三苯双脒抗华支睾吸虫药效与机制的研究
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摘要
根据第二次全国人体寄生虫病分布调查的估算,我国的华支睾吸虫感染人数已达1249万。由于缺乏预防食源性吸虫病的疫苗和人们的饮食方式难以改变,药物化疗仍然是控制该类疾病的主要手段。目前用于治疗华支睾吸虫感染的药物主要是吡喹酮,根据世界卫生组织的推荐,吡喹酮用于治疗华支睾吸虫感染的适宜剂量疗程是每次口服25mg/kg,3次/d,连给2d。该疗法虽有较好的疗效,但应用于大规模群体治疗具有一定的难度,因此,继续寻求新的抗华支睾吸虫病药物仍是十分必要的。近年来动物试验发现顿服单剂三苯双脒对华支睾吸虫和麝猫后睾吸虫有很好的杀灭效果,且其对麝猫后睾吸虫的疗效在临床试验中得到了验证。本论文先通过实验室研究确定三苯双脒对华支睾吸虫的疗效,并初步探讨其抗虫机制及在胆汁中的代谢动力学,然后尝试通过三苯双脒治疗肠道线虫和华支睾吸虫混合感染的病人,评价三苯双脒对感染华支睾吸虫的疗效及安全性,为华支睾吸虫病的现场群体化疗提供参考。
在实验室研究中,我们首先通过观察不同剂量的三苯双脒对体外培养的华支睾吸虫和对感染华支睾吸虫囊蚴的仓鼠的疗效,评价其对体外和体内的华支睾吸虫的作用。该研究明确了三苯双脒对体外培养的华支睾吸虫具有很强的杀灭作用,且对其最低致死剂量仅为吡喹酮的一半；对仓鼠体内的华支睾吸虫童虫和成虫均有好的疗效,其中100mg/kg三苯双脒治疗华支睾吸虫成虫可有高于90%的减虫率,即使剂量低至12.5mg/kg仍可有50%的减虫率,效价强度显著高于吡喹酮。
其次,我们通过观察三苯双脒对华支睾吸虫超微结构的影响,对其抗虫机制进行了初步探讨。大鼠经胃灌服三苯双脒300mg/kg后4h、8h、24h、48h和72h分别剖杀取虫,经预处理后置于透射电镜下观察。结果显示三苯双脒能引起华支睾吸虫皮层乳突的肿胀、破溃和溶解,层皮内杆状颗粒、盘状颗粒和膜样小泡的减少,线粒体和内质网的减少,线粒体形成空泡以及皮层细胞核膜损伤。
再次,本论文对三苯双脒代谢物氨脒在大鼠体内的药物代谢动力学进行了研究。首先建立了大鼠血浆和胆汁中氨脒浓度的测定方法,然后用200mg/kg三苯双脒治疗大鼠后于不同时间点取血样及收集胆汁,同样时间点收集未经治疗的空白大鼠的血样和胆汁,经处理后进样测定,绘制血药浓度—时间曲线、胆汁药物浓度—时间曲线以及胆汁排泄速率和累计排泄量曲线。结果发现氨脒在血浆中的达峰时间Tmax为0.90±0.22h,峰浓度Cmax为8.12±2.05mg/L.而氨脒在胆汁中的达峰时间Tmax为1.15±0.42h,峰浓度Cmax为11.16±2.07mg/L,11h内氨脒的胆汁累积排泄量为40.12±12.00μ g,累积排泄率0.38‰,给药后0.5～3h的胆汁排泄速率最大。
最后,本论文还通过观察三苯双脒治疗肠道线虫和华支睾吸虫混合感染的病人的治愈率、虫卵减少率和不良反应,评价三苯双脒抗华支睾吸虫疗效和安全性。通过伦理审查后,在试验地区采用Kato-Katz法进行基线调查,根据入选标准和排除标准确定拟服药人员,随机分为3组,签订知情同意书及经过临床医生体检后,分别口服吡喹酮(总剂量为75mg/kg)、三苯双脒(400mg,顿服)、三苯双脒(200mg*2次)。部分接受三苯双脒治疗的病人在治疗前和治疗后24h检测血尿常规、心电图和肝肾功能(空腹抽血)。研究人员对服药人员治疗后48h内进行随访,询问有无不良反应并记录具体情况。治疗后3w,收集病人粪样,用Kato-Katz法检测并计数粪样的华支睾吸虫、钩虫、蛔虫、鞭虫和绦虫的虫卵数,计算华支睾吸虫的治愈率和虫卵减少率。然后根据第一次试验结果,邀请未治愈病人,按照同样的操作标准进行第二次相同药物治疗,并评价疗效与安全性。最后所有未治愈的受试者,采用吡喹酮标准疗法进行治疗。本研究发现顿服400mg的三苯双脒组的治愈率和虫卵减少率与吡喹酮组无显著性差异,但不良反应较吡喹酮组少,且吡喹酮组更易出现眩晕的不良反应。
综合以上各部分的研究结果,我们认为三苯双脒对华支睾吸虫具有良好的治疗作用,但是还需开展大规模多中心的临床试验以进一步验证其疗效和评价安全性,为华支睾吸虫病现场群体化疗提供依据。
According to the second national survey on the distribution of human parasitic infections,12.49million Chinese was estimated to be infected with Clonorchis sinensis. Since lack of a vaccine for the prevention of food-borne trematodiasis and difficulties to change human eating behaviors, chemotherapy remains the mainstay for the control of food-borne trematodiasis. Currently, praziquante is the drug of main choice for clonorchiasis treatment. According to the recommendation from WHO, the appropriate treatment schedule is25mg/kg thrice daily for up to2days which results in satisfactory cure rate. However, becauseit is not so convenient to implement this dose schedule of praziquantel in mass treatment of clonorchiasis, it still needs to develop new drugs againstC. sinensis. In recent years, we found that oral administration of tribendimidine at a single dose resulted in potential effect against C. sinensis and Opisthorchis viverrini harbored in rats, and the efficacy of tribendimidine against0. viverrini has been verified in the clinical trial. The purpose of this research is to determine the efficacy and pharmacokinetic parameters in bile though pre-clinical studies, and to explore its parasiticidal mechanism. Then the efficacy and safety of tribendimidine against C. sinensiswill be appraised by a clinical trial in which tribendimidine was used to treat the patients co-infected withintestinal nematodes and C. sinensis. This outcome willprovide the reference for chemotherapy in mass treatment of clonorchiasis.
