Hemin-peptide pharmaceutically acceptable salts thereof and using as anti-viral and virulicide agent

FIELD: chemistry, medicine.

SUBSTANCE: invention relates to hemin-peptide of general formula I , wherein R1 is ArgTrpHisArgLeuLysGlu(OMe)OH; R2 is -OH; Y is Cl; Me is Fe, or pharmaceutically acceptable salts thereof having virulicidal and anti-viral activity, including activity against herpes virus and HIV, and capability for destroying of λ fag, herpes and HIV DNA. Hemin-peptide fragment also is disclosed.

EFFECT: new anti-viral agent.

2 cl, 5 tbl, 5 ex

 

The invention relates to chemistry and medicine, namely to derive hemin, representing the conjugates of hemin Oligopeptide having virulizin and antiviral action, the General formula I:

where R1and R2the deputies, who represent a peptide consisting of not less than 7 amino acid residues; however, the carboxyl group of the peptide can be modified C1-C8alkilany ether, and the side functions of the peptide can be protected, and it is possible that R1=R2or R1≠R2in particular, when R1=-ArgTrpHisArgLeuLysGlu(OMe) - OH, R2=-HE (II); carboxyl group hemin can be modified methyl or other C1-C8ester or physiologically acceptable salt; or its pharmaceutically acceptable salts; Y represents Cl-; Me represents Zn, Cu, Fe, Mn.

It is known that some Geminate have antiviral activity [Repischeva, Hageluken, Twizerimana, Weaponsin, Dnest, Not. //patent No. 2238950, BI 0430, 2002].

Known Geminate, as a rule, insoluble in water, and does not provide direct virilizing actions.

The present invention was the creation of a new water-soluble geminata (II)that has both Viru is echidnas and antiviral action, as well as the ability to destroy natural and recombinant DNA phages and viruses. The object of the invention was new synthetic Geminate (II)corresponding to General formula I and its pharmaceutically acceptable salts, where R1=OH, R2=ArgTrpHisArgLeuLysGlu(OMe) - OH, different from known ones according to the structure of gemination with antiviral effect the solubility and the ability to directly destroy the virus (virulotsidnoe).

Preferred according to the invention was Geminate (II)

corresponding to the General formula I:

where R1=ArgTrpHisArgLeuLysGlu(OMe) - OH, Y-represents Cl-; Me represents Fe.

The proposed Geminate (II) can be synthesized by a solid phase method according to the developed methodology [Evstigneeva R.P., Zheltukhina GA, Zarubina T.V., Nebolsin V.E., Antonenkova T.N., Kostanian I.A., Dranitsyna S.M., Astapov M.V., Surina E.A.// DAN, 2003, t, No. 1, p.1-5] on the polymer with 2-chlorotriethylsilane anchor group in conjunction with Fmoc-strategy with subsequent simultaneous cleavage from the polymer of the target product and its lateral protective groups of the peptides under the action of acid under mild conditions.

After cleaning gel column-chromatography on Sephadex of Geminate (II) was obtained with a yield of 84%, considering the original amino acid in the polymer. Geminate the (II) is highly soluble in water.

Geminate (II) can be obtained in the form of pharmaceutically acceptable salts, for example acetates, chlorides, sulfates, lactates, etc., by varying the nature of the acid with the elimination of Geminate from polymer or turned into one by applying ion-exchange chromatography.

Thus, the proposed Geminate (II) is obtained with high yield and high purity and characterized by electronic and IR spectroscopy, mass spectrometry, TLC.

A preferred variant of the synthesis of Geminate (II) was shown in example 2.

