CN103385995B - Traditional Chinese medicine compound for treating arrhythmia and preparation method thereof - Google Patents
Traditional Chinese medicine compound for treating arrhythmia and preparation method thereof Download PDFInfo
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Abstract
The invention provides a traditional Chinese medicine compound for treating arrhythmia and a preparation method thereof. Pilose asiabell root, pinellia ternate, coptis, winged euonymus twig, ligusticum wallichii, red sage root, red peony root, honey-fried licorice root, spine date seed and polygala root are subjected to water decoction and condensation; the condensed decoction is stood; and the supernatant is collected and sterilized to form the traditional Chinese medicine compound for treating arrhythmia. The traditional Chinese medicine compound for treating arrhythmia has effects of tonifying qi and activating blood, clearing heart and reducing phlegm, and calming the nerves and is mainly used for treating arrhythmia.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to one and treat ARR Chinese medicine compound mixture and preparation method thereof.
Background technology
Arrhythmia (cardiac arrhythmia) is the change of the rhythm of the heart caused by the origin of heart excitement or conduction abnormalities or heart rate.In cardiovascular system diseases, arrhythmia (cardiac arrhythmia) is one of the most serious disease, not only can increase the weight of original heart disease, as accelerated the progress of heart failure, but also can cause patient's sudden death, serious threat human health.Common arrhythmia has sinus tachycardia, sinus bradycardia, arrhythmia, premature beat, paroxysmal tachycardia, atrial fibrillation, atrioventricular block etc.
At traditional Chinese medical science medical domain, arrhythmia belongs to the cardiopalmus category of the traditional Chinese medical science.The traditional Chinese medical science thinks that the ARR active cause of disease has: timidness due to deficiency of the heart, deficiency of heart-blood, hyperactivity of fire caused by deficiency of YIN, flaccidity of the heart-yang, diseases caused by retention of fluid insult the heart, obstruction of collaterals by blood stasis etc.
Current ARR Therapeutic Method is mainly Drug therapy and non-drug therapy.Conventional Antitachycardiac agents medicine is divided into four large classes, comprises channel blocker, beta-blocker.For bradyarrhythmia, generally select the medicine strengthening self-disciplining and accelerate conduction.Although antiarrhythmic drug can reduce arrhythmia episode, but still there is significant limitation.Chinese medicine shows some superiority in treatment arrhythmia, first can alleviate patient's cardio palmus shape by the determination for the treatment of based on pathogenesis obtained through differentiation of symptoms and signs of Chinese medicine; Secondly, Chinese medicine has few side effects, expense is low, compliance good, curative effect is obvious, is convenient to adjust the clinical advantage such as therapeutic regimen at any time.
Summary of the invention
The object of this invention is to provide one and treat ARR Chinese medicine compound mixture and preparation method thereof.
The present invention treats each component raw material medicine weight proportion in ARR Chinese medicine compound mixture: Radix Codonopsis 10-30g, Rhizoma Pinelliae 3-9g, Rhizoma Coptidis 2-15g, Ramulus Euonymi 5-15g, Rhizoma Chuanxiong 10-30g, Radix Salviae Miltiorrhizae 9-30g, Radix Paeoniae Rubra 6-15g, Radix Paeoniae Alba 10-15g, Radix Glycyrrhizae Preparata 6-15g, Semen Ziziphi Spinosae 10-30g, Radix Polygalae 6-10g.
The present invention preferably treats each component raw material medicine weight proportion in ARR Chinese medicine compound mixture: Radix Codonopsis 15g, Rhizoma Pinelliae 9g, Rhizoma Coptidis 10g, Ramulus Euonymi 15g, Rhizoma Chuanxiong 15g, Radix Salviae Miltiorrhizae 30g, Radix Paeoniae Rubra 15g, Radix Paeoniae Alba 15g, Radix Glycyrrhizae Preparata 10g, Semen Ziziphi Spinosae 30g, Radix Polygalae 10g.
The present invention treats the preparation method of ARR Chinese medicine compound mixture, comprises the steps:
A. get weight proportion material medicine Radix Codonopsis, the Rhizoma Pinelliae, Rhizoma Coptidis, Ramulus Euonymi, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Radix Paeoniae Rubra, the Radix Paeoniae Alba, Radix Glycyrrhizae Preparata, Semen Ziziphi Spinosae, Radix Polygalae are for subsequent use;
B. by said medicine decocting 2-4 time, each 0.5-2 hour, concentrated adjust pH, to 6-8, leaves standstill 10-36 hour, gets supernatant, after sterilizing, to obtain final product.
The present invention preferably treats the preparation method of ARR Chinese medicine compound mixture, comprises the steps:
A. get weight proportion material medicine Radix Codonopsis 15g, Rhizoma Pinelliae 9g, Rhizoma Coptidis 10g, Ramulus Euonymi 15g, Rhizoma Chuanxiong 15g, Radix Salviae Miltiorrhizae 30g, Radix Paeoniae Rubra 15g, Radix Paeoniae Alba 15g, Radix Glycyrrhizae Preparata 10g, Semen Ziziphi Spinosae 30g, Radix Polygalae 10g are for subsequent use;
B. by said medicine decocting 3 times, each 1 hour, concentrated adjust pH to 7, left standstill 24 hours, gets supernatant, after sterilizing, to obtain final product.
