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'''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 [[immunocompromise]]d patients, such as [[HIV]]-positive individuals.
'''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 [[immunocompromise]]d patients, such as [[HIV]]-positive individuals. It is also currently being evaluated<ref>{{cite web|title=Pyrimethamine ALS trial|url=http://clinicaltrials.gov/ct2/show/NCT01083667}}</ref> in clinical trials as a treatment for [[ALS]].


==Mechanism of action==
==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.
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. Pyrimethamine has also found to inhibit [[SOD1]], a key protein involved in [[ALS]]


==Mechanism of resistance==
==Mechanism of resistance==

Revision as of 00:56, 19 May 2012

Pyrimethamine
Clinical data
Trade namesDaraprim
AHFS/Drugs.comMonograph
MedlinePlusa601050
Pregnancy
category
  • AU: B3
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailabilitywell-absorbed
Protein binding87%
MetabolismHepatic
Elimination half-life96 hours
ExcretionRenal
Identifiers
  • 5-(4-chlorophenyl)-6-ethyl- 2,4-pyrimidinediamine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.331 Edit this at Wikidata
Chemical and physical data
FormulaC12H13ClN4
Molar mass248.71 g/mol g·mol−1
3D model (JSmol)
  • Clc2ccc(c1c(nc(nc1CC)N)N)cc2
  • InChI=1S/C12H13ClN4/c1-2-9-10(11(14)17-12(15)16-9)7-3-5-8(13)6-4-7/h3-6H,2H2,1H3,(H4,14,15,16,17) checkY
  • Key:WKSAUQYGYAYLPV-UHFFFAOYSA-N checkY
  (verify)

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[1] in clinical trials as a treatment for ALS.

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. Pyrimethamine 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.[2] These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions.[3]

Clinical use

Pyrimethamine is typically given with a sulfonamide and folinic acid:

  • sulfonamides inhibit dihydropteroate synthetase, an enzyme that participates in folic acid synthesis from para-aminobenzoic acid. Hence, sulfonamides work synergistically [citation needed] 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

Pyrimethamine may deplete folic acid in humans, resulting in hematologic side effects associated with folate deficiency.

Side effects include:

Contraindications

Pyrimethamine is contraindicated in patients with:

  • hypersensitivity to pyrimethamine
  • megaloblastic anemia – depletion of folic acid may aggravate this condition

Notes

  1. ^ "Pyrimethamine ALS trial".
  2. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)
  3. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)

References

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