CN101292973B - Use of chicoric acid in preparing medicaments for treating coronary disease - Google Patents
Use of chicoric acid in preparing medicaments for treating coronary disease Download PDFInfo
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- CN101292973B CN101292973B CN2008100508780A CN200810050878A CN101292973B CN 101292973 B CN101292973 B CN 101292973B CN 2008100508780 A CN2008100508780 A CN 2008100508780A CN 200810050878 A CN200810050878 A CN 200810050878A CN 101292973 B CN101292973 B CN 101292973B
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Abstract
The invention relates to a new medicinal use of cichoric acid, in particular to the application in the preparation of the drugs for curing coronary heart disease. The preparation is pure Chinese medicine preparation, which has the significant effect of the treatment of angiocardiopathy caused by myocardial ischemia with rapid disappearance of clinical symptoms.
Description
Technical field
The present invention relates to the new medical usage of chicoric acid, especially the purposes in preparation treatment medicaments for coronary disease belongs to the Chinese medicine and pharmacy technical field.
Background technology
The chicoric acid that the present invention relates to be feverfew embrace the stem hardship sell dish (ripe title: the organic acid chemical compound that extracts Herba Ixeritis Sonchifoliae), structural formula is as follows:
Molecular formula: C
22H
18O
12Molecular weight: 474.
Do not see that by retrieval this material is used for preparing the application for the treatment of medicaments for coronary disease.
Summary of the invention
The invention discloses the purposes of chicoric acid in preparation preparation treatment medicaments for coronary disease.
The present invention, can add one or more natural or synthetic active component that have collaborative or assosting effect with it and make as main active preparation preparation treatment medicaments for coronary disease with chicoric acid.
The treatment medicaments for coronary disease of chicoric acid preparation of the present invention comprises any dosage form on the materia medica.
Following experiment has shown the pharmacological action of chicoric acid of the present invention to coronary heart disease:
Test objective: select akin animal model or test method for use, the preparation treatment coronary heart disease effect of medicine of the present invention is studied, make the evaluation of science for its effectiveness.
Trial drug: chicoric acid is provided by Jilin Academy of Chinese Medicine Sciences, lot number: 20071215, and purity and character: be more than 98%, white crystals, malonaldehyde and superoxide dismutase mensuration test kit build up bio-engineering research by Nanjing to be provided; 6-ketone-prostaglandin F
1aPut and exempt from medicine box and thromboxance B
2Put and exempt from medicine box and provide by Chinese People's Liberation Army General Hospital's East Asia immunological technique institute.
Experimental animal: the Wistar rat, body weight 190～280g is provided by preclinical medicine institute of Jilin University Experimental Animal Center,
The quality certification number: SYXK-(Ji) 2003-0001.
Statistical method: (t check the carrying out statistical analysis of two groups of sample average comparisons is adopted in the expression of x ± s) to experimental data with means standard deviation.
Method and result:
1, chicoric acid brings out the Electrocardiographic influence of rat heart muscle ischemic to pituitrin
1.1 method: careful electric sieve selects 50 of qualified Wistar rats, male and female half and half, and body weight 190～220g is divided into 5 groups at random, that is: matched group, chicoric acid low dosage (100mg/kg) group and chicoric acid high dose (200mg/kg) are organized 10 every group.The equal gastric infusion of each medicine group, every day 1 time, continuous 7 days, matched group was irritated the stomach distilled water, and the administration volume is 5ml/kg.50min behind the last medicine, each is organized all from sublingual vein injection of pituitrin (Shanghai Hefeng Pharmaceutical Co., Ltd.'s product dilutes with normal saline during test) 1u/kg, injects to finish in 10 seconds, trace the electrocardiogram of 20min, measure to give that ST section and T ripple change in the pituitrin 30 seconds.
1.2 result: after the matched group sublingual vein was injected (iv) pituitrin, visible rat ST section and T ripple were all obviously raised, and show that pituitrin can bring out the Acute Myocardial Ischemia in Rats ECG change.Compare with matched group, chicoric acid is low, high dose group changes all improve significantly (p＜0.01 or p＜0.001) to the Acute Myocardial Ischemia in Rats electrocardiogram that the iv pituitrin brings out, point out it can alleviate myocardial ischemia due to the coronary spasm, see Table 1.
