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.
The two drugs bind the same enzymatic targets as the drugs trimethoprim and sulfamethoxazole - dihydrofolate reductase and dihydropteroate synthase, respectively.Pyrimethamine has also been used in several trials to treat retinochoroiditis. Pregnancy consideration
Pyrimethamine is labeled as pregnancy category C in the United States. To date,  not enough evidence on its risks in pregnancy or its effects on the fetus is available. Malaria
It is primarily active against Plasmodium falciparum, but also against Plasmodium vivax. Due to the emergence of pyrimethamine-resistant strains of P. falciparum, pyrimethamine alone is seldom used now. In combination with a long-acting sulfonamide such as sulfadiazine, it was widely used, such as in Fansidar, though resistance to this combination is increasing. Contraindications
Pyrimethamine is contraindicated in people with folate-deficiency anaemia. Side effects
When higher doses are used, as in the treatment of toxoplasmosis, pyrimethamine can cause gastrointestinal symptoms such as nausea, vomiting, glossitis, anorexia, and diarrhea. A rash, which can be indicative of a hypersensitivity reaction, is also seen, particularly in 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.