The present invention treats in the preparation method of ARR Chinese medicine compound mixture, present composition effective ingredient and suitable adjuvant can be made any one preparation on pharmaceutics; The active component of medicine of the present invention can add various customary adjuvant required when preparing different dosage form, as disintegrating agent, lubricant, binding agent etc. are prepared into any one common formulations with the method for Chinese medicinal of routine, as tablet, sugar coated tablet, film coated tablet, enteric coated tablet, powder, capsule, disintegrating tablet, soft capsule, pill, electuary, oral liquid, granule, drop pill, micropill, unguentum, ointment, plaster etc.
The present invention treats in the preparation method of ARR Chinese medicine compound mixture, and weight proportion material medicine method of Chinese medicinal conveniently in step a is made any one oral formulations.
Above-mentioned oral formulations comprises capsule, granule, tablet, oral liquid and pill.
The present invention treats the raw material composition of ARR Chinese medicine compound mixture and process for preparing medicine Raw medicine and Extraction solvent consumption can increase according to corresponding ratio when producing or reduce, as large-scale production can by kilogram or in units of ton, small-scale production also can be in grams, weight can increase or reduce, but the crude drug material weight proportion constant rate between each composition.
The present invention treats in ARR Chinese medicine compound mixture, the invigorating middle warmer of Radix Codonopsis energy, QI invigorating, promotes the production of body fluid; Radix Glycyrrhizae Preparata spleen reinforcing stomach function regulating, Yiqi and vein recovery, Papillary strengthens effect of QI invigorating.The Rhizoma Pinelliae is pungent dryly to reduce phlegm, stopping nausea and vomiting by lowering the adverse flow of QI, dissolving lump and resolving mass; Rhizoma Coptidis enters spleen lung two warp, double enter heart channel, have the effect of the dampness that clears away heart-fire.Ramulus Euonymi, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Radix Paeoniae Rubra share the effect strengthening promoting flow of QI and blood blood stasis dispelling.The Radix Paeoniae Alba, Semen Ziziphi Spinosae, Radix Polygalae share nourishing blood to suppress the hyperactive liver, mind tranquilizing and the heart calming, have the effect of eliminating the phlegm concurrently.All medicines share, not only can from basic QI invigorating, and can also solve the card of the mark realities such as expectorant heat, blood stasis, benefiting QI for activating blood circulation, the resolve phlegm effect that clears away heart-fire is remarkable.
Accompanying drawing explanation
Fig. 1 is cardiac telemetry 2 hours two groups of single-shot premature ventricular beat number scattergrams.
Fig. 2 is the action potential of before and after isopropyl kidney perfusion two groups.
Detailed description of the invention
By the following examples the present invention is described in further details, but this is not limitation of the present invention.
Embodiment 1
A. get weight proportion material medicine Radix Codonopsis 10g, Rhizoma Pinelliae 6g, Rhizoma Coptidis 5g, Ramulus Euonymi 10g, Rhizoma Chuanxiong 20g, Radix Salviae Miltiorrhizae 15g, Radix Paeoniae Rubra 10g, Radix Paeoniae Alba 12g, Radix Glycyrrhizae Preparata 6g, Semen Ziziphi Spinosae 20g, Radix Polygalae 6g are for subsequent use;
B. by said medicine decocting 2 times, each 0.5 hour, concentrated adjust pH to 6, left standstill 10 hours, gets supernatant, after sterilizing, to obtain final product.
Embodiment 2
A. get weight proportion material medicine Radix Codonopsis 12g, Rhizoma Pinelliae 8g, Rhizoma Coptidis 15g, Ramulus Euonymi 12g, Rhizoma Chuanxiong 30g, Radix Salviae Miltiorrhizae 20g, Radix Paeoniae Rubra 12g, Radix Paeoniae Alba 10g, Radix Glycyrrhizae Preparata 8g, Semen Ziziphi Spinosae 15g, Radix Polygalae 8g are for subsequent use;
B. by said medicine decocting 4 times, each 2 hours, concentrated adjust pH to 8, left standstill 36 hours, gets supernatant, after sterilizing, to obtain final product.
Embodiment 3
A. get weight proportion material medicine Radix Codonopsis 15g, Rhizoma Pinelliae 9g, Rhizoma Coptidis 10g, Ramulus Euonymi 15g, Rhizoma Chuanxiong 15g, Radix Salviae Miltiorrhizae 30g, Radix Paeoniae Rubra 15g, Radix Paeoniae Alba 15g, Radix Glycyrrhizae Preparata 10g, Semen Ziziphi Spinosae 30g, Radix Polygalae 10g are for subsequent use;
B. by said medicine decocting 3 times, each 1 hour, concentrated adjust pH to 7, left standstill 24 hours, gets supernatant, after sterilizing, to obtain final product.
Below for the Chinese medicine compound mixture pharmacodynamics of embodiment 3 preparation and study on mechanism experiment, so as to Chinese medicine compound mixture of the present invention beneficial effect is in the application described.
Experimental example 1 Chinese medicine compound Mixture aconitine proarrhythmia is tested
1. materials and methods
1.1 laboratory animal
The healthy male SD rat of cleaning grade, body weight 200 ± 20g, purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., licence is numbered: SCXK(capital) 2012-0001.
