CN1600308A - Application of l-sophocarpine on preparing medication for curing disease caused by coronavirus - Google Patents
Application of l-sophocarpine on preparing medication for curing disease caused by coronavirus Download PDFInfo
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Abstract
An application of sophocarpine in preparing the medicine for treating the medicines caused by coronavirus and the process for preparing the medicine from sophocarpine to treat SARS are disclosed.
Description
Technical field
The present invention relates to a kind of purposes and preparation of antiviral drugs, further, the present invention relates to sophocarpine as purposes of antiviral drugs and preparation method thereof.
Background technology
SARS (Severe Acute Respiratory Syndrome) (Severe Acute Respiratory Syndromes, SARS) be a kind of novel respiratory infectious disease that is popular in China and other parts of the world recently, because it has stronger infectiousness and higher mortality rate, it popular and develop serious threat to China people's life security and healthy, and caused the certain social fear.SARS is main by closely the air spittle and the respiratory infectious disease of contact transmission closely, and the clinical pneumonia that mainly shows as has significant mass-sending phenomenon in family and hospital.Onset is anxious, is first symptom with heating, and body temperature generally is higher than 38 ℃, and idol has fear of cold; Can be with headache, joint aches, muscular soreness, weak, diarrhoea; Cough can be arranged, mostly be dry cough, few expectorant, idol has sputum with blood streaks; Can have uncomfortable in chestly, severe patient occur to breathe quickens, tachypnea, or obviously respiratory distress.The pathogen of now determining SARS is a kind of coronavirus, and many countries and regions are all in the method for setting about studying clinical diagnosis, prevention and treatment SARS.
Produce antibody in the body after discovery SARS patient fully recovers at present, the immunoglobulin that obtains from its blood has certain therapeutic effect.But this approach limitation is very big.On the one hand, be difficult to obtain enough blood sources, can not large-scale production.On the other hand, the blood quantity that this approach obtains seldom can't resemble the check of carrying out strictness, system the product of large-scale production and identify, is easy to cause the propagation of other diseases.On the other hand, can set about research from the genetic engineering field, the antibody drug that exploitation can be produced in batches, search time is too slow, the too huge drawback of development capital but this scheme exists.
SARS virus belongs to RNA viruses, and in the prior art, Coxsackie B virus (CVB) also is a kind of RNA viruses.The inventor passes through years of researches, from numerous Chinese medicine, filter out unique low toxicity simply and obviously resist the Chinese medicine of CVB effect---Radix Sophorae Flavescentis, wherein contain the effective ingredient that resists CVB---sophocarpine monomer (sophocarpine, be called for short SC), now made the higher sophocarpine injection of purity, relevant this technology contents has been open in the patent of CN99119850 at the inventor's application number.Common ground based on SARS virus and Coxsackie B virus existence, the inventor tests at SARS virus, find that sophocarpine also has the active function of tangible anti-SARS virus, maintenance non-infected cells, can determine that thus sophocarpine is resultful to anti-SARS virus.
Radix Sophorae Flavescentis is one of time-honored conventional medicament of China, and the beginning is stated from China's medical literature Shennong's Herbal the earliest, classifies middle product as, has the function of heat clearing and damp drying, wind dispelling insecticide, cures mainly trusted subordinate's feeling of fullness flatulence, lump in the abdomen, jaundice etc.China's pharmacopeia version in 1997 and some areas medicine specimen " Sophora Alopecuroides L. stream soaks sheet " recorded cure mainly bacillary dysentery and enteritis (＜Chinese herbology (middle volume) 〉, in August, 1976 front page, 494-495).Zoopery in recent years proves that Radix Sophorae Flavescentis alkaloid has inhibition, analgesia and cooling effect to nervus centralis, energy human body immunity improving power, and antitumaous effect is arranged.The Radix Sophorae Flavescentis extract Radix Sophorae Flavescentis alkaloid can be treated hepatitis B, and the effect of improving clinical symptoms and liver function, part patient HbeAg being turned out cloudy is arranged.Having document record Radix Sophorae Flavescentis alkaloid to have relievings asthma and the antiarrhythmic effect.The inventor's application number is to disclose the alkaloid that extracts in the patent of CN99119850 from Radix Sophorae Flavescentis---sophocarpine is as the application of the myocarditic medicine of preparation treatment Coxsackie B virus.But do not see the report that uses Radix Sophorae Flavescentis alkaloid preparation treatment SARS virus medicine so far.
The material that from the dry root of cassia leguminous plant Radix Sophorae Flavescentis (Sophora flavescens Ait) and cassia leguminous plant Herba Sophorae alopecuroidis (Sophora alopecuroides L.) and above ground portion thereof, is extracted, separable go out 20 surplus kind of alkaloid, wherein sophocarpine is wherein main a kind of, and molecular formula is C
15H
22ON
2, fusing point is 53-54 ℃, [α] D-32.9 °, (t=15, ethanol), its structural formula is:
Summary of the invention
The object of the present invention is to provide the purposes of a kind of sophocarpine in the medicine of the disease that preparation is caused by coronavirus, the dosage form of described medicine is any dosage form of approving on the pharmaceutics.
Further, the object of the invention also is to provide the purposes of a kind of sophocarpine in the medicine of the SARS (Severe Acute Respiratory Syndrome) (SARS) that preparation is caused by coronavirus.
Technical problem to be solved by this invention also is to provide sophocarpine as the preparation method for preparing the SARS (Severe Acute Respiratory Syndrome) medicine that is caused by coronavirus, and this method comprises the steps:
(1) Herba Sophorae alopecuroidis is pulverized, adding 5-10% aqua ammonia is moistening, extracts through the chloroform reflux, adds the extraction of 7-15% sulphuric acid, obtains total alkaloids:
(2) total alkaloids adds 5-10% hydrochloric acid extraction sophocarpine then by adding the toluene extraction;
(3) regulate pH5-10, sucking filtration again with acetone recrystallization, obtains the sophocarpine elaboration;
(4) the sophocarpine elaboration is dissolved in the water for injection, filters, assay is regulated pH4.0-4.5;
(5) by the fill of 0.65um microporous filter membrane, seal, can make injection in 30 minutes through the sterilization of 100 ℃ of flowing steams.
In the preparation method of the SARS (Severe Acute Respiratory Syndrome) medicine that sophocarpine of the present invention is caused by coronavirus as preparation, the concentration of sophocarpine is between 100-800 μ g/ml in the injection.Better, the concentration of sophocarpine is between 100-600 μ g/ml in the injection.
Sophocarpine of the present invention can effectively stop the biosynthesis (comprising that albumen is synthetic) of coronavirus, and enters into performance antivirus action in the cell, and the structure of sophocarpine is as follows:
In the former research of the present inventor, at a kind of RNA viruses---Coxsackie B virus (CVB) filters out simply low toxicity and the Chinese medicine of obvious anti-CVB---Radix Sophorae Flavescentis wherein contains the effective ingredient that resists CVB from numerous Chinese medicines---the sophocarpine monomer.Because SARS virus is a kind of coronavirus, also belongs to RNA viruses,, thinks that it also has the effect of anti-SARS virus, and, determine that sophocarpine can be used as the active drug of a kind of SARS of treatment through experimental verification according to the mechanism of sophocarpine antagonism virus.
In order to verify the antiviral efficacy of sophocarpine, anti-SARS virus effect especially, the inventor has done deep research.In the external anti-SARS virus screening active ingredients of sophocarpine medicine; with the Vero-E6 cell as virus host cell (permissive cell); the effect of test sample opposing virus infected cell; its detect index be the cytopathy reaction (Cell Pathogenic Effect, CPE) and the infection cell protective rate.Experimental result shows that in in-vitro screening model, the sophocarpine sample shows the activity of tangible anti-SARS virus, protection infection cell when the above concentration of 100 μ g/ml.Then carry out multiple sieve; the experiment screening result further shows once more; sophocarpine shows tangible anti-SARS virus, the infected cell activity effect of protection when the above concentration of 100 μ g/ml; when the following concentration of 100 μ g/ml, certain activity is arranged also, and in above-mentioned experimental concentration, the Vero-E6 cell is not seen the significant cytotoxicity effect.
