amino, alkanoyl or amino group, substituted (C1-C4)alkyl or alkanoyl;

R means hydrogen or (C1-C4)alkyl and

Rx means a side chain that contains optionally substituted by an amino group, or a nitrogen-containing heterocycle (including aromatic nitrogen-containing heterocycles),

or its pharmaceutically acceptable salt or any hydrate.

For example, the appropriate N-bisphosphonates for use in the invention can include the following compounds or their pharmaceutically acceptable salt or any hydrate: 3-amino-1-hydroxypropane-1,1-diphosphonic acid (pamidronate acid), for example, pamidronate (APD); 3-(N,N-dimethylamino)-1-hydroxypropane-1,1-diphosphonic acid, e.g. dimethyl-APD; 4-amino-1-hydroxybutane-1,1-diphosphonic acid (alendronat acid), for example, alendronate; 1-hydroxy-3-(methylpentylamino)propylaminosulfonyl acid (ibandronic acid), for example, ibandronate; 6-amino-1-hydroxyhexane-1,1-diphosphonic acid, for example, aminohexyl-BP; 3-(N-methyl-N-the-pentylamine)-1-hydroxypropane-1,1-diphosphonic acid, for example, methylpentyl-APD(=VM 21.0955); 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid, for example, zoledronicaa acid; 1-hydroxy-2-(3-pyridyl)ethane-1,1-diphosphonic acid (risedronate acid), e.g. risedronate, including N-methylpyridinium salt, for example, iodides N-methylpyridine, such as NE-10244 or NE-10446; 3-[N-(2-phenylthiomethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonic acid; 1-hydroxy-3-(pyrrolidin-1-yl)propane-1,1-diphosphonic acid, e.g., EB 1053 (Leo); 1-(N-phenylenecarbonyl)methane-1,1-diphosphonic acid, e.g. FR 78844 (Fujisawa); tetraethyl ester of 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid, e.g., U 81581 (decision Upjohn); and 1-hydroxy-2-(imidazo[1,2-a]pyridine-3-yl)ethane-1,1-diphosphonic acid, for example, YM 529.

One of the embodiments of the invention are particularly preferred N-bisphosphonate for use in the invention includes a compound of formula II,

where Het means imidazole, oxazolyl, isoxazolyl, oxadiazolyl, thiazole, thiadiazole, pyridine, 1,2,3-triazole, 1,2,4-triazole or benzimidazole radical, which is optionally substituted by alkyl, alkoxyl, halogen, hydroxyl, carboxyla, amino, optionally substituted alkyl or alkanoyl radical or benzyl radical, optionally samisen the m-alkyl, the nitro-group, amino group or aminoalkyl;

A represents a saturated or unsaturated hydrocarbon residue with a straight or branched chain, containing from 1 to 8 carbon atoms;

X' denotes a hydrogen atom, optionally substituted by alkanoyl, or amino group, optionally substituted alkyl or alkanoyl radicals, and

R means a hydrogen atom or an alkyl radical, and its pharmacologically acceptable salts.

In another embodiment, the invention is particularly preferred bisphosphonate for use in the invention includes a compound of formula III,

where Het' denotes a substituted or unsubstituted heteroaromatic 5-membered ring selected from the group consisting of imidazolyl, imidazolyl, isoxazolyl, oxazolyl, oxazolyl, thiazolyl, thiazolyl, triazolyl, oxadiazolyl and thiadiazolyl, where the said ring may be partially providerone and where said substituents are selected from at least one of the groups consisting of (C1-C4)alkyl, (C1-C4)alkoxyl, phenyl, cyclohexyl, cyclohexylmethyl, halogen and amino, and where two adjacent alkyl substituent Het may together form a second ring;

Y means hydrogen or (C1-C4)alkyl;

X represents hydrogen, hydroxy is, the amino group or the amino group, substituted (C1-C4)alkyl, and R means hydrogen or (C1-C4)alkyl;

and its pharmacologically acceptable salts, and isomers.

In another embodiment, the invention is particularly preferred bisphosphonate for use in the invention includes a compound of formula IV,

where Het"' means imidazolidinyl, 2H-1,2,3-, 1H-1,2,4 - or 4H-1,2,4-triazoline, tetrazolyl, oxazolidinyl, isoxazolyl, oxadiazolyl, diazolidinyl or thiadiazolyl radical which is not substituted or is mono - or disubstituted on the carbon atom lower alkyl, (ness.)alkoxyl, phenyl which, in turn, may be mono - or Disaese lower alkyl, (ness.)alkoxyl and/or by halogen, hydroxyl, di(ness.)alkylaminocarbonyl, (ness.)alkylthiophene and/or halogen, and substituted by able to have a Deputy to the nitrogen atom by lower alkyl or phenyl(ness.)the alkyl, which, in turn, may be mono - or di-substituted on the phenyl residue of a lower alkyl, (ness.)alkoxyl and/or halogen, and

R2 means hydrogen, hydroxyl, amino, (ness.)allylthiourea or halogen, lower radicals containing up to 7 carbon atoms, inclusive, or its pharmacologically acceptable salt.

