Daraprim Pyrimethamine - Wikipedia, the free encyclopedia

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 when combined with the sulfonamide antibioticsulfadiazine) to treat Toxoplasma gondii infections in immunocompromised patients, such as 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.[1]

Medical uses[edit]

Pyrimethamine is typically given with a sulfonamide and folinic acid:[2]

• 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.[3] 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.[3] It has been used in the treatment of actinomycosis and isosporiasis, and for the treatment and prevention of Pneumocystis jirovecii pneumonia.[citation needed]

In 2011, researchers discovered that pyrimethamine can increase ß-hexosaminidase activity, thus potentially slowing down the progression of late-onset Tay–Sachs disease.[4] It is being evaluated in clinical trials as a treatment for amyotrophic lateral sclerosis.[5]

Mechanism of resistance[edit]

Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce its effectiveness.[6] These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions.[7]

Side effects[edit]

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.[2]

Contraindications[edit]

Pyrimethamine is contraindicated in patients with:[2]

• Folate-deficiency anaemia
• Epilepsy
• Pregnancy, especially, during the first trimester due to the possible detrimental effects an antifolate such as pyrimethamine might have on organogenesis

Interactions[edit]

Other antifolate agents such as methotrexate and trimethoprim may potentiate the antifolate actions of pyrimethamine, leading to potential folate deficiency anaemia and other blood dyscrasias.[2]

Physicochemistry[edit]

It is a white, colourless, crystalline powder and is practically insoluble in water and slightly soluble in ethanol, chloroform, and acetone.[3] It is unstable in the presence of air and light.[3] It is chemically a diaminopyrimidine derivative.[3]

Mechanism of action[edit]

Pyrimethamine interferes with tetrahydrofolic acid synthesis from folic acid by inhibiting the enzyme dihydrofolate reductase (DHFR).[8] Tetrahydrofolic acid is needed for DNA and RNA synthesis in many species, including protozoa.[8] It has also been found to reduce the expression of SOD1, a key protein involved in amyotrophic lateral sclerosis.[9][10]

Synthesis[edit]

Condensation of phenylacetonitrile with ethyl propionate in the presence of sodium ethoxide gives the cyanoketone (3). Treatment with diazomethane affords the methyl enol ether of that compound (4). Condensation with guanidine affords pyrimethamine (5).

Availability, price[edit]

In the U.S. as of 2015, with the acquisition of Daraprim tablets by Turing Pharmaceuticals,[13] pyrimethamine has become a single-source and specialty pharmacy item, and the cost of pyrimethamine has increased.[14] The cost of a monthly course for a person on 75 mg rose to about $75,000/month, from $13/tablet to $833/tablet.[15] Outpatients can no longer obtain pyrimethamine 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.[14]

References[edit]

1. ^"WHO Model List of EssentialMedicines"(PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
2. ^ abcdRossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. 
3. ^ abcdeBrayfield, A, ed. (13 December 2013). "Pyrimethamine". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 12 April 2014. 
4. ^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 Metabolism102 (3): 356–63. doi:10.1016/j.ymgme.2010.11.163. PMID 21185210. 
5. ^"Pyrimethamine ALS trial". 
6. ^Gatton M.L. et al. (2004). "Evolution of resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum". Antimicrob Agents Chemother48 (6): 2116–23. doi:10.1128/AAC.48.6.2116-2123.2004. PMC 415611. PMID 15155209. 
7. ^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 Chem47 (2): 345–54. doi:10.1021/jm0303352. PMID 14711307. 
8. ^ ab"PRODUCT INFORMATION DARAPRIM TABLETS". TGA eBusiness Services. Aspen Pharmacare Australia Pty Ltd. 5 December 2011. p. 1. Retrieved 12 April 2014. 
9. ^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 Chemistry9: 717–32. doi:10.3762/bjoc.9.82. PMC 3678841. PMID 23766784. 
10. ^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 Degeneration14 (3): 199–204. doi:10.3109/17482968.2012.724074. PMID 22985433. 
11. ^Russell, P. B.; Hitchings, G. H. (1951). "2,4-Diaminopyrimidines as Antimalarials. III. 5-Aryl Derivatives". Journal of the American Chemical Society73 (8): 3763. doi:10.1021/ja01152a060. 
12. ^Logemann, W.; Almirante, L.; Caprio, L. (1954). "Studien in der heterocyclischen Reihe. I. Mitteil.: Eine neue Synthese der 2.4-Diamino-6-alkyl-5-aryl-pyrimidine ("Daraprim")". Chemische Berichte87 (3): 435. doi:10.1002/cber.19540870324. 
13. ^Turing Pharmaceuticals AG Turing Pharmaceuticals AG Acquires U.S. Marketing Rights to DARAPRIM® (pyrimethamine) 10 August 2015, PR Newswire Association LLC
14. ^ abMonica V. MahoneyNew Pyrimethamine Dispensing Program: What Pharmacists Should Know PharmacyTimes, July 17, 2015
15. ^Daraprim Prices, GoodRx, Inc. accessed 9 September 2015, quote: 60x 25 mg tablets varied between US$45,615.80 and US$49,226.25.

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