Abstract
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.
Highlights
Infections with filarial parasites that cause lymphatic filariasis (LF) and onchocerciasis can lead to debilitating symptoms andM
The largest number of DEGs was found after 120 h exposure to both concentrations of FLBZ. 62.6%e78.6% of DEGs had a known C. elegans orthologue
Our results indicate that differentially expressed genes resulting from FLBZ exposure are involved predominantly in structural molecule activity, cuticle, embryogenesis and larval development (Table 4)
Summary
Infections with filarial parasites that cause lymphatic filariasis (LF) and onchocerciasis can lead to debilitating symptoms andM. Flubendazole (FLBZ), a benzimidazole (BZ) anthelmintic, is a candidate macrofilaricide for use in onchocerciasis and LF control programs. 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). 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)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
More From: International Journal for Parasitology: Drugs and Drug Resistance
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.