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DST- Young Scientists

Title: Metabolism and pharmacokinetics of triclabendazole (TCBZ) and anthelmintic action of TCBZ in tropical liver fluke, Fasciola gigantica: in vitro and in vivo validation.

Principal Investigator: Dr. P. A. Ahammed Shareef
Department of Zoology,
PSMO College, Tirurangadi, Malappuram,
Kerala, India. Pin: 676 306.

Scheme: DST- Young Scientists (Start Up Research Grant) (YSS/2015/000902).

Funding Agency: SERB-DST, Govt. of India. (Rs. 36.8 Lakhs)
Period: 15th December 2015 to 14th December 2018 (Three Years)

Summary

The livestock industry substantially empowers the Indian economy and gives employment to millions of people in the country especially for women. Despite having highest livestock population in the world, Indian livestock productivity is much lower than the global average, mainly because of poor health and diseases, including helminth parasitic infections. Fasciolosis, caused by the liver fluke Fasciola hepatica (in temperate region) and F. gigantica (in tropics and sub-tropics), is a parasitic disease causing huge economic loss to livestock sector. Accordning to Planning Commision’s report (2011-12), fasciolosis is the largest single veterinary infection reported from the country, with 317376 cases of infection, 96 deaths and 165 outbreakes. It is zoonotic and about 2.4 million people are infected worldwide and many cases have been reported from India as well.
In the absence of a vaccine, triclabendazole (TCBZ) is the drug of choice to treat this disease both in human as well as animals due to its efficacy to both juvenile and adult stages. However, development of resistance to TCBZ is a major problem with the control of F. hepatica, but not known/reported in F. gigantica. The mechanisms and mode of action of TCBZ in F. gigantica are little studied and most of our understanding on the action of TCBZ in F. gigantica is based on the generalisation of work done in F. hepatica. The drug metabolism of TCBZ by F. gigantica is unknown, while it is well understood in F. hepatica.
In the proposed study, the life cycle of F. gigantica will be established in the lab to ensure a regular supply of parasite material in order to overcome the problems associated with field infection. The action of TCBZ, TCBZ-sulphoxide (TCBZSO) and TCBZ-sulphone (TCBZSO2) will be studied in vitro in both juvenile and adult of F. gigantica by incubating them in these compounds at 15 µg/ml (each of them have different mode/level of action and regional specificity). The anthelmintic action will be studied by histology, SEM, TEM, immunofluorescence, zymography, proteomic and molecular methods/approaches. The results of in vitro studies will be validated in vivo in a goat model both in juvenile and adult stages after a therapeutic dose of 10 mg/kg and the drug action will be studied as above.
The metabolism of TCBZ in the body of infected/treated animal is directly linked with the exposure of parasite to drug metabolites, thereby effective anthelmintic action is accomplished. In the present proposal, the metabolism of TCBZ will be studied in the body of treated animals at 4 and 12 weeks post-infection, using HPLC. The metabolism of TCBZ by F. gigantica will also be studied after in vitro treatment and in vivo following anthelmintic treatment of infected animal with TCBZ by HPLC.
The outcome of the study is expected to generate substantial contribution towards delineating the TCBZ action in F. gigantica.