Turing Pharmaceuticals announced on 24 November 2015, "that it would not reduce the list price of that drug after all", but they would offer patient assistance programs. New York Times journalist Andrew Pollack noted that these programs "are standard for companies selling extremely high-priced drugs. They enable the patients to get the drug while pushing most of the costs onto insurance companies and taxpayers. "The price increase was criticized by physician groups such as HIV Medicine Associates and Infectious Diseases Society of America.In 2016, a group of high school students from Sydney Grammar supported by the University of Sydney prepared pyrimethamine as an illustration that the synthesis is comparatively easy and the price-hike unjustifiable. His team produced 3.7 g for US$20, which would have been worth between US$35,000 and US$110,000 in the United States at the time. Shkreli said the schoolboys were not competition, likely because the necessary bioequivalence studies require a sample of the existing medication provided directly by the company, and not simply purchased from a pharmacy, which Turing could decline to provide. Nonetheless, the students work was featured in The Guardian and Time magazine, and on ABC Australia, the BBC, and CNN.On 22 October 2015, Imprimis Pharmaceuticals announced it had made available compounded and customizable formulations of pyrimethamine and leucovorin in capsules to be taken by mouth starting as low as $99 for a 100-count bottle in the United States.
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.