|Systematic (IUPAC) name|
|Biological half-life||96 hours|
|PDB ligand ID||CP6 (, )|
|Molecular mass||248.71 g/mol|
|(what is this?)|
Pyrimethamine (trade name Daraprim) is a medication used for protozoal infections. It is commonly used as an antimalarial drug (for both treatment and prevention of malaria), and to treat Toxoplasma gondii infections, particularly when combined with the sulfonamide antibiotic sulfadiazine when treating HIV-positive individuals.
It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.
The 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, and is not subject to any unexpired patent. In the United States the market for this product is quite small so no generic manufacturer has emerged. In 2010 GlaxoSmithKline sold the marketing rights for Daraprim to CorePharma and in 2015 the rights were bought by Turing Pharmaceuticals.
- Sulfonamides 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.
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 is widely used, such as in Fansidar though resistance to this combination is increasing. It has been used in the treatment of actinomycosis and isosporiasis, and for the treatment and prevention of Pneumocystis jirovecii pneumonia.
In 2011, researchers discovered that pyrimethamine can increase β-hexosaminidase activity, thus potentially slowing down the progression of late-onset Tay–Sachs disease. It is being evaluated in clinical trials as a treatment for amyotrophic lateral sclerosis.
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.
Pyrimethamine can cause a rash, and if higher doses are used (such as for toxoplasmosis), it can cause gastrointestinal symptoms such as nausea, vomiting, abdominal cramps, dry mouth, weight loss, and diarrhoea. Central nervous system effects include headache, ataxia, and rarely seizures and haematologic side effects such as leucopenia and anaemia.
Pyrimethamine is contraindicated in patients with:
- Folate-deficiency anaemia
- Pregnancy, especially during the first trimester, due to the possible detrimental effects an antifolate such as pyrimethamine might have on organogenesis
It is a white, colourless, crystalline powder; it is practically insoluble in water and slightly soluble in ethanol, chloroform, and acetone. It is unstable in the presence of air and light. It is chemically a diaminopyrimidine derivative.
Mechanism of action
Pyrimethamine interferes with tetrahydrofolic acid synthesis from folic acid by inhibiting the enzyme dihydrofolate reductase (DHFR). Tetrahydrofolic acid is needed 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.
Condensation of p-chlorophenylacetonitrile with ethyl propionate in the presence of sodium methoxide gives the cyanoketone (3). Treatment with trimethyl orthoformate affords the methyl enol ether of that compound (4). Condensation with guanidine affords pyrimethamine (5).
Availability and price
In the United States, as of 2015, with Turing Pharmaceuticals' acquisition of the US marketing rights for Daraprim tablets, Daraprim has become a single-source and specialty pharmacy item, and the cost of Daraprim has increased. The cost of a monthly course for a person on 75 mg dose rose to about $75,000/month, from $13/tablet to $833/tablet, or $750 per tablet. Outpatients can no longer obtain Daraprim from their community pharmacy, but only through a single dispensing pharmacy, Walgreens Specialty Pharmacy, and institutions can no longer order from their general wholesaler, but have to set up an account with the Daraprim Direct program. Presentations from Retrophin, a company formerly headed by Shkreli and from which Turing acquired the rights to Daraprim, suggest that a closed distribution system could prevent generic competitors from legally obtaining the drugs for the bioequivalence studies required for FDA approval of a generic drug.
Martin Shkreli, CEO of Turing, defended the price hike by saying, "If there was a company that was selling an Aston Martin at the price of a bicycle, and we buy that company and we ask to charge Toyota prices, I don't think that that should be a crime." As a result of the backlash, Shkreli hired a crisis public relations firm to help explain his fund's move. Turing Pharmaceuticals announced on November 24, 2015 "that it would not reduce the list price of that drug after all" but they will offer various patient assistance programs. However 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 has been fiercely criticised by physician groups such as HIV Medicine Associates and Infectious Diseases Society of America.
In India, over a dozen pharmaceutical companies manufacture and sell pyrimethamine tablets in India, and, multiple combinations of generic pyrimethamine are available for a price ranging from US$0.04–$0.10 each (3–7 rupees).
On October 22, 2015, Imprimis Pharmaceuticals announced it has made available a formulation of Pyrimethamine and Leucovorin in oral capsules starting as low as $99.00 for a 100 count bottle. 
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- Lange, DJ; Andersen, PM; Remanan, R; Marklund, S; Benjamin, D (April 2013). "Pyrimethamine decreases levels of SOD1 in leukocytes and cerebrospinal fluid of ALS patients: a phase I pilot study.". Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration 14 (3): 199–204. doi:10.3109/17482968.2012.724074. PMID 22985433.
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- "It is Cheaper for an American patient to fly out to India and buy a year's supply of the medication than buy a single Daraprim tablet in the US".
- "There is no reason why the United States cannot have as vigorous a market in generic pharmaceuticals as does India".
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- Daraprim – Package insert (PDF file)
- Fansidar – sulfadoxine and pyrimethamine
- Pyrimethamine page on GoodRx.com drug price transparency web site