复方丹参制剂有效成分及药理作用的比较研究
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摘要
我国中药发展很快,应用日广,但在新药研究,特别是改剂型仿制药中,存在创新发展不够、低水平重复严重、疗效不突出、安仝性不重视、质量不高等问题。尤其是同一药物多种剂型、多家生产,质量混乱,优劣难分,缺少比较研究及上市后再评价,对于临床优选药物、合理用药,十分不利,亟待解决。
复方丹参制剂是治疗心血管疾病的常用中成药,目前共有片剂、滴丸、水丸、微丸、胶囊、软胶囊、气雾剂、颗粒剂、口服液、含片共10种剂型,700多家厂家生产,为临床用药提供了多种选择。相关基础研究和临床研究的广泛开展,为药物应用提供了依据。但是,既往的研究大多以单一剂型为研究对象,剂型比较研究尚未引起足够的重视,不同剂型的特色与优点尚不明确,该类药物在心血管系统用药中的地位也不明晰。本研究以文献分析为基础,选用临床常用、市场占有率较高的两种产品(片剂与滴丸)为研究对象,从药物化学、药理学及不良反应等方面进行比较研究及再评价研究,为临床优选药物提供科学根据。
1.文献研究
1.1复方丹参制剂的研究进展
收集整理复方丹参制剂的质量标准及相关基础研究和临床研究报道,对复方丹参制剂的处方、质量标准、有效成分、药理作用、临床研究、不良反应等进行分析,就其中存在的问题进行探讨,为该类制剂的进一步发展和提高提供参考。
1.2复方丹参制剂治疗冠心病临床研究现状及质量分析
1.2.1方法:检索1994年1月～2008年12月国内外公开发表的有关复方丹参制剂的临床研究报道,对观察组病例数、适应症、治疗方式,以及复方丹参片和滴丸治疗冠心病的疗程、疗效等方面进行分析,并在此基础上就临床研究存在的问题进行探讨。
1.2.2结果:共纳入文献923篇。复方丹参片和复方丹参滴丸是临床研究的主要研究对象。多数研究的观察组病例数少于50例。研究疾病以缺血性心脏病为主。疗程主要集中于2周到1个月。单独使用是目前复方丹参制剂治疗冠心病临床研究中的主要给药方式。在不同的临床研究中,同一种制剂的疗效波动明显。而且,滴丸用作治疗组的疗效明显优于其用作对照组的疗效(P<0.001)。在临床研究的设计与实施中存在诸多问题,如样本量较小、随机与盲法的使用不标准、病例选择和疗效评价标准不规范、阳性药选择不合理、缺少安慰剂对照、缺少随访和依从性控制、统计学处理不合理、对安全性分析重视不足等,严重影响了研究结果的可靠性和科学性。
1.2.3结论:我国复方丹参制剂临床研究的质量有待提高,在设计和实施的过程中存在着诸多问题,影响了研究结果的科学性和客观性。目前尚无法得出一种制剂优于另一种制剂的结论。有关复方丹参制剂的临床疗效评价与比较,还需要更全面、更科学的研究。
1.3复方丹参片与滴丸治疗冠心病心绞痛疗效对比研究的报告质量评价
1.3.1方法:检索1994-2007年国内外公开发表的同时使用复方丹参滴丸和复方丹参片治疗冠心病心绞痛的临床研究,采用CONSORT标准和其他相关评价指标进行报告质量评价。
1.3.2结果:纳入26篇报道,按CONSORT标准和其他相关标准评价,仅2篇(7.6%)报道描述了如何产生随机顺序(其中1篇为半随机),6篇(23.1%)实施单盲,19篇(73.1%)报道不良事件,2篇(7.6%)为多中心研究,2篇(7.6%)描述了中医证型。无研究报道如何执行随机,无研究进行样本含量计算、意向性分析和分层分析,无研究采用安慰剂对照和模拟剂,无研究报道伦理审批和知情同意。
1.3.3结论:我国有关复方丹参片与复方丹参滴丸治疗冠心病的临床研究在提供完整、规范、准确、全面的试验信息等方面存在诸多不足,严重影响了结果的可靠性和科学性。要解决以上问题,使中药有效性评价的研究水平得到整体提高,构建并完善中医药临床疗效评价体系、提高临床试验报告的规范性和准确度必不可少。
1.4复方丹参片与滴丸治疗冠心病心绞痛疗效对比研究的研究质量评价和Meta疗效分析
1.4.1方法:检索1994-2007年国内外公开发表的同时观察复方丹参滴丸和片剂治疗冠心病心绞痛的临床研究,采用Jadad改良评分量表评价研究质量,采用Meta-分析法对疗程为4w的临床研究进行疗效分析。
1.4.2结果:纳入26篇报道,随机和盲法的使用不规范、对研究过程中的撤出与退出事件不重视的现象普遍,Jadad改良评分显示所有研究得分均≤3分,属于低质量报道。Meta-分析结果显示,与复方丹参片相比,复方丹参滴丸治疗冠心病时,心电图、心绞痛、临床症状改善情况的总有效率的合并RR(95%CI)分别为1.30(1.17,1.44)、1.40(1.17,1.67)和1.26(1.10,1.45)。心电图改善总有效率的倒漏斗图分布不对称。
