Wolbachia endobacteria depletion by doxycycline as antifilarial therapy has macrofilaricidal activity in onchocerciasis: a randomized placebo-controlled study

Hoerauf, Achim; Specht, Sabine; Büttner, Marcelle; Pfarr, Kenneth; Mand, Sabine; Fimmers, Rolf; Marfo-Debrekyei, Yeboah; Konadu, Peter; Debrah, Alexander Yaw; Bandi, Claudio; Brattig, Norbert W.; Albers, Anna; Larbi, John Asiedu; Batsa, Linda; Taylor, Mark J.; Adjei, Ohene; Büttner, Dietrich W.

doi:10.1007/s00430-007-0062-1

Cited by 223 publications

(216 citation statements)

References 33 publications

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“…This analysis was done to make the results comparable to earlier studies from this (Albiez et al 1988b;Büttner et al 1988;Hoerauf et al 2003Hoerauf et al , 2008 and other groups (e.g., Awadzi et al 1995aAwadzi et al , b, 1999. It also facilitates tracking down real individual worms in their different read-out characteristics (Wolbachia content, embryogenesis, mf in the human nodule tissue, and vitality), something that is not possible with logistic regression, because numbers are not counted but calculated.…”

Section: Discussionmentioning

confidence: 65%

Efficacy of 5-week doxycycline treatment on adult Onchocerca volvulus

et al. 2008

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The effects of 5-week doxycycline treatment on the depletion of Wolbachia endobacteria from Onchocerca volvulus, on the interruption of embryogenesis and on microfilariae production, and with regard to macrofilaricidal activity were studied. In 2003, in an endemic area in Ghana, 22 onchocerciasis patients received 100 mg/day doxycycline for 5 weeks. Two years after the start of the study, 20 treated and ten untreated patients were nodulectomized and skin microfilariae were counted. The onchocercomas were examined by immunohistology for the presence of Wolbachia, embryogenesis, and vitality of adult filariae. The latter two parameters were further assessed by alternating logistic regression analysis, taking into account the dependency of worms and nodules in patients. Doxycycline resulted in depletion of Wolbachia and in complete interruption of embryogenesis in all worms that were assumed to have been present during treatment. In the treated patients, only 51% of the female worms were alive, compared to 84% in the untreated patients, indicating a moderate but distinct macrofilaricidal activity of doxycycline at this dose. It is concluded that, in areas with ongoing transmission, doxycycline cannot replace regular ivermectin mass treatment because new infections would require repeated rounds of doxycycline. However, doxycycline can be used for the treatment of individuals outside transmission areas, in foci where ivermectin resistance may occur, and in countries where onchocerciasis and loiasis are co-endemic. Abbreviations

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Section: Discussionmentioning

confidence: 65%

Efficacy of 5-week doxycycline treatment on adult Onchocerca volvulus

et al. 2008

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“…Affecting the female worms is a particularly advantageous approach as the female worm can live for up to 15 years, and continues to propagate its eggs and offspring, thus keeping the vicious lifecycle intact. Doxycycline, which targets the endosymbiontic Wolbachia bacteria, is currently the only known macrofilaricidal agent used in the treatment of onchocerciasis (44). It remains to be seen if OvCHT1 is indeed involved in chitin metabolism of the eggshell or if another O. volvulus chitinase exists; however, closantel may be used as a molecular tool to probe this important pathway.…”

Section: Discussionmentioning

confidence: 99%

Repositioning of an existing drug for the neglected tropical disease Onchocerciasis

Gloeckner

Garner

Mersha

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Onchocerciasis, or river blindness, is a neglected tropical disease caused by the filarial nematode Onchocerca volvulus that affects more than 37 million people, mainly in third world countries. Currently, the only approved drug available for mass treatment is ivermectin, however, drug resistance is beginning to emerge, thus, new therapeutic targets and agents are desperately needed to treat and cure this devastating disease. Chitin metabolism plays a central role in invertebrate biology due to the critical structural function of chitin for the organism. Taken together with its absence in mammals, targeting chitin is an appealing therapeutic avenue. Importantly, the chitinase OvCHT1 from O. volvulus was recently discovered, however, its exact role in the worm’s metabolism remains unknown. A screening effort against OvCHT1 was conducted using the Johns Hopkins Clinical Compound Library that contains over 1,500 existing drugs. Closantel, a veterinary anthelmintic with known proton ionophore activities, was identified as a potent and specific inhibitor of filarial chitinases, an activity not previously reported for this compound. Notably, closantel was found also to completely inhibit molting of O. volvulus infective L3 stage larvae. Closantel appears to target two important biochemical processes essential to filarial parasites. To begin to unravel closantel’s effects, a retro-fragment-based study was used to define structural elements critical for closantel’s chitinase inhibitor function. As resources towards the development of new agents that target neglected tropical diseases are scant, the finding of an existing drug with impact against O. volvulus provides promise in the hunt for new therapies against river blindness.

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“…Meanwhile the endosymbiotic nature of O. volvulus with Wolbachia bacteria has led to trials of doxycycline being used to deplete the bacteria and facilitate treatment of the worms. [212][213][214] Corneal infiltrates in non-keratitic diseases show some promise and offer another avenue of exploration: a case report of cryopyrin associated periodic fever syndrome, in which a mutation in the NLRP3 gene causes overexpression of IL-1β, demonstrated successful treatment outcomes with IL-1β monoclonal antibody kanakinumab, 215 and anakira, an IL-1 antagonist, has been used successfully in corneal infiltrates. 216 Currently, there is strong interest in the use of collagen cross-linking (CXL) using ultraviolet-A (UV-A) light and riboflavin is a treatment of infectious keratitis.…”

Section: Potential Targeted Molecular Therapiesmentioning

confidence: 99%