In preclinical studies, we firstly observe the effect of different dose of tribendimidine against C. sinensis in vitro and harbored in hamsters to appraise the efficacy. This part of study indicated tribendimidine exhibited good effect on killing adult C. sinensisin vitro, and the minimal concentration of tribendimidine against C. sinensisin vitro was half of that of praziquantel; tribendimidine exhibited good effect to juvenile and adult ofC. sinensis in hansters. Among these, the100mg/kg tribendimidine induced in over90%worm burden reductions and even the dose of12.5mg/kg could cause50%worm burden reduction; the efficacy potency of tribendimidine was significantly higher than praziquantel.
Secondly, we surveyed the ultrastructure changes of C. sinensis after tribendimidine treatment to explore the parasiticidal mechanism. The rats were orally administrated with300mg/kg tribendimidine and were killed after4h,8h,24h,48h and72h after the treatment, the adult of C. sinensis were pull out from the bile duct of rats and were observed by transmission electron microscope. The apparently morphological alterations on the tegument of C. sinensis after the tribendimidine treatment were found, e.g. cortical mastoids swelled, ulcerated and dissolved, the rod-shaped particles, disc-shaped particles and membrane-like vacuoles in the cortex of tegument reduced as well as mitochondria and endoplasmic net, vacuoles formated in mitochondrial and tegument cell nucleus membrane damaged.
Thirdly, as the metabolite of tribendimidine, the dADT metabolism in rats was studied. At first, the measuring method of the concentration of dADT in the blood and bile was built. Then the blood samples were taken and the biles were collected at different time points after SD rats received the dose of200mg/kg tribendimidine treatment as well as untreated rats. These biological samples were measured and the plasma concentration-time curve and bile drug concentration-time curve were mapped. This study found that Tmax and Cmax of dADT in plasma was0.91±0.20h and8.15±1.83mg/L, and Tmax and Cmax of dADT in bile was1.15±0.42h and11.16±2.07mg/L. The cumulative excretion quantity was40.12±12.00μg within11h, and the cumulative excretion rate was0.38%o. The mean excretion rate from0.5h to3h after treatment is fastest.
Finally, the efficacy and safety of tribendimidine against patients of clonorchiasis was verified and evaluated through the single-center, randomized and open-lable clinical trial. After the ethical review, the baseline surveys in the trial area were carried with Kato-Katz method. Participants were identified based on the inclusion and exclusion criterions and were randomly divided into four groups. After signing informed consent and clinical examination, they were orally administrated praziquantel(the total doseof75mg/kg), tribendimidine (400mg for one single dose), tribendimidine (200mg, twice daily). A part of patients treated with tribendimidine receive the routine detection of blood and urine, liver and kidney function examination and ECG before treatment and24h after treatment. The paitients were followed up within48h after treatment, and were asked to report the adverse reactions which would be recorded. The fecal samples were collected3w after treatment, and detected with Kato-Katz method to count the egg number of C. sinensis, hookworm, Ascaris lumbricoieds and Trichuris trichiura. The cure rate and egg reduction rate were calculated. Then uncured patients were invited to take part in the second treatment with the same operating standards as the first treatment, and the efficacy and safety would be appraised. At last, all uncured patients would receive the praziquantel standard treatment. The trial demonstrated the dose of400mg tribendimidne could cause the similar cure rate and egg reduction rate to that of praziquantel, but the adverse events were less than praziquantel, and more vertigo adverse reactions were seen in praziquantel treatment group.