1.2 Experimental agents and reagent
Chinese medicine compound mixture: Radix Codonopsis, Rhizoma Coptidis, the Rhizoma Pinelliae, Ramulus Euonymi, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Radix Paeoniae Rubra, the Radix Paeoniae Alba, Radix Glycyrrhizae Preparata, Semen Ziziphi Spinosae and Radix Polygalae decoction pieces, purchased from Kang Rentang, are concentrated by east Preparation Room in Hospital decocting in water, medicine final concentration 4.13g/ml;
Aconitine: lot number MUST-11031101, purchased from Man Site bio tech ltd, Chengdu, aconitine solution concentration 10 μ g/ml.
1.3 experimental apparatus
RM6240 type multi-channel signal processing system, Chengdu Instruement Factory;
ALC-IP micro pump, Alcott bio tech ltd, Shanghai;
Cold light operating lamp, analytical balance, electronic scale, computer, sterile surgical instrument, beaker, graduated cylinder, standardize solution bottle, pipettor etc.
1.4 experiment groupings
Blank group (WT): give distilled water 3.48ml/kg/d gavage;
Chinese medicine low dose group (LOW): give Chinese medicine compound mixture 1.74ml/kg/d gavage;
Dosage group (MID) in Chinese medicine: give Chinese medicine compound mixture 3.48ml/kg/d gavage;
Chinese medicine high dose group (HIGH): give Chinese medicine compound mixture 6.96ml/kg/d gavage;
1.5 detection methods and index
Administration 7 days, rat, after 1 hour, with urethane 1.2g/kg intraperitoneal injection of anesthesia, is carried on the back position and is fixed on operating-table by last administration, and electrocardiogram led in record II, and connect electrocardioscope, to observe Electrocardiographic change (chart speed 50mm/s).Aconitine solution (0.5ml/min/kg) is pumped into respectively by femoral vein constant speed, there is premature ventricular beat (PVBs), ventricular tachycardia (VT) in record, quivers (VF) and asystole (CA) time in room, and aconitine consumption when premature ventricular beat, ventricular tachycardia appear in calculating, quiver in room and asystole occurs.
1.6 statistical method
Use SPSS13.0 statistical analysis software, experimental data is with mean ± standard deviation
represent, compare between group and adopt one factor analysis of variance (One-Way ANOVA), P < 0.05 has statistical significance for difference.
2. result
What this experiment adopted is the arrhythogenic classical model of aconitine, and experimental result is in Table 1-1,1-2.
Table 1-1 Chinese medicine compound Mixture aconitine proarrhythmia timetable
* compare with WT, P<0.05, * * and WT compares, P<0.01;
△compare with LOW, P<0.05,
△ △compare with LOW, P<0.01.
Table 1-2 Chinese medicine compound Mixture aconitine proarrhythmia scale
* compare with WT, P<0.05, * * and WT compares, P<0.01;
△ and LOW compares, P<0.01.
Result shows: compare with blank group, the basic, normal, high dosage group of Chinese medicine all obviously can postpone premature ventricular beat, room speed and room and to quiver time of occurrence (P<0.05, P<0.01, and the middle and high dosage group of Chinese medicine also significantly can postpone asystole time of occurrence (P<0.01) P<0.01); The basic, normal, high dosage group of Chinese medicine obviously can increase aconitine consumption (P<0.05 when room speed occurs, P<0.01, P<0.01), and the middle and high dosage group of Chinese medicine can also obviously increase premature ventricular beat, quiver in room and asystole occurs time aconitine consumption (P<0.01).
Compare between Chinese medicine various dose group, compare with Chinese medicine low dose group, the middle and high dosage group of Chinese medicine significantly can postpone premature ventricular beat, room speed and room and to quiver time of occurrence (P<0.01), and can obviously postpone asystole time of occurrence (P<0.05, P<0.01); The middle and high dosage group of Chinese medicine all can significantly increase premature ventricular beat, room speed, room quiver and asystole occurs time aconitine consumption (P<0.01).And in Chinese medicine dosage group and Chinese medicine high dose group quiver in premature ventricular beat, room speed, room, no significant difference (P>0.05) on asystole time of occurrence and on aconitine consumption.
This shows, Chinese medicine compound mixture can postpone various ventricular arrhythmia time of occurrence, and Chinese medicine middle and high dosage group is evident in efficacy.Prompting Chinese medicine compound mixture has anti-aconitine and causes ventricular arrhythmia effect, and clinical common dose (namely dosage group) can be evident in efficacy.
Experimental example 2 Chinese medicine compound Mixture calcium chloride proarrhythmia is tested
1. materials and methods
1.1 laboratory animal
The healthy male SD rat of cleaning grade, body weight 200 ± 20g, purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., licence is numbered: SCXK(capital) 2012-0001.
1.2 Experimental agents and reagent
Chinese medicine compound mixture: Radix Codonopsis, Rhizoma Coptidis, the Rhizoma Pinelliae, Ramulus Euonymi, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Radix Paeoniae Rubra, the Radix Paeoniae Alba, Radix Glycyrrhizae Preparata, Semen Ziziphi Spinosae and Radix Polygalae decoction pieces, purchased from Kang Rentang, are concentrated by east Preparation Room in Hospital decocting in water, medicine final concentration 4.13g/ml;
Calcium chloride: purchased from Alfa company, calcium chloride solution concentration 35mg/ml.
