Photosensitisers for photodynamic therapy

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to a photosensitiser for photodynamic therapy. What is declared is methyl ester 13,17-bis(N-methyl-N,N-diethylammonioethylamide) chlorine e6 ditosylate as a photosensitiser having formula: .

EFFECT: compound is stable, possesses high photobactericidal activity in vitro and high photodynamic effectiveness.

4 dwg, 2 tbl, 9 ex

 

The present invention relates to medicine, namely to photosensitizers (PS) for photodynamic therapy (PDT) of malignant tumors and other pathological conditions.

Photodynamic therapy is based on the use of natural or synthetic FS, which have the ability to selective accumulation (trapnest) in tumor tissue. When exposed to light of a certain wavelength FS enters the activated state, which initiates the formation of cytotoxic agents, singlet oxygen and free radicals, causing the destruction of structural elements tumor tissue.

One of the most effective FS are chlorins (dihydroporphyrin), they are characterized by a strong increase in the intensity of the long wavelength band and its offset in the red region compared to porphyrins. Among them should be mentioned water-soluble mono-L-especillay e6and other various forms of chlorin e6in particular domestic products "Photoditazine", "Radachlorin" and the Belarusian drug "Photolon" (Tran thi Hai Yen, G. C. Ramensky, N. A. Oborotov // Ross. Bioceramic. J. 2009. Vol. 4. S. 99-104), and synthetic chlorins - 5,10,15,20-tetrakis(m-hydroxyphenyl)chlorin (], m-THPC, foscan) and derivatives benzoporphyrin (benzoporphyrin monocerata, ring A) (Ali H., van Lier J. E. // Chem. Re. 1999. Vol.99. P. 2379-2450; Bonnett R. / Chemical Aspects of Photodynamic Therapy. 2000. Gordon and Breach Sci. Publ).

Mono-L-especillay e6(drug NPe6, MACE, Nippon Petrochemical, Tokyo, Japan) absorbs at 664 nm with a molar absorption coefficient of about 25,000 M-1cm-1, characterized by the absence of dermal toxicity.

The vast majority of photosensitizers number of chlorine belong to the anionic type is their solubility in water is achieved by the presence in the molecule of salt-forming carboxyl groups. Their disadvantage is the presence of a at position 13 molecules, coupled with the extension carboxyl group which may have in anionic form a negative effect on their stability during storage, reducing their oxidation potential.

An alternative method of imparting solubility in water is an introduction into the molecule of chlorine cationic substituents, for example residues of salts of Quaternary ammonium bases. Positively charged FS are of special interest for antimicrobial photodynamic therapy (APDT) pathogenic microorganisms.

Antimicrobial PDT is selective oxidative destruction of pathogenic microorganisms in the combined impact of the Federal Assembly and optical radiation corresponding to the spectral composition (Wainwright M. // J. Antimicrob. Chemother. 1998. Vol.42. P. 13-28). About what projects antimicrobial photodynamic therapy are viruses, bacteria, fungi and protozoa microorganisms.

Among microbial pathogens are more resistant to photodynamic effects are gram-negative bacteria (Z. Malik, J. Hanania, Nitzan Y. // J. Photochem. Photobiol. B: Biol. 1990. Vol. 5. P. 281-293), due to low permeability of their outer membrane dye.

The negative charge of the outer surface of viable bacterial cells determines the active linking to them and, accordingly, expressed antibacterial activity of cationic dyes such as methylene blue from class fenotiazinas (Millson C. E., Wilson M, MacRobert, A. J., Bown S. G. // J. Photochem. Photobiol. B: Biol. 1996. Vol. 2. 32. P. 59-66).

Know the use of FS "photosense"® - based sulfonated phthalocyanine hydroxylamine for the treatment of infected wounds and trophic ulcers with antibiotic-resistant microflora (Stranadko E. R., Tolstykh, M. R., M. V. Riabov, Krivikhin D. V. // IX World Congress of the International Photodynamic Association. Abstracts. Miyazaki. 2003. P. 28). However, the anionic nature of this FS is the reason for its lack of effectiveness against gram-negative bacteria.

It is also known cationic derivative of phthalocyanine - polyaminoamide phthalocyanine zinc (drug Holocene"®), which sin is eticheskim FS, along with high photo-induced antitumor activity has a pronounced antimicrobial action (Morozova N. B. Jakubowski, R. I., Chissov Century. And. etc. // Russian oncological journal. 2012. Vol.1. S. 23-28). There is a decrease plurality experienced bacterial suspension in 105times when using Halosense at a concentration of 2 μg/ml and irradiation led source (685 nm). Halogens can be used for photodynamic therapy and fluorescent diagnostics of malignant neoplasms and for antimicrobial PDT.

However, the above FS, including Halogens have insufficiently high treatment efficiency when used for photodynamic therapy and fluorescent diagnostics of malignant neoplasms and for antimicrobial PDT. Thus, the magnitude of inhibition of tumor growth in their use and cure animals do not reach 100%-s values.

The present invention is the search for new FS on the basis of aminopropionic chlorine her superior in its effectiveness listed above FS for photodynamic therapy and fluorescent diagnostics and antimicrobial PDT.

To solve this problem it is proposed to apply a new cationic quaternion derivative of chlorin e6namely methyl ether 13,17-bis(N-methyl-N,N-diethylaminoethylamine) chlorin e6 ditosylate (II).

When heated methylpheophorbide with a large excess of N,N-diethylethylenediamine for 12-15 hours at 40 to 45°is formed With diamide derived methyl ether 13,17-bis(N,N-diethylaminoethylamine) chlorin e6(I). The quaternization reaction of diamide methyl ester p-toluenesulfonic acid in acetonitrile at room temperature, the obtained water-soluble Quaternary salt of the methyl ether 13,17-bis-(N-methyl-N,N-diethylaminoethylamine) chlorin e6ditosylate (II).

The invention is illustrated by the following figures:

Fig.1 - fluorescence Spectrum FS in saline solution (A) and Needle MEM containing 10% ETS (B): solid line - ex tempore, dashed line - 24 hours.

Fig.2 - Dose dependence of inactivation of bacteria E. Coli K12 TG1 test extinguishing bioluminescence (1 - 0.2 μm, 2 - 0.5 µm, 3 - 1 µm, 4 - 2 µm, 5 - 5 µm, 6 µm and 10 µm).

Fig.3 - Dependence of LD90concentration FS: 1 in distilled water, 2 - in saline solution.

Fig.4 - Induced antitumor activity of FS in mice with sarcoma S37: 1 1 mg/kg, 2 to 2.5 mg/kg, 3 - 5.0 mg/kg).

The invention is also illustrated by the following examples, but is not limited to them.

Example 1. Getting 15-methyl ether 13,17-bis(N,N-diethylaminoethylamine) chlorin e6(I). The solution 0.560 g methylpheophorbide and 4.2 ml of N,N-diethyla is iindiana was heated without access of light) at a temperature of 32-37°C for 20 hours. The solution was poured into 400 ml of hexane, the precipitated precipitate was filtered and dried on the filter, and then subjected to chromatographic purification on silica gel. After elution of impurities with chloroform and a mixture of chloroform - methanol in a volume ratio of 30:1, using as eluent a mixture of chloroform - methanol - triethylamine in volume ratios of 10:1:0.15, washed diamine derived, solvent drove to dryness in vacuo, the residue was washed with hexane, dried in vacuum at room temperature. The yield of pure product 0.52 g (69.3 percent). The obtained compound is soluble in chloroform, aromatic hydrocarbons, acetone, alcohol, insoluble in water. The IR spectra exhibit intense amide band at 1651,3 cm-1and a less intense band at 1734,2 cm-1belonging to the ether group. MALDI mass spectrum, m/z 807,522 [M] calculated M 807.11. Electronic absorption spectrum (chloroform), λmax.nm (lg ε): 291 (3,94), 404 (5,17), 502 (4,13), 529 (3,57), 608 (3,66), 664 (4,66); 290 (3,98), 403 (5,11), 501 (4,07), 531 (3,62), 609 (3,63), 663 (4,60).

