In Vitro and In Vivo Studies of Spironolactone as an Antischistosomal Drug Capable of Clinical Repurposing

Abstract

Schistosomiasis is a parasitic flatworm disease that infects over 200 million people worldwide, especially in poor communities. Treatment and control of the disease rely on just one drug, praziquantel. Since funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, from a screening of 13 marketed diuretics, we identified that spironolactone, a potassium-sparing diuretic, had potent antischistosomal effects on Schistosoma mansoni in vitro and in vivo in a murine model of schistosomiasis. In vitro, spironolactone at low concentrations (<10 µM) is able to alter worm motor activity and the morphology of adult schistosomes, leading to parasitic death. In vivo, oral treatment with spironolactone at a single dose (400 mg/kg) or daily for five consecutive days (100 mg/kg/day) in mice harboring either patent or prepatent infections significantly reduced worm burden, egg production, and hepato- and splenomegaly (P < 0.05 to P < 0.001). Taken together, with the safety profile of spironolactone, supported by its potential to affect schistosomes, these results indicate that spironolactone could be a potential treatment for schistosomiasis and make it promising for repurposing.

Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasis

“…However, mefenamic acid is rapidly absorbed after oral administration and it has a short half-life (two hours), which we considered a disadvantage feature for killing parasites that reside in the bloodstream. We then decided to administer mefenamic acid once a day for five consecutive days (100 mg/kg/day), which is also used in drug discovery programs for murine model of schistosomiasis [34,37].…”

“…For in vivo experimental analysis, a parametric Dunnett's multiple-comparison test was applied to compare the vehicle group versus the treated group. In vivo experimental graphics represent data from individual mice and are expressed as scatterplots [34]. A value of P < 0·05 was considered statistically significant.…”

Promethazine Exhibits Antiparasitic Properties In Vitro and Reduces Worm Burden, Egg Production, Hepatomegaly, and Splenomegaly in a Schistosomiasis Animal Model

“…In the murine model of schistosomiasis, promethazine treatment was introduced at an oral dose of 100 mg/kg/day for five successive days at different intervals from the time of infection for the evaluation of stage-specific susceptibility. Similar to praziquantel (22) and other promising antischistosomal compounds (11,23), oral treatment with promethazine was more effective against adult S. mansoni than against the juvenile stage. Indeed, a high total worm burden reduction was achieved with promethazine in patent infections (Ͼ90%), whereas a moderate total worm burden reduction was observed in prepatent infections (ϳ45%).…”

“…It should be emphasized that a single oral dose of 400 mg/kg is the pattern chosen for experimental schistosomiasis (2). However, since this dose exceeds the 50% lethal dose (LD 50 ) of promethazine, we chose 100 mg/kg for five consecutive days, which is also used in drug discovery programs for the murine model of schistosomiasis (11,40).…”

“…In the field of infectious diseases of poverty, it is more difficult to recover the cost for drug development from pharmaceutical sales, whose target population lack financial recourse. Hence, the repurposing of drugs and clinical candidates offer an attractive alternative to de novo drug discovery (7)(8)(9), particularly in terms of reducing time and research and development costs since safety investigations can be reduced (10,11).…”