| With the rapid development and extensive utilization of traditional Chinese medicine (TCM),several serious problems,such as lack of originality innovation,severe low-level repetition,unimpressive curative effect,indifference of drug security and poor quality,have emerged in new drug research,especially in investigation of preparation transformation and imitation medicines.The quality discrepancy among the drugs of different preparations or among the drugs of different manufactories is enormous.It is difficult for selective preference and rational use of medicines in clinic due to the lack of comparison and reassessment of drugs on the market.As common Chinese patent drugs for cardiovascular diseases,compound salvia preparations,produced by over 700 manufacturers,comprise ten kinds of preparation formulations such as tablet,pill,pigment,pellet,capsule,soft capsule,aerosol, granule,oral liquid and troches,which provide numerous choices for clinical utilization.Basic research and further clinical research on them have been extensively carried out.The majority of previous researches focused on single preparation, however,systematic comparison on different formulations has hardly attracted attention,resulting in the ignorance of the characteristics and advantage of respective formulations.In order to provide the basis for clinical use,the comparison and reassessment was carried out on efficacy,pharmacology,medicinal chemistry, pharmacokinetics and adverse reactions between Compound Salvia Pills(CSP) and Compound Salvia Tablets(CST),which are well known commercially and used widely in clinic.1.Literature analysis1.1 Progress of investigation on compound salvia preparationsBased on the related literatures,compound salvia preparations,concerning the prescriptions,quality standards,active ingredients,pharmacological effects,clinical studies,adverse actions and toxicology,were analyzed.The involving problems were explored that is helpful to accelerate the following development.1.2 Status and Quality Analysis of Clinical Studies on Compound Salvia Preparations for Coronary Heart Disease1.2.1 Methods:Based on the published reports hitherto about clinical studies on compound salvia preparations from January 1994 to December 2008,the status of the related study were analyzed including case number,observed disease,curative measurement and period of therapy.The comparison,between CST and CSP,of curative effect on coronary heart disease was also performed.Additionally,the deficiencies of the clinical studies were mentioned.1.2.2 Results:923 reports were involved.CST and CSP were two dominating preparations investigated in the foregoing clinical studies.Most of the reports covered cases less than 50.Clinical studies mainly focused on ischemic diseases,and the treatment period was normally from 2 weeks to 1 month.Single preparation was employed most widely.However,the curative effect of the same preparation varied significantly in different clinical process.Obviously,the effect of CSP as treatment medicine was significantly better than that as control medicine.The deficiencies in the design and execution of the clinical studies resulted in poor reliability and scientificalness of the results.1.2.3 Conclusion:The quality improvement of the current clinical studies remained desirable.The problems in the design and the implementation process affected the scientific nature and objectivity of the findings.The existing research could not approve that one kind of preparation surpasses the other.More general and scientific research is desired so as to obtain an objective assessment for the therapeutic effectiveness of compound salvia preparations.1.3 Report quality assessment of randomized controlled trials on CSP and CST for coronary heart disease1.3.1 Methods:All the published literatures of clinical studies on both CSP and CST for coronary heart disease from 1994 to December 2007 were collected,and each report involved was assessed by the revised CONSORT statement and other self-edited items.1.3.2 Results:26 reports were identified.According to the CONSORT criteria,the generation of the randomization sequence was described in only 2(7.6%) reports,one of which were quasi-randomized,single blinding was applied in 6 reports(23.1%). adverse events were mentioned in 19(73.1%) literatures,multi-center studies were performed in 2 reports(7.8%),while syndrome type of TCM was described in 2 reports(7.6%).No report concerned how the sample size was estimated and how the randomization was implemented.No study,involving placebo control or allocation concealment,was performed.No investigation included the utilization of intent-to-treat(ITT) analysis,correlation analysis,ethical approval or informed consent.All of the studies were related to positive outcome.1.3.3 Conclusion:The test information provided by the clinical researches of CST and CSP on coronary artery disease was not complete,standardized,accurate and comprehensive so as to ensure their scientificalness and reliability.In order to resolve the problems aforementioned,the effectiveness evaluation system should be improved and completed,and the normativity and accuracy of clinical trail reports should be increased simultaneously to improve the research level of TCM.1.4 Methodology quality and therapeutic effectiveness assessment of randomized controlled trials on CST and CSP for coronary heart disease1.4.1 Method:All the published literatures of clinical studies on both CSP and CST for coronary heart disease from 1994 to December 2007 were collected,and each report involved was assessed by the modified Jadad scale.And 4 weeks efficacy in RCTs was analyzed.1.4.2 Results:26 reports were identified.No score was more than 3 points assessed by the Jadad scale,indicating all of them were of poor quality.The Meta-analysis showed that the incorporated RR(95%CI) of CSP on the total effective rate of electrocardiogram,angina pectoris and clinical symptoms,comparing to CST,were 1.30(1.17,1.44),1.40(1.17,1.67) and 1.26(1.10,1.45) respectively.And the distribution of the funnel plot on electrocardiogram was dissymmetrical.1.4.3 Conclusion:The methodology quality of the reports involved is poor.The viability of Meta-analysis result as reference was not sufficient.The present investigation is not adequate so as to ensure which preparation is better.1.5 Overview of adverse reaction of compound salvia preparations1.5.1 Methods:In addition to the literatures of individual cases,all the published literatures of clinical studies from January 1994 to December 2008,wherein compound salvia preparations were singly used and adverse reactions were recorded, were collected.On the basis of lecture analysis,the rate and symptom of adverse reactions were detected as well as the clinical managements.1.5.2 Results:223 clinical researches and 18 individual cases were collected.Among them,the incidence of adverse reactions of CST was 1.91%,while CSP 2.74%.There was no document concerning adverse reaction induced by aerosols or granules.The incidence reported in different documents varied significantly.And the incidence of a drug as control medicine was obviously higher than that of the same drug as treatment medicine.The main adverse reactions were gastrointestinal symptoms,followed by vasodilative response.And the symptoms caused by CSP were much more than those of CST.The main adverse reactions in the literatures of individual cases were gastrointestinal symptoms,followed by cardiovascular responses which were mainly caused by unreasonable drug combination.Most adverse reactions were mild in clinical symptoms.The serious reactions included gastric mucosal bleeding,erosive gastritis,hematuria and shock.Only a part of the patients suffering from adverse reaction were given the symptomatic treatment.1.5.3 Conclusion:The adverse reactions induced by compound salvia preparations were common,which mostly were gastrointestinal symptoms.Most of the reactions were mild.Only a part of the patients suffering from adverse reaction were given the symptomatic treatment.Common adverse reactions had hardly attracted adequate attention,and specific checks were not executed.As a result,the nature of the lesions caused by the agents was still unclear.The medicines should be utilized with care in clinic.2.Pharmacology study2.1 Protective effects of CST and CSP on acute myocardial ischemia in dogs 2.1.1 Methods:The acute ischemia was induced by ligation of left ventricular anterior artery(LAD).The myocardial ischemia degree was measured by the epicardial electrogram.And the area of myocardial infarction was determined by quantitative histological assay(nitro blue tetrazolium chloride,NBT stain).Moreover, the content of Endothelin(ET),as well as the ratio of 6-keto-prostaglandin F1α (6-keto-PGF1α) to thromboxane B2(TXB 2) in plasma,was examined by radio immunological assay.2.1.2 Results:CST and CSP alleviated electrocardiogram(ECG) degree caused by acute myocardial ischemia.The effect of CST and CSP on ECG changes was observed obviously after 15-25 minutes.The effect lasted for over 3 hours.Both of the drugs reduced obviously the infarct size.The effects aforementioned of CST were similar to those of CSP on the same crude drug dosage,while the effects of CST were stronger than those of CSP on the same multiple dosage of clinical administration. Both of the drugs reduced the content of TXB2 in plasma,improved the decrease of the ratio of 6-keto-PGF1αto TXB2,while they did not significantly affect the content of ET and 6-keto-PGF1α.The difference of such effects mentioned above between CST and CSP was slight.2.1.3 Conclusion:The protective effects of CST and CSP on acute myocardial ischemia in dogs could be observed in 5 minutes after administration,became obvious after 15-25 minutes,and lasted for over 3 hours.The effects of CST were similar to those of CSP on the same crude drug dosage,while the effects of CST were stronger than those of CSP on the same multiple dosage of clinical administration in reducing infarct size and alleviating myocardial ischemia degree when compared.2.2 Effects of CST and CSP on platelet aggregation and blood coagulation in rabbits2.2.1 Methods:The rabbits were grouped in accordance with the body weight and the pre-drug rate of platelet aggregation.The post-drug rate of platelet aggregation was evaluated after the medicines were administrated for 5 days.Then the inhibition rate of platelet aggregation was calculated.Thrombin time(TT),prothrombin time(PT), activated partial thromboplastin time(APTT) and fibrinogen(FIB) of plasma were detected.The rate of platelet aggregation induced by collagen(4.8 mg/L),adenosine diphosphate(ADP,47.6μmol/L) and arachidonic acid(AA,782.0 umol/L) was determined by Born's photoextinction.2.2.2 Results:CST and CSP inhibited evidently the platelet aggregation induced by collagen,ADP and AA.The effects of CST were stronger than those of CSP in the same crude drug dosage,and the effects of CST were markedly better than that of CSP in a manner of equal multiple-dosage of clinical dose.Both drugs prolonged TT, however,they did not affect PT,APTT and content of FIB in plasma.2.2.3 Conclusion:CST and CSP could inhibit platelet aggregation and prolongate TT in rabbits,and the effects of CST were stronger than those of CSP.2.3 Effects of CST and CSP in a rabbit model of topical ferric chloride-induced carotid artery thrombosis2.3.1 Methods:The rabbits were grouped in accordance with the body weight.After the medicines were orally administrated preventatively for 7 days,the thrombosis model was established by wrapping the left carotid artery with ferric chloride for 50 minutes.And the moment wrapping the artery was recorded as beginning.The blood was then taken after 3 hours to examine TT,PT and APTT as well as the content of FIB,platelet factor 4(PF4),D-dimer,TXB2 and 6-keto-PGF1α in plasma.And the experimental artery was used to detect thrombus and damage of endothelium after 24 hours.2.3.2 Results:The use of CST or CSP alleviated some changes induced by modling to a certain extent,such as prolongation of TT and APTT,increment of TXB2,and reduction of 6-keto-PGF1α in plasma,while both drugs did not significantly affect PT, FIB,D-dimer and PF4.Thrombus and damage of endothelium induced by FeCl3 were alleviated after CST or CSP administration.The effects of the two drugs mentioned above were similar.2.3.3 Conclusion:Both CST and CSP could alleviate the thrombosis and damage of endothelium induced by ferric chloride to a certain extent.The effect difference between CST and CSP was slight.3.Pharmacochemistry study 3.1 Investigation on the contents of 7 kinds of active ingredients of CST and CSP3.1.1 Method:HPLC was applied.Salvianic acid A,protocatechuic aldehyde and salvianolic acid B were determined by gradient elution using 0.1%(V/V) phosphoric acid-acetonitrile as the mobile phase.The column was maintained at 30℃.The flow rate was 1 ml/min.And the detection wavelength was set at 281 nm. Cryptotanshinone and tanshinoneⅡA were determined using ethanol-water(75:25 by volume) as the mobile phase.The column was maintained at 35℃.The flow rate was 1 ml/min.And the detection wavelength was set at 270 nm.Ginsenoside Rg1 and Rb1 were determined by gradient elution using 0.1%(V/V) phosphoric acid-acetonitrile as the mobile phase.The column was maintained at 30℃.The flow rate was 1 ml/min(22-28 min,0.8 ml/min).And the detection wavelength was set at 203 nm.3.1.2 Results:The content of salvianic acid A and protocatechuic aldehyde of CSP was higher than those of CST,however,the other ingredients of CST were more than those of CSP per gram.In each dose,according to the guidelines,only the content of protocatechuic aldehyde offered by CSP was higher than that by CST,while the content of the other ingredients offered by CST was much higher than that by CSP..3.1.3 Conclusion:When CSP or CST