CN112451653A - Application of glutathione in preparation of medicine for preventing and treating intravascular hemolysis induced by puerarin injection - Google Patents
Application of glutathione in preparation of medicine for preventing and treating intravascular hemolysis induced by puerarin injection Download PDFInfo
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- CN112451653A CN112451653A CN202011571564.2A CN202011571564A CN112451653A CN 112451653 A CN112451653 A CN 112451653A CN 202011571564 A CN202011571564 A CN 202011571564A CN 112451653 A CN112451653 A CN 112451653A
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- hemolysis
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- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 title claims abstract description 137
- RXUWDKBZZLIASQ-UHFFFAOYSA-N Puerarin Natural products OCC1OC(Oc2c(O)cc(O)c3C(=O)C(=COc23)c4ccc(O)cc4)C(O)C(O)C1O RXUWDKBZZLIASQ-UHFFFAOYSA-N 0.000 title claims abstract description 126
- HKEAFJYKMMKDOR-VPRICQMDSA-N puerarin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=CC(C2=O)=C1OC=C2C1=CC=C(O)C=C1 HKEAFJYKMMKDOR-VPRICQMDSA-N 0.000 title claims abstract description 126
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a compatible application method of glutathione and puerarin, which is characterized in that the glutathione and the puerarin are compatible to prepare an injection containing the puerarin, or the glutathione is firstly used and then the puerarin is used, thereby effectively overcoming the accidental hemolytic adverse reaction of the puerarin injection and improving the safety of the puerarin injection administration.
Description
Technical Field
The invention relates to medical application of glutathione, in particular to application in puerarin injection.
Background
Erythrocytes are essential in the blood circulation, and maintaining normal biological function of erythrocytes depends on the integrity and elasticity of the erythrocyte membrane. Once the membrane is lost or increased in fragility, the red blood cells may rupture, forming hemolysis. Free radical mediated oxidation of erythrocyte membranes is believed to be a significant cause of erythroid injury. Oxygen free radicals in cells attack the phospholipid layer of the membrane to induce chain reaction, lipid peroxidation occurs, the fragility of the membrane is increased, and cells swell and break to cause hemolysis. It is known that the survival and function of erythrocytes depends on the integrity of antioxidant protection systems. Once subjected to oxidative damage, erythrocytes are ruptured and destroyed, and hemolysis is shown. the-SH on glutathione is more easily oxidized, thereby protecting hemoglobin, CAT and-SH of lipoprotein on cell membrane in cells from oxidation. The lack of GSH on the one hand causes biomacromolecules in erythrocytes such as CAT, lipoproteins on membranes, and-SH of hemoglobin is very easily oxidized, which results in accumulation of lipid peroxidation products on membranes, hemoglobin denaturation, and formation of Heinz bodies, thereby affecting deformability and fluidity of erythrocytes, and finally hemolysis. Glutathione mitigates the oxidation of membrane lipoproteins and the degenerative process of hemoglobin, thereby inhibiting oxidative hemolysis of red blood cells. Suggesting that glutathione levels are inversely related to oxidative hemolysis. Sickle anemia, the occurrence of hemolysis, is also associated with Glutathione depletion (E.E. Onukak, E.C. Akwiwu, J.O. Akpotuzor et al. glutamaterone and Bilirubin Concentrations as Markerss of Oxidative Stress therapy applied to the University of calcium Teaching Hospital, Calabar Nigeria. International Blood Research & Reviews, 2019,10(2): 1-6). Acetophenylhydrazine is a strong oxidizing agent, and in vivo APH reacts with oxygenated hemoglobin to produce benzodiazine radicals, which denature the hemoglobin molecule and provoke lipid peroxidation of membrane lipids, causing the red blood cell membrane to collapse, eventually leading to hemolysis. The content of glutathione can be obviously reduced by the aid of the acetylphenylhydrazine. The results of the experiments suggest that some biologically active peptides with antioxidant properties are capable of reducing oxidative hemolysis and protecting erythrocytes (Qiao-Hui Zeng, lacing-Wang, Ying-Hui Zhang et al Recovery and identification of biologically active peptides from protein isolates of Spirulina platensis and in vitro infection of inflammatory activity strain-induced extracellular metabolism. J Sci Food Agric, 2020, 100: 3776-. The mild depletion of glutathione peroxidase can cause the oxidation of erythrocytes, resulting in hemolytic anemia. Glutathione peroxidase activity Is maintained, and oxidative stress of erythrocytes Is inhibited, and hemolysis of erythrocytes Is resisted (K. Rankaljeet, G.Preety, R. Pulsatit et al. Protective Role of Selenium againt Hemophilic antigens Is media Through heavy Regulation. Biological Trace Element Research, 2019, 189: 490-500). Therefore, glutathione has a certain effect on preventing hemolysis of erythrocytes.