1.4.3结论:我国有关复方丹参片与滴丸治疗冠心病的临床随机对照研究的质量有待进一步提高。Meta-疗效分析结果仅具部分参考价值,目前尚无法得出一种制剂疗效优于另一种制剂的可靠结论。
1.5复方丹参制剂的不良反应概况
1.5.1方法:检索1994-2008年国内外公开发表的单独使用复方丹参制剂、并进行不良反应观察的临床研究,以及相关个案报道,就该类制剂的不良反应发生率、不良反应症状及临床处置进行分析。
1.5.2结果:共纳入临床研究223篇(累计病例12618例)、个案报道18篇。其中复方丹参制剂的不良反应发生率依次为片剂1.91%、滴丸2.74%,未查阅到气雾剂、颗粒剂引起的不良反应报道。不同文献报道的不良反应发生率波动明显,且同种药物作为对照组的不良反应发生率明显高于作为治疗组的发生率。复方丹参制剂引起的不良反应主要为消化道反应,其次为扩血管反应,其中滴丸的不良反应症状多于片剂。个案报道的不良反应以过敏反应最多,其次为心血管系统反应(多为联合用药不合理导致)。复方丹参制剂引起的不良反应多数症状较轻,较严重不良反应包括胃粘膜出血、糜烂性胃炎、血尿、休克等。仅部分发生不良反应的患者接受了对症治疗。
1.5.3结论:复方丹参制剂引起的不良反应较为常见,以消化道反应为主,多数症状较轻,部分患者接受了对症治疗。临床对于多发症状重视不足,缺乏针对性的系统检查,该类制剂可能引起的病变的性质尚不明确。临床用药应慎重。
2药理学比较研究
2.1复方丹参片与滴丸对犬急性心肌缺血保护作用的比较研究
2.1.1方法:杂种犬42只,按体重随机分为7组:(1)模型对照组;(2)复方丹参片高剂量组,3.04 g生药/kg(临床等效剂量的18倍);(3)复方丹参片中剂量组:1.69 g生药/kg(临床等效剂量的10倍);(4)复方丹参片低剂量组:0.94 g生药/kg(临床等效剂量的5.6倍);(5)复方丹参滴丸高剂量组:3.04 g生药/kg(临床等效剂量的32.4倍);(6)复方丹参滴丸中剂量组:1.69 g生药/kg(临床等效剂量的18倍);(7)复方丹参滴丸低剂量组:0.94 g生药/kg(临床等效剂量的10倍)。结扎冠状动脉前降支制备犬急性实验性心肌缺血模型。结扎冠脉后10min,描记药前心电图,经口插胃管给药(模型组给予等体积蒸馏水)。药后描记心外膜电图,计算心肌缺血程度。氯化硝基四氮唑蓝染色法测定心肌梗死面积。放射免疫法测定血浆血栓素B_2(TXB_2)、6-酮-前列腺素F_(1α)(6-keto-PGF_(1α))、内皮素(ET)含量。
2.1.2结果:复方丹参片与滴丸均有减轻心肌缺血程度的作用,两者均在给药后15-25 min作用较为明显,作用均可达到3小时以上。这两种药物均可显著减少犬心肌梗死范围。以上保护作用,按同等生药剂量比较,片剂与滴丸的作用强度无明显差异。按临床剂量的10倍及18倍量给药,片剂的作用强于滴丸。片剂与滴丸均可降低犬血浆TXB_2含量,改善结扎冠状动脉所导致的犬血浆6-keto-PGF_(1α)/TXB_2比值降低的情况,但对血浆ET、6-keto-PGF_(1α)含量变化的作用不显著。不论是按同等生药剂量比较,还是按临床等效剂量的同等倍数剂量比较,二者的时效关系均无显著性差异。
2.1.3结论:复方丹参片和滴丸对冠脉结扎所致犬急性心肌缺血均具有保护作用,且均5 min起效、15-25 min后作用明显,作用持续3小时以上。按同等生药剂量比较,片剂与滴丸的作用强度无明显差异。按临床剂量的同等倍数剂量比较,在减小心肌梗死范围、降低心肌损伤程度等方面,片剂的作用强于滴丸。
2.2复方丹参片与滴丸对家兔血小板聚集及凝血的影响
2.2.1方法:日本大耳白兔,按体重和药前血小板聚集率随机分组,连续给药5天,取血测定药后血小板聚集率,计算血小板聚集抑制率。测定药后血浆凝血酶时间(TT)、凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)。采用Bom氏比浊法测定胶原(4.8 mg/L)、二磷酸腺苷(ADP,47.6μmol/L)和花生四烯酸(AA,782.0μmol/L)诱导的家兔血小板聚集率。
