New Evidence for Tamoxifen as an Antischistosomal Agent:In Vitro,In Vivoand Target Fishing Studies

Abstract

Background: Praziquantel is the only drug available to treat schistosomiasis, and there is an urgent demand for new anthelmintic agents. Methodology & results: We conducted in-depth in vitro and in vivo studies and report a target fishing investigation. In vitro, tamoxifen was active against adult and immature worms at low concentrations (<5 μM). Tamoxifen at a single dose (400 mg/kg) or once daily for five consecutive days (100 mg/kg/day) in mice harboring either adult (patent infection) or juvenile (prepatent infection) significantly reduced worm burden (30–70%) and egg production (70–90%). Target fishing studies revealed propionyl-CoA carboxylase as a potential target for tamoxifen in Schistosoma mansoni and glucose uptake by S. mansoni was also significantly reduced. Conclusion: Our results provide news evidence of antiparasitic effect of tamoxifen and reveal propionyl-CoA carboxylase as a potential target.

Antiparasitic Properties of Cardiovascular Agents against Human Intravascular Parasite Schistosoma mansoni

“…In both stages of infections, amiodarone was administered using a single oral dose (400 mg/kg) or once daily for five consecutive days (100 mg/kg/day). It should be noted that these doses were selected because they are often used in studies on approaches to drug discovery for schistosomiasis [ 10 , 11 , 12 , 13 , 14 , 15 ]. For comparison, data obtained with the drug of reference (praziquantel at 400 mg/kg) in animals with either chronic or early infections are also presented.…”

“…Thus, our present data are consistent with and expand upon those from these findings and encourage further exploration of cardiovascular agents to search for new antischistosomal agents. In terms of the methodologies employed, the in vitro phenotypic screening, route of administration (oral), dosing regimen applied (400 mg/kg or 100 mg/kg/day), and model of S. mansoni infection (early and chronic) are in accordance with various studies for antischistosomal drug discovery [ 10 , 11 , 12 , 13 , 14 , 15 ].…”

“…The compounds that produced an effect greater than 80% after 72 h post-exposure in the primary screening were further tested using 1:2 serial dilutions from 0.78 to 50 µM for determination of their effective concentration 50% (EC 50 ) and 90% (EC 90 ) [ 13 , 38 ]. Each concentration was tested in five replicates, and experiments were repeated once.…”

“…For comparison, praziquantel was administered at 400 mg/kg to groups of five S. mansoni -infected animals in the same period. As a note, the doses used of amiodarone and praziquantel were based on the protocols recommended for experimental schistosomiasis [ 10 , 11 , 12 , 13 , 14 ]. For each treatment period, infected but only vehicle-treated mice (five mice per group) served as controls.…”

“…In this context, finding new indications for existing drugs, also known as drug repositioning or reprofiling, may be considered a promising strategy to accelerate drug discovery and development in combating schistosomiasis [ 8 , 9 ]. In recent years, using an in vitro phenotypic screening assay against S. mansoni adult worms, we have screened many clinical drugs that have been approved by either the US Food and Drug Administration or its foreign equivalents, and identified several promising compounds [ 10 , 11 , 12 , 13 , 14 , 15 ]. Among these, from a screening of 13 diuretics, we identified that spironolactone, a potassium-sparing diuretic, had potent antischistosomal effects in vitro and in vivo in a mouse model of schistosomiasis [ 15 ].…”