Method for applying photon-capturing tumor therapy

FIELD: medicine.

SUBSTANCE: method involves introducing means containing heavy elements into tumor and expose it to X-ray radiation. A heavy chemical element having number of 53, 55-83 is used. The means contains one or several of said elements with additional ligand introduced as iminodiacetic acid or its derivatives or crownethers or porphyrins and a water-soluble polymer. The means is introduced in systemic or direct way into tumor with following X-ray irradiation of power of 10-200 keV being applied.

EFFECT: increased photon therapy dose concentrated in tumor tissue with concurrently reduced radiation exposure upon the unaffected tissues.

4 cl, 4 dwg, 6 tbl

 

The invention relates to medicine, radiation therapy, and can be used for therapy of malignant tumors with the use of products containing heavy metals.

It is known that the cause of any radiation-induced effect is the absorbed radiation energy in the cells of the body. In particular, the interaction of photons with atoms that are part of the biological tissue, part of the energy of the primary radiation is converted into kinetic energy of the electrons, which produce a damaging effect on the cells of biological tissue. The magnitude of the radiation effect increases monotonically with the increase of the deposited energy in biological tissue.

Physical processes of the interaction of photons with biological tissue are well known. In the energy range of photons existing x-ray machines and therapeutic gamma settings of primary importance are the processes of energy transfer to electrons in the photoelectric effect and Compton scattering. In the photoelectric effect a photon is absorbed by an atom and released photoelectron certain energy. The act of acquisitions completed by the emission of low-energy photons (fluorescence emission) or the emission of Auger electrons with energies close to the ionization potential of the atom. Unlike the photoelectric effect, Compton races is eanie does not lead to the absorption of a photon: the part of the photon energy is converted into kinetic energy of the recoil electrons, and the rest in the energy of the scattered photon, which can further undergo acts of absorption.

It is known that the probability of the photoelectric effect increases significantly for chemical atoms with large nuclear charge Z (like Z4), but also decreases with increasing photon energy E (like E-3). Thus, there is a possibility of increasing the energy deposition in biological tissues (dose) when adding atoms of chemical elements with a large Z the irradiation of photons of a certain spectrum.

The energy transfer from photons to electrons environment is determined by the mass energy absorption coefficient. Absorbed dose is calculated by multiplying this factor by the flow energy of photon radiation in the considered environment. The dependence of the mass ratio of the photon energy for soft biological tissue (Zeff≈7.5) and individual atoms of chemical elements Z≥35 shown in figure 1.

From these data it follows that theoretically you can expect a noticeable increase in the dose of photons in biological tissue when adding heavy chemical elements with Z≥53 in the range of photon energies from ˜10 Kev to ˜200 Kev.

The main side effect in photon radiation therapy of malignant tumors is radiation damage to healthy tissues, pomatomus minimize such lesions suggested a number of ways.

There is a method of treating patients with locally advanced cancers, combining irradiation of the tumor by means of gamma radiation with the use of chemotherapeutic agents 5 - fluorouracil and cisplatin. 5-Fluorouracil is administered daily for 5 days to a total dose of 5 g, and then within 7-9 days daily administered cisplatin and lead area irradiation of the tumor by the photon radiation of gamma-therapeutic mode setup dynamic multifractional to a total dose in the irradiated target 30-32,4 Gr. After 10-12 days, repeat the treatment. While the total dose for the full course of treatment reaches to 64.8 Gy, and the duration of treatment is 36-40 days. [1]. The method allows to increase the radiosensitivity of tumor cells in the dynamic fractionation of the dose. The disadvantage of this method is the presence of toxic side effects with the introduction of cisplatin, the duration of treatment is about 36-40 days, the defeat of normal tissues and different degrees of radiation reaction.

A known method of high-energy therapy [2], according to which the tumor is injected halogenated derivatives of xantinol or their functional derivatives with different classes of natural or synthetic molecules, after which the target is irradiated with ionizing radiation with energies from 1 Kev to 1000 MeV. The disadvantages of the method are: Ogre is icanoe (iodine) using heavy atoms, wide and no reasonable interval used energy ionizing radiation, because the photoelectric effect as well-known physical phenomenon that manifests itself only in strictly defined and known values of the energies of the photon spectrum for each element with a particular value of Z. Therefore, these drawbacks reduce the unconvincing way to illustrate the manifestations of the well - known physical effect photoelectric effect, virtually eliminating the possibility of implementing the method in the clinic.

The known method pharmaceutical application radiation low energy, taken as a prototype [3], in which the tumor is injected with a contrast agent, which consists of atoms of iodine, gadolinium or gold, after which the tumor is irradiated with x-rays with energies from 30 to 150 Kev.

The disadvantage of the prototype method is the use of contrast media in unknown dosage form that does not stay in the irradiated target atoms of these elements at a high level. Special studies show that introduced into the tumor contrast media have a half-life of 9 to 18 min, while the session of the irradiation target x-ray emission lasts more than 10 minutes in Addition, to determine the amount of contrast agent in the tumor use sophisticated special equipment(CT scanner), therefore, since the introduction of the drug until completion of the session of irradiation is not less than 30 min, which reduces the dose of secondary radiation in the irradiated target - i.e. prototype method does not allow to obtain the maximum therapeutic effect. To obtain the effect using x-ray equipment with optimized or high-intensity beams, which complicates and limits the practical application of the method of the prototype in terms of clinics.

The technical problem on which the present invention is directed, is to increase the dose in photon therapy directly to the tumor tissue while reducing radiation exposure to normal tissue.

The problem is solved by the fact that in the method of photon-capture therapy of tumors, including irradiation of the tumor with ionizing radiation, according to the invention a heavy element with atomic number 53, 55-83 introduced into the preparation containing one or more of these elements and with additional content ligand in the form of iminodisuccinic acid or its derivatives, or crown ethers or porphyrin and water-soluble medical polymer; the drug is administered systemically or directly into the tumor and carry out the irradiation of x-rays with energies in the range from 10 to 200 Kev. The technical problem solved by the fact that as the effect is nski polymers used polyvinylpyrrolidon, dextran or polyethylene oxide, enter the product is a mixture of complex compounds of elements with atomic numbers 55-83 and water-soluble aromatic iodine compounds, and the amount of heavy element determined from calibration curves dose-concentration of elements in the tumor."

Necessary to achieve a positive result, the number of atoms of heavy elements in the tumor tissue and the degree of increase of the dose is determined using calibration curves based on the results of research on the phantom and the dose is in the range from 8 to 35 G, with the energy of x-ray radiation in the range from 10 to 200 Kev. The specified range is experimentally proved and is the range in which the effect of increasing doses in the presence of irradiated target elements with Z 53, 55-83.

A positive result obtained by the implementation of the proposed method the photon capture therapy, is to raise at least 20-30% of therapeutic efficacy of this method of radiation therapy in the reduction of not less than 20-30% of therapeutic dose of photon radiation while maintaining therapeutic efficacy.

The technology of preparation of the dosage form with supporting medical polymers, water-soluble complex compounds, the content is asih atoms of elements with atomic numbers (Z) 53, 55-83, inclusive, of the necessary normative-technical documentation and instructions for use. Technology of preparation of drugs and their application tested in the experiment with a positive result, which allows to consider the proposal the applicant meets the criterion of invention "industrial applicability".

Compared with the prototype of the proposed method differs preliminary introduction to the tumor complex compounds of metals and/or Organoelement compounds in dosage form providing increased half-life of the drug from the target to 50 min, which allows the use of serial x-ray sources, which have the majority of medical institutions, and subsequent x-ray irradiation of the tumor, which allows to consider the proposal the applicant meets the criterion of "novelty".

As preparations can be used for diagnostic or chemo-therapeutic anti-cancer agents, such as Magnevist, OmniScan, Ultravist 370, dependant, cisplatin, etc. specially prepared non-toxic complexes of the above heavy metals with organic ligands, as well as their mixtures with joborganization compounds, when added to their medical form medical polymer.

The essence of the image is the shadow is in the biological object (a suspension of tumor cells, malignant tumor, the body with a malignant tumour) enter product containing atoms with atomic number (Z) 53 and 55 to 83, inclusive, after which the biological object is affected by the photon radiation with energies in the range of 10-200 Kev. Drugs with a heavy atom - metal are highly stable complex compounds, for example, complexes with derivatives iminoxyl acid, crown ethers or porphyrins, and drugs with iodine - water-soluble radiopaque contrast agent. The use of mixtures of complex compounds of metals and iodine-containing drugs makes better use of the x-ray installation. The energy range of photon radiation (from 10 to 200 Kev) is experimentally established energy range, which is emitted photon radiation x-ray machine and which may be photoelectric effect.

For the introduction of drugs and compounds used intravenously or intra-humorally route of administration. The introduction of drugs leads to additional secondary radiation, which increases therapeutic effect of radiation therapy. This way we called photon-capture therapy.

The optimal value-energy photon radiation, in which nab is udaetsya maximum photoelectric emission of electrons of different atoms is established experimentally. To do this in a cell with a diameter of 20 mm with a wall thickness of 0.8 mm is placed a thin (10 mg/cm2) thermoluminescent detector TLD-580. In the cuvette poured an aqueous solution of the drug containing element with Z from 53 to 83 inclusive. The content of the element in a solution of 10 mg/ml Layer of solution on the surface of the detector is 0.2 mm solution effect of photon radiation with different amounts of energy.

The proposed method is illustrated by the following examples.

Example 1. In a test tube with a suspension of cells of ascitic Ehrlich carcinoma of mice ELD (13-15 million cells in 1 ml suspension) was introduced 1 ml of a suspension or 0,175 ml Hanks solution (control)or 0,175 ml of 0.5 M solution gadoliniumbased drug (Magnevist, OmniScan, dependant). When using Magnevist in its dosage form was made by polyglucin to a concentration of 1%solution of OmniScan - polyethylene oxide concentrations up to 1%. Dependant contains 1% polyvinylpyrrolidone. Irradiation of cell suspensions in the presence of drugs with gadolinium, and without the preparation was carried out in different physical doses, which was 4.8; 9,8; 13,4 Gr. As a source of photon radiation used installation RUM-17, the voltage of the tube 130-180 kV, a current of 15 mA, an additional filter 0.9 mm A1, focal length - 35 see dose - 1,22 G/min After exposure of 0.15 is l suspension (2 million cells) were injected into the leg muscle of the mice. Dynamics of tumor growth, developing from irradiated suspensions after inoculation of animals, characterized by a delay of tumor growth, the value of which increases with increasing radiation dose (table. 1). Use gadoliniumbased drug increases the value by 2 days compared to control.

Table 1.
The delay of the growth of Ehrlich carcinoma (d), developing from irradiated at different doses suspension
The irradiated suspensionStunting carcinoma (days) at different doses
4,8 Gr9,8 G13,4 G
Without medication113
Medication135

Index to quantify the differences in the dynamics of tumor growth, is the index of tumor growth (IR)reflecting the cumulative effect of anticancer therapy in the experiment and consider the dynamics of the antitumor effect, its intensity and duration. IR control is 1, in the experimental groups during regression of the tumor, the article is stabilizing the solution or the inhibition of its growth it will be less than 1. Values of IR are presented in table 2.

Table 2.
The index of growth of Ehrlich carcinoma developing from irradiated at different doses suspension
The irradiated suspensionThe index of growth of Ehrlich carcinoma
4,8 Gr9,8 G13,4 G
Without medication1,01,01,0
Medication0,520,200,22
p<0,01<0,001<0,01

Example 2. In a test tube with a suspension of cells of ascitic Ehrlich carcinoma of mice ELD (13-15 million cells in 1 ml suspension) was introduced 1 ml of a suspension or 0,175 ml Hanks solution (control)or 0,175 ml of 0.5 M solution gadoliniumbased of the drug, which is a complex of gadolinium with ethylendiaminetetraacetic acid, the content of the polyvinylpyrrolidone - 1%. Irradiation of cell suspensions in the presence of drugs with gadolinium, and without the preparation was carried out in different physical doses, which was 4.8; 9,8; 13,4 Gr. As a source of photon radiation used installation RUM-17, the voltage of the tube 130-180 kV, a current of 15 mA, an additional filter 0.9 m is A1, focal length - 5 see dose - 1,22 G/min After exposure of 0.15 ml of suspension (2 million cells) were injected into the leg muscle of the mice. Dynamics of tumor growth, developing from irradiated suspensions after inoculation of animals, characterized by a delay of tumor growth, the value of which increases with increasing radiation dose. Values of IR are presented in table 3.

Table 3.
The index of growth of Ehrlich carcinoma developing from irradiated at different doses suspension
The irradiated suspensionThe index of growth of Ehrlich carcinoma
4,8 Gr9,8 G13,4 G
Without medication1,01.01,0
Medication0,510,210,23
p<0,01<0,001<0,01

Thus, in vitro experiments demonstrate greater efficiency of photon capture therapy compared with conventional photon therapy.

Example 3. In vivo (37 animals) mice hybrids (CBA×C57B1)F1with interwoven in the Shin ascitic Ehrlich carcinoma intratumoral gadolinium was injected drug dependant (Leca is the only form which contains 1% polyvinylpyrrolidone) based 0,175 ml of 0.5 M solution of 1 cm 3the tumor. After 5 min after injection of the drug into the tumor, locally once were irradiated by photons with energies in the range of 30-60 Kev (RUM-17, the voltage on the tube 180 kV, current - 15 mA, an additional filter - 2 mm A1). The control group (31 mouse were animals intertwined with the tibia Ehrlich carcinoma and irradiated in the same conditions, but without pretreatment with gadolinium drug. The radiation dose from 18,8 to 31.7 G, the dose rate is 4.7 G/min Irradiated animals were observed for 60 days. Calculation of IR tumors (table 4) indicates a statistically significant higher therapeutic efficiency of photon capture therapy with prior intratumoral introduction gadoliniumbased of the drug compared to photon therapy.

Table 4
The index of growth of Ehrlich carcinoma with intratumoral injection of dipetala
Irradiated tumorThe index of growth of Ehrlich carcinoma
18,8 G23,5 Gof 28.2 G31,7 G
Without medication1,01,01,01,0
Medication0,650,500,330,22
p<0,05<0,01<0,01<0,01

When isolated photon irradiation in any case not registered complete regression of the tumor during the study period, while under the influence of dose and 31.7 Grams in terms of photon capture therapy was complete tumor resorption in 30% of mice. Figure 2 presents the mouse F1with transplanted in the left rear leg Ehrlich carcinoma after 51 days after x-ray irradiation at a dose of 31.7 G with prior intratumoral the introduction of Dipetala. Complete tumor resorption. Animals in the zone of irradiation was observed epilation (hair loss). Hair began to recover 30-35 days. In the control group demonstrated strong growth of tumors and to 20-30 days the tumor extends to the whole lower leg and torso. By the end of the observation period all animals fell. Mouse F1with transplanted in the left rear leg Ehrlich carcinoma 30 days after x-ray irradiation at a dose of 31.7 G without the introduction of Dipetala shown in figure 3.

therapeutic efficiency of photon capture therapy is 35-78% higher photon therapy (control).

Example 4. In vivo 60 outbred rats parts of animals (30 pieces) 7-8 day after transplantation, bedro sarcoma C-45 rats before exposure intratumoral has introduced a 0.5 M aqueous solution of a complex of gadolinium with dieti-lantinenpitkakatu acid (content poliglyukina 1%) based 0,175 ml on 1 cm 3the tumor. The remaining animals served as control. Irradiation of tumors was performed on the installation RUM-17 (230 kV, 15 mA; filter: 2.5 mm Cu+1 mm A1; average x-ray energy of 150 Kev; tube Pb+Al with a hole diameter of 30 mm, focal length 35 cm, dose rate of 0.5 Gy/min). The radiation dose was 20; 25 and 30 Gy. Before irradiation the animals were narcoticyou using intraperitoneal injection of thiopental sodium. Comparison of effect of tumor resorption detects (table 5)that if the dose of 20 Gy resorption is observed with the same frequency in the group with drug and no drug, at doses of 25 and 30 Gy preliminary injecting gadolinium increased the number rezorbirovanny tumors with 38 and 60% to 73% and 80%, respectively.

Table 5.
Resorption sarcoma C-45 rats (%) when exposed to x-ray radiation at different doses
Irradiated tumorResorption sarcoma C-45 rats %
20,0 G25,0 G30,0 G
Without medication353860
Medication257380

Thus, the number resorber the data of tumors in rats in conditions of photon capture therapy increases almost two times compared to control.

Example 5. Dog, male, Russian wolfhound, 7 years old, weight 40 kg, body surface 1.17 m2. Diagnosed with osteosarcoma of the distal radial bone (diagnosed on the basis of cytological and histological (trephine biopsy) studies. A course of photon capture therapy: cisplatin at a dose of 70 mg/m2for 30 min to photon irradiation (intravenous, systemic), the content of the polyvinylpyrrolidone in the form of drug - 1%. Photon irradiation: single focal dose of 4 Gy. The total dose of 48 Gy. Relapse-free period of 10 months.

Dog, dog, dog, 3 years. Diagnosis: osteosarcoma of the distal left tibia, delivered on the basis of radiological, cytological, histological studies. Radiation therapy (photon radiation): single focal dose of 5 Gy, total dose of 48 Gy. The death of an animal after 3.5 months after the first session of radiation therapy.

therapeutic efficiency of photon capture therapy of osteosarcoma in dogs is almost 3 times higher than that using a single photon radiation.

Example 6. In a tissue-equivalent phantom at a depth of 2 cm injected gadolinium drug (Magnevist, OmniScan, dipentyl); cisplatin; itorganize contrast agent Ultravist 370; solution of potassium bromide; complex compounds: barium with grounation; PM with nitrilotriacetic the second acid, polivalente, ytterbium with porphyrin, europium and bismuth with diethylenetriaminepentaacetic acid. The concentration of heavy elements was varied in the range from 0 to 30 mg/g Dose at different depths of the phantom were recorded using thermoluminescent detectors TLD-580. The relative increase of the dose in a tissue-equivalent phantom at a depth of 2 cm, depending on changes in local concentrations of the various elements shown in figure 4. Built experimental calibration curves are used to determine the amount of typing for heavy element, and the depth at which measurements are made, corresponds to the depth location of the tumor. The amount of preparation with heavy element calculated by the negative content of the element in 1 ml dosage form of the drug.

Example 7. In a test tube with a suspension of cells of ascitic Ehrlich carcinoma of mice ELD (13-15 million cells in 1 ml suspension) was introduced 1 ml of a suspension or 0,175 ml Hanks solution (control)or 0,175 ml of 0.5 M solution gadoliniumbased drug dependant (the content of polyvinylpyrrolidone - 1%), or a mixture of dipetala 0.100 ml and 0.075 ml of iodine-containing contrast media. Irradiation of cell suspensions in the presence of drugs with gadolinium, and without the preparation was carried out in different physical doses, which was 4.8; 9,8; 13,4 G is. As a source of photon radiation used installation RUM-17, the voltage of the tube 130-180 kV, a current of 15 mA, an additional filter 0.9 mm A1, focal length - 35 see dose - 1,22 G/min After exposure of 0.15 ml of suspension (2 million cells) were injected into the leg muscle of the mice. Dynamics of tumor growth, developing from irradiated suspensions after inoculation of animals, characterized by a delay of tumor growth, the value of which increases with increasing radiation dose (table 6).

Table 6.
The delay of the growth of Ehrlich carcinoma (d), developing from irradiated at different doses suspension
The irradiated suspensionStunting carcinoma (days) at different doses
4,8 Gr9,8 G13,4 G
Without drugs113
With dipetalum135
With dipetalum and iodine-containing medication148

Use gadoliniumbased drug increases the value by 2 days compared with the control, and the combined use of iodine - and adaministered drugs - 3 nights.

Example 8. In tumor sarcoma S-45, intertwined in hip rats, the size of 1-2 cm3introduced 0,175 ml of 0.5 M solution of Magnevist, dipetala labeled with a radionuclide111In, or 0.17 ml triombrast labeled125I. Dosage form of dipetala contains 1% polyvinylpyrrolidone. Dosage forms of the other products do not contain auxiliary medical polymers. Radioactivity of the samples of the drug is 185 kBq. Over the introduction sets the sensor to radiation at a height of 30 cm Tumor shield sheet of lead with a hole diameter of 1 see Register meter readings of radioactivity within 2-3 hours. Determine the half-life of radioactivity from the tumor. For dipetala this value is 50±4 min, Magnevist - 16±2 min, triombrasta - 9±1 min

Example 9. 0,750 g diethylenetriaminepentaacetic acid dissolved in 0.1 n hydrochloric acid, the resulting solution was heated to boiling and make portions 0,466 g of bismuth oxide. After the solution has become transparent, add 5 n sodium hydroxide to a pH of 7.5. Drop down when adding the lye is dissolved when heated. Receive 5 ml of 0.4 M clear, colorless solution of complex compounds of bismuth with diethylenetriaminepentaacetic acid with a pH of 7.5. The solution is cooled in to the room temperature and add to it 50 mg polyvinylpyrrolidone.

Sources of information

1. RF patent №2088288, publ. 27.08.97, class a 61 N 5/10.

2. US Patent 6331286 B1 from 18.122001.

3. US Patent 6366801 B1 from 02.04.2002 prototype.

1. The way the photon-capture therapy of tumors, including the introduction of tumor agent containing a heavy element with the x-ray irradiation of the tumor, characterized in that as a heavy element use the element with atomic number 53, 55-83, the tool contains one or more of such elements, and optionally a ligand in the form of iminodisuccinic acid or its derivatives, or crown ethers or porphyrin and water-soluble medical polymer; the agent is administered systemically or directly into the tumor, followed by exposure to x-rays with energies in the range from 10 to 200 Kev.

2. The method according to claim 1, characterized in that the quality of medical polymers using polyvinylpyrrolidone, dextran or polyethylene oxide.

3. The method according to claims 1 and 2, characterized in that the injectable preparation is a mixture of complex compounds of elements with atomic numbers 55-83 and water-soluble aromatic iodine compounds.

4. The method according to claims 1 and 2, characterized in that the amount of heavy element determined from calibration curves dose - concentration of elements in the tumor."



 

Same patents:

FIELD: medicine, oncology, immunology.

SUBSTANCE: invention relates to humanized antibodies with ErbB2. Invention involves the development of new humanized antibodies raised to tyrosinase receptors of family ErbB2, and to a composition comprising these antibodies. The advantage of invention involves expanding region in using indicated antibodies in cancer treatment wherein receptor of epidermal growth factor, EGFR, is a target of these antibodies.

EFFECT: valuable properties of antibody.

14 cl, 3 tbl, 13 dwg

FIELD: organic chemistry of heterocyclic compounds, biology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of the general formula (1): or (2): or their pharmaceutically acceptable salts, N-oxides or hydrate possessing physiologically active properties, in particular, eliciting ability to induce apoptosis in tumor cells causing their death. In the general formula (1) or (2) X represents sulfur or oxygen atom; Y represents sulfur atom, group -SO, group -SO2, group -NH or group -NR6; R1 represents aryl, substituted aryl, heteroaryl; R2 and R5 represent hydrogen atom, alkyl, allyl, substituted benzyl, group -CH2-C(O)R3, group -CH2-C(O)NR3R4 wherein R3, R4 and R6 represent inert substitute. Also, invention relates to new combinatory libraries for search compound-leaders and candidates for medicinal compounds preparing by screening the combinatory libraries.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: method relates to piperazinedione compounds of formula I wherein and are independently direct bond or double bond; F represents H or CH(RaRb), when is single bong, or C(RaRb), when is double bond; Z represents R3O-(Ar)-B, wherein B represents CH(Rc), when is single bond or C(Rc), when is double bond; Ar represents piridyl; and R3 represents alkyl, aryl, C(O)Rd, C(O)NRdRe or SO2Rd ; R1 and R2 are independently H, C(O)Rd. Compounds of formula I have antitumor activity. Methods for treatment of tumors and angiogenesis inhibition also are disclosed.

EFFECT: new compounds useful in treatment of tumors and angiogenesis inhibition.

42 cl, 23 ex

FIELD: organic chemistry, medicine, gastroenterology, oncology.

