Dysentery may be treatable with cheap arthritis drug

US researchers have discovered that an already approved arthritis drug may offer a cheap, low-dose treatment for the amoebic infections that cause dysentery in humans worldwide. So far they have only tested the drug in lab and animal studies, but they have applied for approval to start clinical trials to test it as a treatment for both amebiasis and the parasite Giardia in humans. The researchers, from University of California - San Diego (UCSD), and University of California - San Francisco (UCSF), write about their findings in the 20 May online issue of Nature Medicine. The antirheumatic drug is called auranofin, marketed as ridaura, and is a form of the precious metal gold. The researchers were screening already approved drugs to find new treatments for the developing world when they made their discovery. Co-senior author James McKerrow is a professor of pathology at UCSF's Sandler Center for Drug Discovery. He told the press: "When we're looking for new treatments for the developing world, we start with drugs that have already been approved." Using a high-throughput drug screen he and his colleagues found that auranofin was 10 times more potent against the parasite Entamoeba histolytica than the current treatment metronidazole. They said their study illustrates the importance of screening existing drugs for new purposes, especially for neglected diseases. McKerrow said that the combination of an off-patent drug and decades of clinical safety data means we may have a global lower-cost solution, with fewer side effects or risks of bacterial resistance, than the current therapy. Every year, 50 million people around the world, most in developing countries, contract amebiasis, a gastrointestinal infection by the parasite Entamoeba histolytica that causes symptoms ranging from mild diarrhea to dysentery with blood and mucus in the stool. The infection spreads through contaminated food and water, and kills around 70,000 people a year, with children being the ones most likely to become severely ill. The parasite Giardia also infects 6-8% of all children in developing countries, causing diarrhea, abdominal cramps and dehydration. The current treatment for both amebiasis and giardiasis is the antibiotic metronidazole, whose side effects include nausea, vomiting, dizziness and headache. Auranofin has been used as a twice-daily tablet for adults with rheumatoid arthritis since 1985, and has been shown to be safe at that dosage. Because the study's lab and animal test findings show auranofin is 10 times more potent that the current therapy, they suggest it could be effective at a low dose, perhaps even on a one-time or limited basis. First author Anjan Debnath is a postdoctoral fellow at UCSF. He said: "This is a drug that you can find in every country. Based on the dosage we're seeing in the lab, this treatment could be sold at about $2.50 per dose, or lower. That cost savings could make a big difference to the people who need it the most." Debnath is a member of McKerrow's team at UCSF. They focus on infectious diseases in the developing world that are not research priorities for pharmaceutical companies. The team set out to create a screen to find small molecule drugs that would kill amoebas safely. One key breakthrough came when Debnath developed a high-throughput screen that could test the molecules in an oxygen-free, or anaerobic, environment, to mimic the amoeba's natural environment. Another key breakthrough was from a company going out of business. Iconix Biosciences, of Menlo, California, offered the team its screening library of 900 approved compounds, each in its own vial. After testing auranofin in the lab, the researchers then tested it in two animal studies. One test was in a mouse model of amebiasis in the colon, which is where the parasite first takes hold, and the other was in a hamster model that shows the impact of infection in the liver. In both animal studies, the team said auranofin was the most effective drug they had ever seen. At very low doses it markedly reduced the number of parasites, inflammation damage and the size of liver abscesses. Armed with this "proof of principle", Debnath has applied to the US Food and Drug Administration (FDA) to grant auranofin Orphan Drug Status. This is a way of fast-tracking new drugs that show promise in treating a neglected or orphan disease (ie one that affects fewer than 200,000 people in the US, or one that is not expected to recover the development and marketing cost). Co-senior author Sharon L Reed, professor in the UCSD Departments of Pathology and Medicine, said: "Because auranofin has already been approved by the FDA for use in humans, we can save years of expensive development." "This new use of an old drug represents a promising therapy for a major health threat, and highlights how research funded by the National Institutes of Health can benefit people around the world," she added.