Puerarin is an isoflavone compound extracted from dried root of Pueraria lobata Ohwi of Leguminosae, 4', 7-dihydroxy-8-beta-D-glucosyl isoflavone. Is widely used for treating cardiovascular diseases clinically. The prior clinical medicine preparation containing puerarin is mainly injection. With the wide use of puerarin, more and more reports about adverse reactions of puerarin are provided in recent years, and the wide attention of the medical field is attracted. By analyzing the adverse reaction of the traditional Chinese medicine in the last 20 years, the puerarin injection is ranked at the 18 th position. The national adverse drug reaction monitoring center reported adverse reactions of puerarin injection in adverse drug reaction information report 3 of 1 month in 2003. Most researchers think that the puerarin injection is prepared by using 50% propylene glycol as a solvent, so that the purity is not enough due to the difference of extraction processes, technologies and the like, and various reactions caused by introducing impurities cannot be avoided (see the analysis of adverse reactions in clinical puerarin injection in xu daohui, Shanghai J.Med., 2006, 40 (8): 71-72; and the clinical application and adverse reactions of puerarin in Xu Shi Guo, Shizhen Chinese medicine, 2005, 16 (12): 1307-1308). After 63 adverse reactions of puerarin reported in main medical journal in 2004 in 2000-year, 40 men and 23 women were discovered; the age is 34-81 (57.5 +/-23.5). In all cases intravenous drip was administered. The administration dosage is 0.4-0.6 g, and the drug diluent is 5% glucose solution, normal saline, 5% glucose saline and the like. The fastest reaction time is 3 min, the slowest reaction time is 13 d, and the reaction time is in the administration process. 47 responders appeared with the first dose and 16 responders appeared with repeated doses. Statistics show that the common adverse reactions include allergy (fever, tremor and the like, 24 cases), anaphylactic shock (4 cases), hemolytic anemia (13 cases), liver damage, kidney damage (7 cases), drug fever (10 cases) and death (5 cases). All cases had no history of allergy, and the patients who stopped taking the drug after the reaction were recovered by symptomatic treatment (except dead cases). The dosage and the used diluent are within the prompting range of the medicine instruction, and all reactions are definitely caused by puerarin. The adverse reaction is independent of the disease, age and sex, and is not related to the drug diluent. It is related to the difference in constitutions of patients, especially the elderly and infirm. The length of the reaction time is related to the slow onset of action of the Chinese medicinal preparation (see the general Rongrong written analysis of 63 cases of adverse reactions of puerarin documents, journal of the modern Chinese and Western medicine combination, 2005, 14 (1): 140). A patient with intravenous injection of puerarin shows acute renal insufficiency and hemolytic anemia after about 10min (see Kunming written "puerarin induced hemolytic anemia", journal of adverse drug reactions, 2003, 5: 291). Therefore, the hemolytic anemia caused by puerarin is caused by puerarin itself.
Disclosure of Invention
The invention aims to provide a new medical application of glutathione, namely the application of the glutathione in a puerarin injection, wherein the glutathione can effectively prevent and treat intravascular hemolysis adverse reaction induced by puerarin.
