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1. Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasisResearch in context

Author

Eloi M. Lago, Marcos P. Silva, Talita G. Queiroz, Susana F. Mazloum, Vinícius C. Rodrigues, Paulo U. Carnaúba, Pedro L. Pinto, Jefferson A. Rocha, Leonardo L.G. Ferreira, Adriano D. Andricopulo, and Josué de Moraes

Subjects
Medicine, Medicine (General), R5-920
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 poverty-associated 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 anti-schistosomal agent suitable for clinical repurposing in the treatment of schistosomiasis. Keywords: Schistosomiasis, Nonsteroidal anti-inflammatory drugs, Mefenamic acid, Anthelmintic, Schistosomicidal activity

Published
2019
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2. Promethazine Exhibits Antiparasitic Properties In Vitro and Reduces Worm Burden, Egg Production, Hepatomegaly, and Splenomegaly in a Schistosomiasis Animal Model

Author

Cristiane S. Morais, Thiago R. Morais, Ana C. Mengarda, Daniel B. Roquini, Josué de Moraes, Susana F. Mazloum, Luiz E. Ferreira, Rogério P. Xavier, Maria Cecília Barbosa da Silveira Salvadori, Ramon M. Cogo, Fernanda de Sá Teixeira, and Pedro Luiz Silva Pinto

Subjects
Drug, medicine.medical_treatment, media_common.quotation_subject, Schistosomiasis, Pharmacology, 03 medical and health sciences, In vivo, medicine, Pharmacology (medical), Experimental Therapeutics, 030304 developmental biology, media_common, 0303 health sciences, biology, 030306 microbiology, business.industry, biology.organism_classification, medicine.disease, Promethazine, Praziquantel, Drug repositioning, Infectious Diseases, Antihistamine, Schistosoma mansoni, business, medicine.drug
Abstract

The treatment and control of schistosomiasis, a neglected disease that affects more than 200 million people worldwide, rely on the use of a single drug, praziquantel. A vaccine has yet to be developed, and since new drug design and development is a lengthy and costly process, drug repurposing is a promising strategy. In this study, the efficacy of promethazine, a first-generation antihistamine, was evaluated against Schistosoma mansoni ex vivo and in a murine model of schistosomiasis. In vitro assays demonstrated that promethazine affected parasite motility and viability, and it induced severe tegumental damage in schistosomes. The 50% lethal concentration (LC(50)) of the drug was 5.84 μM. Similar to promethazine, schistosomes incubated with atropine, a classical anticholinergic drug, displayed reduced motor activity. In an animal model, promethazine treatment was introduced at an oral dose of 100 mg/kg of body weight for five successive days at different intervals from the time of infection for the evaluation of the stage-specific susceptibility (prepatent and patent infections). Various parasitological criteria indicated the following in vivo antischistosomal effects of promethazine: there were significant reductions in worm burden, egg production, hepatomegaly, and splenomegaly. The highest worm burden reduction was achieved with promethazine in patent infections (>90%). Taken together, considering the importance of the repositioning of drugs in infectious diseases, especially those related to poverty, our data revealed the possibility of promethazine repositioning as an antischistosomal agent.

Published
2019

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