tribendimidine and amidantel

The anthelminthic drug tribendimidine has been approved by Chinese authorities for human use in 2004, and a first comprehensive review was published in Acta Tropica in 2005. Here, we summarise further advances made through additional clinical trials and laboratory investigations. Two phase IV trials have been conducted in the People's Republic of China, the first one enrolling 1292 adolescents and adults aged 15-70 years and the second one conducted with 899 children aged 4-14 years who were infected with one or multiple species of soil-transmitted helminths. Oral tribendimidine (single 400mg enteric-coated tablet given to adolescents/adults and 200mg to children) showed high cure rates against Ascaris lumbricoides (90.1-95.0%) and moderate-to-high cure rates against hookworm (82.0-88.4%). Another trial done in school-aged children using a rigorous diagnostic approach found a cure rate against hookworm of 76.5%. A single oral dose of tribendimidine showed only low cure rates against Trichuris trichiura (23.9-36.8%) confirming previous results. Tribendimidine administered to children infected with Enterobius vermicularis (two doses of 200mg each on consecutive days) resulted in a high cure rate (97.1%). Importantly, a series of randomised, exploratory trials revealed that tribendimidine shows interesting activity against the liver flukes Opisthorchis viverrini and Clonorchis sinensis, the tapeworm Taenia spp. and the threadworm Strongyloides stercoralis with respective cure rates of 70.0%, 40.0%, 53.3% and 36.4%. Pharmacokinetic studies in healthy Chinese volunteers indicated that after oral administration of tribendimidine, no parent drug was detected in plasma, but its primary metabolite, p-(1-dimethylamino ethylimino) aniline (aminoamidine, deacylated amidantel) (dADT), was found in plasma. dADT is then further metabolised to acetylated dADT (AdADT). dADT exhibits activity against several species of hookworm and C. sinensis in experimental studies, similar to that of tribendimidine. First studies elucidating the mechanism of action suggested that tribendimidine is an L-type nicotinic acetylcholine receptor agonist. Additional experimental studies revealed that the anti-parasite spectrum of tribendimidine is very broad. Indeed, to date, activity has been documented against 20 different nematode, trematode and cestode species. Taken together, tribendimidine warrants further scientific inquiry, including more comprehensive toxicity appraisals, mechanism of

Topics: Animals; Anthelmintics; China; Helminthiasis; Helminths; Humans; Phenylenediamines

Opisthorchiasis, caused by the foodborne trematode

Topics: Adolescent; Adult; Aged; Animals; Antiplatyhelmintic Agents; Female; Humans; Male; Middle Aged; Models, Biological; Opisthorchiasis; Opisthorchis; Phenylenediamines; Young Adult

Soil-transmitted helminth (STH) infections still remain a major health problem in poor rural settings. The lack of efficacious drugs against all STH species raises interest in drug combinations. Drug-drug interactions (DDIs) are, however, of major concern, so careful

Topics: Animals; Anthelmintics; Area Under Curve; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Therapy, Combination; Helminthiasis, Animal; Helminths; Ivermectin; Male; Phenylenediamines; Pyrantel Pamoate; Rats

Tribendimidine has emerged as potential alternative to praziquantel in the treatment of Opisthorchis viverrini infections. To support its clinical development program, a quantitative high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay was developed for tribendimidine's degradation product deacylated amidantel (dADT) and its acetylated metabolite adADT. Analytical sample preparation included protein precipitation for blood and plasma, and direct processing of dried blood spots (DBS). The analytes were detected by multiple reaction monitoring with electrospray ionization in the positive mode (dADT: 178.3→133.1 m/z, adADT: 220.4→175.1 m/z, tribendimidine 294.3→249.0 m/z). A pentafluorophenyl (PFP) phase Kinetex analytical column (2.6 μm, 100 Å, 50 mm × 4.6 mm) with a 6 min lasting mobile phase gradient program of ammonium acetate and acetonitrile was applied. The method was validated with respect to precision, accuracy, linearity, sensitivity, and selectivity. The analytical range in plasma and blood was 1-1000 ng/ml and in DBS 10-2000 ng/ml (R(2)>0.99). Recoveries determined using four different human blood batches were in the range of 70-90%. Inter- and intra-assay accuracy and precision deviations were at least ≤12.2%. dADT and adADT were stable within the autosampler for 72 h (10°C), for 4 h at room temperature, for 3 month at -80°C, and after three freeze and thaw cycles. DBS samples should be stored at -20°C. The validation results demonstrated that the LC-MS/MS method is precise, accurate and selective and can be applied for pharmacokinetic studies with tribendimidine.

Topics: Acetylation; Antinematodal Agents; Blood Stains; Calibration; Chromatography, High Pressure Liquid; Limit of Detection; Molecular Structure; Phenylenediamines; Reference Standards; Reproducibility of Results; Tandem Mass Spectrometry

Tribendimidine has been registered for the treatment of human soil transmitted helminthiases in China. In the model nematode Caenorhabditis elegans it is an agonist of L-subtype nicotinic acetylcholine receptors and therefore shares its mode of action with levamisole and pyrantel. Besides its broad spectrum of nematicidal efficacy, tribendimidine is efficacious against several trematodes and has been attributed to have anti-cestodal effects. However, there are few published data available for the latter. The efficacy of tribendimidine and its nematicidal metabolite deacylated amidantel against Hymenolepis microstoma were examined for their anti-cestodal potential. Doses of 50 and 100mg/kg body weight deacylated amidantel and 10, 25, 50, and 100mg/kg tribendimidine were administered orally on three consecutive days to mice experimentally infected with eight cysticercoids. Necropsy was performed and the worm burdens were determined one day after the last treatment. Furthermore, levamisole was used in combination with tribendimidine (100mg/kg levamisole plus 10 and 25mg/kg tribendimidine, respectively) and alone (50 and 100mg/kg) to investigate any possible interactions of the partner compounds against cestodes. Tribendimidine showed a very high efficacy at dosages of 50mg/kg or higher. Surprisingly, deacylated amidantel led to no reduction of the worm burden in any of the treatments. Combinations of levamisole with tribendimidine did not augment the effects of tribendimidine alone and as expected levamisole alone also showed no anti-cestodal activity. To our knowledge, this study shows for the first time activity of tribendimidine against a cestode in a controlled laboratory study. Due to the excellent cure rates observed here, multiple tribendimidine treatments might be considered as useful scheme for treatments of cestode, nematode and trematode infections although this would significantly increase both costs and management efforts. Moreover, the differences between tribendimidine and deacylated amidantel indicate at least a strong difference in sensitivity of H. microstoma or a strong difference in drug availability.

Topics: Administration, Oral; Animals; Anthelmintics; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Hymenolepiasis; Hymenolepis; Mice; Phenylenediamines; Treatment Outcome

Topics: Ancylostomiasis; Animals; Anthelmintics; Cricetinae; Dogs; Necatoriasis; Nematode Infections; Nippostrongylus; Phenylenediamines; Pyrantel Pamoate; Rats