摘要
中药和西药联合使用在我国非常普遍,若不合理联用有可能引发严重不良反应,特别是中、西药注射剂联用是导致临床严重不良反应的重要因素之一.中、西药注射剂序贯使用时,是否要考虑用药间隔,是否可以通过建立安全用药“时间窗”避免中西药物相互作用,从而降低不良反应发生风险,值得深入研究.为此,本文以临床上不良反应报道较多的药物联用组合双黄连和利巴韦林注射剂为例,提出基于“时间窗”的中西药注射剂序贯用药风险防控的新设想.研究结果表明,给实验动物同时注射上述两种注射剂,可引起由补体系统成分C5介导的类过敏反应,而二者单独使用时类过敏反应均不明显.进一步对此药物组合不同时间间隔给药方案的考察表明,在4 h以内的不同时间间隔进行序贯给药,仍会引起明显的类过敏反应;而给药间隔超过6 h后类过敏反应则较不明显.进一步基于血清代谢组学分析,也证实了双黄连和利巴韦林注射剂的安全用药“时间窗上述研究结果提示,中、西药序贯使用所导致的药物不良反应确实存在“时间窗”现象,在“时间窗”之后间隔用药可显著降低不良反应发生风险,为提高中药和西药联合使用的安全用药水平提供了新的视角和思路.
The combined use of herbal and traditional medicine with synthetic drugs is a common clinical issue in China,as well as in other countries around the world.The improper combination of Traditional Chinese Medicine(TCM)with synthetic drugs may increase the risk of severe adverse drug reactions(ADRs).In China,the combination of Shuanghuanglian(SHL)and Ribavirin injections(RB)is one such example that has led to a higher risk of pseudo-allergic ADRs,observed during postmarketing safety monitoring.Such combination-related ADRs may be associated with concurrent drug exposure concentrations in vivo.Thus,it is important to administer both formulations at acceptable intervals to prevent ADRs.In this study,we propose an appropriate time interval of administration to reduce ADR risk in combination drug use.SHL and RB combination was then tested in rats.This combination was tested at different administration intervals.Ear weight was chosen as the quantitative index to indicate tissue edema and intensity of pseudo-allergic reactions.Compared to the control group,rats that were simultaneously administered with SHL and RB intravenously,showed different behaviors and symptoms such as ear edema and increase in weight,swelling of limbs and huddling,which were similar to those seen in pseudo-allergic reactions.By contrast,rats administered solely with either RB or SHL did not exhibit obvious pseudo-allergic reactions.With respect to the combination groups at different administration intervals,there were two different types of responses.One of them was similar to the concurrent administration of drug pairs,which occurred in groups at intervals of 0,1.5,2,3.5 and 4 h.The other type was similar to the sole use of RB or SHL,which occurred in groups with intervals of 6,8,12 and 24 h.We also determined serum concentrations of complement C5(C5)and thrombomodulin(THBD),proteins that mediate the complement system and coagulation cascade-depended pseudo-allergic reactions.Results showed that there was significant increase in these two indices in combination groups,with intervals below or equal to 4 h and non-significant increase in combination groups with intervals above or equal to 6 h.These results indicate that a“safe window”of administration interval exists when using the drug pair:SHL and RB,thus reducing the risk of pseudo-allergic reactions.Moreover,we tested serum metabolomic profiles of each group.The principal component analysis revealed that there was an obvious distinction between the rat groups,of both clusters:One cluster included the normal control group where either SHL or RB group was administered and the combination groups that were administered both SHL and RB at intervals of over or equal to 6 h.The other cluster involved combination groups that were administered both drugs at intervals below or equal to 4 h.Thus,the metabolomic results also elucidated a“safe window”administration interval,when using such drug pairs.We then screened out metabolites that might be used to distinguish these two clusters of rat groups.The results of ROC curves showed that compounds of m/z 154.0592,m/z 433.2357,and m/z 331.0528 could distinguish rats where SHL was used after and before 6 h.These metabolites were identified as L-2-Amino-3-(l-pyrazolyl)propanoic acid,[2-hydroxy-l-(6-hydroxy-1-oxo-lH-isochromen-3-yl)butoxy]sulfonic acid and LysoPA(0:0/18:2(9Z,12Z))according to their MS/MS spectrum,respectively.This study verified the hypothesis of the“safe window”of administration interval in combination drug use,including TCM and synthetic drugs.Administered at appropriate intervals,it can reduce ADR risk and prevent safety-related issues from occurring.This study thus provides a new perspective for improving safety,when using Chinese herbal medicines in combination with synthetic medicine.
作者
胡黄婉茵
张雅铭
郝俊杰
杨晓娟
周元园
刘晓熠
秦旭华
肖小河
王伽伯
Huangwanyin Hu;Yarning Zhang;Junjie Hao;Xiaojuan Yang;Yuanyuan Zhou;Xiaoyi Liu;Xuhua Qin;Xiaohe Xiao;Jiabo Wang(College of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China;Institute of Chinese Herbal Medicine,Fifth Medical Center of PLA General Hospital,Beijing 100039,China)
出处
《科学通报》
EI
CAS
CSCD
北大核心
2019年第28期3020-3029,共10页
Chinese Science Bulletin
作者简介
王伽伯,E-mail:wjb0128@126.com;秦旭华,E-mail:qxhjsr@n6.com。