Based on the above results, we believe the tribendimidine has good therapeutic effect againstC. sinensis, but large-scale and mutil-center clinical trials should be carried to further evaluate the efficacy and safety of tribendimidine.
在实验室研究中,我们首先通过观察不同剂量的三苯双脒对体外培养的华支睾吸虫和对感染华支睾吸虫囊蚴的仓鼠的疗效,评价其对体外和体内的华支睾吸虫的作用。该研究明确了三苯双脒对体外培养的华支睾吸虫具有很强的杀灭作用,且对其最低致死剂量仅为吡喹酮的一半；对仓鼠体内的华支睾吸虫童虫和成虫均有好的疗效,其中100mg/kg三苯双脒治疗华支睾吸虫成虫可有高于90%的减虫率,即使剂量低至12.5mg/kg仍可有50%的减虫率,效价强度显著高于吡喹酮。
其次,我们通过观察三苯双脒对华支睾吸虫超微结构的影响,对其抗虫机制进行了初步探讨。大鼠经胃灌服三苯双脒300mg/kg后4h、8h、24h、48h和72h分别剖杀取虫,经预处理后置于透射电镜下观察。结果显示三苯双脒能引起华支睾吸虫皮层乳突的肿胀、破溃和溶解,层皮内杆状颗粒、盘状颗粒和膜样小泡的减少,线粒体和内质网的减少,线粒体形成空泡以及皮层细胞核膜损伤。
再次,本论文对三苯双脒代谢物氨脒在大鼠体内的药物代谢动力学进行了研究。首先建立了大鼠血浆和胆汁中氨脒浓度的测定方法,然后用200mg/kg三苯双脒治疗大鼠后于不同时间点取血样及收集胆汁,同样时间点收集未经治疗的空白大鼠的血样和胆汁,经处理后进样测定,绘制血药浓度—时间曲线、胆汁药物浓度—时间曲线以及胆汁排泄速率和累计排泄量曲线。结果发现氨脒在血浆中的达峰时间Tmax为0.90±0.22h,峰浓度Cmax为8.12±2.05mg/L.而氨脒在胆汁中的达峰时间Tmax为1.15±0.42h,峰浓度Cmax为11.16±2.07mg/L,11h内氨脒的胆汁累积排泄量为40.12±12.00μ g,累积排泄率0.38‰,给药后0.5～3h的胆汁排泄速率最大。
最后,本论文还通过观察三苯双脒治疗肠道线虫和华支睾吸虫混合感染的病人的治愈率、虫卵减少率和不良反应,评价三苯双脒抗华支睾吸虫疗效和安全性。通过伦理审查后,在试验地区采用Kato-Katz法进行基线调查,根据入选标准和排除标准确定拟服药人员,随机分为3组,签订知情同意书及经过临床医生体检后,分别口服吡喹酮(总剂量为75mg/kg)、三苯双脒(400mg,顿服)、三苯双脒(200mg*2次)。部分接受三苯双脒治疗的病人在治疗前和治疗后24h检测血尿常规、心电图和肝肾功能(空腹抽血)。研究人员对服药人员治疗后48h内进行随访,询问有无不良反应并记录具体情况。治疗后3w,收集病人粪样,用Kato-Katz法检测并计数粪样的华支睾吸虫、钩虫、蛔虫、鞭虫和绦虫的虫卵数,计算华支睾吸虫的治愈率和虫卵减少率。然后根据第一次试验结果,邀请未治愈病人,按照同样的操作标准进行第二次相同药物治疗,并评价疗效与安全性。最后所有未治愈的受试者,采用吡喹酮标准疗法进行治疗。本研究发现顿服400mg的三苯双脒组的治愈率和虫卵减少率与吡喹酮组无显著性差异,但不良反应较吡喹酮组少,且吡喹酮组更易出现眩晕的不良反应。
综合以上各部分的研究结果,我们认为三苯双脒对华支睾吸虫具有良好的治疗作用,但是还需开展大规模多中心的临床试验以进一步验证其疗效和评价安全性,为华支睾吸虫病现场群体化疗提供依据。
According to the second national survey on the distribution of human parasitic infections,12.49million Chinese was estimated to be infected with Clonorchis sinensis. Since lack of a vaccine for the prevention of food-borne trematodiasis and difficulties to change human eating behaviors, chemotherapy remains the mainstay for the control of food-borne trematodiasis. Currently, praziquante is the drug of main choice for clonorchiasis treatment. According to the recommendation from WHO, the appropriate treatment schedule is25mg/kg thrice daily for up to2days which results in satisfactory cure rate. However, becauseit is not so convenient to implement this dose schedule of praziquantel in mass treatment of clonorchiasis, it still needs to develop new drugs againstC. sinensis. In recent years, we found that oral administration of tribendimidine at a single dose resulted in potential effect against C. sinensis and Opisthorchis viverrini harbored in rats, and the efficacy of tribendimidine against0. viverrini has been verified in the clinical trial. The purpose of this research is to determine the efficacy and pharmacokinetic parameters in bile though pre-clinical studies, and to explore its parasiticidal mechanism. Then the efficacy and safety of tribendimidine against C. sinensiswill be appraised by a clinical trial in which tribendimidine was used to treat the patients co-infected withintestinal nematodes and C. sinensis. This outcome willprovide the reference for chemotherapy in mass treatment of clonorchiasis.