Actually, the invention relates to the application of glutathione in the preparation of puerarin injection compound preparation, and can also be temporarily matched with puerarin injection in the injection and transfusion modes, or the puerarin injection is applied after the glutathione is applied in the injection and transfusion modes.
In order to achieve the purpose, the invention adopts the technical scheme that: new use of glutathione in preparing puerarin injection is provided. The glutathione and puerarin injection is temporarily matched and applied in the modes of injection and transfusion. The injection of puerarin is applied after glutathione is applied in the modes of injection and transfusion.
The relevant content in the above technical solution is explained as follows:
1. in the scheme, the injection comprises the following medicines in parts by weight: l-50 parts of glutathione and l-50000 parts of puerarin.
2. In the scheme, the injection also comprises 1-50 parts by weight of auxiliary materials and l-10000 parts by weight of water for injection. The auxiliary materials are sodium bicarbonate solution, glucose solution, propylene glycol solution, glucose saline, sodium chloride injection or normal saline.
3. In the scheme, the injection can be clinically acceptable injection, powder injection or infusion.
4. In the above scheme, the preparation method of the injection is as follows:
the powder injection is prepared by mixing glutathione and puerarin and sterilizing; or mixing glutathione, puerarin and sodium chloride, dissolving with injectable water, adjusting pH to 5.0-8.5 with hydrochloric acid or sodium bicarbonate solution, filtering, sterilizing the filtrate, packaging in powder ampoule, and sterilizing again;
the injection is prepared by the following steps. Mixing glutathione, puerarin and sodium chloride, adding injectable water for dissolving, adjusting pH to 5.0-8.5 with hydrochloric acid or sodium bicarbonate solution, filtering, bottling the filtrate, and sterilizing. Or glutathione is prepared from 5% glucose solution, 5% glucose saline, propylene glycol solution (prepared from propylene glycol and normal saline at volume ratio of 1:1, and containing propylene glycol 0.5 ml/ml), sodium chloride injection or normal saline by dissolving, mixing with puerarin injection, filtering, packaging the filtrate in ampoule, and sterilizing.
The infusion is prepared by mixing glutathione, puerarin and sodium chloride, dissolving with injectable water, adjusting pH to 5.0-8.5 with hydrochloric acid or sodium bicarbonate solution, dissolving, filtering, bottling the filtrate in saline glass bottle, and sterilizing. Or glutathione is prepared from 5% glucose solution, 5% glucose saline, propylene glycol solution (prepared from propylene glycol and normal saline at volume ratio of 1:1, and containing propylene glycol 0.5 ml/ml), sodium chloride injection or normal saline by dissolving, mixing with puerarin injection, filtering, packaging the filtrate in ampoule, and sterilizing.
5. In the scheme, the temporary matching application refers to that the puerarin injection is mixed with glutathione to be infused or injected together when being applied in a hospital.
6. In the scheme, the step of applying the glutathione in an injection and transfusion manner and then applying the puerarin injection refers to the step of applying the glutathione in an injection and transfusion manner and then applying the puerarin injection in an injection and transfusion manner in a hospital.
Puerarin has effects in dilating coronary artery and cerebral vessels, reducing oxygen consumption of myocardium, improving microcirculation, and resisting blood platelet aggregation. Clinically, the traditional Chinese medicine composition is used for auxiliary treatment of coronary heart disease, angina, myocardial infarction, retinal artery and vein occlusion, sudden deafness, ischemic cerebrovascular disease, infantile viral myocarditis, diabetes and the like. Puerarin can be mixed with glutathione to make compound puerarin injection for preventing and treating various diseases, such as diabetic peripheral neuropathy, hypertension complicated with diabetes, diabetic nephropathy, acute cerebral infarction, stable angina pectoris, lower limb deep venous thrombosis and vertebrobasilar artery ischemia vertigo. However, puerarin in the puerarin-containing injection is very easy to cause intravascular hemolysis. The glutathione not only has a plurality of physiological activities of protecting liver, strengthening brain and the like, but also has the function of antagonizing intravascular hemolysis adverse reaction induced by puerarin and improves the safety of puerarin injection administration.