Because for outstanding, sophocarpine has antiasthmatic effect to the SARS due to the coronavirus in Chinese medicine with respiratory symptom.In an embodiment of the invention, relevant hemodynamics to dog is studied, find that sophocarpine can make the lung capillary wedge pressure (PCWP) that has raise drop to normal level, in one embodiment of the invention, the 18mmHg of its PCWP before by administration drops to 12mmHg, and keeps stable.The use of sophocarpine also helps the reduction pulmonary vascular resistance, improves the passive congestion of lungs, reduces preload, the afterload of heart, helps the protection to cardiac function.
In embodiments of the present invention, the body giving drugs into nose of rat is proved also for dynamic test that because the concentration of sophocarpine in lungs is considerably beyond blood concentration, and it is longer to hold time, and helps improving lung symptoms, and the removal that helps SARS virus.
In embodiments of the present invention, adopt cell to suppress the pathological changes method and show, the concentration of sophocarpine is when 312ug/ml, and virus disappears to the toxicity of cultured cell.5ug/ml is lower than the sophocarpine of toxic concentration, even also can suppress the pathogenic change effect of virus to cultured cell.
3The H-TdR infiltration method confirms and MTT trace detection method and crystal violet staining assay confirmation, sophocarpine is when high concentration and low concentration,, energy metabolism synthetic to the DNA of cultured cell behind the infective virus and cell survival number average are influential, and are proportionate with the increase of drug level.
In the present invention, sophocarpine empirical tests has tangible anti-SARS virus effect, because SARS virus belongs to a kind of coronavirus, therefore those skilled in the art should understand that, sophocarpine also has certain antivirus action for other the similar coronavirus beyond the SARS virus, and can stop their biosynthesis.
In purposes of the present invention, the effective ingredient sophocarpine is with the injection form administration, but it should be appreciated by those skilled in the art that the medicine that comprises sophocarpine also can be other effective forms, such as the tablet that contains the sophocarpine effective ingredient etc.
Use the medicine of sophocarpine, can effectively improve treatment rate, the minimizing mortality rate of SARS, and not have the significant cytotoxicity effect as SARS.
Sophocarpine can extract acquisition from cassia leguminous plant Radix Sophorae Flavescentis and Herba Sophorae alopecuroidis, therefore use sophocarpine as medicine, and the medicine source is abundant, and toxic and side effects is little, and preparation method is easy and simple to handle, and is with low cost, is applicable to large-scale industrial production.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention:
The extraction of embodiment 1 sophocarpine and the preparation of injection
10kg Herba Sophorae alopecuroidis (containing leaf, flower, stem) is pulverized, and it is moistening to add 5% aqua ammonia, extracts through the chloroform reflux, and the extraction of 8% sulphuric acid obtains total alkaloids; Total alkaloids is extracted with toluene, and by capacity 7% hydrochloric acid extraction sophocarpine, regulate pH8, sucking filtration again with acetone recrystallization, obtains the sophocarpine elaboration, and yield is 0.12%.
Get a certain amount of sophocarpine and be dissolved in the water for injection, after filtration, assay, regulate pH4.0-4.5, again by the fill of 0.65um microporous filter membrane, seal, after 100 ℃ of sterilizations of flowing steam can make injection in 30 minutes.
Embodiment 2 sophocarpine medicine anti-SARS virus screening active ingredients (virus-cellular level model)
Specimen is a sophocarpine; Strain is BJ-01, derives from microorganism epidemic research institute of Beijing Academy of Military Sciences.
1. preliminary examination experiment
With the Vero-E6 cell as virus host cell (permissive cell), the effect of test sample opposing virus infected cell, detect index and be the cytopathy reaction (Cell Pathogenic Effect, CPE) and the infection cell protective rate.
The sophocarpine sample is dissolved in culture fluid or DMSO, is made into suitable initial concentration, 2 times of dilutions, 7 dilution factors.
The Vero-E6 cell inoculation in 96 well culture plates, is placed 37 ℃, 5%CO
2Cultivate, behind the SARS virus infection cell, add the sample of different diluted concentrations respectively, establish virus control, cell contrast and sample contrast.Observed result under the every day mirror, record CPE, and measure OD value with dimethyl diaminophenazine chloride dyeing, carries out the calculating and the assessment of sample anti-SARS virus active function with reference to contrasting.
Test result sees Table 1.
