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Minocycline as a re-purposed anti-Wolbachia macrofilaricide: superiority compared with doxycycline regimens in a murine infection model of human lymphatic filariasis

Sharma, Raman, Aljayyoussi, Ghaith, Tyrer, Hayley, Gamble, Jo, Hayward, Laura, Guimaraes, Ana, Davies, Jill, Waterhouse, David, Cook, Darren, Myhill, Laura, Clare, Rachel, Cassidy, Andrew, Steven, Andrew, Johnston, Kelly, Ford, Louise, Turner, Joseph, Ward, Steve and Taylor, Mark (2016) 'Minocycline as a re-purposed anti-Wolbachia macrofilaricide: superiority compared with doxycycline regimens in a murine infection model of human lymphatic filariasis'. Scientific Reports, Vol 6, p. 23458.

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Abstract

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases, which cause severe morbidities such as elephantiasis, skin disease and blindness, presenting a major public health burden in endemic communities. The anti-Wolbachia consortium (A·WOL: http://www.a-wol.com/) has identified a number of registered antibiotics that target the endosymbiotic bacterium, Wolbachia, delivering macrofilaricidal activity. Here we use pharmacokinetics/pharmacodynamics (PK/PD) analysis to rationally develop an anti-Wolbachia chemotherapy by linking drug exposure to pharmacological effect. We compare the pharmacokinetics and anti-Wolbachia efficacy in a murine Brugia malayi model of minocycline versus doxycycline. Doxycycline exhibits superior PK in comparison to minocycline resulting in a 3-fold greater exposure in SCID mice. Monte-Carlo simulations confirmed that a bi-daily 25–40 mg/Kg regimen is bioequivalent to a clinically effective 100–200 mg/day dose for these tetracyclines. Pharmacodynamic studies showed that minocycline depletes Wolbachia more effectively than doxycycline (99.51% vs. 90.35%) after 28 day 25 mg/Kg bid regimens with a more potent block in microfilarial production. PK/PD analysis predicts that minocycline would be expected to be 1.7 fold more effective than doxycycline in man despite lower exposure in our infection models. Our findings warrant onward clinical investigations to examine the clinical efficacy of minocycline treatment regimens against lymphatic filariasis and onchocerciasis.

Item Type: Article
Subjects: QV Pharmacology > QV 38 Drug action.
QW Microbiology and Immunology > Bacteria > QW 150 Proteobacteria. Rickettsiaceae, Wolbachia
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 880 Filariasis and related conditions (General)
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 885 Onchocerciasis
Faculty: Department: Biological Sciences > Parasitology Department
Digital Object Identifer (DOI): https://doi.org/10.1038/srep23458
Depositing User: Jessica Jones
Date Deposited: 30 Mar 2016 14:40
Last Modified: 06 Feb 2018 13:12
URI: http://archive.lstmed.ac.uk/id/eprint/5827

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