The purpose and the achieved effect of the present invention will be further described below with reference to some tests.
The experiment refers to the technical guidance principle of research on the irritation and hemolysis of traditional Chinese medicines and natural medicines to carry out a preliminary test on the hemolysis test, and the result shows that 4-6mM puerarin can cause 10% hemolysis of rabbit red blood cells of 1%, the occurrence probability of the in vitro hemolysis test is 100%, the hemolysis test results are all reproduced, and the method can be repeated. The method can be used for finding potential accidental hemolysis of the injection, is a feasible test method for carrying out new drug development of the injection and judging whether accidental hemolysis exists, is beneficial to reducing adverse reactions and improving the safety of the injection. The invention takes rabbits as an experimental animal model to research the action and the effect of glutathione on the hemolytic adverse reaction of puerarin solution.
Action and effect of antagonizing hemolytic adverse reaction of puerarin-containing solution by glutathione
Hemolysis test of puerarin injection
The influence of the combination of glutathione and puerarin on rabbit erythrocytes was studied. The administration method of rabbit comprises dividing the group treated with puerarin and the group (puerarin injection + glutathione) into 2 groups, each group containing 5 rabbits. Puerarin injection (15 mg.kg)－1) + glutathione (0.16 g.kg)－1) The composition is administered through ear vein at a dose of 0.16 g/kg/day according to body constitution－1Dosing. The puerarin-treated rabbits were administered with puerarin at 15 mg/kg per day according to body mass－1Dosing. 1 administration cycle, 10 d per cycle. Blood was collected before dosing and 24 h after dosing on day 6 of the week.
Taking red blood cells of a puerarin injection group rabbit, respectively adding a certain dose of glutathione and puerarin, observing the state of the red blood cells and the occurrence rate of hemolysis after 10min, and searching the antagonistic action of the glutathione on the accidental hemolysis of the puerarin injection by using an X2 test statistical analysis experiment result. The results are now reported as follows:
1 materials of the experiment
1.1 test drugs
Glutathione injection (I), glutathione is purchased from Chongqing medicine Yongyou pharmaceutical Limited liability company, 12.29mg of glutathione is accurately weighed by an electronic balance, dissolved in a normal saline solution, and the volume of the glutathione solution is determined to 10mL by a 10mL volumetric flask, so that the injection (I) has the concentration of 4 mmol.L-1. Filtering with microporous membrane (0.22 μm) for sterilization, and storing at 4 deg.C.
Injection agent 2: the injection (i) is diluted to 2 mmol.L-1, 10mL by sterilized normal saline, and stored at 4 ℃ for later use.
Injection (c): the injection (i) is diluted to 1 mmol.L-1, 10mL by sterilized normal saline, and stored at 4 ℃ for later use.
And 4, puerarin injection IV: 2mL of the puerarin powder is provided by Zhejiang Connbei pharmaceutical products GmbH, and the product batch number is 090501, and each mL of the injection contains 50mg of puerarin.
Puerarin injection (250 mM): accurately weighing 1.041g of puerarin powder (purchased from Jiangsu Tiancheng drug Co., Ltd.) by using an electronic balance, dissolving by using 40% dimethyl sulfoxide (DMSO, DZ0231 and AMRESCO), assisting in dissolving by using ultrasound, diluting the physiological saline solution to 9mL, fixing the volume of a volumetric flask to 10mL, and enabling the color of the solution to be colorless (in a configuration environment: carried out in an ultra-clean workbench). The solvent was 40% DMSO solution. Filtering with microporous membrane (0.22 μm) for sterilization, and storing at 4 deg.C.
Compound puerarin injection (sixty percent): 0.04mL of injection and 0.20 mL of injection are uniformly mixed to form 0.24mL of injection. Each mL of the injection contains 41.67mg of puerarin and 204.8 mug of glutathione.
Compound puerarin injection (c): 0.04mL of injection and 0.20 mL of injection are uniformly mixed to form the injection (c), wherein the total volume is 0.24 mL. Each mL of the injection contains 41.67mg of puerarin and 102.4 mug of glutathione.
Compound puerarin injection (b): 0.04mL of injection and 0.20 mL of injection are uniformly mixed and totally 0.24mL is prepared to form the injection. Each mL of the injection contains 41.67mg of puerarin and 51.2 mug of glutathione.
Ninthly, the compound puerarin injection: 0.04mL of injection and 0.099 mL of injection are uniformly mixed to form 0.14mL of injection. Each mL of the injection contains 73.61mg of puerarin and 351.1 mug of glutathione.
Compound puerarin injection r: 0.04mL injection and 0.099 mL injection are mixed to total 0.14mL to form injection in the form of injection in the amount of R. Each mL of the injection contains 73.61mg of puerarin and 175.5 μ g of glutathione.
Compound puerarin injection ≈ 11: 0.04mL of injection and 0.099 mL of injection are mixed uniformly to obtain 0.14mL of injection. Each mL of the injection contains 73.61mg of puerarin and 87.8 μ g of glutathione.
1.2 Experimental animals
10 rabbits (about 2.5 Kg) are provided by the animal experiment center of northwest agriculture and forestry science and technology university. Feeding the chicken at the room temperature of 15-25 ℃ and the relative humidity of 50%.
1.3 reagents, instruments
Sodium chloride injection, Shiyao silver lake pharmaceutical Co Ltd; water for injection is prepared by self; TGL-16B high speed centrifuge, Hunan Star science instruments, Inc.; HPY-01B Biochemical incubator, Huangshi Hengfeng medical appliances Co., Ltd; BIO-RAD680 enzyme-linked immunosorbent assay device; the enzyme label is purchased from Jiangsu Haimen III and Xinya medical instrument factories and is purchased from Yanglinbao Xin equipment Co., Ltd. of Shaanxi province.
2 method
2.1 preparation of erythrocyte suspensions
10 rabbits are divided into puerarin injection group and puerarin injection + glutathione treatment group, and blood is collected 24 h after 6 days of ear marginal vein injection. The hemolysis experiments were performed separately. 10mL of blood is collected from the heart of each rabbit, 160IU of heparin sodium (Jiangsu Wanbang Biochemical medicine, Inc.) is anticoagulated, then the rabbit is placed in a graduated centrifugal tube, the rabbit is centrifuged at 2000 r/min for 10min, the blood plasma is discarded, a proper amount of sodium chloride injection is added for washing, and the rabbit is centrifuged to discard the supernatant and the leucocyte layer. Adding appropriate amount of normal saline, shaking, centrifuging, and repeatedly washing for 3 times until the supernatant is colorless and transparent after centrifuging. The packed red blood cells were diluted with physiological saline to form an 11% (by volume) red blood cell suspension. This completes the preparation of the red blood cell suspension.
2.2 Puerarin solution in vitro hemolysis experiment design
Let the concentration of puerarin solution on erythrocytes be 6mM (0.00259 g.mL)-1). Setting a negative control group, a solvent control group (DMSO is used for replacing puerarin solution to act on erythrocytes), a drug treatment group and a positive control group. The puerarin solution was measured to have a pH of 7.16 using a METTLER TOLEDO benchtop pH meter.
