Method for preparing polymer modified hemoglobin

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to transfusion medicine, namely to a method for preparing polymer modified haemoglobin by the step multifunctional condensation of purified haemoglobin recovered from concentrated red cells in the mixed oxy/deoxy form with a synthetised multifunctional cross-linking agent that is glutaric aldehyde with glutamic acid and sodium glutamate, wherein the first stage of the reaction involves the intramolecular chemical cross-linking of a haemoglobin molecule labile in an aqueous solution; the second stage involves the intramolecular cross-linking of the ready modified haemoglobin molecules to form polymer modified haemoglobin.

EFFECT: invention provides preparing more effective polymer modified haemoglobin in the form of the multifunctional blood substitute having the effective oxygen transfer function, anti-shock and haemodynamic action able to initiate own blood formation.

3 cl, 1 ex, 2 tbl

 

The invention relates to medicine, in particular, Transfusiology and concerns blood drugs with the function of oxygen transport on the basis of hemoglobin.

Currently known methods for producing hemoglobin, one of which hemoglobin receive as a result of destruction of erythrocytes. Another method is based on deoxygenation hemoglobin blood in aqueous solution. Also known is a method of obtaining blood substitute, where to get deoxygenating use of hemoglobin-free erythrocyte leukocyte mass precipitated non-heme proteins, after their removal carry out the concentration of a solution of hemoglobin by ultrafiltration. In addition, there is a method in which their blood and erythrocyte mass remove leukocytes and platelets, washed and are lysed erythrocytes, mean hemoglobin of red blood cells in CO-form is subjected to filtration and heat treatment [EN 2162707, 24.03.1999; EN 2203087, 27.04.2003; EN 2341286, 20.12.2008].

Significant and obvious disadvantages of such analogs are as follows. Hemoglobin resulting from destruction of red blood cells, when injected into the blood stream rapidly eliminated from the blood through the kidneys irreversibly damaging them because of nephrotoxicity. In another case, the introduction of the molecules of hemoglobin in the blood vessels it splits into two separate e is inity, which are nephrotoxicity and have negative side effects on the microflora of the respiratory tract and esophageal tract. These deficiencies significantly reduce the value of drugs and limit its use.

The closest to the essence and the achieved result is a method of producing polyhemoglobin with increased oxygen transport efficiency, including pre-processing and modification of the original components, carrying out the polycondensation reaction, the introduction of terminator [EN 2132687, AK 35/18, 38/42; 10.07.1999]. In this way carry out the reaction of interaction deoxygenating hemoglobin with glutaraldehyde in a buffer solution with a preliminary modification of one of the interacting components of glutaraldehyde and with the completion of the reaction by the addition of substances covering the functional group of the crosslinker.

Having the advantage over similar products, this method of obtaining polyhemoglobin also hides in its essence obvious and significant shortcomings, which consists in insufficient gas transmission activity of the resulting hemoglobin in connection with small size of its molecules and the short time of its functioning in the circulatory system that does not allow effective indicators kislorodna the structure of organs, does not eliminate its nephrotoxicity and shock of the individual after administration of hemoglobin. These drawbacks inherent in the process of feature selection, processing, sequence of operations, modes and parameters, which does not allow to obtain a polyfunctional blood solution, which could be able to initiate their own blood.

The technical task and the positive result of the invention to provide a polymer modified hemoglobin with a higher class of its effectiveness in the form of a polyfunctional blood solution with a function of the effective transport of oxygen with resuscitation and hemodynamic effect, are able to initiate their own blood; a drug with a higher physico-chemical and biological properties: antioxidant, anti-inflammatory and immunomodulatory - to restore the normal functioning of the body.

The specified technical task and the effect is achieved by the developed method for polymer modified hemoglobin, high efficiency is tested by applicants preclinical and clinical trials.

A method of obtaining a polymer modified hemoglobin involves the pre-processing is a modification of the original components, conducting the polycondensation reaction, the introduction of terminator, maintaining step polycondensation isolated from erythrocyte mass of purified hemoglobin in a mixed oxy/deoxy form synthesized with a polyfunctional cross-linking agent is derived glutaraldehyde dipolar ions from a number moneymoneymoney and mononitratebuy acids and peptides based on them, where in the first stage reactions are intramolecular chemical joining of labile in an aqueous solution of hemoglobin molecule, and the second stage is conducted intermolecular joining of already modified molecules of hemoglobin with the formation of polymer modified hemoglobin.

The method is characterized by the fact that the reaction of hemoglobin in a mixed oxy/deoxy form with a polyfunctional cross-linking agent is carried out in a stream of nitrogen or argon at a temperature of 4-15°C.

The method is characterized also by the fact that as a terminator reaction using regenerative systems: sodium borohydride and sodium bisulfite in the range of molar ratios of from 1 to 100%.

An example of the method.

Hemoglobin (GB) receive osmotic hemolysis of erythrocytes blood, purified from cellular and plasma components by methods of high-speed centrifugation and multiple membrane ultra - diafiltration. the volume 5 g % R-RA GB 100 ml.

The staple - derivatives of glutaraldehyde (GA) with glutamic acid (ha) or MSG (GM) in aqueous 0.9% NaCl solution (physiological R-R). The reaction of HA with GC was carried out at t=10°C in a stream of inert gas (nitrogen, argon). To 5.2 ml 3 g % HA was added 6 ml solution GC (5.6 g% R-R) in 6 ml of physiological solution (0.9% NaCl) or GM solution pH=6,8 (3.5 mg of sodium glutamate in 6 ml of physiologic saline). Total staple of 11.2 ml.

Obtaining polymer modified GB (polyhemoglobin, FCB).

100 ml of 5 g% solution GB in 0.9% NaCl, pH=6,85 (pH can be from 6,4÷7.4V - this area pH maximum physiological activity of GB, above and below it is subject to autocycling) is placed in a flask (reactor) with a capacity of ~200 ml. Reaction takes place with constant stirring in a stream of inert gas at t=10°C (interval t° from 6 to 22°C below 6°C, the reaction slows and above 22° - possible auto-oxidation). Stapler type 2 admission (stage 2).

on stage I to deoksigenirovanii GB add half of the stapler (5.6 ml) - the result is PGB with MM (molecular weight srednevekovoi) 72-128 kDa is a mixture of monomer and dimer GB (MMGB=65 kDa) (table 1).

at the second stage is added to the second half of the stapler (5.6 ml). At this stage MMPGB-2reaches 230-320 kDa, which corresponds to 3-5-measures polyhemoglobin.

The reaction is stopped by the addition of the reducing agent sodium borohydride (NaH 4) (60 mg in 10 ml of R-RA) or sodium bisulfite (NaHSO3) (164 mg in 12 ml), it may be the sequential addition of (50/50) each in half the number. The reaction proceeds under stirring for 30 minutes.

Then turn off the current of inert gas, the resulting solution FCB drained and conduct research:

1) Helpanimals chromatography (GPC) on sepharose 6B, balanced 0.05 M phosphate buffer pH 7.2. Determined molecular weight distribution, are calculated srednevekovye molecular weight FCB (calibration), and the content of high molecular weight and low molecular weight fractions PGB-2.

2) oxygen transport function FCB was evaluated on the unit of Hem-O-Scan, filmed curves dissociation of oxyhemoglobin (BWW) is the degree of saturation of the FCB oxygen partial pressure of oxygen (pO2). The efficiency of oxygen transport is the value of P50- partial pressure of oxygen at 50% saturation GB or FCB oxygen. For comparison, samples of GB and FCB were dialyzed against 0.05 M Tris-HCl buffer in 0.9% NaCl (pH=7,4). BWW filmed at 37°C in the range of differential partial pressure of oxygen (pO2) in the range of 0-16 mm Hg.