1.3 experimental apparatus
RM6240 type multi-channel signal processing system, Chengdu Instruement Factory;
ALC-IP micro pump, Alcott bio tech ltd, Shanghai;
Cold light operating lamp, analytical balance, electronic scale, computer, sterile surgical instrument, beaker, graduated cylinder, standardize solution bottle, pipettor etc.
1.4 experiment groupings
Blank group (WT): give distilled water 3.48ml/kg/d gavage;
Chinese medicine low dose group (LOW): give Chinese medicine compound mixture 1.74ml/kg/d gavage;
Dosage group (MID) in Chinese medicine: give Chinese medicine compound mixture 3.48ml/kg/d gavage;
Chinese medicine high dose group (HIGH): give Chinese medicine compound mixture 6.96ml/kg/d gavage;
1.5 detection methods and index
Administration 7 days, rat, after 1 hour, with urethane 1.2g/kg intraperitoneal injection of anesthesia, is carried on the back position and is fixed on operating-table by last administration, and electrocardiogram led in record II, and connect electrocardioscope, to observe Electrocardiographic change (chart speed 50mm/s).Calcium chloride solution (1.5ml/min/kg) is pumped into respectively by femoral vein constant speed, record arrhythmia (Arrhythmia) time of occurrence and asystole time of occurrence (CA), calculate premature ventricular beat (PVBs), ventricular tachycardia (VT), room quiver (VF) incidence rate and occur that arrhythmia and asystole occur time calcium chloride consumption.
1.6 statistical method
Use SPSS13.0 statistical analysis software, experimental data is with mean ± standard deviation
represent, compare between group and adopt one factor analysis of variance (One-Way ANOVA), P < 0.05 has statistical significance for difference.
2. result
This experiment adopts calcium chloride proarrhythmia model, and experimental result is in Table 2-1,2-2,2-3.
Table 2-1 calcium chloride causes ventricular arrhythmia incidence rate (n=10)
Through X 2 test, P>0.05, each group on incidence rate is quivered in premature ventricular beat, ventricular tachycardia and room without significant difference.
Table 2-2 calcium chloride proarrhythmia and asystole time of occurrence
* represent and compare with WT, P<0.01;
△represent and compare with LOW, P<0.01.
Calcium chloride consumption when table 2-3 calcium chloride proarrhythmia and asystole occur
* represent and compare with WT, P<0.05, * * represents and to compare with WT, P<0.01;
△ represents and to compare with LOW, P<0.05; △ △ represents and to compare with LOW, P<0.01.
Result shows: the basic, normal, high dosage group of Chinese medicine all can reduce the premature ventricular beat incidence rate that calcium chloride brings out; And in the incidence rate of ventricular tachycardia, the basic, normal, high dosage group of Chinese medicine does not all demonstrate its superiority; In Chinese medicine, dosage group and Chinese medicine high dose group can reduce the incidence rate of quivering room, but statistically without significant difference (P>0.05).
Compare with blank group, the basic, normal, high dosage group of Chinese medicine all significantly can postpone asystole time of occurrence (P<0.01), and obviously can increase calcium chloride consumption (P<0.05 when asystole occurs, P<0.01, P<0.01); The middle and high dosage group of Chinese medicine also significantly can postpone arrhythmia time of occurrence (P<0.01), and significantly can increase calcium chloride consumption (P<0.01) when arrhythmia occurs.
Compare between Chinese medicine various dose group, compare with Chinese medicine low dose group, the middle and high dosage group of Chinese medicine significantly can postpone arrhythmia time of occurrence (P<0.01), and significantly can increase calcium chloride consumption (P<0.01) when arrhythmia occurs; And the middle and high dosage group of Chinese medicine is to no significant difference (P>0.05) on asystole time of occurrence, but Chinese medicine high dose group can increase calcium chloride consumption (P<0.05) when asystole occurs.
In Chinese medicine, dosage group and Chinese medicine high dose group are without significant difference (P>0.05) on arrhythmia time of occurrence and asystole time of occurrence, and two groups of calcium chloride consumptions when arrhythmia occurs and when asystole occurs are all without significant difference (P>0.05).
This shows, Chinese medicine compound mixture has anti-calcium chloride arrhythmogenic effect, and the effect of middle and high dosage group is remarkable.Prompting Chinese medicine compound mixture has antiarrhythmia effect, and clinical common dose (middle dosage group) can act on significantly.
Experimental example 3 Chinese medicine compound Mixture isopropyl kidney proarrhythmia is tested
1. materials and methods
1.1 laboratory animal
The healthy male SHR rat of cleaning grade, body weight 300 ± 20g, purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., licence is numbered: SCXK(capital) 2012-0001.
1.2 Experimental agents and reagent
Chinese medicine compound mixture: Radix Codonopsis, Rhizoma Coptidis, the Rhizoma Pinelliae, Ramulus Euonymi, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Radix Paeoniae Rubra, the Radix Paeoniae Alba, Radix Glycyrrhizae Preparata, Semen Ziziphi Spinosae and Radix Polygalae decoction pieces, purchased from Kang Rentang, are concentrated by east Preparation Room in Hospital decocting in water, medicine final concentration 4.13g/ml;
Isoproterenol: purchased from sigma company.
1.3 experimental apparatus
BP-98A intelligence non-invasive blood pressure measuring, the soft grand science and technology limited Company in Beijing;
Rodent PACK cardiac telemetry system, French emka company;
Electronic scale, analytical balance, syringe etc.
The mensuration of 1.4SHR rat blood pressure, heart rate
Get male spontaneous hypertensive rat in 14 week age (SHR) 40 to raise 3 days, measure Mus tail blood pressure with BP-98A non-invasive blood pressure measuring.Be placed in Mus bag by rat during pressure measurement and heat, temperature controls at 37 ~ 38 DEG C, keeps quite and arteria caudalis has beat signals for degree with rat, and under rat waking state, measure the tail systolic arterial pressure of rat and heart rate with indirect method, random measurement is averaged for 5 times.
1.5 experiment groupings
Systolic pressure can be included in higher than 140mmHg, and laboratory animal is divided into two groups at random
Blank group (WT): give distilled water 3.48ml/kg/d gavage;
Chinese drug-treated group (CM): give Chinese medicine compound mixture 3.48ml/kg/d gavage.
1.6 detection methods and index
Administration 7 days, last administration is after 1 hour, give isoproterenol (10mg/100g weight) cervical region subcutaneous injection, cardiac telemetry record 2 hours, whether record there is single-shot premature ventricular beat (Single PVBs, SP), paired premature ventricular beat (Paired PVBs, PP), ventricular tachycardia (VT), and add up its incidence rate (SPR, PPR, VTR), occur number and time of occurrence.
1.7 statistical method
Use ecg Auto software data processing, SPSS13.0, Origin8.0 software statistics is analyzed, and experimental data is with mean ± standard deviation
represent, compare between group and adopt t inspection (t-test), P < 0.05 has statistical significance for difference.
2. result
This experiment is under rat waking state, drug-induced by isopropyl kidney, adopts the various arrhythmia of cardiac telemetry technical monitoring (see table 3-2 to 3-7).Animal model is spontaneous hypertensive rat (SHR), SHR rat body weight (Weight), heart rate (HR), systolic pressure (SBP), diastolic pressure (DBP), mean arterial pressure (MBP) testing result are in Table 3-1, and after isopropyl kidney subcutaneous injection, can acute myocardial ischemia be caused, simulate the pathological state of hypertension and myocardial ischemia.
Table 3-1SHR rat body weight, blood pressure and heart rate monitor
Through t inspection, P>0.05, blank group and Chinese drug-treated group there was no significant difference in rat body weight, heart rate, systolic pressure, diastolic pressure and mean arterial pressure is described, two groups have comparability.
Table 3-2 cardiac telemetry 1 hour incidence of arrhythmia (n=20)
Through X 2 test, cardiac telemetry 1 hour, Chinese drug-treated group on single-shot premature ventricular beat and ventricular tachycardia incidence rate lower than blank group, but two groups of no difference of science of statistics, P>0.05.
Table 3-3 cardiac telemetry 1 hour arrhythmia
* represent and compare with WT, P<0.05.
Cardiac telemetry 1 hour, Chinese drug-treated group single-shot premature ventricular beat number is significantly lower than blank group (P<0.05), and paired premature ventricular beat logarithm and ventricular tachycardia occurrence number, two groups of no difference of science of statistics (P>0.05).
Table 3-4 cardiac telemetry 1 hour arrhythmia time of occurrence
Cardiac telemetry 1 hour, Chinese drug-treated group comparatively blank group can postpone single-shot premature ventricular beat, in pairs premature ventricular beat and ventricular tachycardia time of occurrence, but two groups are compared no difference of science of statistics (P>0.05).
Table 3-5 cardiac telemetry 2 hours incidence of arrhythmia (n=20)
Through X 2 test, cardiac telemetry 2 hours, blank group and Chinese drug-treated group on single-shot premature ventricular beat, in pairs premature ventricular beat and ventricular tachycardia incidence rate without significant difference, P>0.05.
Table 3-6 cardiac telemetry 2 hours arrhythmia
* represent and compare with WT, P<0.05.
Cardiac telemetry 2 hours, Chinese drug-treated group occurs that the fast occurrence number in single-shot premature ventricular beat number, in pairs premature ventricular beat logarithm and room is all remarkable in blank group (P<0.05), illustrates that Chinese medicine compound mixture has anti-isopropyl kidney and brings out Arrhythmia.
Table 3-7 cardiac telemetry 2 hours arrhythmia time of occurrences
* represent and compare with WT, P<0.05.
Cardiac telemetry 2 hours, more blank group of Chinese drug-treated group on single-shot premature ventricular beat time of occurrence without significant difference (P>0.05), and Chinese drug-treated group comparatively blank group obviously can extend paired premature ventricular beat and ventricular tachycardia time of occurrence (P<0.05).
Result shows, and cardiac telemetry 1 hour, in Table 3-2,3-3,3-4.Chinese drug-treated group in single-shot premature ventricular beat and ventricular tachycardia incidence rate lower than blank group, but no difference of science of statistics (P>0.05).Chinese drug-treated group single-shot premature ventricular beat number significantly lower than blank group (P<0.05), and on paired premature ventricular beat logarithm and ventricular tachycardia occurrence number, two groups of no difference of science of statistics (P>0.05).Chinese drug-treated group comparatively blank group can postpone single-shot premature ventricular beat, in pairs premature ventricular beat and ventricular tachycardia time of occurrence, but two groups are compared no difference of science of statistics (P>0.05).
