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

Abstract

Background: Treatment and control of schistosomiasis, one of the most insidious and serious parasitic diseases, depend almost entirely on a single drug, praziquantel. Since the funding for drug development for povertyassociated diseases is very limited, drug repurposing is a promising strategy. In this study, 73 nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used in medical and veterinary fields were evaluated for their anti-schistosomal properties. Methods: The efficacy of NSAIDs was first tested against adult Schistosoma mansoni ex vivo using phenotypic screening strategy, effective drugs were further tested in a murine model of schistosomiasis. The disease parameters measured were worm and egg burden, hepato-and splenomegaly. Findings: From 73 NSAIDs, five (mefenamic acid, tolfenamic acid, meclofenamic acid, celecoxib, and diclofenac) were identified to effectively kill schistosomes. These results were further supported by scanning electron microscopy analysis. In addition, the octanol-water partition coefficient, both for neutral and ionized species, revealed to be a critical property for the ex vivo activity profile. Compounds were then tested in vivo using both patent and a prepatent S. mansoni infection in a mouse model. The most effective NSAID was mefenamic acid, which highly reduced worm burden, egg production, and hepato-and splenomegaly. Interpretation: The treatment regimen used in this study is within the range for which mefenamic acid has been used in clinical practice, thus, it is demonstrated the capacity of mefenamic acid to act as a potent antischistosomal agent suitable for clinical repurposing in the treatment of schistosomiasis.

Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective

“…Other systemic reviews and cohort studies are also in agreement with this observation [66][67]. Apart from cancer, NSAIDs have been also repurposed for other clinical complications which include diflunisal-induced osteoprotection against staphylococcal osteomyelitis [68], mefenamic acid-mediated protection against schistosomiasis [69], aspirin and ibuprofen-mediated cryptococcal cell death [70], oxyphenbutazone-induced sensitization of Mycobacterium tuberculosis to host-derived factors and exogenous antimycobacterial compounds [71] and piroxicam-induced dipeptidyl peptidase-4 inhibition as an alternative strategy for regulating glucose metabolism in diabetes mellitus [72]. While observations from drug repurposing studies in pre-clinical and research settings are highly encouraging, further exploration and extensive validations are mandatory before repurposing of NSAIDs in clinical settings.…”

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.…”

“…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 ].…”

A Machine Learning Strategy for Drug Discovery Identifies Anti-Schistosomal Small Molecules

“…Lago et al screened 73 nonsteroidal anti-inflammatory drugs, including a compound screened by us here, niflumic acid, against adult S. mansoni in vitro for 72 h at 50 μM. 58 Niflumic acid was not active in the initial in vitro screen, but other analogs had modest activity (LC 50 values ranged from 20.6 to 37.4 μM), the best of which, mefenamic acid, generated an LC 50 of 11.1 μM. An inspection of the rule book based on these published single metric data ( Table 1 ) shows that these compounds would be considered inactive (rule book scores of zero).…”