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

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 Tukey's 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.

Evaluation of prophylactic efficacy and safety of praziquantel-miltefosine nanocombination in experimental Schistosomiasis mansoni.

The control of schistosomiasis depends exclusively on praziquantel (PZQ) monotherapy with treatment failure due to minor activity against the juvenile stage, re-infection and emerging drug resistance. Improving the antischistosomal therapeutic/prophylactic profile of PZQ is a sensible option to save the clinical benefits of the drug if achieved effectively and safely via a single oral dose. Recently, we developed praziquantel-miltefosine lipid nanocapsules (PZQ 250 mg/kg-MFS 20 mg/kg LNCs) as a nanotechnology-enabled novel drug combination with significant multistage activity against Schistosoma mansoni (S. mansoni) in a murine model. The present study aimed at providing a proof of concept of the chemoprophylactic effect of this nanocombination. A single oral dose of the nanocombination was administered to mice one and seven days before challenge infection with S. mansoni. The protective effect of the nanocombination was assessed parasitologically and histopathologically relative to LNCs singly-loaded with PZQ or MFS and non-treated infected controls. In addition, the safety of the nanocombination was assessed biochemically and histopathologically. Administration of the nanocombination one or seven days pre-infection resulted in a statistically significant reduction in mean worm burden and granulomas size associated with amelioration of hepatic pathology compared to infected non-treated control. Although, the prophylactic effect was significantly reduced upon administration seven days pre-infection compared to administration one day pre-infection, yet, it still exists. Results were explained based on the spectrum of activity of PZQ and MFS and their complementary pharmacokinetic (PK) profiles in addition to the effect of nanoencapsulation on these factors. The novel PZQ-MFS nanocombination offers valuable potentials in PZQ-based mass drug administration programmes by granting radical cure, preventing re-infection, and delaying development of resistance to the component drugs.

Evaluation of newly isolated probiotics in the protection against experimental intestinal trichinellosis.

The potential use of probiotics in controlling enteric infections has generated tremendous interest in the last decade. The protective efficacy of seven oral doses of two newly isolated Egyptian probiotic strains; Lactobacillus acidophilus P110 (L. acidophilus) and Lactobacillus plantarum P164 (L. plantarum) versus Lactobacillus casei ATCC 7469 (L. casei) - against experimental intestinal trichinellosis - was assessed via parasitological, immunological and histopathological parameters, after verifying their in vivo safety and intestinal colonization. Parasitologically, the highest adult count reduction was observed in L. plantarum-fed infected sub-subgroup (56.98, 65.42 and 69.02%) - on the 5th, 12th and 17th days post infection (P.I.), respectively. Lesser percentage reductions were recorded in both the L. casei-fed infected sub-subgroup (36.19, 23.68 and 31.58%) and L. acidophilus-fed infected sub-subgroup (36.50, 11.8 and 7.61%) at the same intervals. On the 28th day post challenge, the highest larval count reduction was in L. plantarum-fed infected sub-subgroup (87.92%). While lower percentage yet still significant were observed in the L. casei-fed infected (74.88%) and L. acidophilus-fed infected sub-subgroups (60.98%). Immunologically, serum IFN-γ levels in the probiotic-fed non infected sub-subgroups were higher than those in the probiotic-fed infected sub-subgroups. Both showed higher levels of IFN-γ than the non probiotic-fed sub-subgroups. Histopathologically, intestinal sections of the probiotic-fed infected sub-subgroups showed amelioration of the inflammation and damage resulting from Trichinella spiralis (T. spiralis) infection. Results indicate that, through mechanical and immunological mechanisms, L. plantarum showed parasitological and histopathological protective superiority with respect to both L. casei and L. acidophilus against murine T. spiralis infection.