Obtaining methyl ester 13,17-bis(N-methyl-N,N-diethylaminoethylamine) chlorin e6of ditosylate (II). The mixture 0.078 g of compound (I) and 0.20 g of methyl ester of p-toluenesulfonic acid in 2.5 ml of acetonitrile was kept in the dark at room temperature for three days, after which the solvent was distilled in vacuum, the residue was washed sulphuric ether and dried in vacuum. Received 0,106 g (yield 93%) of the Quaternary salt (II). The compound is hygroscopic, easily soluble in water, soluble in aqueous ethanol, organic solvents (benzene, chloroform, acetone, DMSO). The electronic absorption spectrum, λmax.nm (lg ε) (water): 286 (3,94), 401 (5,24), 500 (4,04), 529 (3,00), 608 (3,49), 658 (4,60). Found, %: C 63,20; N. Of 7.64, To 7.59; N 8,91, 8,62; S 5,27; 5,03. C63H86N8O10S2. Calculated, %: C 64,20; N 7,28; N 9,51; S 5,44.

Example 2. The stability of the FS in the dynamics.

Assessment of the stability of the FS was performed using absorption and fluorescence methods of analysis. Chlorin II easily soluble in saline solution (0.9% NaCl) to a concentration of 1 mg/ml Solutions for research were prepared ex tempore, reaching a selected concentration by serial dilution of the original solution. Absorption spectra were recorded on a spectrophotometer Genesys 2 (USA) in the wavelength range from 600 to 900 nm. The registration of the fluorescence of solutions held in contact dynamics method for laser spectral analyzer for fluorescent diagnosis "LASA-6" (LLP "BIOSPEC", Russia). Fluorescence was excited He-Ne laser with wavelength generation 632.8 nm, the spectral range from 600 to 900 nm.

The solution of chlorin II stable within days of incubation in saline solution and Needle MEM with 10% fetal calf saw rocky (ETS) at a concentration of 5 μm in dark conditions. In the selected time range did not show any shifts of the Q-band, no decrease of optical density and fluorescence intensity remained symmetry major bands (Fig.1, table 1).

Table 1
The optical density FS in saline solution and Needle MEM containing 10% ETS, λmax666 nm
The incubation periodEx tempore2 hoursafter 4 hoursafter 24 hours
Saline
OD, srvc.ed.0,47±0,030,42±0,040,41±0,020,39±0,03
Wednesday Needle with a content of 10% ETS
OD, srvc.ed.0,59±0,020,58±0,030,55±0,020,53±0,02

Example 3. Photoinduced activity of chlorin (II) in respect of cell culture Ner.

Studies were performed on tumor cells, human epidermoid carcinoma of the hypopharynx (Ner), Paul is obtained from the Institute of Virology. D. I. Ivanovsky RAMS, which was cultivated at 37°C in humidified atmosphere containing 5% CO2.

Cells subcultured in the wells of flat-bottomed 96-well microplate at a concentration of 65 thousand cells/ml of the Tested dye was introduced into the wells after 24 hours after seeding, by varying the concentration from 0.12 to 10 μm. To evaluate the phototoxicity after 0.5, 2 and 6 hours of incubation with FS cells was irradiated with a halogen lamp through a broadband filter KS-10 (λ≥640 nm). The power density was 36,0±1.0 mW/cm2estimated light dose of 10 j/cm2. After irradiation, the cells were incubated overnight under standard conditions. Estimates of survival were determined visually and by the colorimetric method using the MTT-test. Biologically significant effect believed inhibition of cell growth in culture for more than 50% (mean value of three independent tests).

It is revealed that FS showed maximum photoinduced activity relative to cells cultures Ner at 2-hour incubation, IR50was 0,45±0,04 µm, with increasing time of incubation up to 6 hours value IR50practically did not change and amounted 0,52±0.05 microns.

Thus, the results obtained in vitro have shown that the chlorin II has a high photoinduced activity against cell culture Ner.

Example 4 Photobacterium activity in vitro was determined on genetically engineered bioluminescent strain of gram-negative bacteria E. coli K12 TG1. To a suspension of bacteria (3×107CFU/ml) in distilled water add FCS at a concentration of 0.2-10 μm, incubated 10 min in the absence of light and is irradiated with white light source acomp (50 mW/cm, the dose of light 1-9 j/cm2). The evaluation of the results of inactivation of colony forming units (CFU) of bacteria is conducted according to test suppression of bioluminescence. In Fig.2 shows the dose dependence of inactivation of bacteria E. coli K12 TG1 test suppression of bioluminescence. When the concentration of FS 5 μm and the dose of white light 3 j/cm2there is a reduction of SOME 50 times.