Advantages of two-stage submission finisher:

1. There is a stable reproducible results (table 2) MM and fractional composition.

2. The content of low molecular weight fractions PGB-2 (~65 kDa) is reduced to 2-8%, and the yield of polymeric fraction reaches 92-98%.

3. This increases the efficiency of gas transport PGB-2 (compared to GB) (BWW) the value of P50increased ~ 1.5 times.

The results of the method are summarized in tables 1 and 2.

Use as a modifier for the HA instead of the GK - monosodium glutamate (GM) gives a more uniform molecular weight distribution.

GM is well soluble in water: (ha dissolves only when alkalization, slowly). The use of GM that gives standard pH solution (6,7-6,8), and reduces the stage upon receipt of the stapler.

1. A method of obtaining a polymer modified hemoglobin, including pre-processing and modification of the original components, carrying out the polycondensation reaction, the introduction of terminator, wherein the conducting step polycondensation isolated from erythrocyte mass of purified hemoglobin in a mixed oxy/deoxy form synthesized with a polyfunctional cross-linking agent glutaraldehyde with glutamic acid and MSG, where in the first stage reactions are intramolecular chemical joining of labile in an aqueous solution of hemoglobin molecule, and the second is stage spend intermolecular joining of already modified molecules of hemoglobin with the formation of polymer modified hemoglobin.

2. The method according to claim 1, characterized in that the reaction of hemoglobin in a mixed oxy/deoxy form with a polyfunctional cross-linking agent is carried out in a stream of nitrogen or argon at a temperature of 4-15°C.

3. The method according to claim 1, characterized in that as the terminator reaction using regenerative systems: sodium borohydride and sodium bisulfite in the range of molar ratios of from 1 to 100%.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to novel hemin derivatives of general formula pharmaceutically acceptable salts thereof, synthesis method, pharmaceutical and disinfection compositions.

EFFECT: compounds have decomposition effect on lipid membrane, antimicrobial properties, antibacterial and antifungal, and simultaneously virucidal and antimicrobial properties.

15 cl, 2 dwg, 20 ex

FIELD: medicine.

SUBSTANCE: invention relates to novel hemin derivatives of general formula I

where R1=R2 and represent β-alanyl histamine or γ-gutamyl histamine, or β-alanyl histidine, or R1 represents γ-gutamyl histamine; Y represents CI-; Me represents Fen+, where n=2, 3; and where hemin carboxyl group can be modified with methyl or other C1-8 ether their pharmaceutically acceptable salts; method of their obtaining and pharmaceutical compositions.

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9 cl, 1 dwg, 7 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: group of inventions concerns medicine and pharmacology, namely to blood substitutes on the basis of polyhemoglobin. The blood substitute with function of oxygen transfer which basis is made of polymerised glutaric aldehyde haemoglobin received from blood of animals is offered, thus it represents a dry substance and contains not less than 90% of polymerised haemoglobin with molecular mass in a range 192000-320000Da, and methemoglobin content in a blood substitute makes not more than 5%. The pharmaceutical compositions containing the specified blood substitute, containing either polyvinylpyrolidone, or polyoxydin, or physiological saline, or solution of sodium chloride, potassium chloride and magnesium chloride and sodium fumarate are offered. The invention provides blood substitute creation, comparable by efficiency of oxygen transfer with erythrocytes of human blood.

EFFECT: creation of blood substitute, comparable by efficiency of oxygen transfer with erythrocytes of human blood.

