title: [Treatment of rats infected with Clonorchis sinensis using clinical administration regimens of tribendimidine, praziquantel and artesunate].
abstract: OBJECTIVE
  To evaluate the efficacy in treatment of Clonorchis sinensis-infected rats using the administration 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 x d) x 1, 2 or 3 d (bid), 8 or 16 mg/(kg x d) x 3 d; artesunate 12 mg/(kg x d) x 3 d (tid) and 16 mg/(kg x d) x 3 d (bid); praziquantel 143 mg/(kg x d) x 2 or 3 d (tid), 143 mg/(kg x d) x 2 or 3 d (bid), 47.7 or 71.5 mg/(kg x d) x 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 artesunate or praziquantel, or praziquantel 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 non-parametric 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 x d) x 3 d (bid), praziquantel 143 mg/(kg x d) x 3 d (tid), or 143 mg/(kg x d) x 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 x d) x 3 d (tid). But in those treated with artesunate 16 mg/(kg x d) x 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 x d) x 3 d (bid) in combination with praziquantel 143 mg/(kg x d) x 3 d(bid) or artesunate 16 mg/(kg x d) x 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 x d) x 3 d (tid) plus artesunate 12 mg/(kg x d) x 3 d (tid) or praziquantel 143 mg/(kg x d) x 3 d (bid) plus artesunate 16 mg/(kg x d) x 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 x d) x 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 x d) x 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 praziquantel 143 mg/(kg x d) x 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 x d) x 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention Shanghai 200025, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xue
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Xu
authors.forename: Hui-Qin
authors.initials: HQ
authors.lastname: Qiang
authors.forename: Yong-Nian
authors.initials: YN
authors.lastname: Zhang
authors.forename: Shu-Hua
authors.initials: SH
authors.lastname: Xiao
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage* / Q000627:therapeutic use; D037621:Artemisinins / Q000008:administration & dosage* / Q000627:therapeutic use; D000077332:Artesunate; D003003:Clonorchiasis / Q000188:drug therapy*; D003004:Clonorchis sinensis; D008297:Male; D010655:Phenylenediamines / Q000008:administration & dosage* / Q000627:therapeutic use; D011223:Praziquantel / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000871:Anthelmintics; D037621:Artemisinins; D010655:Phenylenediamines; C056017:tribendimidine; D000077332:Artesunate; D011223:Praziquantel