Example 5. The definition of LD90spend on dose dependency of inactivation of bacterial biosensor in saline or distilled water to concentrations of chlorine of 0.2-10 μm. In Fig.3 shows the dependence LD90concentration of chlorin II in distilled water (1) and saline solution (2). For each concentration FS determine the dose of white light, causing inactivation of colony forming units (CFU) of bacteria by 90%.

Comparison of LD90for chlorin and phthalocyaninato FS (Halogens, actication octakis-hainiltonian zinc) in distilled water and in saline solution. In distilled water Halogens 2 times more active in photodynamic inactivation of bacteria (concentration 2 μm LD90is 1 and 2 j/cm2according to the government). However, in saline solution, the activity of Holocene reduced to a greater extent than that of chlorine (II) in saline solution to a concentration of 2 μm LD90is 6 and 5 j/cm2, respectively. This is due to the different mechanism of binding in saline solution with bacterial cells, as demonstrated by the following example.

Example 6. Determination of the Zeta potential of the cells of gram-negative bacteria E. coli K12 TG1.

Measure the surface (Zeta) potential of bacterial cells in distilled water and in saline solution with the addition of FCS or without him. The results are presented in table 2. Photodynamic activity of Holocene manifests itself only in terms of electrostatic binding to bacterial cells, which follows from the neutralization of their Zeta potential in the presence of FCS, and strongly depends on this parameter. The decrease in Zeta potential in saline solution leads to a reduced ability of Holocene contact with bacterial cells and to decrease its photodynamic activity (increase LD90). Action dicating chlorine (II) to a lesser extent due to the neutralization of the Zeta potential of the cells of bacteria. Shift the Zeta potential in saline does not cause such a sharp decrease photodynamic activity of this FS.

Table 2
The Zeta potential of the cells of gram-negative bacteria E. coli K12 TG1
Concentration, µmChlorin (II)Holocene
Diest. waterSalineDiest. waterSaline
0-35 mV-20 mV-35 mV-20 mV
0,2-35 mV-20 mV-22 mV-19 mV
0,5-35 mV-20 mV-14 mV-8 mV
1-34 mV-19 mV-7 mV-1 mV
2-33 mV-19 mV+3,5 MB+1 mV

Example 7. The distribution of chlorin (II) in the tumor S37 and fluorescent is Naya contrast relative to the surrounding tissue.

The estimate of the distribution of FS in the tumor and surrounding tissues was performed in mice with sarcoma S37 in the interval from 5 seconds to 48 hours using local fluorescence spectroscopy (LFS). FS was injected intravenously at a dose of 5.0 mg/kg Fluorescence was detected by the contact method on laser spectral analyzer "LASA-06".

In tumor tissue normalized fluorescence FS were recorded at a maximum level after 1-2 hours after injection and was 8.5±0,9 of 9.7±2.4 services. unit, and then to 48 hours decreased by 45% of the maximum value. The highest level of the normalized fluorescence in the skin (4,8±1.4 services. units) was observed 2 hours after the introduction of chlorin (II), in the muscle (12,0±0.7 services. units) - after 30 minutes. The maximum fluorescent contrast relative to the surrounding normal tissues of the skin were recorded after 1 hour after injection and were 2.8±0.4 services. units, and relatively muscles 48 hours after injection and was 1.8±0.3 services. units

Example 8. Photo-induced antitumor activity of chlorin (II) in animals with sarcoma S37.

Study of photo-induced antitumor activity conducted in animals with sarcoma S37, vaccinated subcutaneously with the outside of the right thigh mice-hybrids F1depending on the dose FS on day 7 after inoculation of the tumor.

In experimental groups, FS animals enter the Lee once intravenously into the tail vein at doses of 1.0, 2.5 and 5.0 mg/kg, respectively. Irradiation was carried out 1 hour after the introduction of the FS. Was used for irradiation led source (FSUE "SSC RF NIOPIK") with a wavelength of 662±14 nm and a power density of 100 mW/cm2(the energy density of 90 j/cm2). Control group animals without exposure.