2.2.2结果:给药5次,复方丹参片与滴丸均可明显抑制胶原、ADP、AA诱导的血小板聚集。按同等生药剂量比较,片剂组的作用具有强于滴丸的趋势。按临床用量的同等倍数剂量进行比较,片剂作用强于滴丸。复方丹参片与滴丸对家兔血浆PT、APTT、FIB无显著影响,仅具有一定的延长血浆TT的作用。
2.2.3结论:复方丹参片和滴丸均具有抑制胶原、ADP、AA诱导的血小板聚集、延长血浆TT时间的作用,且片剂的作用强于滴丸。
2.3复方丹参片与滴丸对FeCl_3致兔颈总动脉栓塞的影响
2.3.1方法:日本大耳白兔,按体重随机分组,连续灌胃给药7天,末次给药前禁食过夜(自由饮水),末次灌胃后10 min,麻醉家兔,分离左侧颈总动脉,用70%FeCl_3浸渍过的滤纸条(0.5×1.0 cm~2)包裹颈总动脉(假手术组用生理盐水浸渍的滤纸条)50 min制备模型,包裹颈总动脉即刻记为开始造模。造模3小时,耳中动脉取血,测定血浆TT、PT、APTT、FIB、D—二聚体(D-dimer)、血小板因子4(PF_4)、TXB_2、6-keto-PGF_(1α)。造模24小时,取造模颈总动脉病理检查血栓形成情况及血管内皮损伤情况。
2.3.2结果:复方丹参片与滴丸可在一定程度上改善造模导致的兔血浆TT、APTT时间缩短、TXB_2明显上升、6-keto PGF_(1α)显著下降的情况,对兔血浆PT、FIB、D-dimer、PF_4的改变虽有改善趋势,但影响不显著。片剂与滴丸可减轻FeCl_3所致血栓栓塞和血管内皮损伤。以上作用,按同等生药剂量比较,这两种药物的作用无明显差异。按临床用量的同等倍数剂量比较,复方丹参片的作用具有强于复方丹参滴丸的趋势。
2.3.3结论:复方丹参片与滴丸均可减轻FeCl_3导致的家兔颈总动脉血管内皮损伤、血栓栓塞等改变,但二者的作用差异不显著。
3药物化学比较研究
3.1复方丹参片与滴丸中8种有效成分的含量比较研究
3.1.1方法:采用HPLC法。丹参素、原儿茶醛、丹酚酸B以0.1%磷酸水溶液和乙腈为流动相,梯度洗脱,流速1 ml/min,柱温30℃,检测波长281 nm。隐丹参酮、丹参酮ⅡA以甲醇-水(75∶25)为流动相,流速1.0 ml/min,柱温35℃,检测波长270 nm条件检测。皂苷成分以0.1%磷酸水溶液和乙腈为流动相,梯度洗脱,流速1 ml/min(22-28 min,0.8 ml/min),柱温30℃,检测波长203nm。
3.1.2结果:每克药品中,复方丹参滴丸仅丹参素、原儿茶醛、三七皂苷R1的含量高于片剂,其余5种有效成分均以复方丹参片中含量较高。按药品说明书提供的服用方法折算,每次服用复方丹参滴丸仅原儿茶醛高于片剂,其余6种成分的摄入量复方丹参片明显高于滴丸。
3.1.3结论:复方丹参片与滴丸中8种有效成分每次服药摄入量差异明显。摄入量差异可能会对二者治疗冠心病心绞痛的疗效强度产生影响,有待进一步研究。
4药代动力学比较研究
4.1复方丹参片与滴丸中丹参素、原儿茶醛、丹酚酸B大鼠在体肠吸收比较研究
4.1.1方法:采用大鼠在体肠灌流模型,观察浓度对复方丹参片与滴丸中丹参素、原儿茶醛、丹酚酸B的肠吸收特性的影响,并比较以上成分在十二指肠、空肠、回肠、结肠的吸收情况。以HPLC法测定灌流前后以上成分的含量变化,以0.1%磷酸水溶液和乙腈为流动相,梯度洗脱,流速1ml/min,柱温30℃,检测波长281 nm。
4.1.2结果:全肠段灌流2h,原儿茶醛的吸收较为完全,而丹参素和丹酚酸B的肠吸收不显著。复方丹参滴丸灌流时,不同浓度组的原儿茶醛总吸收率相似,且单位面积吸收速率与浓度呈正相关。复方丹参片灌流液浓度越高,丹参素和丹酚酸B的2小时全肠段总吸收率越低,且不同浓度下,这两种成分的单位面积吸收速率无明显差异。复方丹参片中这三种成分在不同肠段的吸收,丹参素与丹酚酸B均为:十二指肠>空肠>结肠>回肠,原儿茶醛:十二指肠>空肠>回肠>结肠,而复方丹参滴丸中原儿茶醛的吸收高低依次为十二指肠>回肠>空肠>结肠。
4.1.3结论:复方丹参片中丹参素和丹酚酸B的肠吸收可能存在高浓度饱和现象;复方丹参滴丸中原儿茶醛的大鼠肠吸收机理可能为被动扩散。片剂与滴丸中原儿茶醛的大鼠肠吸收特性存在一定的差异,可能与其他共存成分的影响有关。
综上所述,虽然复方丹参制剂在过去的几十年中得到了长足的发展,相关基础研究和临床研究也得到了拓展和深化,但是,仍存在较多问题,给临床用药带来了隐患。其安全性,尤其是大剂量、长期持续服药的安全性,有待进一步论证。目前尚无充分证据证明该类药物为“速效药”、“强效药”、“长效药”,也无足够的证据表明其优于同类的其他中药。因此,复方丹参制剂不适合用作治疗冠心病心绞痛的“首选药”和“一线用药”,仅可用作常规用药、后续用药或辅助用药。与滴丸相比,复方丹参片有效成分含量较高,药理作用较强,不良反应发生率较低,且药费较少,更适于大众用药,特别是社区医疗、基层用药、医保用药及农村用药。