SUBSTANCE: invention relates to a new agent used in treatment of gastroenteric tumors. Invention describes an agent for treatment of gastroenteric tumors representing compounds of the general formula: A-X1-NO2 or their salts wherein A means -RCO(X)t wherein t represents a whole number from 0 to 1; X means oxygen atom (O); R is taken among the following groups: (IA), (IIA), (IIIA), (IVA), (VA) and (VIA) such as given in the invention claim; X1 in the formula A-X1-NO2 means a bivalent binding bridge taken among the following: -YO- wherein Y means a liner or when possible a branched (C1-C20)-alkylene comprising preferably from 2 to 5 carbon atoms, or possibly a substituted cycloalkylene comprising from 5 to 7 carbon atoms of the formula: wherein n3 means a whole number from 0 to 3; wherein nf means a whole number from 1 to 6 but preferably from 2 to 4; wherein R1f means hydrogen atom (H), -CH3; nf means a whole number from 1 to 6 but preferably from 2 to 4. Invention provides a new medicinal agent used in treatment of gastroenteric tumors.

EFFECT: valuable medicinal properties of agent.

2 cl, 11 tbl, 18 ex

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for prophylaxis of oncological diseases, or infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. In the first embodiment of invention blood extracellular DNA destroying agent, such as DNAase, is administered into blood. In the second embodiment agent, binding to blood extracellular DNA, such as anti-DNA antibody is administered into blood. According to the third embodiment enzyme altering of blood extracellular DNA chemical structure is administered into blood. According to the forth embodiment agent, stimulating synthesis and/or activity of endogenic deoxyribonuclease or agent stimulating synthesis of antibody binding to blood extracellular DNA are administered into blood.

EFFECT: effective method for treatment of abovementioned diseases without side effects when prolonged using of preparation affected on blood extracellular DNA.

7 cl, 11 tbl, 18 ex, 5 dwg

FIELD: medicine, veterinary science.

SUBSTANCE: the present innovation deals with treating malignant tumors. For this purpose, its is necessary to provide a blood supply of an agent that destroys extra-cellular blood DNA. This agent should be introduced in dosages providing alteration of electrophoretic profile of extra-cellular blood DNA. Agent, also, should be introduced at the dosages and modes that provide the level of DNA-hydrolytic activity of blood plasma measured in blood plasma being above 150 Kunz units/l plasma during totally above 12 h daily. Therapy may last without intervals for 2 d, not less. As an agent destroying extra-cellular blood DNA one may apply DNAse, in peculiar case, bovine pancreatic DNAse or recombinant human DNAse. The innovation suggests, also, to apply and agent that binds extra-cellular blood DNA, for example, anti-DNA antibodies. The method provides low-toxic and efficient treatment of tumors, particularly at prolonged, even one's life-long therapy with preparations mentioned.

EFFECT: higher efficiency of therapy.

10 cl, 7 ex, 6 tbl

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating gastric Helicobacter pylori-associated MALT-lymphomas. For this purpose, one should perorally introduce "Vitaflor" preparation as a ferment at daily dosage being not less than 40 g for 4 wk to an empty stomach or in intervals between meals, and in case of no complete regress of lymphoma at monotherapy with "Vitaflor" it is necessary to conduct additional courses of chemotherapy. The method provides cytostatic impact directly upon the tumor and suppresses proliferation of tumoral cells in case of complete absence of chemotherapy-accompanying side effects.

EFFECT: higher efficiency of therapy.

3 cl, 4 ex

FIELD: medicine.

SUBSTANCE: method involves administering local tumor cell radiomodification with following radiation therapy and radical surgical operation being applied. The local radiomodification is carried out by applying endovascular tumor tissue perfusion with 5% Metronidasole via superior rectal artery in superoampular rectal cancer cases and via superior rectal artery and one of internal iliac arteries in medial and inferoampular rectal cancer cases with said blood vessel occlusion done using non-lytic radiopaque emboli. Single remote radiation therapy is carried out at a dose of 10 Gy 1 h later after radiomodification being over. Surgical operation is done not later than in 24 h after the irradiation.

EFFECT: increased radiation therapy destruction effectiveness.

FIELD: organic chemistry, medicine, oncology, biochemistry, pharmacology.

SUBSTANCE: invention relates to the development of a method for inhibition in interaction of metalloproteinase 2 with integrin αvβ3 in host cells. Method involves contact of integrin with the amount of compound inhibiting this interaction and represented by the formula (I): wherein each of G1 and G2 represents independently -NH-C(O)-O-R1, -NH-C(O)-O-(CH2)v-(C6H4)-X3, -NH-C(O)-NH-(CH2)v-(C6H4)-X3, -O-C(O)-NH-(CH2)v-(C6H4)-X3, -O-C(O)-O-(CH2)v-(C6H4)-X3 or -NH-C(O)-CH2-(C6H4)-X3; each of Y1 and Y2 represents independently -OH, (C1-C4)-alkyl, (C1-C4)-hydroxyalkyl, (C1-C4)-alkoxy-group, phenyl, benzyl or -NH2; R1 represents (C1-C4)-alkyl; each of X1 and X2 represents independently halogen atom or (C1-C4)-alkoxy-group; X3 represents halogen atom, nitro-group, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or (C1-C4)-perfluoroalkyl; Z represents -C≡C-, -C6H4-, cis-CH=CH-, trans-CH=CH-, cis-CH2-CH=CH-CH2-, trans-CH2-CH=CH-CH2-, 1,4-naphthyl, cis-1,3-cyclohexyl, trans-1,3-cyclohexyl, cis-1,4-cyclohexyl or trans-1,4-cyclohexyl; A represents hydrogen atom (H) or a covalent bond; each of m and n represents independently a whole number o or 1; t represents a whole number o or 1; each of p, r and v represents a whole number 1 or 2 and under condition that when A means hydrogen atom (H) then t is 0; when A means a covalent bond then t = 1, and when m = 0 then Y1 represents (C1-C4)-hydroxyalkyl, and when n = o then Y2 represents (C1-C4)-hydroxyalkyl. Also, invention describes a method for apoptosis induction involving administration of abovementioned substance in the therapeutically effective dose.

