Dataset Information

Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models.

ABSTRACT: The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of this study was to assess whether 5 daily sub-cutaneous (s.c.) injections of standard flubendazole (FBZ) suspension (10mg/kg), a single s.c. injection (10mg/kg) or 5 daily repeated oral doses of FBZ amorphous solid dispersion (ASD) formulation (0.2, 1.5 or 15mg/kg) mediated macrofilaricidal efficacy against O. ochengi male worms implanted into SCID mice. The direct microfilaricidal activity against circulating B. malayi microfilariae of single dose FBZ ASD formulation (2 or 40 mg/kg) was also evaluated and compared against the standard microfilaricide, ivermectin (IVM). Systemic exposures of FBZ/FBZ metabolites achieved following dosing were measured by pharmacokinetic (PK) bioanalysis. At necropsy, five weeks following start of FBZ SC injections, there were significant reductions in burdens of motile O. ochengi worms following multiple injections (93%) or single injection (82%). Further, significant proportions of mice dosed following multiple injections (5/6; 83%) or single injection (6/10; 60%) were infection negative (drug-cured). In comparison, no significant reduction in recovery of motile adult O. ochengi adult worms was obtained in any multiple-oral dosage group. Single oral-dosed FBZ did not mediate any significant microfilaricidal activity against circulating B. malayi mf at 2 or 7 days compared with >80% efficacy of single dose IVM. In conclusion, multiple oral FBZ formulation doses, whilst achieving substantial bioavailability, do not emulate the efficacy delivered by the parenteral route in vivo against adult O. ochengi. PK analysis determined FBZ efficacy was related to sustained systemic drug levels rather than achievable Cmax. PK modelling predicted that oral FBZ would have to be given at low dose for up to 5 weeks in the mouse model to achieve a matching efficacious exposure profile.

SUBMITTER: Sjoberg HT

PROVIDER: S-EPMC6334903 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models.

Sjoberg Hanna T HT Pionnier Nicolas N Aljayyoussi Ghaith G Metuge Haelly M HM Njouendou Abdel J AJ Chunda Valerine C VC Fombad Fanny F FF Tayong Dizzle B DB Gandjui Narcisse V T NVT Akumtoh Desmond N DN Chounna Patrick W N PWN Ndzeshang Bertrand L BL Lachaud Sophie S Tekle Fetene F Quirynen Ludo L Engelen Marc M Baeten Benny B Steven Andrew A Ward Stephen A SA Taylor Mark J MJ Wanji Samuel S Turner Joseph D JD

PLoS neglected tropical diseases 20190116 1

The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of this study was to assess whether 5 daily sub-cutaneous (s.c.) injections of standard flubendazole (FBZ) suspension (10mg/kg), a single s.c. injection (10mg/kg) or 5 daily repeated oral doses of FBZ amorphous solid dispersion (ASD) formulation (0 ...[more]

PMID: 30650071

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Project description:BackgroundAmong the arthropod-borne nematodes infesting dogs, Onchocerca lupi (Spirurida: Onchocercidae) is of increasing zoonotic concern, with new human cases of infection diagnosed in Turkey, Tunisia, Iran and the USA. Knowledge of the biology of this nematode is meagre. This study aimed at assessing the distribution and periodicity of O. lupi microfilariae from different body regions in naturally infested dogs.Methodology/principal findingsSkin samples were collected from six dogs infested with O. lupi but without apparent clinical signs. Two skin samples were collected from 18 anatomical regions of dog 1 at necropsy. In addition, single skin biopsies were performed from the forehead, inter-scapular and lumbar regions of dogs 2-6, in the morning, afternoon, and at night. Two aliquots of the sediment of each sample were microscopically observed, microfilariae counted and morphologically and molecularly identified. Most of the 1,667 microfilariae retrieved from dog 1 were in the right ear (59.6%), nose (26.5%), left ear (6.7%), forehead (3.0%), and inter-scapular (2.9%) regions. In dogs 2-6, the overall mean number of microfilariae was larger on the head (n = 122.8), followed by the inter-scapular (n = 119.0) and lumbar (n = 12.8) regions. The overall mean number of microfilariae was larger in the afternoon (153.4), followed by night (75.4) and morning (25.8).ConclusionsOnchocerca lupi microfilariae were more common in the head (i.e., ears and nose) than in the remaining part of the dog's body, indicating they tend to aggregate in specific body regions, which are the best sites to collect skin samples for diagnostic purposes. The periodicity pattern of microfilariae of O. lupi and their concentration in specific body regions is most likely a result of the co-evolution with their as-yet-unknown vector. The detection of skin microfilariae in asymptomatic animals, suggests the potential role of these animals as carriers and reservoirs of O. lupi.

Project description:Filarial nematodes are arthropod-borne nematodes that cause a variety of economically important diseases such as onchocerciasis (river blindness), lymphatic filariasis, and heartworm disease. The most widespread filarial disease of humans is lymphatic filariasis, caused by worms in the genera Wuchereria and Brugia. Lymphatic filariasis is an economic and social burden in endemic countries and affects approximately 119 million people worldwide (Michael, 1997). In humans, the worms live in and block the lymph vessels, causing improper flow of lymph, and inflammation of the lymphatic system. The symptoms are fever, swollen limbs and genitals, generalized malaise, and can progress to a debilitating condition known as elephantiasis This research focuses on the transmission of these worms to the disseminating mosquito host, and it is based on the interesting observation that mf must be at least 7 days old to successfully infect the mosquito (de Hollanda, 1982). Newborn mf that have not â??maturedâ?? cannot successfully penetrate the midgut of the mosquito, and subsequently cannot develop to the L3 stage (Fuhrman, 1987). Previous work done by another group 20 years ago suggests that the molecular makeup of the worm surface changes during this maturation process (Furman, 1983 a and b). We used microarray analysis to characterize changes in gene expression that take place during the mf maturation process. Understanding the gene expression changes that occur as the mf mature will allow us to understand the nature of the philological transition that allows mf to move from the human to the mosquito host. With this information in hand, we can eventually identify parasite molecules that could be targeted to either stop parasite reproduction or prevent transmission of the mf to the mosquito. This would stop parasite transmission in endemic areas. Brugia pahangi mature mf (30 days and older) RNA was compared to immature mf (3 days and younger). Three biological replicates were performed each with two technical replicates

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Dataset Information

Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models.

Publications

Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models.

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