Evaluation of the in vitro susceptibility of various filarial nematodes to emodepside

Abstract

Filariae are vector-borne nematodes responsible for an enormous burden of disease. Human lymphatic filariasis, caused by Wuchereria bancrofti, Brugia malayi, and Brugia timori, and onchocerciasis (caused by Onchocerca volvulus) are neglected parasitic diseases of major public health significance in tropical regions. To date, therapeutic efforts to eliminate human filariasis have been hampered by the lack of a drug with sufficient macrofilaricidal and/or long-term sterilizing effects that is suitable for use in mass drug administration (MDA) programs, particularly in areas co-endemic with Loa loa, the causative agent of loiasis. Emodepside, a semi-synthetic cyclooctadepsipeptide, has been shown to have broad-spectrum efficacy against gastrointestinal nematodes in a variety of mammalian hosts, and has been approved as an active ingredient in dewormers for cats and dogs. This paper evaluates, compares (where appropriate) and summarizes the in vitro effects of emodepside against a range of filarial nematodes at various developmental stages. Emodepside inhibited the motility of all tested stages of filariae frequently used as surrogate species for preclinical investigations (Acanthocheilonema viteae, Brugia pahangi, Litomosoides sigmodontis, Onchocerca gutturosa, and Onchocerca lienalis), human-pathogenic filariae (B. malayi) and filariae of veterinary importance (Dirofilaria immitis) in a concentration-dependent manner. While motility of all filariae was inhibited, both stage- and species-specific differences were observed. However, whether these differences were detected because of stage- and/or species-specific factors or as a consequence of variations in protocol parameters among the participating laboratories (such as purification of the parasites, read-out units, composition of media, incubation conditions, duration of incubation etc.) remains unclear. This study, however, clearly shows that emodepside demonstrates broad-spectrum in vitro activity against filarial nematode species across different genera and can therefore be validated as a promising candidate for the treatment of human filariases, including onchocerciasis and lymphatic filariasis.

Keywords: Anthelmintics; Emodepside; Filariae; Lymphatic filariasis; Onchocerciasis; River blindness.

Graphical abstract

Fig. 1

Dose dependent inhibition of filarial motility by emodepside. Emodepside was able to inhibit the motility of all tested filarial species and filarial life-cycle stages in vitro. (A) Calculated dose-response curve for the motility inhibition of A. viteae microfilariae after 2, 24, 48, 72 and 96 h of treatment at emodepside concentrations of 10 μM, 1 μM, 0.1 μM, 0.01 μM. Dose response curves of motility inhibition for (B) B. malayi and B. pahangi microfilariae (MF) after 72 h and (C) adult B. pahangi males and females after 24 h of treatment at emodepside concentrations of 12.5 μM, 3.13 μM, 0.78 μM, 0.195 μM, 0.048 μM, 0.012 μM, 3.0 nM, 0.75 nM and 0.188 nM. (D) Dose-response curve for all tested developmental stages of D. immitis (MF: microfilariae; L3: third stage larvae; L4: fourth stage larvae; adult males; adult females) using different emodepside concentrations (8.93 μM, 1.79 μM, 360 nM, 71.5 nM, 14.3 nM, 2.9 nM, 0.57 nM, and 0.11 nM) after 72 h of drug exposure. (E) Dose-response curve for all tested developmental stages of L. sigmodontis (MF: microfilariae; L3: third stage larvae; adult males; adult females) using different emodepside concentrations (10 μM, 1 μM, 0.1 μM, 0.01 μM) after 72 (L3) or 96 h (MF, adult worm) of drug exposure. (E) Dose-response curve for different emodepside concentrations for O. gutturosa (12.5 μM, 3.13 μM, 0.78 μM, 0.195 μM, 0.048 μM, 0.012 μM, 3.0 nM, 0.75 nM, and 0.188 nM) and for O. lienalis (12.5 μM, 3.13 μM, 0.78 μM, 0.195 μM, 0.048 μM, 0.012 μM and 3.0 nM) for the duration of both assays after 120 h.