EFFECT: improved method for tumor inhibition, expanded assortment of antitumor agents.

37 cl, 9 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: method involves administering local tumor cell radiomodification with following radiation therapy and radical surgical operation being applied. The local radiomodification is carried out by applying endovascular tumor tissue perfusion with 5% Metronidasole via superior rectal artery in superoampular rectal cancer cases and via superior rectal artery and one of internal iliac arteries in medial and inferoampular rectal cancer cases with said blood vessel occlusion done using non-lytic radiopaque emboli. Single remote radiation therapy is carried out at a dose of 10 Gy 1 h later after radiomodification being over. Surgical operation is done not later than in 24 h after the irradiation.

EFFECT: increased radiation therapy destruction effectiveness.

FIELD: medicine.

SUBSTANCE: method involves carrying out radiation treatment combined with textile material application on the tumor. Tumor-transformed vaginal uterus neck portion volume is determined with ultrasonic examination techniques. Koletex napkin impregnated with therapeutic cytostatic preparation dose is used as the textile material. The napkin pattern is produced on the basis of ultrasonic examination data. The napkin is quilted with ligature along the perimeter and fixed at the level of vagina fornix by drawing tightly in purse-string mode. Napkin is changed every 24 h within 10-20 days long treatment course.

EFFECT: improved life quality.

FIELD: medical equipment; X-ray diagnostics.

SUBSTANCE: device can be used in X-ray digital visualization systems. X-ray electron-beam detector has case, conversing member, collecting electrode, deflection system and electron searchlight. Conversing member has to be air-proof gas ionization chamber, which has drift electrode to be output window of the case. Electrodes of signal electrode system of air-proof ionization chamber are withdrawn onto surface of the chamber at the side of collecting electrode, deflection system and electron searchlight.

EFFECT: improved counting characteristics; higher quality of image; widened field of X-ray check.

1 dwg

FIELD: medicine, pediatrics, hematology.

SUBSTANCE: the present innovation could be applied in treating surgical and oncological diseases in children during treating and preventing anemia of different etiology. One should introduce ceruloplasmin at daily single dosage ranged 50-200 mg depending upon child's age against 100-200 ml 0.9%-sodiumchloride solution intravenously by drops at the rate of 40-50 drops/min. Moreover, for preventing and/or treating posthemorrhagic anemia in case of surgical operations one should introduce ceruloplasmin during 2 d before surgical operation, intraoperationally, and for 2-10 d after operation. For preventing and/or treating anemia in case of purulent-septic diseases ceruloplasmin should be introduced during chemotherapeutic days during the whole period of the course conducted, for preventing and treating radiation anemia at the background of radiation therapy ceruloplasmin should be injected once weekly during the whole period of radiotherapy course, for preventing and treating toxic and radiation anemia at the background of chemoradiation therapy ceruloplasmin should be introduced once weekly on the day of chemotherapy during the whole course of chemoradiation treatment. The innovation enables to avoid inflows of erythrocytic mass and donor's blood along with shortened number of procedures on introduction of ceruloplasmin and 4-times decrease in the risk for the development of severe anemia in children due to matching peculiar mode for ceruloplasmin introduction.

EFFECT: higher efficiency of therapy and prophylaxis.

4 cl, 5 ex

FIELD: medicine, oncology.

SUBSTANCE: one should carry out chemoradiation therapy at applying a cytostatic preparation followed by distance and intracavitary irradiation. Depending upon development of tumor lesion during the first 3 or 6 d it is necessary to conduct monochemotherapy only due to introducing proxiphen together with dimethyl sulfoxide at weight ratio of 4.5-5.0 : 0.5-1.5, correspondingly by applications in "Coletex" napkins. Moreover, a napkin should be pre-impregnated in 20%-dimethylsulfoxide solution and fixed with a tough vaginal tamponade by changing napkins every 24 h. Then since the 4th d or the 7th d simultaneously with application it is necessary to carry out contact irradiation and distance impact onto minor pelvis every 4-6 h at single focal dosage (SFD) being 2 Gy at 10 seances 5 times/weekly with high-activity sources of SFD 2 Gy. The innovation provides tumor regress under conditions of no therapeutic complications, thus, improving patients' quality of life.

EFFECT: higher therapy.

3 ex

FIELD: oncology.