Examples of particularly preferred N for use according to the invention are:

2-(1-Mei-2-yl)-1-hydroxyethane-1,1-diphosphonic acid;

2-(1-benzylimidazole-2-yl)-1-hydroxyethane-1,1-diphosphonic acid;

2-(1-Mei-4-yl)-1-hydroxyethane-1,1-diphosphonic acid;

1-amino-2-(1-Mei-4-yl)ethane-1,1-diphosphonic acid;

1-amino-2-(1-benzylimidazole-4-yl)ethane-1,1-diphosphonic acid;

2-(1-Mei-2-yl)ethane-1,1-diphosphonic acid;

2-(1-benzylimidazole-2-yl)ethane-1,1-diphosphonic acid;

2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid;

2-(imidazol-1-yl)ethane-1,1-diphosphonic acid;

2-(4H-1,2,4-triazole-4-yl)-1-hydroxyethane-1,1-diphosphonic acid;

2-(thiazol-2-yl)ethane-1,1-diphosphonic acid;

2-(imidazol-2-yl)ethane-1,1-diphosphonic acid;

2-(2-Mei-4(5)-yl)ethane-1,1-diphosphonic acid;

2-(2-phenylimidazol-4(5)-yl)ethane-1,1-diphosphonic acid;

2-(4,5-dimethylimidazole-1-yl)-1-hydroxyethane-1,1-diphosphonic acid and

2-(2-Mei-4(5)-yl)-1-hydroxyethane-1,1-diphosphonic acid and their pharmacologically acceptable salts.

The most preferred N-bisphosphonates for use in the invention is 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid (zoledronicaa acid) or its pharmacologically acceptable salt.

Pharmacologically acceptable salts are preferably salts with bases, suitable metal salts entering them in groups Ia, Ib, IIa and IIb of the Periodic System of Elements, including alkali metal salts, for example, potassium and especially sodium salts, or salts of alkaline earth metals, preferably calcium or magnesium salts, and also ammonium salts with ammonia or organic amines.

Particularly preferred pharmaceutically acceptable salts are those in which one, two, three, or four, in particular one or two, of the acidic hydrogen atoms bisphosphonates acid replaced by a pharmaceutically acceptable cation, in particular sodium, potassium or ammonium, primarily sodium.

Very preferred group of pharmaceutically acceptable salts is characterized by the presence of one acidic hydrogen atom and one pharmaceutically acceptable cation, in particular sodium, each of the acid groups, phosphonic acid.

All the above-mentioned derivatives of N-bisphosphonates acid is well known from the literature. This includes obtaining them (see, for example, the application for the European patent EP-A-513760, pp. 13-48). For example, 3-amino-1-hydroxypropane-1,1-diphosphonic acid is obtained, as described, for example, in U.S. patent No. 3962432, and the disodium salt as described in U.S. patent No. 4639338 and 4711880, and 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid is obtained, as described, for example, in U.S. patent No. 4939130. Cm. the U.S. patents 477763 and 4687767.

N-Bisphosphonates can be used in the form of an isomer or mixture of isomers, when it comes, usually in the form of optical isomers, such as enantiomers or diastereoisomers, or geometric isomers, typically CIS-TRANS isomers. Optical isomers receive in the form of pure antipodes and/or racemates.

N-Bisphosphonates may also be used in the form of their hydrates or may include other solvents used for crystallization.

N-Bisphosphonates preferably used in the form of pharmaceutical compositions that contain a therapeutically effective amount of the active ingredient optionally together with or in a mixture with inorganic or organic, solid or liquid pharmaceutically acceptable carriers suitable for use.

The pharmaceutical compositions can be, for example, compositions for insertion through the small intestine, as, for example, orally, through the rectum, by aerosol inhalation or injection through the nose, compositions for parenteral administration, such as intravenous or subcutaneous administration, or compositions for percutaneous administration (for example, passive or using electrophoresis).

Preferably the pharmaceutical composition adapted for oral or parenteral (especially intravenous, vnutriarterialno the aqueous or percutaneous) introduction. Intravenous and oral administration, and especially intravenously, are regarded as especially important. Preferably the active ingredient which is N-bisphosphonates, is in a form for parenteral administration, most preferably in a form for intravenous injection.

The specific route of administration and dosage can be chosen when visiting a doctor, taking into account characteristics of the patient, in particular, age, weight, lifestyle, activity and condition of the disease, as the most important factors. Most preferably, however, N-bisphosphonate administered intravenously.

The dosage of N-bisphosphonates for use in the invention may depend on various factors, such as efficacy and duration of action of the active ingredient, route of administration, the species of warm-blooded animals and/or gender, age, weight and individual condition of the warm-blooded animal.

Usually, the dose is selected so that a single dose bisphosphonate active ingredient from 0.002 to 20.0 mg/kg, in particular 0.01 to 10.0 mg/kg, was administered warm-blooded animal weighing approximately 75 kg If desirable, this dose can also be given in the form of several, not necessarily the same partial doses.

The notation "mg/kg" means the number of mg of drug per kg of body weight of a mammal, including humans, exposed to l is teaching.

The above-mentioned dose, or entered as a single dose (preferred), or in several partial doses, can be re-introduced, for example, once every day, once weekly, once every month, once every three months or less often. In other words, the pharmaceutical compositions can be administered schemes, covering ranges from continuous daily therapy to intermittent therapy cycles.

