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In vitro, in vivo and pharmacokinetic investigations for the development of novel treatment options for food-borne trematode infections

English title In vitro, in vivo and pharmacokinetic investigations for the development of novel treatment options for food-borne trematode infections
Applicant Keiser Jennifer
Number 114358
Funding scheme Marie Heim-Voegtlin grants
Research institution Swiss Tropical and Public Health Institute
Institution of higher education University of Basel - BS
Main discipline Pharmacology, Pharmacy
Start/End 01.10.2006 - 30.09.2007
Approved amount 90'480.00
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All Disciplines (2)

Discipline
Pharmacology, Pharmacy
Tropical Medicine

Keywords (8)

Food-borne trematodes; liver flukes; lung flukes; artemisinins; synthetic peroxides (OZ); in vitro/in vivo assays; drug discovery and development; tribendimidine

Lay Summary (English)

Lead
Lay summary
My research focuses on trematode infections that primarily affect poor people in the developing world. Emphasis is placed on food-borne trematodiasis. These diseases affect hundreds of millions of people and they are of considerable public health impact. Effective control approaches and strategies, mainly novel trematocidal drugs, are urgently required to improve health and social wellbeing, mitigate inequity, and alleviate poverty.
Within the frame of my ongoing Marie-Heim Vögtlin fellowship, I have evaluated the in vivo and in vitro efficacy of the artemisinins against selected food-borne trematodes. We found that artesunate and artemether cured patent infections with the intestinal trematode Echinostoma caproni in the mouse and effectively killed juvenile and adult liver flukes, namely Fasciola hepatica and Clonorchis sinensis harboured in the rat. In addition, in preliminary experiments we have identified several synthetic peroxides (1,2,4-trioxolanes; OZ compounds) with activities against food-borne trematodes. For example, a single oral dose of 800 mg/kg OZ78 administered 14 days after mice were infected with E. caproni, effectively killed all worms. In addition, 100% worm burden reductions were achieved with a single, oral dose of 100-300 mg/kg in the F. hepatica and C.sinensis rat models.
Tribendimidine is a promising broad spectrum anthelminthic drug discovered in China. We assessed the effect of tribendimidine on selected food-borne trematodes. The initial experimental focus was on adult E. caproni harboured in mice. Worm burden reductions of 100% were achieved at doses of 125 mg/kg and above. SEM observations were done on adult E. caproni recovered from mice given a single dose of 150 mg/kg tribendimidine intragastrically 2, 4 and 8 hours post-treatment. Severe damage of the tegument, including extensive peeling, formation of blebs, and structural loss of the definition of collar and tegumentary spines were already apparent within 2 hours after drug administration. Furthermore, a single oral dose of 300 mg/kg killed adult C. sinensis in rats and a dose of 400 mg/kg cured Opisthorchis viverrini infections in the hamster.
Our mid term goal is to strengthen the current evidence-base established in laboratory animals that the artemisinins, tribendimidine and OZ can become novel trematocidal drugs. Hence, a major emphasis will be on mechanism of action studies, physicochemical, metabolism, pharmacokinetic(PK) and toxicity studies. Promising drug candidates will be followed up in efficacy and PK studies in larger mammals. In the long term, we hope to contribute in clinical development to (i) elucidate the effect of artemisinin-based combination therapy (ACT) on opisthorchiasis, and (ii) investigate the effect of a single oral dose of tribendimidine and artesunate in C. sinensis-infected patients.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
106221 In vitro, in vivo and pharmacokinetic investigations for the development of novel treatment options for food-borne trematode infections 01.10.2004 Marie Heim-Voegtlin grants

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