中国寄生虫学与寄生虫病杂志 ›› 2010, Vol. 28 ›› Issue (3): 2-171.

• 论著 • 上一篇    下一篇

用三苯双脒、吡喹酮和青蒿琥酯临床给药方案治疗感染华支睾吸虫大鼠的研究

薛剑, 徐莉莉, 强慧琴, 张永年, 肖树华*   

  1. 中国疾病预防控制中心寄生虫病预防控制所,卫生部寄生虫病原与媒介生物学重点实验室,世界卫生组织疟疾、血吸虫病和丝虫病合作中心,上海 200025
  • 收稿日期:1900-01-01 修回日期:1900-01-01 出版日期:2010-06-30 发布日期:2010-06-30

Treatment of Rats Infected with Clonorchis sinensis Using Clinical Administration Regimens of Tribendimidine, Praziquatnel and Artesunate

XUE Jian, XU Li-li, QIANG Hui-qin, ZHANG Yong-nian, XIAO Shu-hua*   

  1. National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention;Key Laboratory of Parasite and Vector Biology, MOH;WHO Collaborating Centre for Malaria,Schistosomiasis and Filariasis,Shanghai 200025,China
  • Received:1900-01-01 Revised:1900-01-01 Online:2010-06-30 Published:2010-06-30

摘要: 【摘要】 目的 观察临床应用三苯双脒、青蒿琥酯和吡喹酮的给药方案治疗感染华支睾吸虫大鼠的疗效。 方法 将临床试用于治疗华支睾吸虫感染的三苯双脒、青蒿琥酯和吡喹酮剂量用不同种属动物等效剂量换算法换算为大鼠用的剂量,并按临床药物联合用药方案,设置了以下的剂量疗程,即三苯双脒16或32 mg/(kg·d)×1 d、2 d和3 d(bid),8 或16 mg/(kg·d)×3 d;青蒿琥酯12 mg/(kg·d)×3 d(tid)和16 mg/(kg·d)×3 d(bid);吡喹酮143 mg/(kg·d)×2或3 d (tid),143 mg/(kg·d)×2 d或3 d(bid)和47.7或71.5 mg/(kg·d)×3 d。151只大鼠(每鼠灌胃感染华支睾吸虫囊蚴50只)分2批,第1批79只大鼠于感染后5周分为13组,每组5~6鼠,其中6组单用三苯双脒、青蒿琥酯或吡喹酮治疗,另7组用三苯双脒与青蒿琥酯或吡喹酮联合治疗,或吡喹酮与青蒿琥酯联合治疗,余8鼠作对照。第2批72只大鼠于感染后6周,分为13组(每组5只),其中7组和6组分别用三苯双脒和吡喹酮的不同剂量疗程治疗,余7鼠作对照。于治疗结束后2 周剖杀小鼠,收集胆管和肝组织内的华支睾吸虫,计算各组的平均虫数和减虫率,用非参数统计方法(Mann?鄄Whitney秩和检验)进行分析。 结果 第1批试验中,三苯双脒16或32 mg/(kg·d)×3 d(bid),吡喹酮143 mg/(kg·d)×3 d(tid)或143 mg/(kg·d)×3 d(bid)各治疗组的平均虫数均明显低于对照组(P﹤0.01),减虫率为94.2%~96.0%。感染大鼠用青蒿琥酯12 mg/(kg·d)×3 d(tid)治疗无效,而16 mg/(kg·d)×3 d(bid)则有57.2%的减虫率,其平均虫数明显低于对照组(P﹤0.05)。三苯双脒16或32 mg/(kg·d)×3 d(bid)与吡喹酮143 mg/(kg·d)×3 d(bid), 或与青蒿琥酯16 mg/(kg·d)×3 d(bid)联合治疗组,各组平均虫数均显著少于对照组(P﹤0.01),减虫率为94.2%~99.4%,即联合治疗的疗效与三苯双脒和吡喹酮单用组相仿,但显著高于青蒿琥酯单用组。吡喹酮143 mg/(kg·d)×3 d(tid)与青蒿琥酯12 mg/(kg·d)×3 d(tid),或吡喹酮143 mg/(kg·d)×3 d(bid)与青蒿琥酯16 mg/(kg·d)×3 d(bid)联合治疗组的减虫率达93.6%~100%。第2批试验中,三苯双脒16或32 mg/(kg·d)×2 d和3 d(bid)治疗组的平均虫数间差异无统计学意义(P<0.05),减虫率为86.5%~95.1%,而三苯双脒32 mg/(kg·d)×1 d(bid)治疗组,减虫率仅为73.0%,但8或16 mg/(kg·d)×3 d(qd)的减虫率为88.3%~92.6%,吡喹酮143 mg/(kg·d)×3 d(tid)治疗组的减虫率为96.9%,若同剂量给药2 d的减虫率降至63.2%,而47.7 mg/(kg·d)×3 d(qd)则无效;吡喹酮143 mg/(kg·d)×2 d和3 d(bid)的减虫率相仿,达87.7~95.1%,若同剂量每日顿服,连服3 d则无效。结论 以人用的三苯双脒、吡喹酮和青蒿琥酯的剂量换算为大鼠用的剂量,并按临床用的疗程治疗感染华支睾吸虫的大鼠,除青蒿琥酯外,均有很好的治疗效果,其中三苯双脒的疗程可由3 d缩减为2 d。由于单用三苯双脒和吡喹酮已有很高的疗效,故它们之间以及和青蒿琥酯的联合治疗不易显现增效作用。