List of abbreviations

DCC is N,N'-dicyclohexylcarbodiimide

DMF - N,N'-dimethylformamide

Ome methyl ether

TLC - chromatography in thin layer

Fmoc - 9-fluorenylmethoxycarbonyl

FmocONsu - 9-fluorenylmethoxycarbonyl

1-NOUT - 1-hydroxybenzotriazole

TFE - triptoreline

DCM - methylene chloride

Mtt - methyldecyl

mTrt - methoxytrityl

TFA - triperoxonane acid

HPLC - high performance liquid chromatography

Experimental part

In the synthesis used L-amino acids and their derivatives firms Reanal (Hungary), Bachem (Switzerland), and we synthesized by known methods [herskowitz AV, Kibirev VK Chemical synthesis of peptides. Kiev: Naukova Dumka, 1992] using FmocONSu. The individuality of the compounds obtained by the was tweedale by TLC on plates Kieselgel 60 F 254Merck(Germany) in the system: n-butanol - pyridine - acetic acid - water 63:36:6:45 (1), n-butanol - pyridine - acetic acid - water 30:20:6:24 (2). Amino acids and peptides on the chromatograms were detected with ninhydrin solution and chlorine-caliginosa reagent and reagent Pauli and Ehrlich reagent. HPLC was carried out on the chromatograph Breeze (Waters) detector (Waters 2487) conditions: column Hm, Symmetry From 8.5 mkm; elution gradient 10→60% phase B for 15 min (buffer A - 0.1%aqueous TFA; buffer B - 0.09%TFA in a mixture of acetonitrile : water 60:40), detection at 280 nm. Hydrolysis of participationof, peptides and gemination conducted in a mixture of 12 n hydrochloric and propionic acid (1:1) at 140°C for 2 h, the Amino acid composition was determined on an automatic amino acid analyzer Biotronic IC5001 (Germany). Values of angles of the specific optical rotation was measured on spectropolarimetry Perkin Elmer 341 (USA). The melting temperature of the substances was determined on thermoprofile table Boetius (Germany). Electronic and IR spectra were recorded on Jasco instruments model UV/VS 7800 Spectrophotometer (Japan) and Perkin ELMER FT-IR 1725X Spectrometer (Sweden). Mass high resolution spectra were recorded on a time-of-flight mass spectrometer with laser desorption ionization (MALDI TOF) Vision 2000 (Thermo Bioanalysis, England).

As the polymer carrier in the synthesis of peptides and gemination which the objects of study were the copolymer of styrene with 1% divinylbenzene, 2-chlorotriethylsilane anchor group with a chlorine content of 1.43 mmol/g of polymer (Bachem, Switzerland). Solid phase synthesis of peptides and gemination carried out in accordance with the Fmoc-strategy [Barlos K., Chatzi O., Gamos D., Stavropouls G. //Int. J.Peptide Protein. Res 1991. V.37. P.513-520]. Load the starting amino acid in the medium was determined by a spectrophotometric method [Dryland A., R.C. Sheppard //J.Chem. Soc. Perkin Trans. I. 1986. N1, P.125-137] and according to quantitative amino acid analysis. The release of the Fmoc-participationof was carried out according to the following scheme: 1) DMF washing 3 min x 2; 2) processing of a 20% solution of piperidine in DMF for 3 min x 1, 11 min x 1; 3) washing DMF 1 Minh. The completeness of the reactions of peptideprophet on the polymer was examined using semi-quantitative ninhydrin test [Kaiser, E., Colescott R.L., Rossinger G.D., Cook, P.J. //Anal. Biochem. 1970. V.34. N2. P.595-598].

Example 1. H-Arg-Trp-His-Arg-Leu-Lys-Glu(OMe)-OH(III)

To 1 g of the polymer (P-C1 1.43 mmol CR), pre-swollen in 10 ml of dichloroethane, was added a freshly prepared solution of 0.548 g (1.43 mmol) of Fmoc-Glu(OMe)-OH and 0.50 ml (3.58 mmol) of triethylamine in 6 ml of dichloromethane, stirred the air for 25 min at 20°C. the Reaction was stopped by adding 20 ml of a mixture methanol-triethylamine (9:1), stirred 1 min Aminoacylation was filtered, washed with digaetano (2 min x 3), DMF (2 min x 2), isopropanol (2 min 2), DMF (2 min x 2), isopropanol (2 min x 2), methanol (2 min x 1), diethyl ether (2 min x 2). Volume one portion of the washing solution 3 ml Contents γ-is amylovora ester of glutamic acid in aminoacylation amounted to 0.45 mmol/g

To a solution of 0.864 g (1.35 mmol) of Fmoc-Lys(mTrt)-OH in 6 ml of DMF under cooling and stirring, was added 0.18 g (1.35 mmol) of 1-NOWT and 0.28 g (1.35 mmol) of DCC. The mixture was stirred air for 20 min, was added to released with the aforementioned method to aminoacylation and was stirred for 30 min, left for 24 h at room temperature, was filtered, washed with DMF (1 Minch 5.). Ninhydrin test samples dipeptidylpeptidase negative.

