The anthelmintic drug praziquantel activates a schistosome transient receptor potential channel

Park, Soo Young; Gunaratne, Gihan S.; Chulkov, Evgeny G.; Moehring, Francie; McCusker, Paul; Dosa, Peter I.; Chan, John D.; Stucky, Cheryl L.; Marchant, Jonathan S.

doi:10.1074/jbc.ac119.011093

Cited by 88 publications

(123 citation statements)

References 34 publications

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“…As the key combination drug, PZQ exerts a direct antischistosomal effect on adult worms by underpinning the parasite Ca 2+ homeostasis resulting in spastic paralysis and rapid vacuolization of the worm surface [44]. Recently, activation of a schistosome transient receptor potential channel by PZQ was shown to support the pharmacological profile of PZQ [45]. To overcome the known shortcomings of PZQ therapy, mainly ineffectiveness against immature worms and inability to ameliorate disease-associated pathology, MFS was included in the nanocombination.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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 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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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…It is also possible that TRP channels, specifically TRP-2 will support the action of cholinergic anthelmintics in manner similar to the response of nicotine that is promoted by TRP-2 in C. elegans 32 . TRP channels are also present in the flatworm helminth, Schistosoma mansoni, that causes schistosomiasis, and a TRPM channel has recently been discovered to be activated by the anthelmintic, praziquantel 33 emphasizing the recognition . One-way ANOVA with Bonferroni post-hoc test; p = 0.006; 95% confidence interval for DEC vs. DEC + miconazole was −400 to −50 pA and for DEC vs. miconazole was −300 to −30 pA; n = 5 from five worms.…”

Section: Discussionmentioning

confidence: 99%

Diethylcarbamazine activates TRP channels including TRP-2 in filaria, Brugia malayi

et al. 2020

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Diethylcarbamazine is an important classic drug used for prevention and treatment of lymphatic filariasis and loiasis, diseases caused by filarial nematodes. Despite many studies, its site of action has not been established. Until now, the consensus has been that diethylcarbamazine works by activating host immune systems, not by a direct action on the parasites. Here we show that low concentrations of diethylcarbamazine have direct and rapid (<30 s) temporary spastic paralyzing effects on the parasites that lasts around 4 h, which is produced by diethylcarbamazine opening TRP channels in muscle of Brugia malayi involving TRP-2 (TRPC-like channel subunits). GON-2 and CED-11, TRPM-like channel subunits, also contributed to diethylcarbamazine responses. Opening of these TRP channels produces contraction and subsequent activation of calcium-dependent SLO-1K channels. Recovery from the temporary paralysis is consistent with inactivation of TRP channels. Our observations elucidate mechanisms for the rapid onset and short-lasting therapeutic actions of diethylcarbamazine.

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“…As the key combination drug, PZQ exerts a direct antischistosomal effect on adult worms by underpinning the parasite Ca 2+ homeostasis resulting in spastic paralysis and rapid vacuolization of the worm surface [44]. Recently, activation of a schistosome transient receptor potential channel by PZQ was shown to support the pharmacological pro le of PZQ [45]. To overcome the known shortcomings of PZQ therapy, mainly ineffectiveness against immature worms and inability to ameliorate disease-associated pathology, MFS was included in the nanocombination.…”

Section: Discussionmentioning

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

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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 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.

show abstract

The anthelmintic drug praziquantel activates a schistosome transient receptor potential channel

Cited by 88 publications

References 34 publications

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

Diethylcarbamazine activates TRP channels including TRP-2 in filaria, Brugia malayi

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

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