本研究反映了我国中药研究及新药开发中的一些普遍性问题,严重阻碍了中药研究水平的提高及新药研制的创新发展。加强上市中药的比较研究和再评价工作,对于提高中药治病救人的水平、提高中药安全性和有效性、确保中药产品的质量稳定十分必要。
本研究的创新性主要有以下几点:
①以复方丹参制剂为例,探讨中药研究及新药发展过程中存在的一些普遍性问题,为提高中药研究和新药开发水平,以及中药再评价提供参考。
②从生产工艺、质量标准、治疗效果、不良反应等方面对复方丹参制剂进行多指标评价,为临床合理用药提供依据。
③联合使用药理学、药物化学和药代动力学试验手段,对复方丹参片与滴丸进行比较研究和上市后再评价,较为全面地探讨二者的异同。
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 analysis
1.1 Progress of investigation on compound salvia preparations
Based 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 Disease
1.2.1 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 disease
1.3.1 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 disease
1.4.1 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 preparations
1.5.1 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 study
2.1 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 F_(1α) (6-keto-PGF_(1α)) to thromboxane B_2(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 TXB_2,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 rabbits
2.2.1 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 thrombosis
2.3.1 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(PF_4),D-dimer,TXB_2 and 6-keto-PGF_(1α) 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 TXB_2,and reduction of 6-keto-PGF_(1α) in plasma,while both drugs did not significantly affect PT, FIB,D-dimer and PF_4.Thrombus and damage of endothelium induced by FeCl_3 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 CSP
3.1.1 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 Rg_1 and Rb_1 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 study
4.1 Investigation on the absorption of Salvianic acid A,protocatechuic aldehyde and salvianolic acid B of CST and CSP in rats' intestine
4.1.1 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.
复方丹参制剂是治疗心血管疾病的常用中成药,目前共有片剂、滴丸、水丸、微丸、胶囊、软胶囊、气雾剂、颗粒剂、口服液、含片共10种剂型,700多家厂家生产,为临床用药提供了多种选择。相关基础研究和临床研究的广泛开展,为药物应用提供了依据。但是,既往的研究大多以单一剂型为研究对象,剂型比较研究尚未引起足够的重视,不同剂型的特色与优点尚不明确,该类药物在心血管系统用药中的地位也不明晰。本研究以文献分析为基础,选用临床常用、市场占有率较高的两种产品(片剂与滴丸)为研究对象,从药物化学、药理学及不良反应等方面进行比较研究及再评价研究,为临床优选药物提供科学根据。
1.文献研究
1.1复方丹参制剂的研究进展
收集整理复方丹参制剂的质量标准及相关基础研究和临床研究报道,对复方丹参制剂的处方、质量标准、有效成分、药理作用、临床研究、不良反应等进行分析,就其中存在的问题进行探讨,为该类制剂的进一步发展和提高提供参考。
1.2复方丹参制剂治疗冠心病临床研究现状及质量分析
1.2.1方法:检索1994年1月～2008年12月国内外公开发表的有关复方丹参制剂的临床研究报道,对观察组病例数、适应症、治疗方式,以及复方丹参片和滴丸治疗冠心病的疗程、疗效等方面进行分析,并在此基础上就临床研究存在的问题进行探讨。
1.2.2结果:共纳入文献923篇。复方丹参片和复方丹参滴丸是临床研究的主要研究对象。多数研究的观察组病例数少于50例。研究疾病以缺血性心脏病为主。疗程主要集中于2周到1个月。单独使用是目前复方丹参制剂治疗冠心病临床研究中的主要给药方式。在不同的临床研究中,同一种制剂的疗效波动明显。而且,滴丸用作治疗组的疗效明显优于其用作对照组的疗效(P<0.001)。在临床研究的设计与实施中存在诸多问题,如样本量较小、随机与盲法的使用不标准、病例选择和疗效评价标准不规范、阳性药选择不合理、缺少安慰剂对照、缺少随访和依从性控制、统计学处理不合理、对安全性分析重视不足等,严重影响了研究结果的可靠性和科学性。
1.2.3结论:我国复方丹参制剂临床研究的质量有待提高,在设计和实施的过程中存在着诸多问题,影响了研究结果的科学性和客观性。目前尚无法得出一种制剂优于另一种制剂的结论。有关复方丹参制剂的临床疗效评价与比较,还需要更全面、更科学的研究。
1.3复方丹参片与滴丸治疗冠心病心绞痛疗效对比研究的报告质量评价
1.3.1方法:检索1994-2007年国内外公开发表的同时使用复方丹参滴丸和复方丹参片治疗冠心病心绞痛的临床研究,采用CONSORT标准和其他相关评价指标进行报告质量评价。
1.3.2结果:纳入26篇报道,按CONSORT标准和其他相关标准评价,仅2篇(7.6%)报道描述了如何产生随机顺序(其中1篇为半随机),6篇(23.1%)实施单盲,19篇(73.1%)报道不良事件,2篇(7.6%)为多中心研究,2篇(7.6%)描述了中医证型。无研究报道如何执行随机,无研究进行样本含量计算、意向性分析和分层分析,无研究采用安慰剂对照和模拟剂,无研究报道伦理审批和知情同意。
1.3.3结论:我国有关复方丹参片与复方丹参滴丸治疗冠心病的临床研究在提供完整、规范、准确、全面的试验信息等方面存在诸多不足,严重影响了结果的可靠性和科学性。要解决以上问题,使中药有效性评价的研究水平得到整体提高,构建并完善中医药临床疗效评价体系、提高临床试验报告的规范性和准确度必不可少。
1.4复方丹参片与滴丸治疗冠心病心绞痛疗效对比研究的研究质量评价和Meta疗效分析
1.4.1方法:检索1994-2007年国内外公开发表的同时观察复方丹参滴丸和片剂治疗冠心病心绞痛的临床研究,采用Jadad改良评分量表评价研究质量,采用Meta-分析法对疗程为4w的临床研究进行疗效分析。
1.4.2结果:纳入26篇报道,随机和盲法的使用不规范、对研究过程中的撤出与退出事件不重视的现象普遍,Jadad改良评分显示所有研究得分均≤3分,属于低质量报道。Meta-分析结果显示,与复方丹参片相比,复方丹参滴丸治疗冠心病时,心电图、心绞痛、临床症状改善情况的总有效率的合并RR(95%CI)分别为1.30(1.17,1.44)、1.40(1.17,1.67)和1.26(1.10,1.45)。心电图改善总有效率的倒漏斗图分布不对称。
1.4.3结论:我国有关复方丹参片与滴丸治疗冠心病的临床随机对照研究的质量有待进一步提高。Meta-疗效分析结果仅具部分参考价值,目前尚无法得出一种制剂疗效优于另一种制剂的可靠结论。
1.5复方丹参制剂的不良反应概况
1.5.1方法:检索1994-2008年国内外公开发表的单独使用复方丹参制剂、并进行不良反应观察的临床研究,以及相关个案报道,就该类制剂的不良反应发生率、不良反应症状及临床处置进行分析。
1.5.2结果:共纳入临床研究223篇(累计病例12618例)、个案报道18篇。其中复方丹参制剂的不良反应发生率依次为片剂1.91%、滴丸2.74%,未查阅到气雾剂、颗粒剂引起的不良反应报道。不同文献报道的不良反应发生率波动明显,且同种药物作为对照组的不良反应发生率明显高于作为治疗组的发生率。复方丹参制剂引起的不良反应主要为消化道反应,其次为扩血管反应,其中滴丸的不良反应症状多于片剂。个案报道的不良反应以过敏反应最多,其次为心血管系统反应(多为联合用药不合理导致)。复方丹参制剂引起的不良反应多数症状较轻,较严重不良反应包括胃粘膜出血、糜烂性胃炎、血尿、休克等。仅部分发生不良反应的患者接受了对症治疗。
1.5.3结论:复方丹参制剂引起的不良反应较为常见,以消化道反应为主,多数症状较轻,部分患者接受了对症治疗。临床对于多发症状重视不足,缺乏针对性的系统检查,该类制剂可能引起的病变的性质尚不明确。临床用药应慎重。
2药理学比较研究
2.1复方丹参片与滴丸对犬急性心肌缺血保护作用的比较研究
2.1.1方法:杂种犬42只,按体重随机分为7组:(1)模型对照组;(2)复方丹参片高剂量组,3.04 g生药/kg(临床等效剂量的18倍);(3)复方丹参片中剂量组:1.69 g生药/kg(临床等效剂量的10倍);(4)复方丹参片低剂量组:0.94 g生药/kg(临床等效剂量的5.6倍);(5)复方丹参滴丸高剂量组:3.04 g生药/kg(临床等效剂量的32.4倍);(6)复方丹参滴丸中剂量组:1.69 g生药/kg(临床等效剂量的18倍);(7)复方丹参滴丸低剂量组:0.94 g生药/kg(临床等效剂量的10倍)。结扎冠状动脉前降支制备犬急性实验性心肌缺血模型。结扎冠脉后10min,描记药前心电图,经口插胃管给药(模型组给予等体积蒸馏水)。药后描记心外膜电图,计算心肌缺血程度。氯化硝基四氮唑蓝染色法测定心肌梗死面积。放射免疫法测定血浆血栓素B_2(TXB_2)、6-酮-前列腺素F_(1α)(6-keto-PGF_(1α))、内皮素(ET)含量。
2.1.2结果:复方丹参片与滴丸均有减轻心肌缺血程度的作用,两者均在给药后15-25 min作用较为明显,作用均可达到3小时以上。这两种药物均可显著减少犬心肌梗死范围。以上保护作用,按同等生药剂量比较,片剂与滴丸的作用强度无明显差异。按临床剂量的10倍及18倍量给药,片剂的作用强于滴丸。片剂与滴丸均可降低犬血浆TXB_2含量,改善结扎冠状动脉所导致的犬血浆6-keto-PGF_(1α)/TXB_2比值降低的情况,但对血浆ET、6-keto-PGF_(1α)含量变化的作用不显著。不论是按同等生药剂量比较,还是按临床等效剂量的同等倍数剂量比较,二者的时效关系均无显著性差异。
2.1.3结论:复方丹参片和滴丸对冠脉结扎所致犬急性心肌缺血均具有保护作用,且均5 min起效、15-25 min后作用明显,作用持续3小时以上。按同等生药剂量比较,片剂与滴丸的作用强度无明显差异。按临床剂量的同等倍数剂量比较,在减小心肌梗死范围、降低心肌损伤程度等方面,片剂的作用强于滴丸。
2.2复方丹参片与滴丸对家兔血小板聚集及凝血的影响
2.2.1方法:日本大耳白兔,按体重和药前血小板聚集率随机分组,连续给药5天,取血测定药后血小板聚集率,计算血小板聚集抑制率。测定药后血浆凝血酶时间(TT)、凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)。采用Bom氏比浊法测定胶原(4.8 mg/L)、二磷酸腺苷(ADP,47.6μmol/L)和花生四烯酸(AA,782.0μmol/L)诱导的家兔血小板聚集率。
2.2.2结果:给药5次,复方丹参片与滴丸均可明显抑制胶原、ADP、AA诱导的血小板聚集。按同等生药剂量比较,片剂组的作用具有强于滴丸的趋势。按临床用量的同等倍数剂量进行比较,片剂作用强于滴丸。复方丹参片与滴丸对家兔血浆PT、APTT、FIB无显著影响,仅具有一定的延长血浆TT的作用。
2.2.3结论:复方丹参片和滴丸均具有抑制胶原、ADP、AA诱导的血小板聚集、延长血浆TT时间的作用,且片剂的作用强于滴丸。