To a solution of 0.48 g (1.35 mmol) of Fmoc-Leu-OH in 6 ml of DMF under cooling and stirring, was added 0.18 g (1.35 mmol) of 1-NOWT and 0.28 g (1.35 mmol) of DCC. The mixture was stirred air for 20 min, was added to released dipeptidylpeptidase and was stirred for 30 min, left for 24 h at room temperature. Tripeptidylpeptidase was filtered, washed as described for dipeptidylpeptidase. Ninhydrin test is negative.

To a solution of 0.535 g (1.35 mmol) of Fmoc-Arg-OH in 6 ml of DMF under cooling and stirring were added 0.415 ml (1.35 mmol) 3.25 N model HC1 in dioxane. The mixture was stirred for 20 min at 0°C, was added 0.18 g (1.35 mmol) of 1-NOWT and 0.28 g (1.35 mmol) DCC was stirred for 20 min, was added to released tripeptidylpeptidase and was stirred for 30 min, left for 24 h at room temperature. Tetrapeptide was filtered, washed as described for dipeptidyl is alimera. Ninhydrin test positive. The reaction was repeated with 1.2 equivalent of the carboxyl component. Left for 2 hours Ninhydrin test is negative.

To a solution of 0.856 g (1.35 mmol) of Fmoc-His(Mtt)-OH in 6 ml of DMF under cooling and stirring, was added 0.18 g (1.35 mmol) of 1-NOWT and 0.28 g (1.35 mmol) of DCC. The mixture was stirred air for 20 min, was added to released tetrapeptides and was stirred for 30 min, left for 24 h at room temperature. Pentapeptides was filtered, washed as described for dipeptidylpeptidase. Ninhydrin test is negative.

To a solution of 0.576 g (1.35 mmol) of Fmoc-Trp-OH in 3 ml of DMF under cooling and stirring, was added 0.18 g (1.35 mmol) of 1-NOWT and 0.28 g (1.35 mmol) of DCC. The mixture was stirred air for 20 min, was added to released pentapeptidnykh and was stirred for 30 min, left for 24 h at room temperature. Exopeptidases was filtered, washed as described for dipeptidylpeptidase. Ninhydrin test is negative.

To a solution 0.369 g (0.93 mmol) of Fmoc-Arg-OH in 6 ml of DMF under cooling and stirring was added 0.29 ml (0.93 mmol) 3.25 N model HC1 in dioxane. The mixture was stirred for 20 min at 0°C, was added 0.13 g (0.93 mmol) of 1-NOWT and 0.19 g (0.93 mmol) DCC was stirred for 20 min, was added to the released hexapeptides the measure and was stirred for 30 min, left for 24 h at room temperature. Heptapeptide was filtered, washed as described for dipeptidylpeptidase. Ninhydrin test positive. The reaction was repeated with 1.5 equivalent of the carboxyl component. Left for 2 hours Ninhydrin test positive. The reaction was repeated with 1.5 equivalent of the carboxyl component. Left for 2 hours Ninhydrin test is negative.

Received 0.680 g heptapeptide Fmoc-Arg-Trp-His(Mtt)-Arg-Leu-Lys(mTrt)-Glu(OMe)-OP (II). Banding was performed according to the method [K. Barlos, Chatzi O., Gamos D., Stavropouls G.// Int. J.Peptide Protein. Res. 1991. V.37. P.513-520]. To 0.13 g released heptapeptide was added 4 ml of a mixture of CH3COOH-TFE-DCM. The suspension was stirred 2 h at 20°With, then the resin was separated, washed with a mixture of CH3COOH-TFE-DCM. The solvent from the filtrate was removed in vacuum. The residue is triturated with ether, the precipitated precipitate was separated, was dried in vacuum over P2O5. The target substance was perioadele 4 ml medical ester of 1 ml n-butyl alcohol. The output of 0.037 g (62%), considering the original amino acid in the polymer, Rf 0.17 (1). Mass spectrum, m/z: [M]+1038.5. HPLC: individual peak, retention time 11.386 minutes