Reaction of table 1 cytopathy and infection cell protective rate testing result
Ultimate density CPE cytoprotective rate cytotoxicity rate
(μg/ml) (EC_)％ (CC_)％
100 ++ 78 23
20 +++ 14 33
4 ++++ 8 16
Cytopathy political reform (CPE): with "+" expression cytopathy degree,＞25%+, 25%-50%++, 50%-75%+++,＞75%++++.
Infected cytoprotective rate: by comparing the OD value of virus control, cell contrast and sample contrast, calculation sample is to the protection activity of virus infected cell, protective rate＞EC
20Tentatively be considered to sample the cell of viral infection is had the certain protection effect, antiviral activity is arranged.
Sample cell toxicity: if the cytotoxicity of sample and cell contrast ratio are greater than 50 (＞CC
50) time, do not give and estimate and protective rate calculating.
As seen, the sophocarpine sample shows the activity of tangible anti-SARS virus, protection infection cell when the above concentration of 100 μ g/ml in in-vitro screening model.
2. retrial experiment (multiple sieve)
By cell culture, observe the drug effect of the sophocarpine sample anti-SARS virus of a plurality of various dose continuously.Step be (1) with Vero-E6 as host cell; (2) infective virus; (3) directly microscopic examination of cytopathy (CPE); (4) cytoactive staining dyeing is directly dyeed with dimethyl diaminophenazine chloride.
Institute's test sample product are in external anti-SARS pathological changes screening active ingredients; show through experiment screening result once more; when the above concentration of 100 μ g/ml, show tangible anti-SARS virus, the infected cell activity effect of protection; its EC50 is about 127 μ g/ml, and in above-mentioned experimental concentration the Vero-E6 cell is not seen the significant cytotoxicity effect.
Adopt cell to suppress the pathological changes method and show, during sophocarpine high concentration (as 312 μ g/ml), virus disappears to the toxicity of cultured cell.The sophocarpine that is lower than toxic concentration also can suppress the pathogenic change effect of virus to cultured cell, is 67% with micro-raji cell assay Raji confirmation suppression ratio to virus when sophocarpine is 99%, 25 μ g/ml to the suppression ratio of body inner virus during at 200 μ g/ml.
In addition, when the viral infection plural number is 5 (MOI=5), by
3The H-TdR infiltration method confirms, sophocarpine is when 200-3.125 μ g/ml, and MTT trace detection method, crystal violet staining assay confirm that sophocarpine is when 200 μ g/ml-1.5625 μ g/ml,, energy metabolism synthetic to the DNA of cultured cell behind the infective virus and cell survival number average are influential, its measured value is proportionate with the increase of drug level, γ is respectively 0.9818,0.9727, and 0.9219.
The sophocarpine pharmacological evaluation of embodiment 3 animals
1. dog
In dog class animal, insert pulmonary artery with float catheter through head and neck or femoral vein, enter pulmonary capillary, continuous monitoring lung hair wedge is pressed, dynamic observe sophocarpine lung hair wedge is pressed the influence that changes, test result confirms that sophocarpine can make the lung hair wedge drops that has raise to normal level.
With the A dog through anesthesia and make tracheal intubation after measuring blood pressure be 149/89mmHg, HR (EKG) shows 148/ fen, PCWP is 17-18mmHg and held stationary.6mg/kg sophocarpine injection is added among the 5%GS20ml, slowly inject with per minute 1ml speed, PCWP reduces to 9mmHg by 17mmHg, go up to 13mmHg after 10 minutes, added 5%GS20ml with 8mg/kg sophocarpine injection again after being separated by 20 minutes and slowly inject, do not see that PCWP continues to descend, and be stable at the 12-13mmHg level with per minute 1ml speed, this moment blood pressure 119/70mmHg, about HR130/ divides.Experimental result shows A dog injection back blood pressure drops, and is stable when making the PCWP that has raise drop to certain level gradually, no longer descends.