Preferably N-bisphosphonates administered in doses of the same magnitude as the dose used in the treatment of malignant disorders amenable to the classical treatment of derivatives bisphosphonates acid, for example, tumor-induced hypercalcemia or bone metastases in MM or breast cancer. In other words, preferably derivatives of N-bisphosphonates acid injected in doses that would be similarly therapeutically effective in the treatment of tumor-induced hypercalcemia or bone metastases in MM or breast cancer, that is preferably they are added in doses, which would also effectively inhibited bone resorption and invasion and growth of metastases.

Finished dosage forms in the form of a standard single dose preferably contain from about 1% to about 90% of the active ingredient and finished dosage forms are not in the form with andartes single dose preferably contain from about 0.1% to about 20% of the active ingredient. Form of a standard single dose for oral administration, such as capsules, tablets or coated tablets contain, for example, from about 1 mg to about 500 mg of the active ingredient.

Pharmaceutical preparations for insertion through the small intestine and for parenteral administration are, for example, those presented in the pharmaceutical forms with the standard dose, as, for example, pills, tablets or capsules and also ampoules. They are made known fact follows, for example, by conventional mixing, granulating, the preparation of drugs mixed with honey or syrup, dissolution or lyophilization. For example, pharmaceutical preparations for oral administration can be obtained by mixing the active ingredient with solid carriers, when the granulating the resulting mixture and processing the mixture or granulate, if desired or necessary after the addition of suitable auxiliary means in the internal contents of the tablets or pills.

Suitable carriers are in particular fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, preparations of cellulose and/or calcium phosphates, for example tricalcium phosphate or secondary acidic calcium phosphate, and also binders, such as starch the paste, using, for example, corn, wheat, rice or potato starch, gelatin, tragant, methylcellulose and/or polyvinylpyrrolidone and, if desired, disintegrators, such as the above-mentioned starches, also carboximetilkrahmal, polyvinylpyrrolidone cross-stitching, agar or alginic acid or its salt, such as sodium alginate. Auxiliary means are mainly regulating the turnover of funds and lubricants, for example silicic acid, talc, stearic acid or its salts, such as magnesium stearate or calcium, and/or polyethylene glycol. The internal contents of the pills provide suitable coatings that may be resistant to gastric juices, using, inter alia, concentrated sugar solutions, which may not contain the Arabian gum, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or solutions in suitable organic solvents or mixtures of solvents for the coating of glaze, or to obtain resistant to gastric juice coatings, solutions of suitable preparations of cellulose, such as cellulose acetate phthalate or phthalate of hydroxypropylmethylcellulose. Dyes or pigments can be added to the coating for the tablets or coated tablets, for example, with the purpose of the identifier is tion or to indicate different doses of active ingredient.

Other oral input pharmaceutical preparations are prepared from gelatin capsules with a dry content and also soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Capsules with a dry content can contain the active ingredient in the form of a granulate, for example, in a mixture with fillers, such as lactose, binders, such as starches, and/or means, which imparts lubricity, such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it is also possible to add stabilizers.

Finished dosage forms for parenteral administration are primarily injectable fluids that are effective with the introduction of various ways, as, for example, intravenously, intraarterially, intramuscularly, intraperitoneally, intranasally, intradermally, subcutaneously, preferably intravenously. Such liquids are preferably isotonic aqueous solutions or suspensions which can be prepared before use, for example, from liofilizovannyh medications that contain is only one active ingredient or together with a pharmaceutically acceptable carrier. The pharmaceutical preparations can be sterilized and/or may contain auxiliary agents, such as preservatives, stabilizers, humectants and/or emulsifiers, soljubilizatory, salts for regulating osmotic pressure and/or buffers. The preferred forms for parenteral administration are solutions for intravenous infusion, preferably containing from about 1 mg to about 20 mg of the active substance in a single standard dose of, for example, in the solution for infusion volume of about 5 to 200 ml, for example, for infusion over a period of time from about 1 minute to about 1 hour or more. Such preferred form for parenteral administration is generally entered at intervals of approximately once per week to about once per 3 months.

N-Bisphosphonates for use in the invention can be administered in combination with other active substances or therapies used to treat prostate cancer, and associated metastases.

Thus, the invention includes a method of treating prostate cancer, covering a combined treatment with N-bisphosphonates and other means against prostate cancer, or anti-cancer therapy of a prostate gland.

The invention further includes the combination is stimulated composition for simultaneous, separate or combined treatment of prostate cancer, comprising an effective amount of N-bisphosphonates and effective amount of another anti-prostate cancer.

Suitable means against prostate cancer include cytotoxic chemotherapeutic agents such as doxorubicin, daunorubicin etc., cisplatin, etc., Taxol, hormonal agent, for example, LHRH and its analogues, steroids and modifiers biologic response.

Suitable therapy against prostate cancer include radiation therapy to treat tumors vasculites and/or skeletal localization.

Other therapeutic agents that may be used in combination with N-bisphosphonates in the treatment of prostate cancer, are described further in the section "Description of clinical trials".

Suitable finished dosage forms for transdermal application include an effective amount of the active ingredient with the carrier. Useful carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host body. Usually percutaneous devices exist in the form of a bandage comprising a supporting member, a reservoir containing the compound optionally with carriers, optionally with the reg is yuushi speed barrier for delivery of the active ingredient from the skin of the host body with a controlled and predetermined rate over a prolonged period of time, and targeting in order to secure the attachment device to the skin.

The following examples illustrate the invention described above. In the following examples, the term "active ingredient" should be understood as any of the derivatives of N-bisphosphonates acid, mentioned above, used according to the present invention.