PDT efficacy was assessed using generally accepted in experimental Oncology criteria:

- inhibition of tumor growth SRW=[(Vto-Vop)/Vto]·100%, where Vopand Vto- the volume of tumors in the experimental and control groups, respectively;

- the criterion of cure KI=[PI/No]·100%, where PI and No is the number of treated animals and the total number of animals in the experimental group, respectively.

Tumor volume was calculated according to the formula: V=d1·d2·d3where d1d2and d3three mutually perpendicular diameters of the tumor.

Measurement of tumor volume held within 21 days after irradiation using electronic digital calipers STORMtm 3C301 "Central". The animals were observed 50 days.

In experienced groups within one day after irradiation the animals were formed intense edema in the impact zone, which continued until 5-10 days. When using chlorine (II) at a dose of 1.0 mg/kg SRW was 94,9 - 100%, CI - 75%. For doses of 2.5 and 5.0 mg/kg revealed an even higher efficiency is e: 100% SRAW during the whole observation period, 100% cure animals within 50 days of observation (Fig.4).

Example 9. The pharmacokinetics of chlorin (II).

The pharmacokinetics was studied using LFS in organs and tissues of intact mice at a dose of 5.0 mg/kg Maximum in the fluorescence spectrum of chlorin (II) in the tissues of animals were recorded at 669±2 nm. Fluorescent form it quickly (within 5-30 minutes) was entered into the internal organs and tissues of the body, mainly in the liver, kidney and spleen, and then decreased at different speeds. Maximum fluorescence of chlorin (II) in the blood was determined immediately after intravenous and within 24 hours was reduced by 94% of the maximum value and after 7 days was not registered.

In the internal organs after 24 hours the level of the normalized fluorescence was decreased in the liver by 33%, kidney - 45%, spleen - 47% of the maximum value. Fluorescent form of chlorine (II) was determined in the internal organs more than 7 days. The residual quantity of the FS at this period was in the liver 47% renal 20% and spleen 25% of the maximum value.

In the skin the maximum value of the fluorescence was recorded 2 hours after injection of the dye, then the normalized fluorescence was decreased after 24 hours accounted for 73% of the maximum value, and after 7 days - 25%. This indicates the slow elimination of chlorine (II leather. In the muscle after 24 hours the level of the normalized fluorescence was also decreased by 81%, fat - 29%. A residual amount of chlorine (II) in the muscle (8%) and adipose tissue (24%) were recorded over 7 days.

The data obtained indicate a slower circulation of chlorin (II) in mammals compared with chlorines of natural origin and its excretion is mainly through the liver with the bile and the kidneys in the urine.

Thus, the proposed FS is quite stable in solution in dark conditions and in light, has a high Photobacterium activity in vitro, high photodynamic efficiency, but at a slower circulation in mammals compared with chlorines of natural origin. This feature of the proposed FS can imagine and clinical interest for mnogochasovoj therapy with a single dose FS, enhancing efficiency and reliability of treatment.

Methyl ether 13,17-bis-(N-methyl-N,N-diethylaminoethylamine) chlorin e6ditosylate as photosensitizer for photodynamic therapy.



 

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17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a set, containing calcium sulphate hemihydrates, pressed particles of calcium sulphate dehydrate, additionally containing one or more therapeutically, preventively and/or diagnostically active substances, and sodium-carboxymethylcellulose (Na-CMC) and a water medium, including water. The ratio R of sodium-carboxymethylcellulose and calcium sulphate in the set constitutes from 0.1 mg of sodium-carboxymethylcellulose (calculated as Na-CMC)/g of calcium sulphate to 8 mg of sodium-carboxymethylcellulose (calculated as Na-CMC)/g of calcium sulphate. When mixed, the said components of the set form a bioresorbable ceramic composition. The invention also relates to the application of the set for the treatment of a disease or condition, associated with prostate. Also claimed is a composition ready for application in the form of a paste for introduction to a patient during the time period from 5 minutes to 1 hour before hardening, obtained by mixing the components of the set. Also claimed are: a hardened composition and a method of obtaining the hardened composition or the composition ready for application.