The corresponding components were added to the tubes separately, taking care of the order of addition, as shown in Table 1 below. After each addition of one ingredient, shake gently. After all the components in the system are added into the system, the mixture is gently shaken and uniformly mixed, and then the mixture is placed in a biochemical incubator at 37 ℃ for incubation. After 10min hemolysis and coagulation reactions were observed. The condensation reaction determination method comprises: if the solution has reddish brown or brownish red flocculent precipitate, it will not disperse after shaking, indicating that there is agglutination of red blood cells, if the aggregate can be uniformly dispersed after shaking, it will be false agglutination, if the aggregate is not shaken, it will be true agglutination. The tubes were then centrifuged at 5000rpm/min and the color of the supernatant visually observed. The supernatant was collected and the light absorption (OD value) was measured at a wavelength of 540 nm. According to 2005 technical guidance principle of stimulation and hemolysis research of traditional Chinese medicine and natural medicine, the hemolysis rate (%) of each tube of each group is calculated according to a formula:
hemolysis rate (%) = (drug-treated OD value-negative control OD value)/(positive control OD value-negative control OD value)
Reference evaluation criteria: the hemolysis rate >5% indicates that hemolysis occurred and was statistically processed.
TABLE 1 puerarin solution and glutathione in vitro hemolysis experiment grouping design
3 results
The puerarin is 15 mg/kg daily according to body mass－1When the dosage is treated, 0.16 g.kg is simultaneously administered－1Glutathione at the dose, no hemolysis was found in the experimental rabbits. The test also considers the influence of 40 mu M, 20 mu M and 10 mu M glutathione on the red blood cells of 5 rabbits injected with puerarin when the puerarin concentration is 6mM, and simultaneously carries out the sporadic hemolysis experimental study of the fourth and fifth puerarin injections, and the experimental results are all recorded in detail. By X2The results of the test statistical analysis are shown in Table 2.
Note: a P <0.01 compared to saline negative group; b P <0.01 compared with puerarin injection group
The results show that: the saline group showed no hemolysis, and the water for injection showed complete hemolysis: compared with the normal saline group, the puerarin Injection (IV) and (V) are all hemolyzed, and the occurrence rate of hemolysis is very different from that of the normal saline group (P)<0.01); the results of the hemolysis test are reproduced, which shows that the hemolysis test method is stable and reliable, and the test results can be repeated. Comparing with the fourth and fifth puerarin injections, the compound puerarin injections are sixty, seventy, eighty, nina, R,
No hemolysis appears in all groups, the compound puerarin injection (sixty percent, eight percent, nine percent) and one in the R,
The hemolysis incidence rate of each group is very different from that of the fourth and fifth groups of puerarin injection (P)<0.01)；Comparing with normal saline, the compound puerarin injection (sixth, seventh, eighth, ninth, third, ninth, tenth) is,
The occurrence rate of hemolysis of each group is not different from that of the normal saline group (P)>0.05); compound puerarin injection (sixty percent, seventy percent, eight percent, nine percent) and (nine percent),
The concentration of each group of puerarin is identical to that of puerarin injection, and its every group is 6mM, but the compound puerarin injections, and nina, and r
Respectively contains 40 muM, 20 muM and 10 muM glutathione, and the puerarin injection (r) and (c) do not contain glutathione.
The above results suggest: the glutathione with different concentrations and the puerarin are compatible for application, can antagonize hemolytic adverse reactions induced by the puerarin, and can reduce the incidence rate to the normal saline level.
The above experimental results show that: the puerarin can initiate hemolysis, the injection containing the puerarin can initiate hemolysis, and the adverse hemolysis reaction containing the puerarin can be eliminated after the glutathione is added.
The above test results suggest: the puerarin injection and the injection prepared by the puerarin and the glutathione have no hemolytic reaction.
Therefore, when the puerarin-containing injection is prepared or used, the glutathione is added, so that hemolytic adverse reactions caused by puerarin can be eliminated, and the safety of puerarin injection administration is improved.
The invention has the advantages that: when the puerarin-containing injection is prepared or applied, glutathione is added, so that the injection has good antagonism to intravascular hemolysis adverse reaction induced by puerarin, is low in price, has no toxic or side effect, and is safe.
