Previous work has suggested that triclabendazole, a member of the benzimidazole group of compounds, possessed efficacy against Schistosoma mansoni. In view of recent indications in praziquantel treatment failures and loss of sensitivity, it is imperative that new anti-schistosomals are developed as contingent treatment options, while resistance alleles, if any, remain at low frequencies. While recent studies have indicated that triclabendazole monotherapy exert weak anti-schistosomal effects, the combinatorial application of triclabendazole with praziquantel has not been explored. To assess this hypothesis, triclabendazole and its metabolites were initially assessed against the many life-stages of Schistosoma mansoni in vitro. Combinatorial drug and isobologram analyses against adult Schistosoma mansoni was also performed, and subsequently applied against other parasitic models (Giardia duodenalis and Haemonchus contortus) to assess the specificity of such effects. Subsequently, the drug combinations were assessed against Schistosoma mansoni in vivo. To further assess the suitability of combinatorial drug applications, an economic model was developed to project the cost-efficacy of praziquantel-triclabendazole drug combinations in a global focus. It was concluded that triclabendazole and its metabolites possessed good efficacy against immature schistosomula, albeit weak efficacy against adult Schistosoma mansoni. Upon combination with praziquantel, however, a strong synergistic effect against adult worms were observed in vitro. Praziquantel and triclabendazole were also shown to possess unique and independent ovicidal modes of action that can be of clinical significance. More importantly, in vivo drug trials concluded that the combinations exerted additive effects against Schistosoma mansoni harbored in mice. Economic modeling and cost-effectiveness analyses further demonstrated the feasibility of this drug combination, and may represent a new line of treatment against mansonial schistosomiasis
| Identifer | oai:union.ndltd.org:ADTP/257130 |
| Date | January 2007 |
| Creators | sbong@murdoch.edu.au, Sze How Bong |
| Publisher | Murdoch University |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://www.murdoch.edu.au/goto/CopyrightNotice, Copyright Sze How Bong |
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