关键词: 三苯双脒, 青蒿琥酯, 吡喹酮, 华支睾吸虫, 联合治疗, 疗效, 大鼠

Abstract: 【Abstract】 Objective To evaluate the efficacy in treatment of Clonorchis sinensis-infected rats using the adminis-tration regimens of tribendimidine, artesunate and praziquantel applied in clinical treatment of clonorchiasis. Methods The doses of tribendimidine, artesunate and praziquantel used in clinical treatment of clonorchiasis were converted to the doses used in rats by the method of equal effective dose conversion among different animals, while the administration regimens of the drugs were designed basing on the regimens used in clinical trials. Thus, the following dose schedules were set up, i.e., tribendimidine 16 or 32 mg/(kg·d)×1, 2 or 3 d (bid), 8 or 16 mg/(kg·d)×3 d; artesunate 12 mg/(kg·d)×3 d(tid) and 16 mg/(kg·d)×3 d(bid); praziquantel 143 mg/(kg·d)×2 or 3 d (tid), 143 mg/(kg·d)×2 or 3 d(bid), 47.7 or 71.5 mg/(kg·d)×3 d. 151 rats were divided into 2 batches and each rat was infected orally with 50 metacercariae of C. sinensis. In the first batch of test, 79 rats were divided into 13 groups of 5-6 rats 5 weeks post-infection. Among them 6 groups were treated orally only with tribendimidine, artesunate or praziquantel, while other 7 groups were treated with tribendimidine combined with artesuante or praziquantel, or praziquatel combined with artesunate. The remaining 8 untreated rats served as control. In the second batch of test, 72 rats were divided into 13 groups of 5 rats. Among them, 7 and 6 groups were treated with tribendimidine and praziquantel, respectively, 6 weeks post-infection. The remaining 8 untreated rats served as control. Rats were sacrificed 14 days post-treatment, worms were recovered from the bile duct and the liver tissue. The mean worm reduction rate was calculated and compared among the groups by nonparametric method (Mann-Whitney test). Results In the first batch of test, the mean worm burdens in rats infected with C. sinensis and treated orally with tribendimidine 16 or 32 mg/(kg·d)×3 d(bid), praziquantel 143 mg/(kg·d)×3 d (tid), or 143 mg/(kg·d)×3 d (bid) were significantly lower than that of the control (P﹤0.01) with mean worm burden reductions of 94.2%-96.0%. No efficacy was seen when infected rats were treated orally with artesunate 12 mg/(kg·d)×3 d(tid). But in those treated with artesunate 16 mg/(kg·d)×3 d(bid), the mean worm burden was significantly lower than that of the control (P﹤0.05) with a mean worm reduction of 57.2%. In combined treatment, the infected rats treated with tribendimidine 16 or 32 mg/(kg·d)×3 d(bid) in combination with praziquantel 143 mg/(kg·d)×3 d(bid) or artesunate 16 mg/(kg·d)×3 d(bid), the difference of mean worm burden between each combined treatment group and control group was statistically significant (P﹤0.01) with mean worm reductions of 94.2%-99.4% which revealed that the worm reduction rate in combined treatment group was similar to the corresponding group treated with tribendimidine or praziquantel alone, but significantly higher than that of the group treated with artesunate alone. In infected rats treated with praziquantel 143 mg/(kg·d)×3 d(tid) plus artesunate 12 mg/(kg·d)×3 d(tid) or praziquantel 143 mg/(kg·d)×3 d(bid) plus artesunate 16 mg/(kg·d)×3 d(bid), the mean worm burden reductions were 93.6%-100%. In the second batch of test, the efficacy of tribendimidine obtained from infected rats treated with the drug 16 or 32 mg/(kg·d)×2 d(bid) and 3 d(bid), the difference of mean worm burdens between them was not statistically significant with mean worm reductions of 86.5%-95.1%. When rats were treated with tribendimidine 32 mg/(kg·d)×1 d(bid), the mean worm reduction was 73.0%, while the dose of the drug was given to the rats at 8 or 16 mg/kg daily for 3 days the mean worm reduction rates were 88.3%-92.6%. Treatment of praziquatnel 143 mg/(kg·d)×3 d (tid) resulted in a worm reduction of 96.9%, if the treatment course reduced to 2 d, the rate was 63.2%. Similar results were obtained in rats treated with praziquantel 143 mg/(kg·d)×2 d(bid) and 3 d(bid). Finally, administration of praziquantel at a daily dose of 47.7 or 71.5 mg/kg for 3 d exhibited no effect against C. sinensis. Conclusion When the dose schedules of tribendimidine, artesunate and praziquantel used in humans are converted to the doses for use in rats, tribendimidine and praziquantel exhibit satisfactory effect against C. sinensis, but artesunate shows no or less effect; the treatment course of tribendimidine can be reduced from 3 d to 2 d. Since tribendimidine and praziquantel used alone have endorsed high efficacy against C. sinensis in rats, combinations among the 3 drugs do not show better effect.

Key words: Tribendimidine, Artesuante, Praziquantel, Clonorchis sinensis, Combined treatment, Efficacy, Rat