Abstract
Background: Schistosomiasis control has been centered to date on praziquantel, with shortcomings involving ineffectiveness against immature worms, reinfection and emergence of drug resistance. Strategies based on drug repurposing and/or praziquantel combination therapy proved effective, though with some limitations. Combining such strategies with nanotechnology would further augment therapeutic benefits. Nanocarrier-mediated delivery of multiple drugs in schistosomiasis control has not been documented to date. Our objective was to combine drug repurposing, combinational therapy and nanotechnology for the development of a single oral fixed dose nanocombination to improve praziquantel therapeutic profile. This was based on praziquantel and an antischistosomal repurposing candidate miltefosine, co-loaded into lipid nanocapsules in reduced doses. Methods: Two fixed dose lipid nanocapsule formulations were prepared at two concentration levels of praziquantel and miltefosine. Their antischistosomal activity in comparison with control singly loaded lipoid nanocapsules was assessed in Schistosoma mansoni- infected mice. Single oral dos of 250mg praziquantel-20mg miltefosine/kg and 125mg praziquantel-10mg miltefosine/kg were administered on the initial day of infection, 21st and 42nd days post infection. Scanning electron microscopy, parasitological and histopathological studies were used for assessment. In vivo data were subjected to analysis of variance and post hoc test (Tukey) was used for pairwise comparisons. Results: Lipid nanocapsules showed a mean diameter of 58 nm and high entrapment efficiency of both drugs (>95%). Compared to singly loaded lipid nanocapsules, the larger dose praziquantel-miltefosine nanocombination exerted high antischistosomal efficacy in terms of % reduction of worm burden, particularly when given against invasive and juvenile worms, and amelioration of hepatic granulomas. Scanning electron microscopy revealed extensive tegumental damage with noticeable deposition of nanostructures. Conclusions: A fixed dose praziquantel-miltefosine nanocombination offers great potential as a novel single dose oral antischistosomal therapy offering multistage activity and protection against hepatic pathology. The novel drug repurposing/combination therapy/nanotechnology multiple approach has the potentials of improving the therapeutic profile of praziquantel, achieving radical cure, hindering resistance to the component drugs, and simplifying praziquantel chemotherapy. Key words: Praziquantel, miltefosine, lipid nanocapsules, Schistosoma mansoni, nanocombination, multistage activity, tegumental targeting, scanning electron microscopy. [LE1] [LE1]
Chitosan mediated nanoparticles from Saccharomyces cerevisiae and its Mosquito Larvicidal Activity