was administrated,obvious difference of the ingestion of such 7 components was existed.Further detailed study is desired due to the possibility that such ingestion difference would lead to the variation in therapy effectiveness.4.Pharmacokinetics study4.1 Investigation on the absorption of Salvianic acid A,protocatechuic aldehyde and salvianolic acid B of CST and CSP in rats' intestine4.1.1 Methods:In situ perfusion model in rats was used to evaluate the influence of the concentration on the intestinal absorption of salvianic acid A,protocatechuic aldehyde and salvianolic acid B in CST and CSP.The absorption of such ingredients in duodenum,jejunum,ileum and colon were measured.HPLC was applied to examine the content of Salvianic acid A,protocatechuic aldehyde and salvianolic acid B.The involved gradient elution used 0.1%(V/V) phosphoric acid-acetonitrile as the mobile phase.The column was maintained at 30℃.The flow rate was 1 ml/min.And the detection wavelength was set at 281 nm.4.1.2 Results:After reperfusion of 2 hours,the absorption of protocatechuic aldehyde in the intestinal was more obvious than that of salvianic acid A or salvianolic acid B.The absorption of protocatechuic aldehyde of CSP was similar in different groups,and the absorption rate per unit area was positively correlated with the concentration.Higher the concentration of CST perfusion fluid,lower the absorptions of salvianic acid A or salvianolic acid B.And there were no significant difference in the absorption rates per unit area in different groups of both of the ingredients.The absorption of salvianic acid A,salvianolic acid B or protocatechuic aldehyde of CST was different.The details were as follows:for salvianic acid A or salvianolic acid B,duodenum> jejunum> colon> ileum;for protocatechuic aldehyde, duodenum> jejunum> ileum> colon.Besides these,the absorption of protocatechuic aldehyde of CSP was duodenum> ileum> jejunum> colon.4.1.3 Conclusion:The absorption in rat intestine of salvianic acid A and salvianolic acid B of CST may have saturation effect resulting from high concentration. Protocatechuic aldehyde of CSP may be absorbed by passive diffusion.The difference of protocatechuic aldehyde absorption between CST and CSP in rat intestine is supposed to be concerned with the interference caused by other coexisting ingredients.Although the compound salvia preparations have been extensively studied in the past few decades,generally speaking,there are still some problems resulting in the potential risk in clinic.Their safety,especially in large dosage and in long-term prolonged administration,needs to be further verified.Currently,there is no sufficient evidence indicating that such drugs are "quick-acting medicine","powerful medicine" or "long-acting medicine".And there is no sufficient evidence proving they are better than other Chinese medicine or western medicine of the same class. For angina pectoris,therefore,the compound salvia preparations are suitable as "conventional medication","follow-up medication" or "complementary medicine" rather than as "preferred drugs" or "first-line drugs".Due to higher levels of active ingredients,stronger pharmacological effects,fewer adverse reactions and less description charge,CST is more suitable than CSP for public use,especially for community medicine,primary care,medical insurance and rural health care.The problems discussed in the present paper exist extensively in TCM research and in the new drugs exploitation,which have hindered the raise of the level of TCM research and the innovation of new drug investigation.The enhancement of the comparison and reassessment of medicines on the market is necessary for TCM to increase the ability to cure the sickness to save the patient,to improve the effectivity and security,and to ensure the quality stability.The novelties of the present research are as follows:1.Some common problems involved in TCM research and new drug development were discussed taken the example of compound salvia preparations,which is helpful as reference for the improvement of the level of TCM investigation and new drug exploitation,as well as for the reassessment of the medicines on the market.2.Multiple index of the compound salvia preparations such as process,quality standards,curative effect and adverse reaction were evaluated to provide reference for their utilizations in clinic.3.The comparison between CST and CSP and the reassessment of them was performed on pharmacology,pharmacochemistry and pharmacokinetics to investigate their differences and similaritilies comprehensively.
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