| 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. |
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