Elsevier

Acta Tropica

Volume 126, Issue 2, May 2013, Pages 115-126
Acta Tropica

Review article
Advances with the Chinese anthelminthic drug tribendimidine in clinical trials and laboratory investigations

https://doi.org/10.1016/j.actatropica.2013.01.009Get rights and content

Abstract

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 400 mg enteric-coated tablet given to adolescents/adults and 200 mg 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 200 mg 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 action studies and clinical investigation as it holds promise as a broad spectrum anthelminthics.

Introduction

Soil-transmitted helminthiases are parasitic worm infections caused by the roundworm Ascaris lumbricoides, the whipworm Trichuris trichiura and two species of hookworm, Ancylostoma duodenale and Necator americanus (Bethony et al., 2006, Knopp et al., 2012). More than 5 billion people are at risk of soil-transmitted helminthiases (Pullan and Brooker, 2012), with over a billion people currently infected with at least one, often two or all three main soil-transmitted helminth species (Bethony et al., 2006, Steinmann et al., 2010, Utzinger, 2012). Yet, soil-transmitted helminthiases have been tagged as neglected tropical diseases, as they are intimately linked with poverty and chiefly affect poor people in tropical and subtropical parts of the world (Hotez et al., 2007, Utzinger et al., 2012).

The current global strategy to control soil-transmitted helminthiases is preventive chemotherapy, which refers to the regular large-scale administration of anthelminthic drugs to entire at-risk populations, especially school-aged children (WHO, 2006, WHO, 2010). At present, the World Health Organization (WHO) features four anthelminthic drugs on their model list of essential medicines for the treatment of soil-transmitted helminth infection, albendazole, levamisole, mebendazole and pyrantel pamoate (WHO, 2011a). Albendazole and mebendazole are the most widely used anthelminthics with dozen of millions of people treated every year (WHO, 2011b). However, these four drugs have all been developed in the 1960s and 1970s, initially for the veterinary market, and hence they lack optimisation for human use (Geary et al., 2010, Keiser and Utzinger, 2010, Olliaro et al., 2011). Moreover, there is considerable concern that growing drug pressure might result in the development of resistant parasite strains. Indeed, several recent studies carried out in different epidemiological settings reported unexpectedly low cure rates after single-dose albendazole or mebendazole administrations against hookworm and T. trichiura in school-aged children (Albonico et al., 2003, Flohr et al., 2007, Knopp et al., 2010, Steinmann et al., 2011, Ayé Soukhathammavong et al., 2012). A systematic review and meta-analysis concluded that a single dose of albendazole or mebendazole shows high efficacy against A. lumbricoides infection, poor efficacy against T. trichiura infection, whereas albendazole is more efficacious than mebendazole against hookworm infection (Keiser and Utzinger, 2008). In view of these observations, along with global policies and experiences from veterinary public health (Geerts and Gryseels, 2000, Horton, 2003), there is a need to develop new anthelminthic drugs, ideally with different mechanisms of action than the current armamentarium (Hagel and Giusti, 2010, Keiser and Utzinger, 2010, Olliaro et al., 2011).

Towards the end of the 1970s, a new class of chemical compounds of aminophenylamidines was reported to have a broad spectrum of activity against intestinal nematodes, filariae and cestodes. In particular, amidantel (ADT, BAY d 8815; Fig. 1a) showed high efficacy against hookworm and large roundworm harboured in dogs (Thomas, 1979, Wollweber et al., 1979). In 1980, a first clinical study in man indicated that amidantel is highly efficacious against A. lumbricoides and A. duodenale, whereas only few patients infected with N. americanus were cured (Rim et al., 1980). In 1983, Chinese scientists synthesised amidantel and its derivatives and pursued detailed structure-activity relationship studies. Eventually, tribendimidine (Fig. 1b) was selected and this compound further progressed in the drug development pipeline (Yao and Chen, 1986). After many years of scientific inquiry, including detailed pre-clinical and clinical studies, in early 2004, tribendimidine was approved by the Chinese Food and Drug Administration for the treatment of soil-transmitted helminth infections in man. In the following year, we published a review in Acta Tropica that summarised – for the first time – the pharmacological, toxicological, laboratory and clinical data available at the time (Xiao et al., 2005). Key characteristics of tribendimidine were highlighted, namely its good safety profile and the high efficacy against A. lumbricoides. Although tribendimidine only showed low efficacy against T. trichiura, it was found that a single dose of tribendimidine shows equal or even higher efficacy against hookworm (particularly N. americanus, which is the dominant hookworm species in the People's Republic of China (P.R. China)) than albendazole or other anthelminthics currently in use.

Here, we review advances made with tribendimidine over the past 8 years. First, we summarise results from recent clinical trials done in P.R. China, including two phase IV trials against soil-transmitted helminth infection in children and adolescents/adults. Next, we highlight key findings from a series of randomised, exploratory trials focussing on other helminth infections (clonorchiasis, opisthorchiasis, strongyloidiasis and taeniasis). Moreover, we provide an update on pharmacokinetic investigations and first insights gained from mechanism of action studies. We summarise the latest laboratory investigations, emphasising the wide spectrum of activity of tribendimidine against a broad array of nematode, trematode and cestode species. Our review is concluded with an outlook and a perspective of open research needs.

Section snippets

Efficacy of tribendimidine against soil-transmitted helminth infection

In 2006, a clinical trial was conducted in Guizhou province, P.R. China to further assess the efficacy and safety of tribendimidine against soil-transmitted helminth infections (Tang et al., 2008). Children aged 4–14 years were screened with the Kato-Katz technique (Katz et al., 1972) and those found with soil-transmitted helminth eggs in their stool were treated with a single oral dose of tribendimidine (200 mg). Three to four weeks post-treatment, children were re-examined with the same

Pharmacokinetic study of tribendimidine in humans

In order to accurately determine the mother compound tribendimidine and its primary metabolite p-(1-dimethylamino ethylimino) aniline (aminoamidine, deacylated amidantel) (dADT), a sensitive and selective liquid chromatography-mass spectrometric (LC–MS) method has been developed. It was found that tribendimidine is rapidly degraded into dADT in the intestine, which explains why no parent drug was detected in human plasma by LC–MS. Hence, the method was applied for determination of dADT in human

Mechanism of action and resistance

The model nematode Caenorhabditis elegans was used to explore the mechanism of action of tribendimidine. It was observed that when C. elegans were exposed to tribendimidine, they rapidly lost motility, followed by extensive body damage, developmental arrest, reductions in fecundity, which eventually progressed to death. Early studies suggested that tribendimidine – similar to levamisole and pyrantel pamoate – activate L-type acetylcholine receptors in C. elegans (Hu et al., 2009). Amidantel and

Discussion and research needs

The results summarised here were largely obtained from clinical trials with tribendimidine carried out in P.R. China over the past 8 years, including a multi-centre phase IV trial with more than 2000 individuals aged 4–70 years who were infected with soil-transmitted helminths. The data confirm that tribendimidine, administered at a single oral dose of 200 mg to children and 400 mg to adolescents/adults is safe and efficacious. Indeed, at the recommended treatment schedule (single oral dose of 200

Acknowledgement

This study is supported by international collaboration on drug and diagnostics innovation of tropical diseases in P.R. China (International S&T Cooperation 2010DFB73280).

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