|Systematic (IUPAC) name|
|Pregnancy cat.||B3 (AU) C (US)|
|Legal status||Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)|
|Mol. 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 is also used (combined with the sulfonamide antibiotic sulfadiazine) in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals. It is also currently being evaluated in clinical trials as a treatment for ALS. In 2011, researchers discovered that pyrimethamine can increase ß-hexosaminidase activity, thus potentially slowing down the progression of Late-Onset Tay–Sachs disease.
- 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 that is converted to tetrahydrofolate (the primary active form of folic acid) in vivo without relying on dihydrofolate reductase. By doing so, folinic acid reduces side effects related to folate deficiency.
It is primarily active against plasmodium falciparum, but it also has activity against plasmodium vivax. Due to the emergence of pyrimethamine-resistant strains of P. falciparum pyrimethamine alone is seldom used nowadays, but in combination with a long-acting sulfonamide like sulfadiazine it is still widely used, even though resistance to this combination is on the up. It has also been used in the treatment of actinomycetoma, isosporiasis and for the treatment and prevention of pneumocystis jirovecii pneumonia.
Mechanism of resistance
Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce the effectiveness of pyrimethamine. 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 (like for toxoplasmosis) it can cause GI symptoms like nausea, vomiting, abdominal cramps, dry mouth, weight loss and diarrhoea, CNS effects like headache, ataxia and rarely seizures and haematologic side effects like 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 like pyrimethamine might have on organogenesis.
It is a white, colourless, crystalline powder and 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 ALS.
- "Pyrimethamine ALS trial".
- Osher, E; Fattal-Valevski, A; Sagie, L; Urshanski, N; Amir-Levi, Y; Katzburg, S; Peleg, L; Lerman-Sagie, T; Zimran, A; Elstein, D; Navon, R; Stern, N; Valevski, A (March 2011). "Pyrimethamine increases β-hexosaminidase A activity in patients with Late Onset Tay Sachs.". Molecular Genetics and Metabolism 102 (3): 356–63. doi:10.1016/j.ymgme.2010.11.163. PMID 21185210.
- Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
- Brayfield, A, ed. (13 December 2013). "Pyrimethamine". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 12 April 2014.
- Gatton M.L. et al. (2004). "Evolution of resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum". Antimicrob Agents Chemother 48 (6): 2116–23. doi:10.1128/AAC.48.6.2116-2123.2004. PMC 415611. PMID 15155209.
- Sirichaiwat C. et al. (2004). "Target guided synthesis of 5-benzyl-2,4-diamonopyrimidines: their antimalarial activities and binding affinities to wild type and mutant dihydrofolate reductases from Plasmodium falciparum". J Med Chem 47 (2): 345–54. doi:10.1021/jm0303352. PMID 14711307.
- "PRODUCT INFORMATION DARAPRIM TABLETS". TGA eBusiness Services. Aspen Pharmacare Australia Pty Ltd. 5 December 2011. p. 1. Retrieved 12 April 2014.
- Limpert, AS; Mattmann, ME; Cosford, ND (2013). "Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)." (PDF). Beilstein Journal of Organic Chemistry 9: 717–32. doi:10.3762/bjoc.9.82. PMC 3678841. PMID 23766784.
- 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.