The anthelmintic effects of flubendazole on Brugia pahangi

Da, Denham; Samad, Rasheda; Sy, Cho; Rr, Suswillo; Sc, Skippins

doi:10.1016/0035-9203(79)90018-x

Cited by 51 publications

(39 citation statements)

References 4 publications

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“…Flubendazole (FLBZ), a benzimidazole anthelmintic approved for the treatment of infections due to gastrointestinal nematodes of livestock 11 and humans, [12][13][14] is an appealing candidate to address these concerns. 15 As a general feature, FLBZ elicits much greater effects on adults and developmental stages of filariae than mf in animal models after parenteral administration [16][17][18] and in a single O. volvulus human trial. 19 Human trials were restricted because of problems related to the route of administration; macrofilaricidal effects are only observed with parenteral administration as available formulations of the drug have very limited oral bioavailability.…”

Section: Introductionmentioning

confidence: 99%

“…Another important consideration is that it can take weeks to months for FLBZ to produce macrofilaricidal effects. [16][17][18][19] In the meantime, circulating mf not killed by FLBZ are available to be ingested by the mosquito host, furthering the reinfection cycle. IVM treatment of infected jirds suppresses the development of Brugia malayi and Brugia pahangi mf within a mosquito host that has fed on treated animals, 23 suggesting that drugs which are not directly microfilaricidal may have effects on mf that are only detectable in a model that requires development.…”

Section: Introductionmentioning

confidence: 99%

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Potential Role for Flubendazole in Limiting Filariasis Transmission: Observations of Microfilarial Sensitivity

O’Neill

Njouendou

Dzimianski

et al. 2018

The American Journal of Tropical Medicine and Hygiene

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Flubendazole (FLBZ) is a potent and efficacious macrofilaricide after parenteral administration. Studies in animal models and one trial in patients infected with revealed that FLBZ elicits minimal effects on microfilariae (mf). Severe complications after ivermectin (IVM) treatment of patients with high microfilaraemia are of great concern. We examined the potential of FLBZ to rapidly kill mf, the phenomenon proposed to underlie the complications. Mf of were exposed to FLBZ, its reduced metabolite, albendazole, or IVM in vitro. Viability of mf was unaffected by FLBZ (10 μM, 72 hours); similar results were obtained with mf of We also measured the effects of FLBZ on transmission of mf. were fed FLBZ-exposed mf and dissected 24 hours or 14 days postfeeding to count mf that crossed the midgut and developed to infective L. FLBZ impaired the ability of mf to cross the midgut, regardless of duration of exposure (≥ 2 hours). FLBZ also prevented the development of mf to Ls, irrespective of duration of exposure or concentration. FLBZ is not microfilaricidal under these conditions; however, it blocks transmission. These results support the possibility that FLBZ may be a useful macrofilaricide in loiasis regions and may limit transmission from treated individuals.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Potential Role for Flubendazole in Limiting Filariasis Transmission: Observations of Microfilarial Sensitivity

O’Neill

Njouendou

Dzimianski

et al. 2018

The American Journal of Tropical Medicine and Hygiene

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“…Initially introduced for treatment of livestock for the control of gastrointestinal (GI) parasitic nematode infections (Bradley et al., 1983), FLBZ was subsequently approved for the same indication in humans (Horton, 1990), for which it is highly efficacious (Yangco et al., 1981, Kan, 1983). FLBZ has exhibited very high macrofilaricidal efficacy when administered parenterally in experimental filariasis models (Denham et al., 1979, Mak, 1981, Mackenzie and Geary, 2011) and in a human trial in onchocerciasis (Dominguez-Vazquez et al., 1983). Although available formulations of the drug afford very limited oral bioavailability, recent efforts have been made to re-formulate FLBZ to enable oral dosing (Mackenzie and Geary, 2011, Ceballos et al., 2014, Longo et al., 2014).…”

Section: Introductionmentioning

confidence: 99%

Profiling the macrofilaricidal effects of flubendazole on adult female Brugia malayi using RNAseq