SUBSTANCE: invention is directed, in particular, to treatment of patients with Ewing's sarcoma and osteogenic sarcoma at different stages of malignant process. Method comprises chemotherapy and beam therapy. Samples of venous blood are taken from children in age of 5 to 12 years in amounts not larger than 5% of the total volume of circulating blood per 1 introduced dose of chemical preparation and, from adolescents and young persons, in amount of 200 ml. Then 4 courses of polychemotherapy are fulfilled with autoblood according to standard treatment schemes for given diseases, taking into account stages of disease, in recommended doses. Between 2nd and 3rd chemotherapy courses, radiotherapy is fulfilled on metastatic focuses in lungs. After 4 courses of induction autohemo-chemotherapy, local therapy on the primary focus (radiotherapy and/or surgical treatment) is fulfilled and also radiotherapy on metastatic focuses in other bones, after which follows consolidation involving chemical preparation of the second line.

EFFECT: improved remote results of treatment , suppressed metastatic focuses, reduced tumor dimensions, and weakened toxic manifestations of therapy.

2 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with measuring radioactivity in alive organisms and could be applied for detecting really absorbed dosage under conditions of intra-operational impact. The method suggested includes detecting clinical volume for the target of radiation impact including the volume of healthy tissues to be subjected for radiation impact, developing the plan of radiation impact based upon data obtained with the help of tissue-equivalent phantoms, location in interest sites of clinical volume of sterilized separate fragments of dosimetric device being the matrix of functional units and designed as thermoluminescent detectors being hermetically isolated at the distance of 10 mm between their edges and fixed between the layers of flexible biocompatible material, registering the location of detectors, performing the séance for intra-operational radiation therapy followed by removing the fragments of dosimetric device out of target's volume. Information should be read from thermoluminescent detectors.

EFFECT: higher accuracy of measuring.

1 cl, 1 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with treating malignant tumors of central bronchi and trachea due to argonoplasmatic recanalization of tracheal lumen and/or bronchi, at power being 60-90 W followed by brachitherapy at source's trajectory length being 5-20 cm, pace of 5 mm and the depth of reference isodose being 10 mm against the source. Moreover, one should move applicator above and below the tumor ranged 1-3 cm to apply the dose ranged 14-28 Gy once weekly per 7 Gy. Additionally, one should carry out distance radiation therapy 5 times weekly per 1-2 Gy up to total focal dose of 30-40 Gy. The present innovation enables to highly increase the passability of respiratory tract in case of malignant stenosis and prevent the development of their relapse.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine, neurooncology.

SUBSTANCE: one should carry out chemotherapy and irradiation till radical dosage. Moreover, 2-3 d before the onset of radiation therapy and during the whole course of irradiation one should indicate the intake of indometacin at daily dosage being 300 mg, and 8-14 d before the end of therapy course or the stage of radiation therapy it is necessary to conduct chemotherapeutic cycle with vincristine at total dosage being 4 mG and lomustine at total dosage 160-240 mg. At performing a split course of irradiation the intake of indometacin should be indicated between the stages. The innovation enables to increase radio sensitivity of malignant tumor, suppress angiogenesis, proliferative activity and increased cytotoxic activity of chemopreparations.

EFFECT: higher efficiency of therapy.

1 cl, 3 ex

FIELD: medicine, oncology, gynecology.

SUBSTANCE: method involves external irradiation and using chemopreparations combined with autoplasma. External irradiation in the dose 2 Gr is carried out from 1 to 4 day of treatment followed by intravenous administration of cisplatin on 5 day in the dose 10 mg with 250 ml of physiological solution. On the following day 10 ml of autoplasma incubated with 10 mg of cisplatin is administrated by paratumoral route by right and left of tumor into paravaginal cellular tissue and by intratumoral route into projection of cervical channel. Blood cellular elements are incubated with 600 mg of cyclophosphane and reinfused by intravenous drop route. Effects are repeated in indicated sequence once per a week, 4 times per treatment course. Method provides increasing percent of tumor regression due to the complex effect on tumor, enhancing the topical concentration of cytostatic drug and prolongation of its contact in malignant growth zone, and providing radiosensibilizing effect in diminishing the general toxic effect of therapy. Invention can be used in treatment of patients with topically disseminated forms of uterus cervix cancer at the stage T3NxM0.

EFFECT: improved and enhanced treatment method.

1 ex

FIELD: medicine, radiology, pharmacy.

SUBSTANCE: invention relates to an agent used in contrasting in carrying out the diagnostic radiology that comprises tantalite of at least one element taken among the group including yttrium, lanthanum, cerium, praseodymium, neodymium, samarium, europium, gadolinium, terbium, holmium, erbium, thulium, ytterbium, lutecium or bismuth, organic additive and water wherein the natural polysaccharide with acid functional groups is used as an organic additive in the definite ratio of components. Invention provides preparing an agent exhibiting uniform distribution of insoluble particles, high effectiveness of absorption in the low dose given to a patient, and high degree of contrasting, the combination of high adhesion to mucosa tissue of organs and good fluidity in applying the external stress that results to increasing reliability of results in carrying out the diagnosis. Invention can be used as X-ray contrast agent in X-ray assay of different organs.

EFFECT: valuable properties of agent.

3 cl, 9 ex

Up!