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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
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 n...
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Published in: | Scientific reports 2016-03, Vol.6 (1), p.23458, Article 23458 |
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Main Authors: | , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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. |
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ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/srep23458 |