Macrofilaricidal Activity and Amelioration of Lymphatic Pathology in Bancroftian Filariasis after 3 Weeks of Doxycycline Followed by Single-Dose Diethylcarbamazine

Abstract

Abstract. In a placebo controlled trial, the effects of 21-and 10-day doxycycline treatments (200 mg/day) followed by single dose diethylcarbamazine (administered 4 months post treatment) on depletion of Wolbachia endobacteria from Wuchereria bancrofti , filaricidal activity, and amerlioration of scrotal lymph vessel dilation were studied in 57 men from Orissa, India. The 21-day doxycycline course reduced Wolbachia in W. bancrofti by 94% before diethylcarbamazine administration. After 12 months, all patients with this treatment were amicrofilaremic and different from the 10-day doxycycline (42.9%) and placebo (37.5%) groups, and significantly fewer were positive for scrotal worm nests (6.7%) compared with 10-day doxycycline (60%) and placebo (66.7%). Average scrotal lymph vessel diameters were reduced from 0.7 cm pre-treatment to 0.02 cm in patients after 21 days of treatment, while no significant changes were seen in the other groups. This latter feature confirms the beneficial effects of doxycycline on lymphatic dilation and thus adds to the existing evidence that doxycycline, in addition to being macrofilaricidal, may be used to prevent or reverse lymphatic pathology.

Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis

“…Indeed, this promotes anti- Wolbachia therapies as a safe drug development strategy for to administer to L. loa co-endemic target populations 67 who are at risk of severe neurological adverse reactions to rapid acting filaricides and thus provides a potential solution to problem areas of Central Africa toward an end game of onchocerciasis elimination 68 . Clinical trials with doxycycline have shown that depletion of Wolbachia from filarial nematodes can deliver significant macrofilaricidal activity when administered for 4 or more weeks 38,40–42,51 . However, the long period of administration and contraindications in children and pregnant women present logistical challenges to widespread scale-up in resource poor settings of Sub-Saharan Africa.…”

Wolbachia and Its Implications for the Immunopathology of Filariasis

“…Interestingly, a major surface protein of Wolbachia from D. immitis has been shown to provoke chemiokinesis and IL-8 production in canine neutrophils in vitro [29]; 3) filarial worm extracts stimulate cells in vitro to produce proinflammatory cytokines in a TLR-dependent manner and this effect is abolished with antibiotic-mediated removal of Wolbachia [26]. Furthermore, this effect is not present with extracts of filarial worms that do not harbour Wolbachia; 4) chronic pathology in lymphatic filariasis (elephantiasis, hydrocele) is correlated with a strong specific humoral response to the WSP [30]; 5) treatment with doxycycline, which decreases Wolbachia load, reduces pathology in patients affected by lymphatic filariasis [31].…”

Comparison of Doxycycline, Minocycline, Doxycycline plus Albendazole and Albendazole Alone in Their Efficacy against Onchocerciasis in a Randomized, Open-Label, Pilot Trial

“…Depletion of Wolbachia leads to long-term sterilization and to a macrofilaricidal effect. This has been shown first in animal models [22–24] and was successfully translated into clinical trials in human onchocerciasis [15] and lymphatic filariasis [21, 25]. A recent meta-analysis on the available data from clinical trials in onchocerciasis has shown that the 3 so far used regimens, doxycycline (DOX) 200 mg/day for 4 weeks, DOX 200 mg/day for 6 weeks [15], and DOX 100 mg/day for 5 weeks [26] are broadly equivalent, in particular with regards to the sterilizing effects of adult female worms [27], and therefore DOX treatment with 200 mg/day for 4 weeks can be considered as a “standard” anti-wolbachial therapy for onchocerciasis.…”