Single oral fixed-dose praziquantel-miltefosine nanocombination for effective control of experimental schistosomiasis mansoni

Abstract

Background The control of schistosomiasis has been centered to date on a single drug, praziquantel, with shortcomings including treatment failure, reinfection, and emergence of drug resistance. Drug repurposing, combination therapy or nanotechnology were explored to improve antischistosomal treatment. The aim of the present study was to utilize a novel combination of the three strategies to improve the therapeutic profile of praziquantel. This was based on a fixed-dose nanocombination of praziquantel and miltefosine, an antischistosomal repurposing candidate, co-loaded at reduced doses into lipid nanocapsules, for single dose oral therapy. Methods Two nanocombinations were prepared to provide 250 mg praziquantel-20 mg miltefosine/kg (higher fixed-dose) or 125 mg praziquantel-10 mg miltefosine/kg (lower fixed-dose), respectively. Their antischistosomal efficacy in comparison with a non-treated control and their praziquantel or miltefosine singly loaded counterparts was assessed in murine schistosomiasis mansoni. A single oral dose of either formulation was administered on the initial day of infection, and on days 21 and 42 post-infection. Scanning electron microscopic, parasitological, and histopathological studies were used for assessment. Preclinical data were subjected to analysis of variance and Tukeyʼs post-hoc test for pairwise comparisons. Results Lipid nanocapsules (~ 58 nm) showed high entrapment efficiency of both drugs (> 97%). Compared to singly loaded praziquantel-lipid nanocapsules, the higher nanocombination dose showed a significant increase in antischistosomal efficacy in terms of statistically significant decrease in mean worm burden, particularly against invasive and juvenile worms, and amelioration of hepatic granulomas (P ≤ 0.05). In addition, scanning electron microscopy examination showed extensive dorsal tegumental damage with noticeable deposition of nanostructures. Conclusions The therapeutic profile of praziquantel could be improved by a novel multiple approach integrating drug repurposing, combination therapy and nanotechnology. Multistage activity and amelioration of liver pathology could be achieved by a new praziquantel-miltefosine fixed-dose nanocombination providing 250 mg praziquantel-20 mg miltefosine/kg. To the best of our knowledge, this is the first report of a fixed-dose nano-based combinatorial therapy for schistosomiasis mansoni. Further studies are needed to document the nanocombination safety and explore its prophylactic activity and potential to hinder the onset of resistance to the drug components.

An adjuvant effect of Metformin as an anti-fibrotic agent when administered with the anti-schistosomal Praziquantel in Schistosoma mansoni infected mice

“…Therefore, PZQ /Met combination has a synergistic effect and has both anti-schistosomal and anti-fibrotic effects on infected mice. The same effects were obtained when PZQ was combined with artemether, mefloquine, pentostam, as well as the nanocombinations of PZQ-Meltofosine (Utzinger et al, 2001;El-Lakany et al, 2011;Khayeka-Wandabwa et al, 2013;Eissa et al, 2020).…”

Potential application of nanotechnology in the treatment, diagnosis, and prevention of schistosomiasis

“…Moreover, a single dose of PZQ-LNCs substantially improve efficacy and decreased worm burden, hepatic pathology improvement, and substantial damage to the fluke suckers and tegument (Amara et al, 2018). Whereas PZQ-lipid Nano-capsule at a dose rate of 250 mg PZQ-20 mg miltefosine/kg demonstrates a substantial increase in antischistosomal efficacy in terms of statistical augmentation in mean worm load, particularly against invasive and early-stage worms, as well as improvement in hepatic granulomas (Eissa et al, 2020b), The prophylactic role of a single oral dose of PZQ-MFS LNCs was evaluated and demonstrate that when compared to an infected non-treated control, administration of the nano combination one or 7 days before infection resulted in a significantly substantial drop in mean worm burden and granuloma size, as well as improvement in hepatic pathology (Eissa et al, 2020a).…”

Tunable Polymeric Mixed Micellar Nanoassemblies of Lutrol F127/Gelucire 44/14 for Oral Delivery of Praziquantel: A Promising Nanovector against Hymenolepis nana in Experimentally-Infected Rats

“…PRZ is a heterocyclic pyrazinoisoquinoline employed as the cornerstone drug modality against diverse parasitic diseases occasioned by cestodes as well as trematodes in both human and veterinary medicine. Also, it is broadly utilized in hydatid management campaigns in addition to treatment of neurocysticercosis, clonorchiosis, opisthorchosis and schistosomiasis [ 9 ]. The PRZ mechanism of action is linked with spurring calcium influx with subsequent upsurge in its intracellular levels of helminthes.…”