摘要
目的研究合成的候选药物奥美克松与舒更葡糖的药效与安全性。方法 40只比格犬分为5组检测药效:正常对照组(生理盐水)、舒更葡糖8 mg·kg-(1阳性对照组)和奥美克松2,8和32 mg·kg^(-1)组。分别给予比格犬2轮罗库溴铵1.0 g·L^(-1)后,按分组分别给予比格犬生理盐水、奥美克松或舒更葡糖,计算每只动物第一轮和第二轮滴注后第4个与第1个刺激强度比值(T4/T1)恢复至50%,75%及90%的时间。再将240尾斑马鱼分为8组(每组30尾),通过检测类胰蛋白酶相对诱导水平进行致敏性实验:正常对照组(有斑马鱼和底物)、C48/80阳性组、舒更葡糖和奥美克松各250,500和1000 ng组。此外,还将斑马鱼(每组30尾)分为正常对照组和舒更葡糖、奥美克松各75,250和750 ng组,计算心率,并在显微镜下观察出血情况,进行安全性评价。结果比格犬药效实验结果显示,奥美克松2,8和32 mg·kg^(-1)剂量下T4/T1恢复至50%,75%和90%的时间相比正常对照组均显著下降(P<0.01),说明这些剂量的奥美克松均能明显逆转罗库溴铵诱导的神经肌肉阻滞作用;与舒更葡糖8 mg·kg^(-1)组相比,奥美克松各剂量下T4/T1恢复至50%,75%和90%的时间与之相当,表明奥美克松在逆转罗库溴铵诱导的方面的效果与舒更葡糖相近。斑马鱼致敏实验结果显示,奥美克松250 ng组的类胰蛋白酶水平与舒更葡糖250 ng组的相近,表明两者的低剂量组均无显著致敏作用;奥美克松500和1000 ng组相比舒更葡糖相同剂量组,其类胰蛋白酶水平分别下降了90.6%和96.4%(P<0.01),表明舒更葡糖组存在显著致敏作用,且较高剂量下的过敏反应更为严重,而奥美克松相应剂量下未见致敏作用。斑马鱼心率模型中,相比正常对照组,奥美克松75 ng和舒更葡糖75 ng组心率相近,未见降低;而舒更葡糖250 ng组心率下降了10%(P<0.01),同一剂量下奥美克松组表现稳定。舒更葡糖750 ng组心率相比对照组降低了21%
OBJECTIVE To compare the efficacy and safety of a synthesized candidate adamgammadex with the only marketed selective relaxant binding agent sugammadex.METHODS Forty beagle dogs were divided into 5groups (8 beagles per group)for efficacy test.normal saline group (normal control),sugammadex 8mg·kg^-1(positive control)group,and adamgammadex 2,8and 32mg·kg^-1 groups,respectively.Rocuronium bromide 1.0g·L^-1 was given by two separate iv administrations to induce intense neuromuscular blockade (NMB).Beagle dogs received treatment according to groups after the second administration of rocuronium.The time interval from adamgammadex or sugammadex administration to recovery of the fourth twitch to the first twitch of train-of-four (TOF)ratios (T2T1)to 50%,75%, and 90%was calculated.Zebrafish were divided into 8 groups (30per group)for sensitizing test by detecting relative levels of tryptase,normal control group (with both zebrafish and substrate),compound 48/804mg·kg^-1 positive control,sugammadex or adamgammadex 250,500and 1000ng per fish groups,respectively.In addition,zebrafish (30per group)were divided into normal control (treated with ultrapure water),sugammadex or adamgammadex 75,250,or 750ng per fish groups,respectively. Heart rate (HR)was counted,and a microscope was used to observe bleeding for safety assessment. RESULTS In the beagle dog efficacy test,compared to normal control group,the recovery time of T4/T1 to 50%,75%,and 90% in adamgammadex 2,8and 32mg·kg^-1 groups was decreased (P<0.01), suggesting that adamgammadex had effectively reversed rocuronium-induced NMB.Compared to sugammadex 8mg·kg^-1 positive control group,the recovery time of T4/T1 to 50%,75% and 90% following adamgammadex 2,8 and 32mg·kg^-1 treatment was simillar,suggesting that adamgammadex worked in pretty much the same way as sugammadex in reversing rocuronium-induced NMB.In the zebrafish sensitizing test,compared to sugammadex 250ng group,the tryptase level in adamgammadex 250ng group hardly changed,suggesting that there were no si
作者
漆又毛
漆莹贝
余葆春
劳乔聪
李春启
朱狄峰
揭清
QI You-mao;QI Ying-bei;YU Bao-chun;LAO Qiao-cong;LI Chun-qi;ZHU Di-feng;JIE Qing(Hangzhou Adamerck Pharmlabs Inc.,Academician Workstation,Hangzhou 310011,China;College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China;Hunter Biotechnology Inc.,Hangzhou 310012,China)
出处
《中国药理学与毒理学杂志》
CAS
CSCD
北大核心
2018年第7期515-527,共13页
Chinese Journal of Pharmacology and Toxicology
基金
The project supported by National Science and Technolgy Major Project of China(2012ZX09103-101-012)
National Science and Technology Major Project of China(2016ZX09101066)
National Innovation Fun for Small and Medium Technology Based Firms(12C26213302758)~~
