|Systematic (IUPAC) name|
|Pregnancy cat.||B3 (AU) C (US)|
|Legal status||℞ Prescription only|
|Mol. mass||248.71 g/mol|
| (what is this?)
Pyrimethamine (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 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 have discovered that Pyrimethamine can increase ß-hexosaminidase activity, thus slowing down the progression of Late-Onset Tay–Sachs disease.
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 found to inhibit SOD1, a key protein involved in ALS.
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.
- 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.
Use in mass drug administrations
Pyrimethamine has been extensively used as monotherapy in mass drug administrations in Asia and South America, which is likely to have contributed to the emergence and spread of pyrimethamine-resistant Plasmodium falciparum strains.
Side effects include:
- hypersensitivity reactions
- megaloblastic anemia
- atrophic glossitis
- cardiac arrhythmias
- pulmonary eosinophilia (rare)
- hyperphenylalaninemia (particularly when used with a sulfonamide)
- Stevens–Johnson syndrome (particularly when used with a sulfonamide)
- toxic epidermal necrolysis (particularly when used with a sulfonamide)
Pyrimethamine is contraindicated in patients with:
- hypersensitivity to pyrimethamine
- megaloblastic anemia – depletion of folic acid may aggravate this condition
- "Pyrimethamine ALS trial".
- 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.