Examples

Example 1: Capsules containing coated pills active ingredient, for example, pentahydrate disodium salt pamidronic acid as the active ingredient:

The core of pills:

Active ingredient (base)197,3 mg
Microcrystalline cellulose52,7 mg
(Avicel® pH 105)

+ Internal coating:

Cellulose HP-M 60310.0 mg
The polyethylene glycol2.0 mg
Talc8.0 mg

+ Resistant to gastric juice outer coating:

Eudragit®L 30 D (solid)90,0 mg
Tricylcic is at 21,0 mg
The non®AF2.0 mg

Water

Talc7,0 mg

The mixture of active ingredient, for example, disodium salt pamidronic acid, avicula®pH 105 moistened with water and mixed, extruded from a syringe, form balls of spherical shape. Dried pills then cover in the fluidized bed inner coating consisting of cellulose HP-M 603, polyethylene glycol (PEG) 8000 and talc, and water resistant to gastric juice coating comprising Eudragit® L 30 D, teeterboro ester of citric acid and non®AF. The pills are coated sprinkle talcum powder and fill these capsules (capsule size 0) using a serial machine for filling capsules, for example, machine Hafliger and Hag.

Example 2: Monolithic adhesive transdermal system containing as the active ingredient, for example, 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid:

Composition:

Polyisobutylene (PIB) 3005,0 g

(Oppanol B1, BASF)

PIB 350003.0 g

(Oppanol 10, BASF)

PIB 12000009.0 g

(Oppanol 100, BASF)

hydrogenated hydrocarbon resin43,0 g

(Escorez 5320, Exxon company)

1-dodecylsulfate-2-he20,0 g

(Azone, firm Nelson Res., Irvine/CA)

the active ingredient
Only100.0 g

Preparation:

The above ingredients together dissolved in 150 g of boiling at a certain temperature boiling petroleum fractions 100-125 by prokachivanija on a roller deck with a drive device. The solution was applied on a polyester film (Hostaphan, Kalle) using tool for distribution, using the doctor blade (300 mm), giving a coverage of about 75 g/m2. After drying (15 minutes at 60° (C) is applied as the Stripping film processed silicon polyester film (thickness 75 mm, Laufenberg). Prepared system stamp in the desired shape and size from 5 to 30 cm2using the press device. Prepared system sealed separately in sachets of aluminium the authorized paper.

Example 3: a Vial containing 1.0 mg dry liofilizovannyh 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid (mixture of its sodium salt). After diluting 1 ml of water get solution (concentration 1 mg/ml) for intravenous infusion.

Composition:

active ingredient (free diphosphonic acid)1.0 mg
mannitol46,0 mg
trinacria salt of citric acid
in the form of dihydrate about3.0 mg
water1 ml
water for injection1 ml

In 1 ml of water active ingredient titrated dihydrate trinational salt of citric acid to a pH of 6.0. Then add mannitol and the solution is subjected to lyophilization, freeze-dried is placed into the vial.

Example 4: a Vial containing the active ingredient, for example, pentahydrate disodium salt pamidronic acid dissolved in water. Solution (concentration 3 mg/ml) is used for intravenous infusion after dilution.

Composition:

the active ingredient19,73 mg

(5.0 mg of anhydrous active ingredient)tab

mannitol250 mg
water for injection5 ml

Description of clinical trials

1. The objectives of the study

The first aim of this study is to evaluate the effectiveness of treatment zoledronate acid (4 mg or 8 mg) in addition to antitumor therapy compared with only one anti-tumor therapy to prevent the emergence associated with changes in the bones of skeletal events in patients with prostate cancer with metastatic bone disease in history, whose disease progressed according to biochemical data [i.e. the observed increased level of prostate specific antigen in serum (PSA)], despite hormonal first-line therapy for metastatic disease.

Associated with changes in the bones of the skeleton events (SRE) is defined as pathologic fractures, the phenomenon of compression of the spinal cord, the effects in the bone surgery, radiation therapy bone (including the use of radioisotopes) and at change of antineoplastic therapy to treat bone pain. Thus, SRE are the primary endpoints in this study. Key endpoints of the assessment of efficiency is the proportion of patients with at least one SRE and time to the first SRE.

Utoro is the aim of the study is to assess the impact of therapy zoledronate acid on pain indicators, on the use of analgesic money on vitality indicators of life quality, on time completion of participation in active research and evaluate the safety and tolerability of zoledronate. Assess changes in bone resorption and formation markers. Density measurement of inorganic substances in bones are patients in the clinical centers. In addition, evaluating the time development of the disease in the bones and the time of full development of the disease.

The third objective of the study is to evaluate the use of health care data related production costs.

2. The plan of study

2.1. The General plan of the study

This study is an international, multicenter, randomized, double-blind experience with parallel control study using a placebo. A group of patients for this study consists of patients with prostate cancer with a history of disease, including metastatic bone disease, patients with increased concentration of PSA in syvorotke (see section 2.3.2), despite hormonal therapy as first-line treatment for metastatic disease. Elevated levels of PSA in serum is documented by three consecutive measurements of the increase in serum PSA (i.e. the third, Ural branch of the Yan PSA must be > the second level of PSA, which > the first level of PSA, which > very low concentrations of serum PSA achieved during hormonal therapy first-line metastatic prostate cancer), each dimension separated from each other, at least two weeks. Elevated levels of serum PSA is "early" phenomenon in the development of progressive metastatic disease. Although the growing lesion can be detected when studying x-ray bone (bone scan and/or examination of the bones), without affecting the eligibility of the patient for the study, patients who developed pain in the bones from the time that their best response to first-line hormonal therapy for metastatic disease prior to the study (visit 2 - the date of randomization and the start of study drug therapy), are excluded from the study.

In addition, changes in hormonal schema first line before visit 1 (visit for screening) is also an exclusion criterion. In other words, the scheme of anticancer treatment may be changed during the study (including visits from 1 to 34) at the discretion of the attending physician, in addition to the use of cytotoxic chemotherapy to and including visit 2 (subsequent use of cytotoxic chemotherapy in the study time is asaeda). Other exclusionary criteria include (see section 2.3.2.) the level of serum testosterone at visit 1 above limits when castration (≥50 ng/ml), the use of radiation therapy for bone within three months from visit 2 (includes the application of radioisotopes) and prior or current (up to and including visit 2) the use of cytotoxic chemotherapy (the use of cytotoxic chemotherapy allowed during the study after visit 2 at the discretion of the treating physician).

Patients are selected by randomization using a double-blind experience for the introduction of either 4 mg zoledronate intravenously or 8 mg zoledronate intravenously or carry out intravenous infusion of placebo every three weeks in addition to antitumor therapy. The assigned value in the randomized treatment should be 1:1:1. In addition, all patients should receive 500 mg of oral calcium and multivitamin tablet (containing 400-500 ON vitamin D) daily throughout the study.

Discovered phenomena associated with changes in the bones of the skeleton (SRE)register and take into account during the study for each patient to determine the percentage of patients who showed at least one SRE, to determine the time to first SRE and the velocity of propagation associated with skel is the fact painful phenomena (see section 4). The time development of the disease in the bones centrally assessed (chief radiologist) by reviewing serial radiographic studies. The time of full development of the disease is determined by the attending physician of the patient: by conducting centralized estimates (main rengenology) serial radiographic examinations of the bones; by conducting centralized assessments (chief radiologist) corresponding serial radiographic studies locations noskeletnih tumors, if they are available; by definition serial serum PSA levels and by evaluating serial measurements of weight of patients. Quality of life, health status, use of health care and related costs, pain and indicators on the use of analgesics define the series in the course of the study. This information is also collected for those patients who cease active treatment within 24 months from the date of randomization to the study. Information about adverse events observed during the treatment of patients, collected throughout the study.

Methodology the study will be performed with prerandomization visits for examination (visit 1), which can last up to 14 days for the BA is easen estimates. The randomization was performed at visit 2 prior to study drug administration after reviewing the data it needs and after a full examination and making that assessment. The study is being conducted in two phases, phase 1, phase efficacy and safety, and phase 2, an extended phase. The primary efficacy analysis carried out on completion of phase 1, phase efficacy and safety, including 60 weeks (20 cycles) study treatment. Phase 2 includes an additional 36 weeks (12 cycles) study treatment. The first objective of phase 2 is to ensure the safety of long-term treatment zoledronate and receiving data on survival, however, efficacy data continue to accumulate. At least, registering five hundred and fifty patients to ensure 519 patients (173 patients in group processing)that meet the criteria for treatment according to the Protocol. No preliminary analyses are planned.

Patients are not excluded from the study only because of the discovery associated with changes in the bones of the skeleton occurrence or progression of the disease during the study, as the study aims to evaluate the total number associated with changes in the bones of the skeleton of the phenomena that take place throughout the ongoing study (24 months). To the ome this, anticancer therapy may be changed without becoming a cause of temporary exclusion of patients from the study. Patients who stopped therapy, continue to explore the purpose of data collection associated with changes in the bones of the skeleton phenomena, the development of the disease, anticancer therapy, the use of health care and related production costs, quality of life, pain and indicators related to analgesic funds.

Regarding survival data are collected for each patient randomly selected for the study, and collected at intervals of 6 months after the patient has ceased to do research, to 24 months after the first visit referred the patient to participate in the study.

In tables 1-2 summarize the research plan:

*After visiting 2 related research visits should take place on a set day of the study with a deviation of not more than from -3 to + 7 days.

The duration of the study

The time allowed for registration of patients: 12 months

The duration of participation of the individual patient:

15 months (60 weeks) phase 1

9 months (36 weeks) phase 2

The total duration of treatment: 24 months (96 weeks)

General prodoljitel the ability of the study: 36 months.

2.2. The studied population

2.2.1 Criteria for inclusion and exclusion

Criteria for inclusion

- Signed consent to the information received.

- Patients 18 years of age or older.

- Histologically confirmed diagnosis of prostate cancer.

- Patients must have or had objective evidence of metastatic bone disease. Objective evidence of metastatic bone disease is defined as multiple foci (>3) increased activity on bone scan. If there ≤3 foci of increased activity on bone scan, additional radiographic studies or data biopsy to confirm the presence osteopatichesky or osteolytic malignant bone lesions. Patients who had achieved a complete response to hormonal therapy first line and the current scan in normal bone, still have the right to be registered for this study because of bone metastases have been previously documented during the course of a clinical study of the patient.

- Patients must be demonstrated biochemical disease progression despite therapy with hormonal first-line treatment (medical or surgical whom I castration). Biochemical disease progression is determined as follows.

Three dimensions of successively higher serum PSA, each separated from each other, at least two weeks. The third dimension of serum PSA should be ≥0.4 ng/ml.

Hormone therapy first-line metastatic disease is defined as follows.

The original scheme of hormonal treatment used to treat metastatic prostate cancer. Hormonal therapy is conducted in a set neoadjuvant or adjuvant when there is no clinical evidence of metastatic disease, will not be considered as hormonal first-line therapy for metastatic disease according to the objectives of this study.

- The patient must have an effective status according to electrocorticogram (ECOG) 0,1 or 2.

Exclusionary criteria

- Bone pain due to metastatic bone disease developed since the best response to hormonal therapy first-line metastatic disease.

- Prior or current (up to or including visit 2) treatment with cytotoxic chemotherapy (subsequent use of cytotoxic chemotherapy during the study allowed).

- Hormonal replacement therapy the first Lin is and the outline of hormonal therapy second-line prior to visit 1 (subsequent change in hormonal therapy in a patient during the visit 1 or during the study not an exclusion criteria or a violation of Protocol).

- The level of serum testosterone (at visit 1) above the level of castration (≥50 ng/ml).

- Radiation therapy to bone (including radioactive isotopes) within 3 months prior to visit 2.

- Pre-treatment bisphosphonates tool.

Therapy calcitonin, mithramycin or gallium nitrate for 2 weeks prior to the date of randomization (visit 2).

- The use of other investigational drugs (drugs not intended for any indication) within 30 days prior to the date of randomization (visit 2).

- Failure modes medication history and patients who are treated according to the researcher, as potentially untrustworthy or incapable of giving informed consent.

The concentration of creatinine in serum >3.0 mg/DL (265 µmol/l).

- Adjusted (adjusted for serum albumin) concentration of calcium in serum <8.0 mg/DL (2.00 mmole/l) or ≥ 11.6 mg/DL (2,90 mmole/l).

- Any other neoplasm in history in the last five years, except nemelkokletochnogo skin cancer.

- Patients with confirmed severe cardiovascular disease, occurred in the period of 6 months prior to randomization (defined as an uncontrollable heart failure with for the fully phenomena), with not curable hypertension or with symptomatic coronary artery disease.

2.3. Therapy

2.3.1. Therapy with the use of the investigational medicinal product and standard therapy

Patients enter zoledronate or placebo by 5-minute intravenous infusion every three weeks for 24 months.

The patients received 500 mg of calcium intake from food every evening during the study. Calcium is supplied by the research Department in the form of a medicinal product with the attached label. Each package has affixed to it a label with instructions to take one dose daily in the evening during meals". Patients also receive one multivitamin tablet for oral administration daily in the morning during the research provided by the research Department in the form of a medicinal product with the attached label. Each pack is supplied attached to it a label with instructions to take one dose daily in the morning while eating".

The investigational medicinal product (zoledronate) comes pharmacist in each centre. The drug is packaged in the usual way with attached on the outside label. Labels for medicines meet the legal requirements of each country and are printed in the language of the country. They are not nagauta information on the patient.

The name and dose of the medicinal product provided on each bottle.

Zoledronate is supplied in vials containing 4 mg of liofilizirovannogo product (4000 mcg).

The test substance is stored in a lockable place in each center until, when he returned to the firm Novartis at the end of the study. The pharmacist is responsible for the preparation of the investigational medicinal product. Documentation of the use of the investigational product and amount received for each visit, is stored for each patient.

If the prepared solutions zoledronate may not be used immediately, they should be cooled and stored at temperatures 36-46°F (2-8° (C), the solutions can be used within eight hours.

As zoledronate can harden on the glass, the solutions of the investigational medicinal product should be prepared in plastic syringes, bottles and tubes. Zoledronate administered intravenously to each patient by a 5-minute infusion. Zoledronate 4 mg of each vial are dissolved in 5 ml of sterile water for injection. An appropriate volume of the prepared zoledronate mixed with an appropriate volume of saline (0.9%) saline to a total volume flow of the solution was 50 ml Each patient will get the same thing the investigational medicinal product and the same dose throughout the study (visit 2-33) depending on the processing group, to which it is assigned.

Therapy in groups provides (table 3)

4 mg of zoledronate in 50 ml of isotonic solution for intravenous infusion every 3 weeks plus 500 mg of calcium taken orally with meals (daily), and one multivitamin tablet taken orally daily;

8 mg of zoledronate in 50 ml of isotonic solution for intravenous infusion every 3 weeks plus 500 mg of calcium taken orally with meals (daily), and one multivitamin tablet taken orally daily;

placebo in 50 ml of isotonic solution for intravenous infusion every 3 weeks plus 500 mg of calcium taken orally with meals (daily), and one multivitamin tablet taken orally daily.

Table 3
The study in 3 groups double-blind experience
Drug therapyVisitingThe total number of # vialsThe volume of the prepared solution doseAdded volume of isotonicTotal inflow volume
Zoledronate 4 mg isotonic, intravenously every 3 weeks2-331 vial containing 4.0 mg/vial, dissolution of p is avodat sterile water for injection 5 ml/vial 5.0 ml45 ml50 ml
Zoledronate 8 mg isotonic, intravenously every 3 weeks2-332 bottles with 4.0 mg/vial, dissolution is carried out with sterile water for injection 5 ml/vial10 ml40 ml50 ml
Placebo in isotonic, intravenous, number 3 weeks2-33not usednot used50 ml50 ml

Originally performed infusion of 50 ml for 5 minutes; after that he made the change and perform the infusion of 100 ml for 15 minutes with the purpose of increasing security for the kidneys. Further amendment in accordance with the Protocol provided for the reduction of the dose by zoledronate acid group with a dose of 8 mg to 4 mg to Patients who have already received 8 mg, reduced the dose on subsequent visits, and patients re-randomized to group with a dose of 8 mg, received only 4 mg.

2.4. Concomitant therapy

Permitted the following types of therapy:

Standard antineoplastic therapy, including commercially available cytotoxic chemotherapeutic drugs, hormonal drugs, steroids and biological response modifiers.

Standard radiation therapy for the treatment of vasculitic and/or skel is the shaft tumour sites.

Standard commercially available funds representing the cytokine/ colony-stimulating factor.

Therapy commercially available medicines, except those on which you can expect harmful effects on osteoclast activity (e.g., calcitonin, mithramycin, gallium nitrate, any other bisphosphonates). So, if the attending physician determines that a medical condition studied a patient (e.g., osteoporosis or tumor induced hypercalcemia) requires the use of an inhibitor osteoclastic bone resorption, it is necessary to stop the active participation of the patient in the study and the patient should be monitored with respect to the data on the phenomena associated with changes in the bones of the skeleton (see section 2.3.3).

- Corticosteroid therapy in the case of spinal cord compression or other of the detected indications.

3. RESULTS

At least one associated with changes in the bones of the skeleton phenomenon was discovered at 33.2% and 38.5% of patients in the groups receiving 4 mg of zoledronate acid (N=214) and 8/4 mg of zoledronate acid (N=221), compared to 44.2 per cent in the placebo group (N=208, p=0,021 and 0,222 against placebo). Pathological fractures were observed in 13,1% and 14.9% of patients in the groups receiving 4 mg and 8/4 mg of zoledronate acid, and 22.1% of the patients from the group treated with placebo (p=0.015 and p=0.054 vs. placebo). Sredneural to the first phenomenon, associated with changes in the bones of the skeleton, was not reached in the group treated with 4 mg of zoledronate acid, and was 363 and 320 days in the groups receiving 8/4 mg, and placebo, respectively (p=0.011 and 0,491 against placebo). Zoledronicaa acid 4 mg, pour in for 15 minutes, was well tolerated.

Infusion of 4 mg of zoledronate acid for 15 minutes every 3 weeks significantly reduced associated with changes in the bones of skeletal events in patients with metastatic prostate cancer, poorly amenable to hormonal therapy.

1. The use of N-bisphosphonates in the preparation of drugs for the treatment of osteopatichesky metastases associated with prostate cancer.

2. The use according to claim 1, in which enter in the composition of the medicinal product N-bisphosphonate use in addition to antitumor therapy.

3. The use according to claim 1 or 2, in which N-bisphosphonate compound represented by formula I

where X is hydrogen, hydroxyl, amino, alkanoyl or amino group, substituted (C1-C4)alkyl or alkanoyl;

R means hydrogen or (C1-C4)alkyl; and

Rx means a side chain that contains optionally substituted by an amino group, or a nitrogen-containing heterocycle (including Aro eticheskie nitrogen-containing heterocycles), or its pharmaceutically acceptable salt or any hydrate.

4. The use according to claim 1 or 2, in which N-bisphosphonate means one of the following compounds or pharmaceutically acceptable salt or any hydrate: 3-amino-1-hydroxypropane-1,1-diphosphonic acid(pamidronate acid); 3-(N,N-dimethylamino)-1-hydroxypropane-1,1-diphosphonic acid, (alendronate acid); 1-hydroxy-3-(methylpentylamino)propylaminosulfonyl acid (ibandronate acid); 6-amino-1-hydroxyhexane-1,1-diphosphonic acid; 3-(N N-methyl-N-n-pentylamine)-1-hydroxypropane-1,1-diphosphonic acid; 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid; 1-hydroxy-2-(3-pyridyl)ethane-1,1-diphosphonic acid (risedronate acid); 3-[N-(2-phenylthiomethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonic acid; 1-hydroxy-3-(pyrrolidin-1-yl)propane-1,1-diphosphonic acid; 1-(N-phenylenecarbonyl)methane-1,1-diphosphonic acid, tetraethyl ester of 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid and 1-hydroxy-2-(imidazo[1,2-a]pyridine-3-yl)-ethane-1,1-diphosphonic acid.

5. The use according to claim 1 or 2, which used N-bisphosphonate is a 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid (zoledronic acid) or its pharmacologically acceptable salt.



 

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 1 tbl, 69 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out 5-10 sessions of general magnetotherapy beginning from 3-rd day after surgical intervention in static mode: magnetic field rotation frequency is equal to 100 Hz, magnetic field intensity of 30 oersted, magnetic field shape is sinusoid half-cycle, raising time being equal to 30 s, time of recession 30 s; the number of procedures is equal to 15. Then, remote radiation therapy is administered 4 weeks later after surgical intervention. The treatment is applied to removed kidney bed and lymphatic collectors in single stage in classical fractioning mode at a doze of 2 Gy 5 times a week within 5 weeks up to reach total doze of 50 Gy with general magnetotherapy being concurrently applied in 1 session per day mode, the number of procedures being equal to 25. The first biotherapy course with recombinant human alpha tumor necrosis factor (TNF-α) is given at a dose of 2 mln units 2 weeks later after the radiation therapy being done. Total З biotherapy courses are to be given with 21 days long pause available between the courses.

EFFECT: enhanced effectiveness of treatment; reduced risk of postoperative complications; increased immune activity.

FIELD: medicine.

SUBSTANCE: method involves excising basic tumor as one-stage operation by means of high-energy СО2 laser or cytoreduction operation is carried out (basic tumor component removal) using laser output power of 20-40 W at the first stage. Remote photodynamic therapy is applied by irradiating the whole vulva surface with radiation dose of 100-150 J/cm2, power density of 50-70 mW/cm2 and irradiating tumor localization zone with radiation dose of 200-300 J/cm, power density of 150-200 mW/cm at the second stage. Additional interstitial laser irradiation with radiation dose of 200-300 J is optionally carried out at radiation power of 200-300 mW in tumor invasion zone.

EFFECT: enhanced effectiveness of organ-retaining and sparing treatment; accelerated treatment course; reduced risk of postoperative complications.

2 cl

FIELD: medicine, oncology.

SUBSTANCE: during the first day of therapy it is necessary to affect the lesion focus with alternating magnetic field at induction being 5-160 mTl, frequency of 50-100 Hz for about 7-10 min. Out of peripheral vein one should sample blood into two vials with hemoconservant per 100 ml/each; one vial should be supplemented with doxorubicin at the dosage of 50 mg/sq. m, the second vial - with 5-fluorouracil 750 mg/sq. m. Both vials should be incubated. Then it is necessary to inject intravenously by drops the content of the first, and then of the second vial for a patient. During the period since the first day up to the seventh one it is necessary to introduce cyclophosphan intramuscularly per 200 mg/sq. m. Since the first up to the tenth day of therapy one should affect with alternating and direct magnetic field. On the eighth day after seances of magnetic therapy one should repeatedly introduce anti-tumor chemopreparations at the same dosages and sequence. In two weeks it is necessary to repeat the above-mentioned curative impacts. In two weeks after the last introduction of chemopreparations one should fulfill surgical removal of lesion focus. The innovation enables to avoid side toxic manifestations of chemopreparations and notching of sutures and, also, healing due to secondary tension.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: pharmaceutical industry, in particular agent having cytostatic and apoptosis-inducing activity.

SUBSTANCE: claimed agent represents β-Asparagine, obtained by extraction of ground burdock roots having specific particle size with heated water in specific raw materials/extractant ratio; decoction, extract separation, concentration up to dry residue in concentrate, filtering, and double recrystallization.

EFFECT: agent with high cytostatic and apoptosis-inducing (anti-tumor) activity.

5 dwg, 2 tbl

FIELD: medicine, oncology.

SUBSTANCE: method involves carrying out lumbal puncture to a patient in post-operative period, subarachnoid space is catheterized, and 5 ml of liquor is removed followed by incubation of liquor with nimustine taken in the dose 5 mg in vitro at temperature 38°C for 30 min, and liquor is administrated into subarachnoid space through catheter. Procedure is carried out 2 times with interval for 7 days. Since the second day after onset of this procedure distant gamma-therapy on bed of removed tumor is carried out up to the total focus dose 60 Gr. Method provides stable remission, decreasing toxicity of chemopreparation, frequency of adverse by-side effects and significant reducing the cost of chemotherapy. Invention can be used in carrying out the adjuvant chemoradiation therapy of brain malignant glial tumors.

EFFECT: improved method of chemoradiation therapy, enhanced effectiveness of method.

1 ex

FIELD: medicine, oncology, gynecology.

SUBSTANCE: method involves trepanopuncture of flank bone wing, aspiration of bone marrow suspension in the amount 150-200 ml followed by incubation of suspension with chemopreparations cisplatin and cyclophosphan at temperature 37°C for 40 min in doses above therapeutic ones. Doxorubicin is not incubated with bone marrow suspension and chemopreparations are administrated separately by intravenous route, by drops in indicated order in day when the bone marrow suspension has been taken, and this procedure is repeated with interval for 3-4 weeks but totally 4 times per one treatment course. Proposed method provides attaining the stable anti-tumor effect up to the complete tumor regression in this category of patients showing high tolerance to chemotherapy, and in practical absence of adverse toxic responses. Invention can be used in treatment of patients with relapses of ovary and uterus body cancer in case absence effectiveness of other methods of treatment or in case of their low effectiveness.

EFFECT: improved method of treatment.

2 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method for increasing osseous mass in osteoporosis disease. Method involves using sets containing standard doses of bisphosphonates in the amount sufficient for using in "impact" period from 7 to 180 days, and standard doses of bisphosphonate for the following using in supporting period. Bisphosphonate is chosen from group consisting of risedronate, alendronic acid, pamidronate, tiludronate, clodronate, cimadronate, ibandronate, zoledronate and their salts and esters. Standard doses of bisphosphonate in "impact" period are by 3-6 times higher as compared with standard doses of bisphosphonate in supporting period. Using sets of bisphosphonates in the given ratio of doses in "impact" and supporting periods provides increasing the osseous mass in osteoporosis of different genesis.

EFFECT: improved treatment method.

6 cl, 4 ex

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