摘要
目的研究石杉碱甲(Hup A)衍生物石杉碱甲-水杨醛(Hup A-SA)和石杉碱甲-反式肉桂醛(Hup A-TCA)对神经性毒剂梭曼(GD)的体外、体内预防效应及安全性。方法采用改良Ellman法体外测定Hup A及其衍生物Hup A-SA和Hup A-TCA对乙酰胆碱酯酶(AChE)的抑制效应及对GD的体外预防效应。小鼠灌胃给予Hup A(2 mg·kg^(-1))、Hup A-SA(2.86 mg·kg^(-1))和Hup A-TCA(2.94 mg·kg^(-1)),分别于给药后12、24 h肌内注射1×LD;剂量的GD,观察并记录各组小鼠的中毒症状及死亡情况。小鼠灌胃给予Hup A(4~10 mg·kg^(-1))、Hup A-SA(15~55 mg·kg^(-1))和Hup A-TCA(5~40 mg·kg^(-1)),记录小鼠的中毒症状及14 d内的死亡情况,使用Bliss法计算半数致死剂量(LD;)。结果 Hup A、Hup A-SA、Hup A-TCA均浓度依赖性地抑制AChE活性,其半数抑制浓度(IC;)分别为(0.36±0.05)、(1.36±0.03)和(0.62±0.03)μmol·L^(-1)。3种药物与AChE预孵育,均可显著提高GD的IC;值;体内预防给药12 h后以GD攻击,3种药物小鼠存活率均提高,分别为66.67%、75%和100%;预防给药24 h后以GD攻击,2个衍生物组仍有部分动物存活,而Hup A组动物全部死亡,2种衍生物体内预防GD的时效性较Hup A更长。急性毒性研究显示,3种药物小鼠灌胃的LD;值分别为7.20、45.75和16.42 mg·kg^(-1),衍生物安全性提高。结论 Hup A-SA和Hup A-TCA均通过可逆地抑制AChE活性发挥GD中毒预防作用,预防时间较Hup A长,且安全性更高。
Objective To determine the in vitro and in vivo intoxication and safety of Hup A derivatives (Hup A-SA and Hup A-TCA) against soman (GD).Methods Modified Ellman method was applied in vitro to determine the inhibiting effect of Hup A and its derivatives on AChE and their preventive effect against soman intoxication.The mice were pretreated with Hup A (2 mg·kg^(-1)),Hup A-SA (2.86 mg·kg^(-1)),and Hup A-TCA (2.94 mg·kg^(-1)) orally.The poisoning symptoms and death rates of each group were observed and recorded 12 h or 24 h after challenged with 1×LD;dose of GD (im).In the acute toxicity study,the mice were given Hup A,Hup A-SA or Hup A-TCA orally.Their poisoning symptoms and death rates within 14 d were recorded,and the median lethal doses (LD;) were calculated by Bliss method.Results Hup A,Hup A-SA and Hup A-TCA all inhibited the activity of AChE in a concentration-dependent manner with IC;values at (0.36±0.05) μmol·L^(-1),(1.36±0.03) μmol·L^(-1)and (0.62±0.03) μmol·L^(-1),respectively.The IC;values of GD inhibiting AChE pretreated with Hup A,Hup A-SA or Hup A-TCA were increased significantly as compared with those of the non-pretreated groups.The mice were pretreated with prophylactic drugs of Hup A,Hup A-SA or Hup A-TCA 12 hours in advance improved the survival rates of mice challenged with GD,and the survival rates of mice were 66.67%,75%,and 100%,respectively.If given 24 hours in advance,some mice in the two derivative groups survived,while all mice died in the Hup A group.The effective time of preventing soman in the two derivatives groups was longer than that of Hup A group.The LD;values of the mice given Hup A,Hup A-SA and Hup A-TCA orally were 7.20 mg·kg^(-1),45.75 mg·kg^(-1)and 16.42 mg·kg^(-1),respectively,and the safeties of the derivatives were enhanced.Conclusion The Hup A-SA and Hup A-TCA can prevent GD poisoning by reversibly inhibiting the activity of AChE,with longer prevention time and safer effect than those of Hup A.
作者
崔雅岚
张瑞华
靳倩
石童
王陈
陈学军
李丽琴
CUI Ya-lan;ZHANG Rui-hua;JIN Qian;SHI Tong;WANG Chen;CHEN Xue-jun;LI Li-qin(State Key Laboratory of NBC Protection for Civilian,Beijing 102205)
出处
《中南药学》
CAS
2021年第12期2502-2507,共6页
Central South Pharmacy