Cardiac telemetry 2 hours, in Table 3-5,3-6,3-7.Chinese drug-treated group comparatively blank group on single-shot premature ventricular beat, in pairs premature ventricular beat and ventricular tachycardia incidence rate without significant difference, P>0.05.Chinese drug-treated group occurs that single-shot premature ventricular beat number, in pairs premature ventricular beat logarithm and room speed occurrence number are all starkly lower than blank group (P<0.05).Chinese drug-treated group and blank group on single-shot premature ventricular beat time of occurrence without significant difference (P>0.05), and Chinese drug-treated group comparatively blank group can the paired premature ventricular beat of significant prolongation and ventricular tachycardia time of occurrence (P<0.05).
Cardiac telemetry single-shot premature ventricular beat number distribution in 2 hours as shown in Figure 1, a blank group generation premature ventricular beat array interpolation is different larger, and have individual number significantly to peel off, numerical value reaches 236, numerical value more than neutrality line is obviously more than Chinese drug-treated group, and dispersion is larger; And Chinese drug-treated group premature ventricular beat number entirety maintains a lower level, most numerical value is below neutrality line.This shows, Chinese medicine compound mixture has the control action of macroscopic view to the isopropyl kidney premature ventricular beat brought out under rat waking state, thus prompting Chinese medicine compound mixture is to the protective effect of heart.
This shows, Chinese medicine compound mixture has anti-isopropyl kidney and brings out ventricular arrhythmia effect.Prompting is under pathological state, and Chinese medicine compound mixture has anti-premature ventricular beat effect, and long duration of action is more remarkable.
Experimental example 4 Chinese medicine compound Mixture Arrhythmia Mechanism Study is tested
1. material
1.1 laboratory animal
The healthy male SD rat of cleaning grade, body weight 200 ± 20g, purchased from Hua Kang biotech inc, Beijing, licence is numbered: SCXK(capital) 2009-0007.
1.2 Experimental agents
Chinese medicine compound mixture: Radix Codonopsis, Rhizoma Coptidis, the Rhizoma Pinelliae, Ramulus Euonymi, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Radix Paeoniae Rubra, the Radix Paeoniae Alba, Radix Glycyrrhizae Preparata, Semen Ziziphi Spinosae and Radix Polygalae decoction pieces, purchased from Kang Rentang, are concentrated by east Preparation Room in Hospital decocting in water, medicine final concentration 4.13g/ml;
Isoproterenol (Iso): purchased from American sigma company;
Collagenase II type (collagenase type2): purchased from American Washington company;
Bovine serum albumin (BSA): purchased from American Sigma company;
Sodium chloride (NaCl), potassium chloride (KCl), hydroxyethyl piperazine second sulfacid (HEPES), glucose (D-Glucose), sodium hydroxide (NaOH), calcium chloride (CaCl
2), potassium hydroxide (KOH), magnesium chloride (MgCl
2), potassium dihydrogen phosphate (KH
2pO
4), magnesium sulfate (MgSO
4), L-type glutamic acid (L-Glutamic), taurine (Taurine), ethylene glycol diethyl ether ethylenediamine tetraacetic acid (EDTA) (EGTA), adenosine disodium triphosphate (Na
2the purchased from American Alfa company such as ATP);
Dimethyl sulfoxide (DMSO): purchased from American Sigma company.
1.3 main solution preparations
Without calcium tyrode's solution (Tyrode solution, mmol/L): NaCl140.0, KCl5.4, MgCl
21.0, HEPEs10.0, D-Glucose10.0, NaOH are adjusted to pH7.4;
There is calcium tyrode: adding 1.8mmol/L CaCl without on calcium tyrode basis
2;
KB liquid (mmol/L): KOH80.0, KCl40.0, KH
2pO
425.0, MgSO
43.0, L-Glutamic50.0, Taurine20.0, EGTA1.0, D-Glucose10.0, KOH are adjusted to pH7.2;
Digestive system: containing 60%Collagenase type2+20%BSA+50 μm of ol/L Ca
2+without calcium tyrode's solution;
Liquid (mmol/L) in action potential electrode: NaCl10.0, KCl120.0, MgCl
25.0, HEPEs20.0, EGTA5.0, Na
2aTP3.0, KOH are adjusted to pH7.2;
To drug solns: for there being calcium tyrode+10 μm of ol/L Iso;
Bath solution: for there being calcium tyrode.
1.4 experimental apparatus
Osmometer Fiske210, ADVANCE company of the U.S.; PH agent PB-21, German Sartorius company; Microelectrode draws instrument, DMI-Universal Puller; Amplifier EPC10, HEKA company of the U.S.; Micro-behaviour MP-225, U.S. SUTTER INSTRUMENT COMPANY; Microscope IX71, Japanese OLYMPUS company; Microelectrode B15014F, Wuhan Wei Tan scientific instrument company limited; Langendorff perfusion device; 800 electric centrifuges, Suzhou Weir experimental article company limited; Water purification machine Elix, MIILIPORE company of the U.S.; KQ-200KDE type high power numerical control ultrasonic cleaner, Kunshan Ultrasonic Instruments Co., Ltd.; Thermostat water bath, PolyScience company of the U.S.; BT100-2J peristaltic pump, Baoding LanGe constant flow pump Co., Ltd; Suction filter pump and filter membrane, MILLIPORE company of the U.S.; Electronic scale, analytical balance, computer, bottle,suction, syringe, test tube, dropper, Eppendorf manages, pipettor etc.
1.5 experiment groupings
SD male rat is divided into two groups at random:
Blank group (WT): give distilled water 3.48ml/kg/d gavage;
Chinese drug-treated group (CM): give Chinese medicine compound mixture 3.48ml/kg/d gavage.
Administration 7 days, cores dirty, cell separation.
1.6 ventricular muscle cells are separated
Adopt collagenase method acute isolation rat left ventricle myocyte.Select healthy adult male SD rat (body weight 220 ~ 250g), in preoperative 15 minutes lumbar injection heparin (1000U/kg), 10% chloral hydrate solution (0.35g/kg) anesthesia, open breast, take out with one section of aortal heart rapidly, be placed in 4 DEG C of tyrode cleanings and cleaning and removing residual blood, and be hung on rapidly the enterprising row aorta retroperfusion of Langendorff device, at 36.7 DEG C, 6ml/min, constant speed perfusion.Switch after what 100% oxygen was saturated have calcium tyrode perfusion to be about 3min 100% oxygen saturated without calcium tyrode perfusion 5min, then switch liquor recycling perfusion rapidly, and continue to pass to 100% oxygen.Synchronous monitoring perfusion pressure in perfusion, when perfusion pressure returns to a little less than initial perfusion pressure, stop digestion, now heart lighter, that touches is soft.With 10ml without calcium Zinciodati Comp solution perfusion cleaning and removing residual Digestive system, then clip left ventricle in KB liquid.
Cut off heart with eye scissors along transverse axis in the middle part of ventricle, insert in KB liquid, tear up, carefully blow and beat with suction pipe, 200 eye mesh screens filter, the centrifugal about 30s of 500rpm.Abandoning supernatant, change KB liquid once, interval 6min changes KB liquid again, preserves in KB liquid.
1.7 patch clamp experiments
1.7.1 electrode preparation
Select internal diameter 1.05mm, external diameter 1.5mm, the soft glass capillary tube of wall thickness 0.45mm, be placed in microtubule electrode and draw on instrument, draw through three steps, cut open light and form.Charge the impedance of electrode solution rear electrode and be about 2 ~ 6M Ω.
1.7.2 whole-cell patch-clamp current clamp record
Adopt full cell currents tongs technology logging mode C-CLAMP.Cell bath keeps constant speed perfusion.
1.7.3 high impedance sealing-in
First the cell deposited in high potassium KB liquid is progressively answered calcium before experiment, use 0.6mmol/L respectively, 1.2mmol/L, 1.8mmol/L are containing Ca
2+the multiple calcium of tyrode gradient, interval 6min.The measurement of action potentials of cells is can be used for after leaving standstill half an hour.Get several cell suspension and add cell pool (about 1ml), lie against and be connected with on the inverted microscope of micromanipulator, leave standstill 10min, after cell is fully adherent, use tyrode perfusion, flow velocity is 2ml/min.Liquid in electrode is charged, resistance about 2 ~ 6M Ω in glass electrode.Choose shaft-like, band is clear, test without the ventricular muscle cell of spontaneous contractions.Electrode gives malleation to electrode before falling into extracellular fluid, to prevent from being infected with by impurity into liquid rear electrode tip.After electrode enters liquid, point is driven into liquid and compensates, and compensates the potential difference between recording electrode and reference electrode.Micro-behaviour is regulated to make the cell of eletrode tip gradually to selected close.When eletrode tip touches cell membrane, impose slight negative pressure, treat that loop resistance value rises to rapidly G Ω level, show that the high resistance sealing-in (gigaseal) between electrode and cell membrane is formed.
1.7.4 full cell pattern
After high impedance (>1G Ω) sealing-in is formed, compensating electrode electric capacity.Then negative pressure gently inhales cell membrane and reinforcing gradually, and be that larger cell capacitance electric current appears suddenly in the map of current of straight line originally until visible, at this moment just define full cell pattern, after rupture of membranes, resistance is greater than 100M Ω.Give cell capacitance to compensate, make figure as far as possible straight.
1.7.5 the setting of stimulus parameter
This experimental record be the action potential (action potential, AP) of rat ventricular myocytes.Stimulus modelity is pulsewidth 5ms, electric current 900pA.
1.8 Testing index
With Patch Clamp operation of recording current potential, after be recorded to action potential in tyrode, stablize 10min, be converted to the perfusate being added with 10 μm of ol/L Iso, perfusion 30min.Resting potential (resting potential before and after record Iso perfusion, RP), action potential amplitude (action potential amplitude, APA), overshot (overshoot, OS), the maximum depolarization speed of action potential (maximum, Vmax), action potential duration, APD (action potential duration, APD), action potential multipole to 25%, 50%, time (action potential duration at25%, 50%, 90%) of 90%.