In preclinical studies, we firstly observe the effect of different dose of tribendimidine against C. sinensis in vitro and harbored in hamsters to appraise the efficacy. This part of study indicated tribendimidine exhibited good effect on killing adult C. sinensisin vitro, and the minimal concentration of tribendimidine against C. sinensisin vitro was half of that of praziquantel; tribendimidine exhibited good effect to juvenile and adult ofC. sinensis in hansters. Among these, the100mg/kg tribendimidine induced in over90%worm burden reductions and even the dose of12.5mg/kg could cause50%worm burden reduction; the efficacy potency of tribendimidine was significantly higher than praziquantel.
Secondly, we surveyed the ultrastructure changes of C. sinensis after tribendimidine treatment to explore the parasiticidal mechanism. The rats were orally administrated with300mg/kg tribendimidine and were killed after4h,8h,24h,48h and72h after the treatment, the adult of C. sinensis were pull out from the bile duct of rats and were observed by transmission electron microscope. The apparently morphological alterations on the tegument of C. sinensis after the tribendimidine treatment were found, e.g. cortical mastoids swelled, ulcerated and dissolved, the rod-shaped particles, disc-shaped particles and membrane-like vacuoles in the cortex of tegument reduced as well as mitochondria and endoplasmic net, vacuoles formated in mitochondrial and tegument cell nucleus membrane damaged.
Thirdly, as the metabolite of tribendimidine, the dADT metabolism in rats was studied. At first, the measuring method of the concentration of dADT in the blood and bile was built. Then the blood samples were taken and the biles were collected at different time points after SD rats received the dose of200mg/kg tribendimidine treatment as well as untreated rats. These biological samples were measured and the plasma concentration-time curve and bile drug concentration-time curve were mapped. This study found that Tmax and Cmax of dADT in plasma was0.91±0.20h and8.15±1.83mg/L, and Tmax and Cmax of dADT in bile was1.15±0.42h and11.16±2.07mg/L. The cumulative excretion quantity was40.12±12.00μg within11h, and the cumulative excretion rate was0.38%o. The mean excretion rate from0.5h to3h after treatment is fastest.
Finally, the efficacy and safety of tribendimidine against patients of clonorchiasis was verified and evaluated through the single-center, randomized and open-lable clinical trial. After the ethical review, the baseline surveys in the trial area were carried with Kato-Katz method. Participants were identified based on the inclusion and exclusion criterions and were randomly divided into four groups. After signing informed consent and clinical examination, they were orally administrated praziquantel(the total doseof75mg/kg), tribendimidine (400mg for one single dose), tribendimidine (200mg, twice daily). A part of patients treated with tribendimidine receive the routine detection of blood and urine, liver and kidney function examination and ECG before treatment and24h after treatment. The paitients were followed up within48h after treatment, and were asked to report the adverse reactions which would be recorded. The fecal samples were collected3w after treatment, and detected with Kato-Katz method to count the egg number of C. sinensis, hookworm, Ascaris lumbricoieds and Trichuris trichiura. The cure rate and egg reduction rate were calculated. Then uncured patients were invited to take part in the second treatment with the same operating standards as the first treatment, and the efficacy and safety would be appraised. At last, all uncured patients would receive the praziquantel standard treatment. The trial demonstrated the dose of400mg tribendimidne could cause the similar cure rate and egg reduction rate to that of praziquantel, but the adverse events were less than praziquantel, and more vertigo adverse reactions were seen in praziquantel treatment group.
Based on the above results, we believe the tribendimidine has good therapeutic effect againstC. sinensis, but large-scale and mutil-center clinical trials should be carried to further evaluate the efficacy and safety of tribendimidine.
引文
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