[Effect of tribendimidine, artesunate, artemether and praziquantel, administered intragastrically at single, multiple or combined doses, to rats infected with Clonorchis sinensis].
OBJECTIVE
To assess the efficacy of single, multiple or combined oral doses of tribendimidine, artesunate, artemether and praziquantel against Clonorchis sinensis in rats.


METHODS
A total of 147 rats, each infected with 50 C. sinensis metacercariae, were used in experimental chemotherapy. All the drugs used were administered intragastrically 42-44 d after infection. (1) Sixty infected rats were randomly divided into 11 groups (4-5 rats per group) and the following drug dose-schedules were applied, i.e. under the same total dose tribendimidine or praziquantel was given at a single dose of 150 mg/kg, or given at smaller divided doses of 75 mg/kg (qd for 2 d), 50 mg/kg (qd for 3 d), 25 mg/kg (tid for 2 d); artesunate or artemether was given at a single dose of 75 mg/kg, or given a half dose of 37.5 mg/kg daily for 2 days. (2) Eighty-seven infected rats were randomly divided into 15 groups (4-6 rats per group) for combined treatment with the following drug administration regimens, i.e. artesunate or artemether 30 mg/kg plus praziquantel 150 mg/kg or tribendimidine 50 mg/kg and 75 mg/kg, respectively; tribendimidine 50 mg/kg plus praziquantel 150 mg/kg; tribendimidine 75 mg/kg plus praziquantel 187.5 mg/kg. A single dose of each drug mentioned above was also involved. Untreated C. sinensis-infected rats served as control. Rats were killed 14 days post-treatment, worms recovered from the bile duct and the liver tissue, mean worm burden reduction calculated and mean worm burden compared between the groups using non-parametric method (Mann-Whitney test).


RESULTS
Rats infected with C. sinensis and treated at a single 150 mg/kg dose of either tribendimidine or praziquantel resulted in a worm reduction of 57.2% and 63.8%, respectively. Whilst administration of tribendimidine at smaller but multiple doses given within 2-3 days at the same total dosage resulted in a slightly higher worm reduction (77.1%-79.4%), the opposite trend was observed for praziquantel (50.6%-54.2%). However, for both tribendimidine and praziquantel, the difference of mean worm burden lacked statistical significance between single and multiple doses. Infected rats administered either artesunate or artemether at a single dose of 75 mg/kg or a daily dose of 37.5 mg/kg for 2 days, the worm reduction was 100% and 90.4%-98.5%, respectively. Combined treatment with low doses of tribendimidine (50 mg/kg or 75 mg/kg) plus praziquantel (150 mg/kg or 187.5 mg/kg) resulted in a worm reduction of 74.9%-100%, which were higher than those of 26.9%-79.6% obtained from a single dose of each drug used. High worm reduction of 74.4%-97.9% was also observed when administering a low dose of artesunate or artemether (30 mg/kg) plus a low dose of tribendimidine (50 mg/kg or 75 mg/kg) or praziquantel (150 mg/kg). Mean worm reduction of 24.8%-79.6% were seen when drugs used at single doses.


CONCLUSIONS
The investigation confirmed that tribendimidine, artesunate, artemether-and praziquantel are all efficacious against C. sinensis, and that drug combination acts synergistically.
Xiao
Shu-Hua
SH
National Inst.of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Key Lab. of Parasite and Vector Biology, MOH, WHO Collaborating Centre for Malaria, Schistosomiasis and Filariasis, Shanghai 200025, China. shxiao4@hotmail.com
Xue
Jian
J
Tanner
Marcel
M
Zhang
Yong-Nian
YN
Keiser
Jennifer
J
Utzinger
Jürg
J
Qiang
Hui-Qin
HQ
Liu
Xiao-Yun
XY
D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage / Q000494:pharmacology; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage* / Q000494:pharmacology; D000077332:Artesunate; D003003:Clonorchiasis / Q000188:drug therapy*; D003004:Clonorchis sinensis / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D008297:Male; D021261:Parasitic Sensitivity Tests; D010655:Phenylenediamines / Q000008:administration & dosage* / Q000494:pharmacology; D011223:Praziquantel / Q000008:administration & dosage* / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000871:Anthelmintics; D037621:Artemisinins; D010655:Phenylenediamines; C056017:tribendimidine; D000077332:Artesunate; D011223:Praziquantel; D000077549:Artemether