EFFECT: control of the time of the set and composition hardening.

13 cl, 12 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics and represents method of treating prostate cancer, which includes introduction to patient of composition, which contains degarelix lyophilisate or its pharmaceutically acceptable salt and excipient, dissolved in solvent, in initial dose 200-300 mg of degarelix in concentration 20-80 mg of degarelix per ml of solvent with the following after 14-56 days after initial dose supporting dose 320-55 mg of degarelix in concentration 50-80 mg of degarelix per ml of solvent, possibly with one or more than one following additional supporting dose 320-550 mg of degarelix in concentration 50-80 mg of degarelix per ml of solvent, introduced with interval from 56 days to 112 days between each supporting dose.

EFFECT: invention provides long release of degarelix from obtained depot of medication without increase of occurrence of side effects.

11 cl, 1 ex, 2 dwg, 4 tbl

FIELD: medicine.

SUBSTANCE: using the human placental perfusate cells in preparing a therapeutic agent for suppressing tumour cells proliferation in an individual having the tumour cells, wherein the placental perfusate cells represent a collection of nuclear cells of the placental perfusate. Using natural killer cells of CD56+, CD16- recovered from the placenta for preparing the therapeutic agent for suppressing the tumour cells proliferation in the individual having the tumour cells. Using the combined natural killer cells in preparing the therapeutic agent for suppressing the tumour cells proliferation in the individual having the tumour cells, wherein the above combined natural killer cells comprise the natural killer cells recovered from the placental perfusate, and the natural killer cells recovered from the umbilical blood, and wherein the umbilical blood is recovered from the placenta, which is used to prepare the above placental perfusate. A method for suppressing the tumour cells proliferation in vitro, involving the tumour cells contact to the human placental perfusate cells, wherein the placental perfusate cells represent the collection of the nuclear cells from the placental perfusate. The method for suppressing the tumour cells proliferation in vitro, involving the tumour cell contact to the number of the natural killer cells prepared of placental CD56+, CD16-. The method for suppressing the tumour cells proliferation in vitro, involving the tumour cells contact to the combined natural killer cells, wherein the above combined natural killer cells involve the natural killer cells recovered from the placental perfusate, and the natural killer cells recovered from the umbilical blood, and wherein the umbilical blood is recovered from the placenta, which is used for prepare the above placental perfusate. A composition applicable in suppressing the tumour cells proliferation, containing the recovered natural killer cells of CD56+, CD16-, wherein the above natural killer cells are recovered from the placental perfusate, and wherein the above natural killer cells make at least 50% cells in the composition.

EFFECT: placental perfusate cells and methods for using them enable suppressing the tumour cells proliferation effectively.

40 cl, 13 tbl, 6 ex, 11 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology. What is presented is a polypeptide containing two binding fragments presented by antibodies; the first of them binds to CD3e(epsilon) chain epitope of a human or a primate, other than a chimpanzee, particularly Callithrix jacchus, Saguinus oedipus and Saimiri sciureus; the second one - to EGFR, Her2/neu or IgE of a human or a primate, other than a chimpanzee, with the above CD3e epitope containing the amino acid sequence Gln-Asp-Gly-Asn-Glu. There are also disclosed a coding sequence of the nucleic acid, a vector, a host cell and a method for preparing the above peptide, as well as a pharmaceutical composition and using the polypeptide in preventing, treating or relieving a proliferative disease, a malignant disease or an immunological disorder.

EFFECT: invention provides the clinical improvement of T-cell redistribution and the enhanced safety profile.

17 cl, 8 tbl, 26 dwg, 26 ex

FIELD: medicine.

SUBSTANCE: method involves the endoscopically controlled introduction of Coletex-D gel into a fistulous passage from the oesophagus until filled completely. The following exposure to a laser light at wavelength 0.66 mcm, output power 15-45 mWt/cm2 covers a fistulous passage mouth for 5-7 minutes to be repeated in the same mode every second day. The course of the laser light exposure makes 8-10 procedures.

EFFECT: method provides the adequate therapy requiring no abdominal surgeries and the lower risk of chest and abdominal injuries, the shorter rehabilitation period by improved sealing of the fistulous passage, fistula healing, reduced inflammatory process.

2 ex

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