CN112336710A - Application of glutamine in preparing medicine for preventing and treating puerarin injection induced intravascular hemolysis - Google Patents
Application of glutamine in preparing medicine for preventing and treating puerarin injection induced intravascular hemolysis Download PDFInfo
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- CN112336710A CN112336710A CN202011571951.6A CN202011571951A CN112336710A CN 112336710 A CN112336710 A CN 112336710A CN 202011571951 A CN202011571951 A CN 202011571951A CN 112336710 A CN112336710 A CN 112336710A
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- puerarin
- injection
- glutamine
- hemolysis
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- 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 124
- 239000007924 injection Substances 0.000 title claims abstract description 124
- 238000002347 injection Methods 0.000 title claims abstract description 124
- 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 124
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 206010018910 Haemolysis Diseases 0.000 title claims description 41
- 239000003814 drug Substances 0.000 title claims description 21
- 206010022822 Intravascular haemolysis Diseases 0.000 title claims description 7
- 239000000243 solution Substances 0.000 claims description 28
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 238000001802 infusion Methods 0.000 claims description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 9
- 239000008103 glucose Substances 0.000 claims description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
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- 239000000463 material Substances 0.000 claims description 5
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- 206010067484 Adverse reaction Diseases 0.000 abstract description 19
- 230000006838 adverse reaction Effects 0.000 abstract description 19
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 7
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- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 2
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- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 235000010575 Pueraria lobata Nutrition 0.000 description 1
- 241000219781 Pueraria montana var. lobata Species 0.000 description 1
- 244000088415 Raphanus sativus Species 0.000 description 1
- 235000006140 Raphanus sativus var sativus Nutrition 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
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- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
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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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
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- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a compatible application method of glutamine and puerarin, which is characterized in that the glutamine and the puerarin are prepared into an injection containing the puerarin, or the glutamine 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 glutamine, in particular to application in puerarin injection.
Background
Depletion of glutamine from erythrocytes is associated with oxidative stress and hemolysis of erythrocytes. Glutamine has an antioxidant effect, and changes in glutamine levels in erythrocytes affect the intracellular redox environment, thereby affecting the integrity of the cell membrane, resulting in hemolysis (Morris Claudia R, Suh Jung H, Hagar Ward et al. erythrocytic glutamine depletion, altered redox environment, and pulmony hypertension in single cell disease. Blood, 2008, 111(1): 402-. Glutamine is capable of protecting against Oxidative damage to erythrocytes caused by hydroxyl radicals (Hua-Tao Li a, b, c, Lin Feng a, b, c, Wei-Dan Jiang et al, Oxidative stress parameters and anti-Oxidative stress to hydroxyl radishes in tissue microorganisms: Protective effects of glutamine, alanine, citrulline and proline, aqueous toxicity, 2013, 126: 169-.
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 novel medical application of glutamine, namely the application of the glutamine in puerarin injection, wherein the glutamine can effectively prevent and treat intravascular hemolysis adverse reaction induced by puerarin.
Actually, the invention relates to the application of glutamine in preparing 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 glutamine is applied in the injection and transfusion modes.
In order to achieve the purpose, the invention adopts the technical scheme that: new use of glutamine in preparing puerarin injection is provided. The glutamine and puerarin injection is temporarily matched and applied in the modes of injection and transfusion. The puerarin injection is applied after the glutamine 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 glutamine 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 glutamine and puerarin and sterilizing; or mixing glutamine, puerarin and sodium chloride, dissolving in water for injection, 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 glutamine, puerarin and sodium chloride, dissolving in water for injection, adjusting pH to 5.0-8.5 with hydrochloric acid or sodium bicarbonate solution, filtering, bottling the filtrate, and sterilizing. Or glutamine is prepared from 5% glucose solution, 5% glucose saline, propylene glycol solution (prepared from propylene glycol and normal saline at a 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 glutamine, 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 glutamine is prepared from 5% glucose solution, 5% glucose saline, propylene glycol solution (prepared from propylene glycol and normal saline at a 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 the glutamine for transfusion or injection at the same time when being applied in a hospital.
6. In the above scheme, the application of the glutamine followed by the puerarin injection in the injection and infusion modes means that the glutamine is applied in the injection and infusion modes and then the puerarin injection is applied in the injection and infusion modes in hospitals.
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 glutamine 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 invention provides a novel preparation method of puerarin injection, which is characterized in that the glutamine has a plurality of physiological activities of protecting liver, strengthening brain and the like, and the inventor proves that the glutamine can antagonize the intravascular hemolysis adverse reaction induced by puerarin and improve 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 glutamine on the hemolytic adverse reaction of puerarin solution.
Action and effect of glutamine for antagonizing hemolytic adverse reaction of puerarin-containing solution
Hemolysis test of puerarin injection
The influence of the combination of glutamine and puerarin on rabbit erythrocytes was studied. The administration method of rabbit comprises dividing the group treated with puerarin and the group (puerarin injection + glutamine) into 2 groups, each group containing 5 rabbits. Puerarin injection (15 mg.kg)－1) + Glutamine (0.45 g.kg－1) The composition is administered through ear vein at a dose of 0.45 g/kg/day according to body constitution－1Dosing. Puerarin and its preparation methodThe 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.