Example 2. Nα-[6 (7)-(Protohemin IX)-yl] - Arg-Trp-His-Arg-Leu-Lys-Glu(OMe)-OH (II)

Was unblocked 0.172 g heptapeptides and there was added thereto a solution (0.23 mmol) 6(7)-mono-N-oxysuccinimide the ether protohemin IX in 7 ml of DMF, was stirred for 30 min and left for 24 h at room temperature. Hemihepatectomy was separated, washed with DMF (1 min x 7). Ninhydrin test is negative. To getinitialvalue was added 6 ml of a mixture of CH3COOH-TFE-DCM, stirred 2 hours, the Polymer was separated, washed with a mixture of CH3COOH-TFE-DCM, 1 min x 4. The solvent from the filtrate was removed in vacuum. The residue is triturated with ether, the precipitated precipitate was separated, was dried in vacuum over P2O5. The product was purified column gel chromatography. Output 0.109 g (84%). Rf 0.34 (2). Electronic spectrum (methanol), λ.maxnm (ε·10-3): 398.40 (67.42), 499.80 (5.62), 536.0 (4.39), 620.20 (1.46). Mass spectrum, m/z: [M]+1636.5. Amino acid analysis: Glu 1.42 (1), Leu 0.76 (1), Lys 0.60 (1), His 1.34 (1), Arg 1.89 (2). The content of peptide material in Geminate (II)defined quantitative amino acid analysis, accounts for 83% of theoretical.

Example 3. Testing geminata (II) for antiviral activity. Antiviral activity of Geminate (II) was investigated in lymphoblastoid cells MT-4 after a preliminary or simultaneous with the virus entering the cell culture.

The test results presented in table 1.

Table 1

The results of the study of the antiviral action geminata (II) from whom Oseni of human immunodeficiency virus (HIV-1) on model crops lymphoblastoid cells MT-4
The drug concentrationtoxicityHIV infection
Cell viability, %The number of cells x 106/mlCell viability, %The number of cells x 106ml
Control cells (intact cells)901.7--
The control virus (infected cells)--420.4
Retrovir, 10-6M891.7881.7
The compound (II), 10-6M761.1752.0
The compound (II), 10-5M851.3851.5

In addition, the antiviral activity of Geminate (II) was determined by enzyme linked immunosorbent assay for viral protein R-24 HIV gag characterizing HIV replication in the cell.

The test results presented in table 2.

Table 2

The antiviral activity of compound (II) by determining the level of viral protein p-24-gag HIV enzyme immunoassay methodanalysis on the model of the culture of lymphoblastoid cells MT-4
Conditions of experienceThe optical density
The concentration of compound (II) mcm
00.51.010
Control cells (intact cells)0.05
The control virus (infected cells)1.775
Retrovir-0.238--
The compound (II)-1.8640.3480.273

The data obtained indicate that Geminate(P) at a concentration of 10-6-10-5M has an antiviral effect, in particular anti-HIV, expressed in the inhibition of virus replication in cell culture in vitro, comparable to the antiviral activity of known drug Retrovir".

Example 4. The study of the cytotoxicity of Geminate (II) in respect of transplantable cell cultures.

To study the cytotoxicity of Geminate(P) used culture diploid fibroblasts of the human embryo and human cell culture green monkey VERO. It is shown that Geminate (II) at a concentration of 10-4M not OK the shows cytotoxic effect on both used transplantable cell culture.

Example 5. Testing geminata (II) on virulizin activity.

To identify virulizin activity was investigated the influence of Geminate (II) the integrity and infectivity of the DNA virus herpes simple in composition of whole virion, and isolated. In addition, we studied the inuence of Geminate (II) on DNA phage λ and recombinant DNA HIV.

As whole virus used viral suspension obtained from infected VERO cells at the peak of infection by freezing and thawing followed by removal of cell residues by centrifugation. The initial titer of the virus herpes simple, type 1, strain P2 was 5 log10TWL50/. Isolation of DNA was carried out by the alcohol method.

The integrity of the viral DNA was determined using the method of polymerase chain reaction using a pair of primers glycoprotein (UL2) fragment size - po

The presence of amplicons for DNA herpes virus was determined by electrophoresis, the comparison was carried out with standard DNA herpes virus and phage. The amount of DNA is conventionally meant in + in comparison to the control DNA (++++). Geminate (II) was dissolved in sterile distilled water, the initial concentration of 10-3M

Isolated DNA of phage lambda incubated for one hour with gemination (II) at a concentration of 10-4 M at room temperature. As control was used distilled water. In the data analysis of agarose gel electrophoresis in the track with ragovoy DNA after exposure to the drug amplicon DNA phage was absent, whereas the use of water instead of Geminate (II) band of the amplified DNA did not differ from the strip with the control sample DNA phage. Similar results were obtained after exposure of the DNA of the herpes virus with gemination (II) for 50 minutes (table 3).

Table 3

The influence of Geminate (II) on the integrity of the viral DNA
Viral DNAThe impact of Geminate (II)The results of PCR analysis
Concentration, MThe exposure time, min
DNA of phage λ0.00+++
10-4M30++
10-4M60-
DNA virus herpes simple0.00+++
10-4M30+++
10-4M60-

Conducted IP is the study of infectious herpes virus (vaccinated cultural environment, not containing cells and cell debris, infectious titer 5 log10TCD50) showed that when exposed to Geminate for 30 minutes at concentrations of 10-5and 10-4M is not observed degradation of DNA. With increasing duration of exposure to 60 minutes there is a reduction in the number of amplified DNA, but only at higher concentrations of the substance 10-4M With increasing exposure time up to two hours there is a complete degradation of viral DNA in both concentrations of the substances (table 4).

Table 4

The influence of Geminate (II) on DNA of the herpes virus in the composition of whole virion
No. of samplesThe concentration of the substance, MThe exposure time, min
153060120
110-4+++++++++0
210-5+++++++++++0
3Placebo++++++++++++++
4The control virus+++++++++++ +++

Simultaneous with the HIV virus or prior making geminata(II) in the cell culture is observed protective effect (continued viability of cells), which practically coincide with the "Retrovir" at similar concentrations. This cytotoxicity compared to intact (without virus) cells is not present in the concentration range 10-6-10-5M

At a concentration of 10-5-10-4M under the action of Geminate (II) there is a complete degradation of isolated viral DNA (herpes, phage λ) for 1 h, and in the composition of whole virion - 2 hours

Thus, Geminate according to the invention, in particular Geminate (II)corresponding to General formula I, has a significant Kosovo - and time-dependent antiviral and virulizin activity and can be used for biomedical purposes. Geminate according to the invention can find application in the treatment of viral diseases.

1. Geminate corresponding to General formula (I):

where R1=-ArgTrpHisArgLeuLysGlu(OMe) - OH, R2=-OH, Y is Cl-; Me represents Fe, or its pharmaceutically acceptable salt with virulizin and antiviral activity, including in relation to herpes virus and HIV, and the ability to destroy the DNA of phage λ, herpes and the ICH.

2. The movie Geminate General formula (I), where R1=-TrpHisArgLeuLysGlu(OMe) - OH, R2=-OH, preserving virulizin and antiviral activity, as well as the ability to destroy the DNA of phages and viruses, natural and recombinant.



 

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The invention relates to a derivative of hemin or their pharmaceutically acceptable salts and inhibitors of proteolytic enzymes, which are the compounds of General formula (I)

where R1and R2- substituents, which may represent amino acids, derivatives of amino acids, peptides, consisting of 1-15 amino acid residues, derived peptides consisting of 1-15 amino acid residues, and-carboxyl group of amino acids or peptides and side groups of amino acids or peptides can be modified, and it is possible that R1=R2or R1R2=OH; carboxyl group of the porphyrin can be modified methyl or other C2-C8-ester or a physiologically acceptable salt; Y-represents Cl-CH3SOO-; Me represents Fe, with the exception of compounds where

