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Short-course quinazoline drug treatments are effective in the Litomosoides sigmodontis and Brugia pahangi jird models.

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Hübner, Marc P, Gunderson, Emma, Vogel, Ian, Bulman, Christina A, Lim, K C, Koschel, Marianne, Ehrens, Alexandra, Frohberger, Stefan J, Fendler, Martina, Tricoche, Nancy, Voronin, Denis, Steven, Andrew, Chi, Victor, Bakowski, Malina A, Woods, Ashley K, Petrassi, H Michael, McNamara, Case W, Beerntsen, Brenda, Chappell, Laura, Sullivan, William, Taylor, Mark J. ORCID: https://orcid.org/0000-0003-3396-9275, Turner, Joseph D. ORCID: https://orcid.org/0000-0002-2185-5476, Hoerauf, Achim, Lustigman, Sara and Sakanari, Judy A (2019) 'Short-course quinazoline drug treatments are effective in the Litomosoides sigmodontis and Brugia pahangi jird models.'. International Journal for Parasitology: Drugs and Drug Resistance, Vol 12, pp. 18-27.

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Abstract

The quinazolines CBR417 and CBR490 were previously shown to be potent anti-wolbachials that deplete Wolbachia endosymbionts of filarial nematodes and present promising pre-clinical candidates for human filarial diseases such as onchocerciasis. In the present study we tested both candidates in two models of chronic filarial infection, namely the Litomosoides sigmodontis and Brugia pahangi jird model and assessed their long-term effect on Wolbachia depletion, microfilariae counts and filarial embryogenesis 16-18 weeks after treatment initiation (wpt). Once per day (QD) oral treatment with CBR417 (50 mg/kg) for 4 days or twice per day (BID) with CBR490 (25 mg/kg) for 7 days during patent L. sigmodontis infection reduced the Wolbachia load by >99% and completely cleared peripheral microfilaremia from 10-14 wpt. Similarly, 7 days of QD treatments (40 mg/kg) with CBR417 or CBR490 cleared >99% of Wolbachia from B. pahangi and reduced peritoneal microfilariae counts by 93% in the case of CBR417 treatment. Transmission electron microscopy analysis indicated intensive damage to the B. pahangi ovaries following CBR417 treatment and in accordance filarial embryogenesis was inhibited in both models after CBR417 or CBR490 treatment. Suboptimal treatment regimens of CBR417 or CBR490 did not lead to a maintained reduction of the microfilariae and Wolbachia load. In conclusion, CBR417 or CBR490 are pre-clinical candidates for filarial diseases, which achieve long-term clearance of Wolbachia endosymbionts of filarial nematodes, inhibit filarial embryogenesis and clear microfilaremia with treatments as short as 7 days.

Item Type: Article
Subjects: QX Parasitology > Helminths. Annelida > QX 203 Nematoda
QX Parasitology > Helminths. Annelida > QX 301 Filarioidea
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1016/j.ijpddr.2019.12.001
Depositing User: Cathy Waldron
Date Deposited: 22 Jan 2020 15:35
Last Modified: 22 Jan 2020 15:35
URI: https://archive.lstmed.ac.uk/id/eprint/13558

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