2.3复方丹参片与滴丸对FeCl_3致兔颈总动脉栓塞的影响
2.3.1方法:日本大耳白兔,按体重随机分组,连续灌胃给药7天,末次给药前禁食过夜(自由饮水),末次灌胃后10 min,麻醉家兔,分离左侧颈总动脉,用70%FeCl_3浸渍过的滤纸条(0.5×1.0 cm~2)包裹颈总动脉(假手术组用生理盐水浸渍的滤纸条)50 min制备模型,包裹颈总动脉即刻记为开始造模。造模3小时,耳中动脉取血,测定血浆TT、PT、APTT、FIB、D—二聚体(D-dimer)、血小板因子4(PF_4)、TXB_2、6-keto-PGF_(1α)。造模24小时,取造模颈总动脉病理检查血栓形成情况及血管内皮损伤情况。
2.3.2结果:复方丹参片与滴丸可在一定程度上改善造模导致的兔血浆TT、APTT时间缩短、TXB_2明显上升、6-keto PGF_(1α)显著下降的情况,对兔血浆PT、FIB、D-dimer、PF_4的改变虽有改善趋势,但影响不显著。片剂与滴丸可减轻FeCl_3所致血栓栓塞和血管内皮损伤。以上作用,按同等生药剂量比较,这两种药物的作用无明显差异。按临床用量的同等倍数剂量比较,复方丹参片的作用具有强于复方丹参滴丸的趋势。
2.3.3结论:复方丹参片与滴丸均可减轻FeCl_3导致的家兔颈总动脉血管内皮损伤、血栓栓塞等改变,但二者的作用差异不显著。
3药物化学比较研究
3.1复方丹参片与滴丸中8种有效成分的含量比较研究
3.1.1方法:采用HPLC法。丹参素、原儿茶醛、丹酚酸B以0.1%磷酸水溶液和乙腈为流动相,梯度洗脱,流速1 ml/min,柱温30℃,检测波长281 nm。隐丹参酮、丹参酮ⅡA以甲醇-水(75∶25)为流动相,流速1.0 ml/min,柱温35℃,检测波长270 nm条件检测。皂苷成分以0.1%磷酸水溶液和乙腈为流动相,梯度洗脱,流速1 ml/min(22-28 min,0.8 ml/min),柱温30℃,检测波长203nm。
3.1.2结果:每克药品中,复方丹参滴丸仅丹参素、原儿茶醛、三七皂苷R1的含量高于片剂,其余5种有效成分均以复方丹参片中含量较高。按药品说明书提供的服用方法折算,每次服用复方丹参滴丸仅原儿茶醛高于片剂,其余6种成分的摄入量复方丹参片明显高于滴丸。
3.1.3结论:复方丹参片与滴丸中8种有效成分每次服药摄入量差异明显。摄入量差异可能会对二者治疗冠心病心绞痛的疗效强度产生影响,有待进一步研究。
4药代动力学比较研究
4.1复方丹参片与滴丸中丹参素、原儿茶醛、丹酚酸B大鼠在体肠吸收比较研究
4.1.1方法:采用大鼠在体肠灌流模型,观察浓度对复方丹参片与滴丸中丹参素、原儿茶醛、丹酚酸B的肠吸收特性的影响,并比较以上成分在十二指肠、空肠、回肠、结肠的吸收情况。以HPLC法测定灌流前后以上成分的含量变化,以0.1%磷酸水溶液和乙腈为流动相,梯度洗脱,流速1ml/min,柱温30℃,检测波长281 nm。
4.1.2结果:全肠段灌流2h,原儿茶醛的吸收较为完全,而丹参素和丹酚酸B的肠吸收不显著。复方丹参滴丸灌流时,不同浓度组的原儿茶醛总吸收率相似,且单位面积吸收速率与浓度呈正相关。复方丹参片灌流液浓度越高,丹参素和丹酚酸B的2小时全肠段总吸收率越低,且不同浓度下,这两种成分的单位面积吸收速率无明显差异。复方丹参片中这三种成分在不同肠段的吸收,丹参素与丹酚酸B均为:十二指肠>空肠>结肠>回肠,原儿茶醛:十二指肠>空肠>回肠>结肠,而复方丹参滴丸中原儿茶醛的吸收高低依次为十二指肠>回肠>空肠>结肠。
4.1.3结论:复方丹参片中丹参素和丹酚酸B的肠吸收可能存在高浓度饱和现象;复方丹参滴丸中原儿茶醛的大鼠肠吸收机理可能为被动扩散。片剂与滴丸中原儿茶醛的大鼠肠吸收特性存在一定的差异,可能与其他共存成分的影响有关。
综上所述,虽然复方丹参制剂在过去的几十年中得到了长足的发展,相关基础研究和临床研究也得到了拓展和深化,但是,仍存在较多问题,给临床用药带来了隐患。其安全性,尤其是大剂量、长期持续服药的安全性,有待进一步论证。目前尚无充分证据证明该类药物为“速效药”、“强效药”、“长效药”,也无足够的证据表明其优于同类的其他中药。因此,复方丹参制剂不适合用作治疗冠心病心绞痛的“首选药”和“一线用药”,仅可用作常规用药、后续用药或辅助用药。与滴丸相比,复方丹参片有效成分含量较高,药理作用较强,不良反应发生率较低,且药费较少,更适于大众用药,特别是社区医疗、基层用药、医保用药及农村用药。