Me=Fe3+, Y-=Cl-,

R1=-LeuLeuValPheOMe, R2=-OH; R1=-ValPheOMe, R2=-OH; R1=-LeuHisOMe,

R2=-OH; R1=-LeuHisAlaOMe, R2=-OH; R1=-LeuHisNHC10H20COOMe, R22=-LeuHisNHC10H20COOMe; R1=-Lys(Tfa)AlaAlaOMe, R2=-OH;

R1=-ValPheOMe, R2=-LeuHisOMe; R1=-LeuLeuValPheOMe, R2=-LeuHisOMe;

R1=-LeuLys(Tfa)LeuOMe, R2=-OH; R1=-LeuLys(Tfa)LeuOMe, R2=-LeuHisOMe;

R1=-Lys(Tfa)AlaAlaOMe, R2=-AlaHisLys(Cbz)LeuOMe; R1=-GlyOBzl,

R2=-GlyOBzl; R1=-HisOMe, R2=-HisOMe; R1=-LeuHisOMe, R2=-LeuHisOMe;

R1=-LeuHisLeuGlyCys(Bzl)OBzl, R2=-LeuHisLeuGlyCys(Bzl)OBzl;

R1=-LeuHisOMe, R2=-OEt; R1=-LeuHisLeuGlyCys(Bzl)OBzl, R2=-OEt; R1=-OBzl,

R2=-OBzl; R1=-OBzl, R2=-OH; R1=-AlaOMe, R2=-OBzl; R1=-HisOMe, R2=-OBzl;

R1=-LeuHisOMe, R2=-OBzl; R1=-LeuHisLeuGlyCys(Bzl)OBzl, R2=-OBzl;

R1=-LeuHisAlaLys(Cbz)GlyCys(Bzl)OBzl, R2=-OBzl; R1=-LeuHisLys(Cbz)OMe,

R2=-OH; R1=-LeuHis(Bzl)Lys(Cbz)OMe, R2=-OH; R1=-LeuHisOMe, R2=-OMe;

R1=-LeuHis(Bzl)Lys(Cbz)OMe, R2=-OMe; R1=-AlaLeuAlaPheAlaCys(Bzl)OMe,

R2=-LeuHis(Bzl)Lys(Cbz)OMe; R1=-AlaLeuAlaPheAlaCys(Bzl)OBzl,

R2=-LeuHis(Bzl)Lys(Cbz)OMe; R1=-LeuHisAlaLys(Cbz)Cys(Bzl)OBzl,

R2=-LeuHis(Bzl)Lys(Cbz)OMe; R1=-LeuHisOMe, R2=-OMe;

R1=-GlyProArgGlyGlyOMe, R2=-OH;

R1=-ArgProProGlyPheSer(Bzl)PheArgGlyGlyOMe, R2=-OH,

two ways to get hemin derivatives of General formula I, hemin derivatives of the formula I, formerly known above, as inhibitors of proteolytic enzymes: the HIV protease, pepsin, trypsin, chymotrypsin

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1 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates, in particular, to novel tetrapyrrole macroheterocycles - diphenyloctaalkylporphynes that can be used as a coloring substance of optical filters. Invention describes 5-(4'-acrylmidophenyl)-2,8,12,13,17,18-hexamethyl-3,7-dibutylporphyne (I) and 5-(3'-acrylamidophenyl)-2,8,12,13,17,18-hexamethyl-3,7-dibutylporphyne (II) as a coloring substance of optical filters. These compounds show maximum absorption in the range 624 nm and can be used for preparing colored polymers used as optical filter.

EFFECT: valuable properties of compound.

1 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to derivatives of 2-aminonicotine amide of the formula (I): , to methods of their synthesis and a pharmaceutical composition based on thereof inhibiting activity of receptor tyrosine kinase vessel endothelial growth factor (VEGF) and to corresponding method for inhibition of activity of VEGF-receptor tyrosine kinase. It is suggested that this activity will allow offering the curative effect in proliferative diseases associated with angiogenesis, in particular, in treatment of tumors, retinopathy or age degeneration of yellow (corneal) spot.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 42 ex

FIELD: medicine, ophthalmology, ophthalmooncology.

