Widely used for menstrual period pain relief, the anti-inflammatory drug mefenamic acid has now proven to be effective in the treatment of schistosomiasis.
In experiments conducted at Guarulhos University (UnG) in São Paulo State, Brazil, with FAPESP’s support, the drug reduced the parasite burden by more than 80% in mice infected with the worm Schistosoma mansoni. This percentage exceeds the gold standard for drug efficacy recommended by the World Health Organization (WHO).
The results of the research, published in EbioMedicine, an open access journal owned by The Lancet, suggest that mefenamic acid can be more efficacious than praziquantel, the only existing medication for the disease. However, the anti-inflammatory drug cannot be prescribed for patients with schistosomiasis until it has been approved following clinical trials.
The discovery was made in a drug repositioning study conducted at UnG’s Center for Research on Neglected Diseases in which 73 nonsteroidal anti-inflammatory drugs (NSAIDs) sold in Brazil and other countries were evaluated for anti-schistosomal properties. Five proved efficacious in the treatment of the disease, and among these, mefenamic acid yielded the most promising results.
“In vitro tests showed that mefenamic acid affected the motility and viability of schistosomes and caused severe damage to the tegument [ enveloping membrane]. The drug’s precise action mechanism in this type of infection is not yet clear, but this isn’t the most important matter right now, as the mechanisms of the drugs used to treat verminosis are also poorly understood. Hence, the significance of drug repositioning studies for neglected diseases such as schistosomiasis,” said Josué de Moraes, a professor at UnG and last author of the article.
Schistosomiasis affects more than 240 million people worldwide according to the WHO, and only one drug has been used to treat the disease for 40 years.
“Praziquantel doesn’t work against juvenile worms, and its efficacy is generally limited. After so much time without any alternative treatment, and with praziquantel being prescribed both for humans and animals, the parasite must have developed resistance to the drug,” Moraes said.
Mefenamic acid also proved to be more efficacious than praziquantel because it kills the larvae of the parasite.
“At present the patient has to wait until the juvenile schistosomes become adults and only then take the medication,” Moraes explained. “This means that if the treatment isn’t repeated, the parasite’s lifecycle isn’t interrupted, and the patient continues to suffer from the disease. People who are infected owing to a lack of proper sanitation tend to contribute to the dissemination of the worms in the environment and expose the population to the risk of infection. Good sanitation is evidently the ideal solution, but mefenamic acid is also important to ensure prevention.”
Moraes stressed that drug repositioning or repurposing studies have become more common, especially for diseases classed as neglected because they affect large numbers of people but lack research, vaccines and advanced treatment.
This is the case for schistosomiasis, which is mostly transmitted in places without proper basic sanitation by contact with water containing infected snails. The schistosomes occupy the infected patient’s mesenteric veins and liver.
There are no vaccines, although advanced studies are in progress at the Oswaldo Cruz Foundation (Fiocruz) in Rio de Janeiro. The disease is usually asymptomatic in the first few weeks. If it becomes chronic, it can cause severe health problems and even death.
“The discovery and development of a new drug costs USD 1.5 billion on average. This kind of money isn’t available to treat neglected diseases, as there’s no profit to be made, so we’re looking to existing drugs to combat the parasite. We can leapfrog several stages. Clinical trials won’t be needed to verify toxicity, interaction with other medications, and so on. We still need to perform trials in humans, but not the whole series. The overall process is less costly,” Moraes said.
The group at UnG’s Center for Research on Neglected Diseases also analyzed the effects of 13 widely marketed diuretics on schistosomes. The results are published in Antimicrobial Agents and Chemotherapy, a journal of the American Society of Microbiology (ASM).
Spironolactone, typically prescribed for high blood pressure, was the only diuretic that had potent anti-schistosomal effects in vitro and in vivo in a murine model. “However, a comparison between the two studies shows mefenamic acid to be more efficacious,” Moraes said.
The article “Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasis” (doi: 10.1016/j.ebiom.2019.04.029) by 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 can be read at: www.ebiomedicine.com/article/S2352-3964(19)30268-3/fulltext.
The article “In vitro and in vivo studies of spironolactone as an anti-schistosomal drug capable of clinical repurposing” (doi: 10.1128/AAC.01722-18) by Rafael A. Guerra, Marcos P. Silva, Tais C. Silva, Maria C. Salvadori, Fernanda S. Teixeira, Rosimeire N. de Oliveira, Jefferson A. Rocha, Pedro L. S. Pinto and Josué de Moraes can be read at: https://aac.asm.org/content/63/3/e01722-18.