Adding certain amount of glutamine and puerarin into red blood cells of rabbit of puerarin injection, respectively, observing red blood cell state and hemolysis incidence after 10min, and using X2The test result of statistical analysis is tested, and the antagonistic action of glutamine on the accidental hemolysis of the puerarin injection is searched. The results are now reported as follows:
1 materials of the experiment
1.1 test drugs
Glutamine injection (I), wherein glutamine is purchased from Chongqing Yaoyou pharmaceutical Limited liability company, 5.84mg of glutamine is accurately weighed by an electronic balance, dissolved in physiological saline solution, and the glutamine solution is subjected to constant volume to 10mL by a 10mL volumetric flask, so that the injection (I) has the concentration of 4mmol-1. Filtering with microporous membrane (0.22 μm) for sterilization, and storing at 4 deg.C.
Injection agent 2: the injection (r) is diluted to 2 mmol.L with sterilized normal saline-110mL, stored at 4 ℃ until use.
Injection (c): the injection (r) is diluted to 1 mmol.L with sterilized normal saline-1，10mL， 4℃
And (5) storing 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 97.3 μ g of glutamine.
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 48.6 μ g of glutamine.
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 24.3 mug of glutamine.
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 166.8 mug of glutamine.
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 83.4 μ g of glutamine.
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 41.7 μ g of glutamine.
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 + glutamine 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). Design negative
Control group, solvent control group (DMSO is used to replace puerarin solution to act on erythrocytes), drug treatment group and 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 tube)
Group OD value-negative control group OD value)
Reference evaluation criteria: the hemolysis rate >5% indicates that hemolysis occurred and was statistically processed.
TABLE 1 puerarin solution and glutamine in vitro hemolysis experiment grouping design
3 results
The puerarin is 15 mg/kg daily according to body mass－1When the dosage is treated, 0.45 g.kg is simultaneously administered－1Glutamine at the dose, no hemolysis was found in the experimental rabbits. The test also considers the influence of 40 muM, 20 muM and 10 muM glutamine on the red blood cells of 5 rabbits injected with puerarin when the puerarin concentration is 6mM, and simultaneously carries out the occasional hemolysis experimental study of the four and five aspects of the puerarin injection, 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 is less than 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 the fifth groups of puerarin injections, the compound puerarin injections (P <0.01) have no hemolysis in the groups of (VI), (III; compared with the normal saline, the hemolysis incidence of each group of compound puerarin injections (P >0.05) and (b) does not differ from that of the normal saline; the compound puerarin injections (sixty percent, nine, eight, 11) have the same puerarin concentration (6 mM), but the compound puerarin injections (sixty percent, nine, seven, eight, nine, ten, nine, ten, twelve and twelve groups of puerarin injections (sixty percent, nine, ten, twelve, eleven, twelve and fifty percent) contain glutamine. The above results suggest: the compatibility application of glutamine and puerarin with different concentrations can antagonize hemolytic adverse reactions induced by puerarin and reduce the incidence rate to the normal saline level.
The above experimental results show that: the puerarin can induce hemolysis, the injection containing the puerarin can induce hemolysis, and the hemolysis adverse reaction containing the puerarin can be eliminated after the glutamine is added.
The above test results suggest: the puerarin injection and the injection prepared by the puerarin and the glutamine have no hemolytic reaction.
Therefore, when the puerarin-containing injection is prepared or used, the glutamine is added, so that the hemolytic adverse reaction caused by the 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 used, glutamine is added, so that the injection has better antagonism to intravascular hemolysis adverse reaction induced by puerarin, and has the advantages of low price, no toxic or side effect and safety.
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 glutamine 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 glutamine 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 7.5mg of glutamine, 2g of puerarin and 9g of sodium chloride into 1000mL of water, adjusting the pH value to 5.0-8.5 by using lmol/l hydrochloric acid or sodium bicarbonate solution, filtering, filling the filtrate into a 250mL saline glass bottle, and sterilizing at 100 ℃ for 30min to obtain the 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 glutamine in preparing medicine for preventing and treating intravascular hemolysis induced by puerarin injection.
2. Use according to claim 1, characterized in that: the injection of puerarin is administered after glutamine is administered by infusion.
3. Use according to claim 1, characterized in that: the puerarin injection and the glutamine injection are mixed evenly before use and then applied in an infusion way.
4. Use according to claim 2, characterized in that: the glutamine infusion is applied first, and then the puerarin injection is applied.
5. Use according to claim 1, characterized in that: comprises the following medicaments in part by weight: 1-50 parts of glutamine 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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Citations (3)
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| EP0367271A2 (en) * | 1988-11-04 | 1990-05-09 | Sumitomo Seika Chemicals Co., Ltd. | Improved red blood cell preservative solution |
| CN104042602A (en) * | 2014-05-28 | 2014-09-17 | 西北农林科技大学 | Application of sodium glutamate in puerarin injection |
| US20190388376A1 (en) * | 2018-06-20 | 2019-12-26 | Axcella Health Inc. | Compositions and methods for the treatment of hemoglobinopathies and thalassemias |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0367271A2 (en) * | 1988-11-04 | 1990-05-09 | Sumitomo Seika Chemicals Co., Ltd. | Improved red blood cell preservative solution |
| CN104042602A (en) * | 2014-05-28 | 2014-09-17 | 西北农林科技大学 | Application of sodium glutamate in puerarin injection |
| US20190388376A1 (en) * | 2018-06-20 | 2019-12-26 | Axcella Health Inc. | Compositions and methods for the treatment of hemoglobinopathies and thalassemias |
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