| ObjectiveTo evaluate the efficacy and safety of coadministered statins and butylphthalide?NBP?in patients with acute ischemic stroke;to investigate the effects of atorvastatin?ATV?on p harmacokinetics of NBP in rats and to simultaneously observe the impacts of concomitant NBP and ATV on hepatic function of rats.Methods1.Meta analysis of the efficacy and safety of statins and NBP combination in patients with acute ischemic stroke.CNKI,WANGFANG,CBM,VIP,Pub Med,EMBASE and The Cochrane Library were search ed for the randomized controlled trials of one of statins and NBP combination and literature retrieval time limit was from the establishment of the special databases to december 2017.Two reviewers independently screened literature,extracted data and assessed the methodological quality of the included trials using the Cochrane risk of bias assessment tool.Statistical ana lyses were performed by Rev Man5.3.2.The effect of ATV on the pharmacokinetics of NBP and the impact of NBP alone or concomitant NBP and ATV on the hepatic function of ratsNBP was extracted from plasma samples by protein precipitati ng-acetonitrile.APhenomenexKinetexC 18?50mm×2.10mm,1.7?m?wasused.The chromatographic separation w as accomplished using gradient elution with a mobile phase composed of acetonitrile and water containing 0.1%formic acid.The gradient elution was stopped at 3.5min;the flow rate and injection volume were set at 0.3 m L/min,and 3?L,respectively.The quantitation of NBP in rat plasma was performed by multiple reaction monitoring?MRM?mode at m/z 191.1?145.1for NBP and m/z?285.6?193.1 for diazepam?IS?.14 rats were randomly divided into NBP group and NBP plus ATV group.NBP group were intragastrically administrated with once-daily NBP,and NBP plus ATV group were intragastrically given with once-daily NBP and ATV,for consecutive 7 days.The blood samples were collected predose and at different time poin ts postdose on the7th day.The aftermentioned UPLC-MS/MS was used to determine NBP concentrations in rat plasma.Meanwhile,The automatic biochemical analyzer measured the serum levels of ALT,A ST,TBIL and DBIL.The pharmacokinetic parameters were calcul ated using DAS 2.0.The statistical analys es were performed via the SPSS12.0.Results1.Seventeen clinical trials with 1244 participants were included for meta-analysis.The meta-analysis indicated that in addition to routine therapy,the cotherapy with a statin and NBP may have advantages over the monotherapy with a statin in terms of the changes in the National Institute of Health stroke scale?NIHSS??weighted mean difference?WMD?:-3.45,95%CI-4.30 to-2.61,P<0.001?,CRP level?WMD:-4.12,95%CI-4.76 to-3.48,P<0.001?,IL-6?WMD:-0.12,95%CI-0.16 to-0.08,P<0.001?,and Barthel Index?BI??WMD:16.56,95%CI 12.63 to 20.50,P<0.001?.Conversely,there was no difference between the cotherapy and the monotherpy in accordance with the rate of their adverse reactions?RR=0.95,95%CI 0.53 to 1.71,P=0.87?.2.The linear range of NBP was 5–1000ng·m L-1 with lower limit of quantification?LLOQ?of 5ng·m L-1.The intra-and inter-day precisions were acceptable with the RSD values below<±15%.The pharmacokinetic resear-ch showed that the AUC0-t,t1/2,and CL of NBP were 1735.384±249.965ng·h·m L-1,1.856±0.432h,and 0.04±0.006L·h-1·kg-1 respectively,in NBP grou p;the AUC0-t,t1/2,and CL of NBP were 2857.868±706.808ng·h·m L-1,3.413±0.921h and 0.024±0.005 L·h-1·kg-1 respectively,in NBP plus ATV group.Fu rthermore,there was significant difference in the AUC0-t,t1/2,and CL of N BP.between the two groups?P<0.05?.Nevertheless,Cmax,Tmax,Vd and MRT of NBP in NBP group were markedly different from those of NBP in NBP plus ATV group?P>0.05?.Moreover,there was no significant difference in serum AST,ALT,TBIL and DBIL levels between the two groups?P>0.05?.Conclusions1.On a basis of routine therapy,the cotherapy of NBP and a statin significantly was superior to a statins alone in efficacy for patients with acute ischemic stroke.Moreover,this medication cotherapy possessed good safty.2.ATV markedly affected the pharmacokinetic profile of NBP in rats.Therefore,when ATV and NBP are used concomitantly in clinical practice,cautions should be exercised.In addition,the coadministration of ATV and NBP did not harm the hepatic function of rats. |
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