O’Neill

Ballesteros

Tritten

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

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The use of microfilaricidal drugs for the control of onchocerciasis and lymphatic filariasis (LF) necessitates prolonged yearly dosing. Prospects for elimination or eradication of these diseases would be enhanced by the availability of a macrofilaricidal drug. Flubendazole (FLBZ), a benzimidazole anthelmintic, is an appealing candidate. FLBZ has demonstrated potent macrofilaricidal effects in a number of experimental rodent models and in one human trial. Unfortunately, FLBZ was deemed unsatisfactory for use in mass drug administration campaigns due to its limited oral bioavailability. A new formulation that enables sufficient bioavailability following oral administration could render FLBZ an effective treatment for onchocerciasis and LF. Identification of drug-derived effects is important in ascertaining a dosage regimen which is predicted to be lethal to the parasite in situ. In previous histological studies, exposure to FLBZ induced damage to tissues required for reproduction and survival at pharmacologically relevant concentrations. However, more precise and quantitative indices of drug effects are needed. This study assessed drug effects using a transcriptomic approach to confirm effects observed histologically and to identify genes which were differentially expressed in treated adult female Brugia malayi. Comparative analysis across different concentrations (1 μM and 5 μM) and durations (48 and 120 h) provided an overview of the processes which are affected by FLBZ exposure. Genes with dysregulated expression were consistent with the reproductive effects observed via histology in our previous studies. This study revealed transcriptional changes in genes involved in embryo development. Additionally, significant downregulation was observed in genes encoding cuticle components, which may reflect changes in developing embryos, the adult worm cuticle or both. These data support the hypothesis that FLBZ acts predominantly on rapidly dividing cells, and provides a basis for selecting molecular markers of drug-induced damage which may be of use in predicting efficacious FLBZ regimens.

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“…Flubendazole is an anthelmintic compound (Denham et al 1979) long known to be highly effective against nematodes such as the Toxocara species of carnivores. Toxocara canis worms were obtained from untreated dogs.…”

Section: Introductionmentioning

confidence: 99%

In vitro studies on the effects of flubendazole against Toxocara canis and Ascaris suum

Hanser

Mehlhorn

Hoeben

et al. 2002

Parasitology Research

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Adult Toxocara canis and Ascaris suum were incubated in vitro in media containing 0.1, 1, 10 or 100 micro g/ml flubendazole in order to study drug-derived effects. This incubation was done for 8 h and repeated (in some groups) after 24 h for another 8 h. The onset and intensity of flubendazole-derived effects were dosage-dependent and time-dependent, i.e. the same grade of damage was reached when incubating for a longer period at a low dosage or for a shorter period in medium containing a high amount (10 or 100 micro g/ml) of flubendazole. A repeated incubation in drug-containing medium was superior to a single exposure. Flubendazole is apparently able to penetrate into the worm's interior via the cuticle. This became evident in worms with sealed orifices, which showed identical damage to worms which were not sealed. The type of tissue damage due to flubendazole was identical in both worm species when exposed to any of the drug dosages used. The principal mode of action of flubendazole was based on the complete reduction of microtubuli-polymerisation inside the parasite's cells. This apparently led to the complete destruction of the hypodermis, muscle layer and intestine. Flubendazole also stopped the formation of gametes. Summarising, even low concentrations of flubendazole (0.1 micro g/ml) led to significant and irreversible damage in all worms studied.

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The anthelmintic effects of flubendazole on Brugia pahangi

Cited by 51 publications

References 4 publications

Potential Role for Flubendazole in Limiting Filariasis Transmission: Observations of Microfilarial Sensitivity

Potential Role for Flubendazole in Limiting Filariasis Transmission: Observations of Microfilarial Sensitivity

Profiling the macrofilaricidal effects of flubendazole on adult female Brugia malayi using RNAseq

In vitro studies on the effects of flubendazole against Toxocara canis and Ascaris suum

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