SUBSTANCE: one should intravenously inject a photosensitizer photosens at 0.1-1.0 mg/kg patient's body weight. In about 48-72 h since the moment of photosens injection it is important to detect the presence of preparation's therapeutic dosage in the tumor. For this purpose one should specify the coefficient of contrast degree between the tumor and healthy adjacent tissues. Planning of photodynamic therapy should be fulfilled individually by orienting to concrete values of the coefficient of contrast degree in a concrete patient. At the value of coefficient of contrast degree being ≥4, but under 10 it is necessary to irradiate with low single dosages (ranged 80-150 mW/sq. cm) by increasing the number of seances conducted (up to 10). At the value of the above-mentioned coefficient being ≥10.0 irradiation should be carried out once or during 2-3 seances at high single radiation dosages (ranged 150-800 mW/sq. cm). The innovation enables to optimize therapy in patients with intraocular tumors.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to using dicarboxylic acids of the general formula (2): R-CONH-OH (2) wherein R means -HO-HNCO, -HO-NHCOCH-(OH)CH(OH), -HOOC-CH2CH2, -HO-OCCH=CH as inhibitors of metastasis and agents enhancing chemotherapeutic activity of antitumor preparations. Also, invention relates to a method for enhancing effectiveness of cytostatics in carrying out cytostatic chemotherapy of tumors. Method is carried out by using cytostatics in combination with derivatives of dicarboxylic acids of the formula (2). Also, invention relates to a method for inhibition of metastasizing process. Method is carried out by effect of the known cytostatics and derivatives of dicarboxylic acid of the formula (2) on tumor. Proposed substances provide enhancing antitumor and anti-metastatic activity of known cytostatics based on using derivatives of dicarboxylic acids.

EFFECT: valuable medicinal properties of agents and preparations, enhanced effectiveness of metastasizing inhibition.

4 cl, 4 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: method involves impregnating sterile gauze napkins with Tactivin solution, in the amount of 100 mcg per each napkin, and imposing it on mammary gland. Then, variable magnetic field treatment is applied. When applying the procedure one day and one hour prior to operation the napkins are arranged on both sides with respect to nodular formation, 3 cm far from it. When carrying out the procedure at the third day after operation, napkins are placed directly onto zone under operation.

EFFECT: reduced risk of complications in postoperative period.

FIELD: medicine.

SUBSTANCE: method involves concurrently giving Cyclopheron and Licopid under immunogram control at traditional doses and courses. Thus, if even one of parameters of immunogram, carried out in 2 months after treatment, does not reach normative limits, additional Licopid administration is applied under traditional preventive scheme.

EFFECT: enhanced effectiveness of immunocorrective and immononormalizing treatment; reduced risk of complications.

FIELD: medicine, pharmaceutical agents.

SUBSTANCE: disclosed is indolylacetic acid and sodium, potassium and lithium salts thereof having immunomodulatory (based on leukocyte levels in patient blood suffering from viral infection or after cytoctatic chemotherapy), anti-inflammation (based on normalizing of erythrocyte sedimentation rate and after ascyte treatment) and anti-tumor properties (in patient suffering from lymphoma and carcinoma). Said salts are produced by treatment of indolylacetic acid with solution of NaOH, or KOH, or LiOH, addition of heated distilled water in obtained solution, keeping at the same temperature to produce bright solution, followed by cooling and drying.

EFFECT: preparation with increased effectiveness, having no allergic action and other site effects.

3 cl, 5 ex

FIELD: medicine, pharmaceutical agents.

SUBSTANCE: disclosed is A-naphthylacetic acid and sodium, potassium and lithium salts thereof having immunomodulatory (based on leukocyte levels in patient blood suffering from viral infection), anti-inflammation (based on normalizing of erythrocyte sedimentation rate and monocytes in patient blood) and anti-tumor properties (in patient suffering from lymphomatoid granulomatosis and carcinoma of lung). Said salts are produced by treatment of A-naphthylacetic acid with solution of NaOH, or KOH, or LiOH, addition of heated distilled water in obtained solution, keeping at the same temperature to produce bright solution, followed by cooling and drying.

EFFECT: preparation with increased effectiveness, having no allergic action and other site effects.

3 cl, 5 ex

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