With the B dog through anesthesia and make tracheal intubation after, insert optical fiber Swan-Ganz float catheter by the right lateral thigh vein and survey hair wedge pressure, after treating the heart rate and blood pressure stabilization of dog, survey its PCWP, anesthesia back finds that this dog has the hypertension heart failure, and respiratory secretions increases simultaneously, finds cardiac enlargement after opening breast, measuring blood pressure is 270/206mmHg for the first time, and PCWP is 23mmHg.Sophocarpine injection 6mg/kg (11.5kg, total amount is 69mg) is added among the 5%GS250ml, with the lasting intravenous drip of the speed of per minute 1ml (containing sophocarpine 0.27mg), after 90 minutes, this dog blood pressure drops is to 154/114mmHg, and PCWP is 12mmHg, and heart rate drops to 116 times/minute.The result makes the PCWP that has raise also descend gradually when showing injection back blood pressure drops, be held stationary but reduce to after the stable tendency, no longer descends.
2. rat
In the experiment of isolated rat heart coronary artery perfusion, confirm that sophocarpine can increase coronary flow, under hypoxia perfusion situation, improve resisting oxygen lack to cardiac muscle.
Sophocarpine in Wistar rat pharmacokinetics test, confirm that drug level far surpasses blood concentration in lungs, and it is longer to hold time.When blood drug level was 7.3350 μ g/ml, the concentration in the lungs tissue was 13.104 μ g/ml; When blood drug level was 4.7870 μ g/ml, the concentration in the lungs was 10.402 μ g/ml; When blood drug level was 2.8479 μ g/ml, the concentration in the lungs was 5.1240 μ g/ml; When blood drug level was 1.222 μ g/ml, the concentration in the lungs was 2.5091 μ g/ml; And concentration can measure in 9-15 hour.
Claims (6)
1. the purposes of sophocarpine in the medicine of the disease that causes by coronavirus of preparation.
2. the purposes of sophocarpine as claimed in claim 1 in the medicine of the disease that preparation is caused by coronavirus is characterized in that, the purposes of sophocarpine in the medicine of the SARS (Severe Acute Respiratory Syndrome) that preparation is caused by coronavirus.
3. sophocarpine is characterized in that in the preparation method of the medicine for preparing the SARS (Severe Acute Respiratory Syndrome) that is caused by coronavirus this method comprises the steps:
(1) Herba Sophorae alopecuroidis is pulverized, the aqua ammonia that adds 5-10% is moistening, extracts through the chloroform reflux, adds the sulphuric acid extraction of 7-15%, obtains total alkaloids;
(2) total alkaloids adds the hydrochloric acid extraction sophocarpine of 5-10% then by adding the toluene extraction;
(3) regulate pH5-10, sucking filtration again with acetone recrystallization, obtains the sophocarpine elaboration;
(4) the sophocarpine elaboration is dissolved in the water for injection, filters, assay is regulated pH4.0-4.5;
(5) by the fill of 0.65um microporous filter membrane, seal, can make injection in 30 minutes through the sterilization of 100 ℃ of flowing steams.
3. sophocarpine according to claim 2 is characterized in that in the preparation method for preparing the SARS (Severe Acute Respiratory Syndrome) medicine that is caused by coronavirus the concentration of sophocarpine is between 100-800 μ g/ml in the injection.
4. sophocarpine according to claim 3 is characterized in that in the preparation method for preparing the SARS (Severe Acute Respiratory Syndrome) medicine that is caused by coronavirus the concentration of sophocarpine is between 100-600 μ g/ml in the injection.
5. the purposes of sophocarpine according to claim 1 in the medicine of the disease that preparation is caused by coronavirus is characterized in that the dosage form of described medicine is any dosage form of approving on the pharmaceutics.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100431538C (en) * | 2006-06-20 | 2008-11-12 | 鞠洪福 | An anticancer pharmaceutical composition and preparation method thereof |
| CN101717398B (en) * | 2008-10-09 | 2015-03-25 | 江苏康缘药业股份有限公司 | Sophocarpine-series derivative as well as preparation method and purposes thereof |
-
2003
- 2003-09-28 CN CN 03151269 patent/CN1286460C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100431538C (en) * | 2006-06-20 | 2008-11-12 | 鞠洪福 | An anticancer pharmaceutical composition and preparation method thereof |
| CN101717398B (en) * | 2008-10-09 | 2015-03-25 | 江苏康缘药业股份有限公司 | Sophocarpine-series derivative as well as preparation method and purposes thereof |
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| CN1286460C (en) | 2006-11-29 |
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