combination with sulfonamides. Central nervous system effects include ataxia, tremors, and seizures. Hematologic side effects such as thrombocytopenia, leukopenia, and anemia can also occur. Interactions Other antifolate agents such as methotrexate and trimethoprim may potentiate the antifolate actions of pyrimethamine, leading to potential folate deficiency, anaemia, and other blood dyscrasias. Mechanism of action Pyrimethamine interferes with the regeneration of tetrahydrofolic acid from dihydrofolate by competitively inhibiting the enzyme dihydrofolate reductase. Tetrahydrofolic acid is essential for DNA and RNA synthesis in many species, including protozoa. It has also been found to reduce the expression of SOD1, a key protein involved in amyotrophic lateral sclerosis. Other medications Pyrimethamine is typically given with folinic acid and sulfadiazine. Sulfonamides (e.g. sulfadiazine) inhibit dihydropteroate synthetase, an enzyme that participates in folic acid synthesis from para-aminobenzoic acid. Hence, sulfonamides work synergistically with pyrimethamine by blocking a different enzyme needed for folic acid synthesis. Folinic acid (leucovorin) is a folic acid derivative converted to tetrahydrofolate, the primary active form of folic acid, in vivo, without relying on dihydrofolate reductase. Folinic acid reduces side effects related to folate deficiency in the patient. Mechanism of resistance Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce its effectiveness. These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions. History Nobel Prize-winning American scientist Gertrude Elion developed the drug at Burroughs-Wellcome (now part of GlaxoSmithKline) to combat malaria. Pyrimethamine has been available since 1953. In 2010, GlaxoSmithKline sold the marketing rights for Daraprim to CorePharma. Impax Laboratories sought to buy CorePharma in 2014, and completed the acquisition, including Daraprim, in March 2015. In August 2015, the rights were bought by Turing Pharmaceuticals. Turing subsequently became infamous for a price hike controversy when it raised the price of a dose of the drug in the U.S. market from US$13.50 to US$750, a 5,500% increase. Society and culture Economics In the United States in 2015, Turing Pharmaceuticals was criticized for increasing the price 50-fold, from US$13.50 to $750 a tablet, leading to a cost of $75,000 for a course of treatment reported at one hospital. United States In the United States, in 2015, with Turing Pharmaceuticals' acquisition of the US marketing rights for Daraprim tablets, Daraprim became a single-source and specialty pharmacy item, and the price was increased. The cost of a monthly course for a person on