1.9 statistical method
By Fit Clamp, Origin8.0, Excel2007, SPSS13.0 process also statistical analysis experimental data, experimental data is with mean ± standard deviation
represent, compare between group and adopt t inspection (t-test), P < 0.05 has statistical significance for difference.
2. result
Before and after isoproterenol (Iso) perfusion, the action potential of two groups is shown in Fig. 2, two groups of resting potentials (RP), overshot (OS), action potential amplitude (APA) and action potential 0 phases maximum climbing (Vmax) compare in Table 4-1, and two groups of action potential duration, APDs compare in Table 4-2.
Table 4-1 ventricular muscle cell resting potential, overshot, amplitude and maximum climbing comparison sheet
Table 4-2 ventricular muscle action potential duration comparison sheet
* represent and compare with WT, P<0.05; * represents and to compare with WT, P<0.01;
△represent and compare in group before and after Iso perfusion, P<0.05;
△ △represent and compare in group before and after Iso perfusion, P<0.01.
Result shows: Chinese drug-treated group RP, OS, APA compare with blank group, without significant difference (P>0.05); Chinese drug-treated group Vmax compares with blank group Vmax, also without significant difference (P>0.05).
Before Iso perfusion, Chinese drug-treated group APD, APD
50, APD
90comparatively blank group obviously extends (P<0.05); After Iso perfusion, blank group and Chinese drug-treated group APD all comparatively all obviously extend (P<0.01, P<0.05) before Iso perfusion, and blank group APD
50with APD
90comparatively also significant prolongation (P<0.01) before Iso perfusion.Iso can pass through excited beta receptor, make (the adenylyl cyclase of adenyl cyclase in cell, AC) activate, in cell, cAMP raises, by protein kinase A (protein kinase A, PKA), cause the phosphorylation of calciphorin, cause the change of L-type calcium channel configuration, the number of functional calcium passage is increased, calcium window current also increases, thus extends action potential duration, APD.Main and the Ca of the prolongation of ventricular muscle cell APD
2+interior stream and K
+outflow relevant, these two kinds of electric currents are main electrical current of ventricular muscle cell multipole 2 phase, infer thus, APD, APD
50, APD
90prolongation may be to Ca
2+interior stream or K
+outflow played caused by inhibitory action.
After Iso perfusion, compare between group, Chinese drug-treated group APD, APD
50, APD
90comparatively blank group significantly shortens (P<0.01), and prompting Chinese medicine has the antagonism Iso effect that causes APD to extend, may with suppress plateau Ca
2+electric current and multipole later stage K
+current related.
In sum, Chinese medicine compound mixture of the present invention has the effect of rat ventricular caused by obvious anti-aconitine, calcium chloride and isopropyl kidney, and Chinese medicine compound mixture can resist the prolongation that isoproterenol causes rat ventricular myocytes action potential duration, APD, above-mentioned effect is that it treats ARR pharmacological basis, and Chinese medicine compound mixture may be by suppressing plateau Ca
2+electric current and multipole later stage K
+electric current and play antiarrhythmic effect.
Claims (6)
1. the ARR Chinese medicine compound mixture for the treatment of, it is characterized in that, in this Chinese medicine compound mixture, each component raw material medicine weight proportion is: Radix Codonopsis 10-30g, Rhizoma Pinelliae 3-9g, Rhizoma Coptidis 2-15g, Ramulus Euonymi 5-15g, Rhizoma Chuanxiong 10-30g, Radix Salviae Miltiorrhizae 9-30g, Radix Paeoniae Rubra 6-15g, Radix Paeoniae Alba 10-15g, Radix Glycyrrhizae Preparata 6-15g, Semen Ziziphi Spinosae 10-30g, Radix Polygalae 6-10g.
2. Chinese medicine compound mixture as claimed in claim 1, it is characterized in that, in described Chinese medicine compound mixture, each component raw material medicine weight proportion is: Radix Codonopsis 15g, Rhizoma Pinelliae 9g, Rhizoma Coptidis 10g, Ramulus Euonymi 15g, Rhizoma Chuanxiong 15g, Radix Salviae Miltiorrhizae 30g, Radix Paeoniae Rubra 15g, Radix Paeoniae Alba 15g, Radix Glycyrrhizae Preparata 10g, Semen Ziziphi Spinosae 30g, Radix Polygalae 10g.
3. a preparation method for the mixture of Chinese medicine compound described in claim 1 or 2, comprises the steps:
A. get weight proportion material medicine Radix Codonopsis, the Rhizoma Pinelliae, Rhizoma Coptidis, Ramulus Euonymi, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Radix Paeoniae Rubra, the Radix Paeoniae Alba, Radix Glycyrrhizae Preparata, Semen Ziziphi Spinosae, Radix Polygalae are for subsequent use;
B. by said medicine decocting 2-4 time, each 0.5-2 hour, concentrated adjust pH, to 6-8, leaves standstill 10-36 hour, gets supernatant, after sterilizing, to obtain final product.
4. preparation method as claimed in claim 3, is characterized in that, the weight proportion material medicine method of Chinese medicinal conveniently described in step a is made any one oral formulations.
5. preparation method as claimed in claim 4, it is characterized in that, described oral formulations comprises capsule, granule, tablet, oral liquid and pill.
6. the application of Chinese medicine compound mixture described in a claim 1 or 2 in the ARR medicine of preparation treatment.
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