Table 1 chicoric acid to pituitrin bring out the Electrocardiographic influence of Acute Myocardial Ischemia in Rats (x ± s, n=10)
Compare with matched group
*P＜0.05,
*P＜0.01,
* *P＜0.001
2, chicoric acid is to the protective effect of rat acute myocardial infarction
2.1 method:
90 of Wistar rats, the male and female dual-purpose, body weight 260～280g is divided into 6 groups at random, that is: sham operated rats, infarction model group, chicoric acid low dosage (100mg/kg) group and chicoric acid high dose (200mg/kg) are organized 15 every group.The equal gastric infusion of each medicine group, every day 1 time, continuous 7 days, matched group was irritated the stomach distilled water, and the administration volume is 5ml/kg.30min behind the last medicine behind rat mensuration normal ECG, presses literature method and makes myocardial infarction model
[1]Under etherization, rat is faced upward the position, be fixed on the operating-table, 3～4 intercostals are opened breast from the left side, expose heart, in between pulmonary conus and left atrium, find out the arteria coronaria left anterior descending branch, with No. 0 line ligation immediately it, send heart back to thoracic cavity, and extrude thoracic cavity inner blood and gas, close the thoracic cavity rapidly, wholely open the breast time and be no more than 30 seconds.Not ligation of sham operated rats and only put surgical thread.Treat the ligation arteria coronaria after 24 hours,, measure rat II lead electrocardiogram with pentobarbital sodium 30mg/kg i.p anesthesia.Then, abdominal aortic cannulation is got blood, surveys serum paraoxonase creatine phosphate kinase (CK) and lactic acid dehydrogenase (LDH) activity.With 3500 revolutions per seconds of centrifugal bloods of LDZ5-2 centrifuge, get blood plasma, measure plasma viscosity, and survey whole blood lowly cut, in cut, height cuts viscosity.Take out rat heart rapidly,, remove atrium and fatty tissue, weigh with normal saline flush away chambers of the heart inner blood.With 4～5 of ventricle crosscuts, put in chlorination nitro blue tetrazolium (NB-T) phosphate buffer, take out the back fully in 37 ℃ of water bath with thermostatic control dyeing.Normal structure dyeing, ischemic tissue does not dye.Downcut ischemic tissue and weigh, with the percentage calculation myocardial infarct size (MIS) of ischemic myocardium and ventricle weight in wet base.
2.2 result
2.2.1 chicoric acid is to the Electrocardiographic influence of rats with acute myocardial infarction
Respectively organize II lead electrocardiogram T before the ligation and involve the equal no significant difference of ST section (p＞0.05).Behind the acute myocardial infarction 24 hours, infarction model group II lead electrocardiogram T involved the ST section and all obviously raises, and with sham operated rats comparing difference significantly (p＜0.05～p＜0.001), changed with tangible ischemic electrocardiogram during prompting rat acute myocardial infarction., high dose group low with infarction model group comparison chicoric acid raised the effect of all having clear improvement (p＜0.05～p＜0.001) to above-mentioned ECG T wave and ST section, sees Table 2.
Table 2 chicoric acid to the influence of rats with acute myocardial infarction II lead electrocardiogram (x ± s, n=10)
Compare with the infarction matched group
*P＜0.05,
*P＜0.01,
* *P＜0.001
2.2.2 chicoric acid is to the influence of rats with acute myocardial infarction MIS, CK and LDH
Compare with sham operated rats, infarction model group MIS and serum CK, LDH activity all obviously increase (p＜0.01 or p＜0.001), and prompting rat acute myocardial infarction model is set up successfully.Compare with the infarction model group, chicoric acid is low, high dose group all can obviously be dwindled MIS, reduces serum CK and LDH activity (p＜0.05 or p＜0.01), sees Table 3.
Table 3 chicoric acid to rats with acute myocardial infarction MIS and serum CK, the active influence of LDH (x ± s, n=10)
Compare with the infarction matched group
*P＜0.05,
*P＜0.01,
* *P＜0.001
2.2.3 chicoric acid is to the influence of rats with acute myocardial infarction whole blood and plasma viscosity
With sham operated rats relatively, infarction model group whole blood is low to be cut, in cut, Gao Qie and plasma viscosity all obviously increase (p＜0.05 or p＜0.01), increasing with blood viscosity during prompting rat acute myocardial infarction.Compare with the infarction model group, chicoric acid is low, high dose group all can obviously reduce whole blood low cut, in cut, Gao Qie and plasma viscosity (p＜0.05 or p＜0.01), see Table 4.
Table 4 chicoric acid to the influence of rats with acute myocardial infarction whole blood and plasma viscosity (x ± s, n=10)
Compare with the infarction matched group
*P＜0.05,
*P＜0.01
3, chicoric acid is to the protective effect of rat myocardial ischemia and reperfusion damage (MIRI)
3.1 method: 120 of Wistar rats, the male and female dual-purpose, body weight 250～280g is divided into 6 groups at random, that is: sham operated rats, infarction model group, chicoric acid low dosage (100mg/kg) group and chicoric acid high dose (200mg/kg) are organized 20 every group.The equal gastric infusion of each medicine group, every day 1 time, continuous 7 days, matched group was irritated the stomach distilled water, and the administration volume is 5ml/kg.30min behind the last medicine, behind rat mensuration normal ECG, under etherization face upward the position and be fixed in operating-table, 3～4 intercostals are opened breast from the left side, expose heart, in between pulmonary conus and left atrium, find out the arteria coronaria left anterior descending branch, except that sham operated rats only the not ligation of threading, all the other each group is all with No. 0 line ligation arteria coronaria immediately, during ligation with a tiny latex pipe pad between blood vessel and ligature, send heart back to thoracic cavity, and extrude thoracic cavity inner blood and gas, close the thoracic cavity rapidly, open the breast time to be no more than 30 seconds.Each treated animal ligature of loosening when ligation 30min pours into again.After pouring into 120min again, with pentobarbital sodium 30mg/kg intraperitoneal injection of anesthesia, abdominal aortic cannulation is got blood, surveys serum CK and LDH activity with the COBAS-FARA automatic biochemistry analyzer; Press kit method and survey serum malonaldehyde (MDA) content, erythrocuprein (SOD) activity; Other gets blood anticoagulant separated plasma, surveys metabolite 6-ketone PGF1 and the thromboxane B2 level of blood plasma PGI2 and TXA2 with putting the method for exempting from [2].Get to cut open behind the blood and get rat heart, clean hematocele in the chambers of the heart, remove atrial tissue and fat, weigh with normal saline, with 4～5 of myocardium of left ventricle crosscuts, immerse then in the NB-T phosphate buffer, put 37 ℃ of waters bath with thermostatic control, take out after waiting to dye fully, normal structure dyeing, ischemic tissue does not dye.The cutting-out ischemic myocardium is weighed, with the percentage calculation infarction size MIS of ischemic myocardium and left ventricle weight in wet base.
3.2 result: the 3.2.1 chicoric acid is to MIRI rat MIS and serum CK, the active influence of LDH
Compare with sham operated rats, irritating model group MIS and serum CK and LDH activity more all obviously increases (p＜0.05 or p＜0.01).The MIS that chicoric acid is low, high dose group all can obviously be dwindled the myocardial ischemia reperfusion injury rat reduces serum CK and LDH activity, and irritates model group comparing difference significantly (p＜0.05 or p＜0.01) again, sees Table 5.
Table 5 chicoric acid to MIRI rat MIS and the active influence of CK, LDH (x ± s, n=10)
With irritate model group more relatively
*P＜0.05,
*P＜0.01,
* *P＜0.001
3.2.2 chicoric acid is to the influence of MIRI rat blood serum LPO and SOD
Compare with sham operated rats, irritating model group Serum LPO content more obviously increases, and active obviously reduce (p＜0.05 or p＜0.01) of SOD shows when rat myocardial ischemia and reperfusion damages with the accumulation of interior free yl and the reduction of activities of antioxidant enzymes.Chicoric acid is low, high dose group all can all can significantly reduce Serum LPO content, improves activity of SOD in serum, and irritates model group comparing difference significantly (p＜0.05 or p＜0.01) again, sees Table 6.
Table 6 chicoric acid to the influence of MIRI rat blood serum LPO and SOD (x ± s, n=10)
With irritate model group more relatively
*P＜0.05,
*P＜0.01
3.2.3 chicoric acid is to the influence of MIRI rat plasma PGI2 and TXA2
Compare with sham operated rats, irritate model group blood plasma TXA2 again and obviously raise, PGI2 and PGI2/TXA2 ratio obviously reduce (p＜0.05 or p＜0.01).Chicoric acid is low, high dose group all can all can obviously reduce the blood plasma TXA2 level of myocardial ischemia reperfusion injury rat, increases blood plasma PGI2 level and PGI2/TXA2 ratio, and irritates model group comparing difference significantly (p＜0.05 or p＜0.01) again, sees Table 7.
Table 7 chicoric acid to the influence of MIRI rat plasma PGI2 and TXA2 (x ± s, n=10)
With irritate model group more relatively
*P＜0.05,
*P＜0.01
Conclusion: bring out Model Rats with Acute Myocardial Ischemia at pituitrin, after the matched group sublingual vein was injected (iv) pituitrin, visible rat ST section and T ripple were all obviously raised, and show that pituitrin can bring out the Acute Myocardial Ischemia in Rats ECG change.With matched group relatively, the Acute Myocardial Ischemia in Rats electrocardiogram that chicoric acid is low, high dose group is brought out the iv pituitrin changes and all improves significantly (p＜0.01 or p＜0.001), points out it can alleviate myocardial ischemia due to the coronary spasm.
At the rat acute myocardial infarction model, respectively organize II lead electrocardiogram T before the ligation and involve the equal no significant difference of ST section (p＞0.05).Behind the acute myocardial infarction 24 hours, infarction control Group II lead electrocardiogram T involved the ST section and all obviously raises, with sham operated rats comparing difference significantly (p＜0.05～p＜0.001).Compare with the infarction model group, chicoric acid is low, high dose group is raised the effect of all having clear improvement (p＜0.05～p＜0.001) to above-mentioned ECG T wave and ST section; Compare with sham operated rats, infarction model group MIS and serum CK, LDH activity all obviously increase (p＜0.01 or p＜0.001).Compare with the infarction model group, chicoric acid is low, high dose group all can obviously be dwindled MIS, reduces serum CK and LDH activity (p＜0.05 or p＜0.01); With sham operated rats relatively, infarction model group whole blood is low to be cut, in cut, Gao Qie and plasma viscosity all obviously increase (p＜0.05 or p＜0.01).Compare with the infarction model group, chicoric acid is low, high dose group all can obviously reduce whole blood low cut, in cut, Gao Qie and plasma viscosity (p＜0.05 or p＜0.01).
At the rat myocardial ischemia and reperfusion damage model, compare with sham operated rats, irritating model group MIS and serum CK and LDH activity more all obviously increases (p＜0.05 or p＜0.01).The MIS that chicoric acid is low, high dose group all can obviously be dwindled the myocardial ischemia reperfusion injury rat reduces serum CK and LDH activity, and irritates model group comparing difference significantly (p＜0.05 or p＜0.01) again; Compare with sham operated rats, irritating model group Serum LPO content more obviously increases, and active obviously reduce (p＜0.05 or p＜0.01) of SOD.Chicoric acid is low, high dose group all can all can significantly reduce Serum LPO content, improve activity of SOD in serum, with irritate model group comparing difference significantly (p＜0.05 or p＜0.01) again, compare with sham operated rats, irritate model group blood plasma TXA2 again and obviously raise, PGI2 and PGI2/TXA2 ratio obviously reduce (p＜0.05 or p＜0.01).Chicoric acid is low, high dose group all can all can obviously reduce the blood plasma TXA2 level of myocardial ischemia reperfusion injury rat, increases blood plasma PGI2 level and GI2/TXA2 ratio, and irritates model group comparing difference significantly (p＜0.05 or p＜0.01) again.
Good effect of the present invention is: be pure Chinese medicinal preparation, clinical symptom disappearance is rapid, the cardiovascular disease that treatment is caused by myocardial ischemia etc., and particularly the coronary heart disease effect is remarkable.
The specific embodiment
The present invention mixes by proper proportion as pharmaceutically acceptable carrier of main active and one or more or excipient with chicoric acid, make the pharmaceutical composition that is applicable to the different dosage form that uses clinically, for example it is mixed with the injection that can supply drug administration by injection such as intravenous, intramuscular, intraperitoneal, subcutaneous, marrowbrain intracavity, perhaps make the tablet, granule, drop pill, electuary, liquid preparation, powder agent, pill, capsule and the suspending agent that are suitable for oral administration, and the spray, aerosol, cream, ointment and the suppository that are applicable to topical.
The preparation treatment medicaments for coronary disease that is used to disclosed by the invention is formed pharmaceutical preparation by chicoric acid and the 99.9-0% pharmaceutic adjuvant of 0.1-100%.
To be suitable for the solution that the outer approach of gastrointestinal tract is wanted in order preparing, for example can to use distilled water, water for injection, isotonic sodium chlorrde solution or glucose solution, perhaps low solution (for example 1-100mM) phosphate buffered saline (PBS) (PBS) is as carrier or excipient.
In order to prepare tablet, powder agent, suspending agent or the capsule that is suitable for oral administration, can use sucrose, galactose, corn starch, gelatin, lipid, microcrystalline Cellulose, Pulvis Talci etc. as carrier or excipient.Be suitable in the preparation of oral administration at these, also can contain other proper additive, for example solubilizing agent, disintegrating agent, lubricant, absorption enhancer, antiseptic, correctives, diluent, adsorbent, excipient, dispersant, surfactant, coloring agent etc.
Preferably pharmaceutical composition of the present invention being made route of administration is the injection that intravenous or intramuscular injection are suitable for these route of administration, for example injection, lyophilized injectable powder etc.
Claims (1)
1. chicoric acid is preparing the purposes for the treatment of in the medicaments for coronary disease.
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