The invention is further described below with reference to the following examples:
the specific implementation mode is as follows:
example i: (preparation of Compound puerarin injection)
Taking 15mg of glutathione and 10 g of puerarin, adding 9g of sodium chloride, adding water to 1000mL, adjusting the pH to 5.0-8.5 by using 1mol/l hydrochloric acid or sodium bicarbonate solution, filtering, encapsulating the filtrate in an ampoule of 2, 5 or 10mL, and sterilizing at 100 ℃ for 30min to obtain the injection. The product can be used for the adjuvant treatment of coronary heart disease, angina pectoris, myocardial infarction, retinal artery and vein occlusion, sudden deafness, ischemic cerebrovascular disease, infantile viral myocarditis, diabetes, etc. The product can be injected intravenously or intramuscularly, each time is l-500 mL, 1-3 times a day, l 0-20 days is a treatment course, and the product can be continuously used for 2-3 treatment courses.
Example 2: (preparation of Compound puerarin powder for injection)
And (3) encapsulating 30mg of glutathione and 1g of puerarin in a 10mL ampoule of the powder injection, and sterilizing at 100 ℃ for 30min to obtain the powder injection. The product can be used for the adjuvant treatment of coronary heart disease, angina pectoris, myocardial infarction, retinal artery and vein occlusion, sudden deafness, ischemic cerebrovascular disease, infantile viral myocarditis, diabetes, etc. When in application, the prepared powder injection of l to 5000mg is mixed with sodium chloride injection or normal saline injection evenly, and intravenous injection or intramuscular injection can be carried out, wherein l to 500mL of the powder injection is carried out each time, l to 3 times a day, 10 to 20 days are a treatment course, and the powder injection can be continuously used for 2 to 3 treatment courses.
Example 3: (preparation of Compound puerarin infusion)
Adding glutathione 7.5mg, puerarin 2g, and sodium chloride 9g into water to 1000mL, adjusting pH to 5.0-8.5 with lmol/l hydrochloric acid or sodium bicarbonate solution, filtering, bottling the filtrate in 250mL saline glass bottle, and sterilizing at 100 deg.C for 30min to obtain infusion. The product can be used for the adjuvant treatment of coronary heart disease, angina pectoris, myocardial infarction, retinal artery and vein occlusion, sudden deafness, ischemic cerebrovascular disease, infantile viral myocarditis, diabetes, etc. When the Chinese medicinal composition is applied, intravenous injection or intramuscular injection can be directly carried out, wherein the Chinese medicinal composition is used for 1-3 times per day by l-500 mL each time, and l 0-20 days are a treatment course and can be continuously used for 2-3 treatment courses.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (7)
1. Application of glutathione in preparing medicine for preventing and treating intravascular hemolysis induced by puerarin injection is provided.
2. Use according to claim 1, characterized in that: glutathione is applied in infusion mode, and then puerarin injection is used.
3. Use according to claim 1, characterized in that: the puerarin injection and the glutathione injection are mixed evenly before use and then applied in an infusion way.
4. Use according to claim 2, characterized in that: glutathione is firstly used for transfusion, and then puerarin injection is used.
5. Use according to claim 1, characterized in that: comprises the following medicaments in part by weight: 1-50 parts of glutathione and 1-50000 parts of puerarin.
6. Use according to claim 1, 2, 3, 4, characterized in that: contains 1-50 parts by weight of auxiliary materials.
7. An adjuvant according to claim 6, characterized in that: the auxiliary materials are sodium bicarbonate solution, glucose solution, propylene glycol solution or sodium chloride injection.
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Non-Patent Citations (3)
| Title |
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| YAN-XI ZHOU 等: "Puerarin: A Review of Pharmacological Effects", 《PHYTOTHERAPY RESEARCH》, pages 1 - 15 * |
| 朱丹平 等: "葛根素注射液联合还原型谷胱甘肽治疗糖尿病肾病的疗效观察", 《重庆医学》, vol. 46, no. 25, pages 3520 - 3522 * |
| 苏子仁 等: "葛根素注射液溶血不良反应机理研究", 《2006第六届中国药学会学术年会》, vol. 1, pages 65 - 66 * |
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