Schistosoma egg-induced liver pathology resolution by Sm-p80-based schistosomiasis vaccine in baboons

Le, Liu; Molehin, Adebayo J.; Nash, Stewart; Sennoune, Souad R.; Ahmad, Gufran; Torben, Workineh; Zhang, Weidong; Siddiqui, Afzal A.

doi:10.1016/j.pathol.2018.01.004

Cited by 25 publications

(20 citation statements)

References 30 publications

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“…A further objective of the study was to keep the doses of PZQ and MFS at the lowest level for effective therapy. Although the amounts of PZQ and MFS entrapped in the higher dose PZQ-MFS nanocombination were already reduced relative to the free drug forms [16,43], an attempt was made to assess the effect of halving the dose of both drugs on the combined antischistosomal activity of a second lower dose xed dose nanocombination using the same procedures (Figs. 2 & 5, Group II).…”

Section: Discussionmentioning

confidence: 99%

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

Eissa

El‐Azzouni

El-Khordagui

et al. 2020

Preprint

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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 nontreated 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, the 21st and 42nd days post infection. Scanning electron microscopic, parasitological and histopathological studies were used for assessment. Preclinical data were subjected to analysis of variance and Tukey 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 dose nanocombination 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 microscopic 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.

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Section: Discussionmentioning

confidence: 99%

“…Specimens of the liver of mice of all study groups were xed in 10% neutral buffered formalin. Parra nembedded histological sections, 5 μm-thick, were stained with hematoxylin and eosin (H&E) [43]. Pathological changes in the hepatic parenchyma were observed and the mean size of granulomas was determined.…”

Section: Histopathological Examinationmentioning

confidence: 99%

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

Eissa

El‐Azzouni

El-Khordagui

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…A further objective of the study was to keep the doses of PZQ and MFS at the lowest level for effective therapy. Although the amounts of PZQ and MFS entrapped in the higher dose PZQ-MFS nanocombination were already reduced relative to the free drug forms [16,43], an attempt was made to assess the effect of halving the dose of both drugs on the combined antischistosomal activity of a second lower xed-dose nanocombination using the same procedures (Figs. 2, 5; Group II).…”

Section: Discussionmentioning

confidence: 99%

“…Samples of the liver of mice of all study groups were xed in 10% neutral buffered formalin. Parra nembedded histological sections (5 μm-thick) were stained with hematoxylin and eosin (H&E) [43].…”

Section: Histopathological Examinationmentioning

confidence: 99%

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

Eissa

El‐Azzouni

El-Khordagui

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

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“…Furthermore, it has also been shown that Sm-p80 has a therapeutic effect in vaccinated baboons through decreasing the numbers of established worms, reducing the retention of eggs in tissues and decreasing the number of eggs excreted in faeces [112]. More recent data on recombinant Sm-p80 showed a worm reduction of 33.33% -53.13% and 38% in mice and baboon respectively [113,114] and also in baboon significant reduction in hepatic egg (67.7%) [115] and 93.45% reduction on pathology producing female worms was reported [116]. Moreover, vaccine immunogenicity of Sm-p80 was assessed using RNA sequencing and it is revealed that the vaccine candidate induced both cellular and humoral immune response and a predominant Th1,Th2 and Th17 gene signature was obtained [117].…”

Section: Strategies For the Development Of Novel Vaccines For Schistomentioning

confidence: 98%

T cell mediated immunity to Schistosoma japonicum infection and vaccination

Tebeje¹

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Schistosoma egg-induced liver pathology resolution by Sm-p80-based schistosomiasis vaccine in baboons

Cited by 25 publications

References 30 publications

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

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

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

T cell mediated immunity to Schistosoma japonicum infection and vaccination

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