10 cl, 1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: offered is method of blood substitute production and related installation for method implementation. Method of blood substitute production includes production of deoxygenated haemoglobin, its polymerisation and purification. Production of deoxygenated haemoglobin includes haemolysis of water addition to erythrocytic mass, stroma separation, non-heme protein precipitation and removal from produced haemoglobin solution. Polymerisation includes processing of produced deoxygenated haemoglobin with modified glutaric aldehyde and restoration with sodium borane, with purification including ultra filtration. Deoxygenated haemoglobin is produced using leukocyte-free erythrocytic mixture. Non-heme proteins are precipitated by concentrated sodium chloride solution added to haemoglobin solution. Removal of non-heme proteins is followed with ultra filtration concentration of haemoglobin solution. Haemoglobin is produced in polymeric disposable containers, while deoxygenation and polymerisation are carried out in gas vortex reactor with nitrogen atmosphere within 1-6 hours each. Diafiltration purification is performed in polymeric disposable containers on shutoff dampers to produce end product molecular weight within 100 kDa to 450 kDa. Method allows for simplified production of polyhaemoglobin with lowered cost and higher outcome. Related installation for method implementation includes series haemoglobin production area, haemoglobin polymerisation reactor and end-product purification system. Haemoglobin production area contains series haemolysis tank with filtration manifold for stroma separation, non-heme protein precipitation tank with filtration manifold for removal of precipitated non-heme proteins. End product purification system contains ultra filtration tanks and units with shutoff dampers. All tanks within haemoglobin production area are polymeric disposable containers. Non-heme protein precipitation tank is connected to the tank for concentrated solution of sodium chloride. Polymerisation reactor is designed as gas vortex unit. End product purification system tanks are polymeric disposable containers. Haemoglobin production area, haemoglobin polymerisation reactor and end product purification system, as well as all tanks and units are interconnected by means of sterile rapid-action coupling.

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FIELD: medicine.

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6 cl

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23 cl, 15 ex

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.

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2 cl, 5 tbl, 5 ex

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79 cl, 28 dwg, 44 tbl

FIELD: chemistry of natural organic compounds, medicine, oncology, pharmacy.

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5 cl, 1 tbl, 9 ex

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;

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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

FIELD: medicine, pharmaceutics.

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5 cl, 12 dwg, 6 tbl, 4 ex

FIELD: medicine.

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EFFECT: method reduces a rate of recurrence.

3 tbl, 3 ex

Immunomodulator // 2497514

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, and represents an immunomodulator for treating chronic hepatitis, hepatic cancer, lymphatic sarcoma, chronic leukemia, and for improving the functions of liver and blood-forming organs, for enhancing the immunobiological body characteristics, prepared by mixing 1000 ml of an aqueous infusion of sandy everlasting blossom, pepper mint herb and chicory herb with 50 ml of bovine serum containing leukaemia oncovirus antibodies, 20 ml of wild rosemary infusion, 40 g of ascorbic acid, 2 g of sorbic acid, 0.2 g of folic acid until the ingredients are dissolved completely, with adding 60 g of liver powder, 30 g of lymphatic node powder, 30 g of young bovine spleen powder; the prepared solution is settled at room temperature for 24 hours, then kept at a boiling water bath for 30 minutes and cooled for 6-8 hours at room temperature; the settled solution is filtered, wherein the aqueous herbal solution is prepared by mixing equal proportions of the separately prepared aqueous infusions of 40 g of pepper mint herb in 1000 ml of water, 30 g of sandy everlasting blossom in 1000 ml of water and 30 g of chicory herb in 1000 ml of water, while the wild rosemary infusion is prepared by infusing 60 g of ground wild rosemary blossom in 1000 ml of 70% purified ethanol.

EFFECT: invention provides creating the high-efficacy agent and reducing the length of treatment.

FIELD: medicine.

SUBSTANCE: invention refers to veterinary science, and may be used for normalising spontaneous erythrocyte aggregation (SEA) in newborn piglets suffered acute hypoxia at birth. That is ensured by prescribing crezacin 4 mg/kg a day of fed-on plan in the morning for five days combined with gamavit 0.03 mg/kg intramuscularly once a day in the morning for five days in the newborn piglets suffered acute hypoxia at birth.

EFFECT: method enables normalising SEA in the newborn piglets, normalising weight gain, reducing death loss and improving the quality of meat products.

3 ex

FIELD: medicine.

SUBSTANCE: invention relates to veterinary, and can be applied for normalisation of spontaneous erythrocyte aggregation (SEA) in piglets with dairy-vegetative nutrition with bronchitis. For this purpose to piglets of diary-vegetative nutrition with bronchitis simultaneously prescribed are crezacine in dose 4 mg/kg per day in scheme of drinking in the morning for five days and gamavit in dose 0.03 mg/kg per day intramuscularly one time per day, for five days.

EFFECT: method makes it possible to normalise level of SEA in piglets, reduce mortality, normalise weight gain, and increase quality of obtained from them in future meat production.

3 ex

FIELD: medicine.

SUBSTANCE: invention refers to veterinary science, and may be used for normalising spontaneous erythrocyte aggregation (SEA) in sows with arthritis. That is ensured by prescribing crezacin 4 mg/kg a day of fed-on plan in the morning for five days combined with gamavit 0.03 mg/kg intramuscularly once a day in the morning for five days.

EFFECT: method enables normalising SEA in sows, reducing death loss and improving the quality of the produced piglets and meat products.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosubstituted pyrazolon azo derivatives of formula

or pharmaceutically acceptable salts thereof, intermediate compounds of formula ,

as well as methods for production thereof, a pharmaceutical composition containing a compound of formula (II), and use thereof as a therapeutic agent, which is a thrombopoietin (TPO) mimetic, as well as use thereof as agonists of the thrombopoietin receptor. Values of substitutes in formulae (I) and (IA) are given in the claim.

EFFECT: obtaining bicyclosubstituted pyrazolon azo derivatives.

12 cl, 58 ex

FIELD: medicine.

SUBSTANCE: invention refers to veterinary science, and may be used for normalising spontaneous erythrocyte aggregation in suckling piglets with arthritis. That is ensured by prescribing crezacin 4 mg/kg a day of fed-on plan in the morning for five days combined with gamavit 0.03 mg/kg intramuscularly once a day in the morning for five days in the suckling piglets with arthritis.

EFFECT: method enables normalising spontaneous erythrocyte aggregation in piglets, reducing death loss, normalising weight gain, and improving the quality of meat products.

3 ex

FIELD: medicine.

SUBSTANCE: invention refers to veterinary science, and may be used for normalising spontaneous erythrocyte aggregation in newborn piglets with dyspepsia. That is ensured by prescribing crezacin 4 mg/kg a day of fed-on plan in the morning for five days combined with gamavit 0.03 mg/kg intramuscularly once a day in the morning for five days.

EFFECT: method enables normalising spontaneous erythrocyte aggregation in newborn piglets, normalising weight gain, reducing death loss and improving the quality of meat products.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics and medicine and deals with application of trecresan as medication, which modulates concentration of ferritin in blood serum.

EFFECT: medication has high efficiency.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of biotechnology and deals with method of dividing swine blood into plasma and erythrocyte mass. Claimed method includes mixing blood with anticoagulant during its sampling from animal. As anticoagulant, two-component solution is used: 4% solution of sodium citrate (Na2C6H5O7) with addition of citric acid until pH from 5.0 to 6.0 is achieved, it is mixed with blood in ratio 1:10 or 0.75% solution of sodium phosphate disubstituted (Na2HPO4) with addition of citric acid until pH from 5.0 to 5.5 is achieved, its is mixed with blood with ratio 1:4. Blood mixed with anticoagulant is cooled to temperature 4°C, centrifuged with frequency of rotation 4000÷5000 rev/min and process duration 5÷15 min.

EFFECT: claimed invention makes it possible to preserve nativity and prevent undesirable hemolysis of erythrocytes which results in increase of purity of obtained blood fractions.

3 tbl, 1 ex

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