本研究反映了我国中药研究及新药开发中的一些普遍性问题,严重阻碍了中药研究水平的提高及新药研制的创新发展。加强上市中药的比较研究和再评价工作,对于提高中药治病救人的水平、提高中药安全性和有效性、确保中药产品的质量稳定十分必要。
本研究的创新性主要有以下几点:
①以复方丹参制剂为例,探讨中药研究及新药发展过程中存在的一些普遍性问题,为提高中药研究和新药开发水平,以及中药再评价提供参考。
②从生产工艺、质量标准、治疗效果、不良反应等方面对复方丹参制剂进行多指标评价,为临床合理用药提供依据。
③联合使用药理学、药物化学和药代动力学试验手段,对复方丹参片与滴丸进行比较研究和上市后再评价,较为全面地探讨二者的异同。
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 analysis
1.1 Progress of investigation on compound salvia preparations
Based 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 Disease
1.2.1 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 disease
1.3.1 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 disease
1.4.1 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 preparations
1.5.1 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 study
2.1 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 F_(1α) (6-keto-PGF_(1α)) to thromboxane B_2(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 TXB_2,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 rabbits
2.2.1 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 thrombosis
2.3.1 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(PF_4),D-dimer,TXB_2 and 6-keto-PGF_(1α) 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 TXB_2,and reduction of 6-keto-PGF_(1α) in plasma,while both drugs did not significantly affect PT, FIB,D-dimer and PF_4.Thrombus and damage of endothelium induced by FeCl_3 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 CSP
3.1.1 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 Rg_1 and Rb_1 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 study
4.1 Investigation on the absorption of Salvianic acid A,protocatechuic aldehyde and salvianolic acid B of CST and CSP in rats' intestine
4.1.1 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.
引文
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