Moxidectin is a macrocyclic lactone belonging to milbemycin family closely related to ivermectin and is currently progressing towards Phase III clinical trial against human infection with the filaria Onchocerca volvulus (Leuckart, 1894). There is a single report on the microfilaricidal and embryostatic activity of moxidectin in case of the human lymphatic filarial parasite Brugia malayi (Brug, 1927) in Mastomys coucha (Smith) but without any adulticidal action. In the present study, the in vitro and in vivo antifilarial efficacy of moxidectin was evaluated on, B. malayi. In vitro moxidectin showed 100% reduction in adult female worm motility at 0.6 μM concentration within 7 days with 68% inhibition in the reduction of MTT (3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide dye) (which is used to detect viability of worms). A 50% inhibitory concentration (IC50) of moxidectin for adult female parasite was 0.242 μM, for male worm 0.186 μM and for microfilaria IC50 was 0.813 μM. In adult B. malayi-transplanted primary screening model (Meriones unguiculatus Milne-Edwards), moxidectin at a single optimal dose of 20 mg/kg by oral and subcutaneous route was found effective on both adult parasites and microfilariae. In secondary screening (M coucha, subcutaneously inoculated with infective larvae), moxidectin at the same dose by subcutaneous route brought about death of 49% of adult worms besides causing sterilisation in 54% of the recovered live female worms. The treated animals exhibited a continuous and sustained reduction in peripheral blood microfilaraemia throughout the observation period of 90 days. The mechanism of action of moxidectin is suggested to be similar to avermectins. The in silico studies were also designed to explore the interaction of moxidectin with glutamate-gated chloride channels of B. malayi. The docking results revealed a close interaction of moxidectin with various GluCl ligand sites of B. malayi.

• MeSH
• Brugia malayi drug effects   metabolism   MeSH
• Chloride Channels chemistry   metabolism   MeSH
• Filaricides therapeutic use   MeSH
• Filariasis drug therapy   parasitology   MeSH
• Gerbillinae MeSH
• Catalytic Domain MeSH
• Protein Conformation MeSH
• Macrolides therapeutic use   MeSH
• Murinae MeSH
• Helminth Proteins genetics   metabolism   MeSH
• Protein Binding MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Mastomys natalensis pretreated with diethylcarbamazine (DEC), levamisole or centperazine were exposed to the standard inoculum of infective larvae of Brugia malayi. Percentage 'take' of infection, duration of prepatent period, course of microfilaraemia and number of adult worms recovered were compared with those of untreated infected Mastomys (control). DEC and centperazine did not alter the 'take' (DEC/centperazine: 100%; control: 88.24%) and the average prepatent period (DEC: 105.44 days; centperazine: 105.18 days, control: 109.20 days). In levamisole pretreated animals on the other hand, the 'take' was much lower (68.18%) with extended prepatent period (125.87 days). However, unlike centperazine and control, the course of microfilaraemia was identical in DEC and levamisole pretreated animals. The average adult worm recovery was significantly high in centperazine pretreated animals being 14.09 as against 8.12, 7.46 and 8.42 in DEC, levamisole pretreated and control animals, respectively.

• MeSH
• Brugia growth & development   immunology   MeSH
• Diethylcarbamazine pharmacology   therapeutic use   MeSH
• Elephantiasis, Filarial immunology   parasitology   prevention & control   MeSH
• Filaricides pharmacology   therapeutic use   MeSH
• Levamisole pharmacology   therapeutic use   MeSH
• Muridae MeSH
• Disease Susceptibility MeSH
• Piperazines pharmacology   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH