Pyrimethamine

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Pyrimethamine
Pyrimethamine2DACS.svg
Pyrimethamine-3D-balls.png
Clinical data
Pronunciation /ˌpɪrˈmɛθəmin/
Trade names Daraprim
AHFS/Drugs.com Monograph
MedlinePlus a601050
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
By mouth
ATC code P01BD01 (WHO)
QP51AX51 (WHO) (combinations)
Legal status
Legal status
Pharmacokinetic data
Bioavailability well-absorbed
Protein binding 87%
Metabolism Liver
Biological half-life 96 hours
Excretion Kidney
Identifiers
IUPAC name: 5-(4-chlorophenyl)-6-ethyl- 2,4-pyrimidinediamine
CAS Number 58-14-0 YesY
PubChem (CID) 4993
IUPHAR/BPS 4800
DrugBank DB00205 YesY
ChemSpider 4819 YesY
UNII Z3614QOX8W YesY
KEGG D00488 YesY
ChEBI CHEBI:8673 YesY
ChEMBL CHEMBL36 YesY
PDB ligand ID CP6 (PDBe, RCSB PDB)
Chemical and physical data
Formula C12H13ClN4
Molar mass 248.71 g/mol
3D model (Jmol) Interactive image
  (verify)

Pyrimethamine, sold under the trade name Daraprim, is a medication used with leucovorin to treat toxoplasmosis and cystoisosporiasis.[1][2] It is also used with dapsone as a second line option to prevent Pneumocystis jiroveci pneumonia (PCP) in people with HIV/AIDS. It was previously used for malaria but is no longer recommended due to resistance. Pyrimethamine is taken by mouth.[1]

Common side effects include gastrointestinal upset, severe allergic reactions, bone marrow suppression. It should not be used in people with folate deficiency that has resulted in anemia. There is concern that it may increase the risk of cancer.[1] While occasionally used in pregnancy it is unclear if pyrimethamine is safe for the baby.[3] Pyrimethamine is classified as a folic acid antagonist. It works by inhibition folic acid metabolism and therefore the making of DNA.[1]

Pyrimethamine was discovered in 1952 and come into medical use in 1953.[1][4] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[5] In the United States in 2015 it was not available as a generic medication and the price was increased from 13.50 USD to 750 USD a tablet (75,000 USD for a course of treatment).[6][2][7] In other areas of the world it is available as a generic and costs as little as 0.05 to 0.10 USD per dose.[8]

Medical uses[edit]

Pyrimethamine is typically given with a sulfonamide and folinic acid.[9]

It is used for the treatment of toxoplasmosis, actinomycosis, and isosporiasis, and for the treatment and prevention of Pneumocystis jirovecii pneumonia.[citation needed]

Toxoplasmosis[edit]

Pyrimethamine is also used in combination with sulfadiazine to treat active toxoplasmosis. The two drugs bind the same enzymatic targets as the drugs trimethoprim and sulfamethoxazole - dihydrofolate reductase and dihydropteroate synthase, respectively.

Pyrimethamine has also been used in several trials to treat retinochoroiditis.[10]

Pregnancy consideration[edit]

Pyrimethamine is labeled as pregnancy category C in the United States.[11] To date, not enough evidence on its risks in pregnancy or its effects on the fetus is available. [11][12]

Malaria[edit]

It is primarily active against Plasmodium falciparum, but also against Plasmodium vivax.[13] 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 was widely used, such as in Fansidar, though resistance to this combination is increasing.[13]

Contraindications[edit]

Pyrimethamine is contraindicated in people with folate-deficiency anaemia[9]

Side effects[edit]

When higher doses are used, as in the treatment of toxoplasmosis, pyrimethamine can cause gastrointestinal symptoms such as nausea, vomiting, glossitis, anorexia, and diarrhea.[14][12] A rash, which can be indicative of a hypersensitivity reaction, is also seen, particularly in combination with sulfonamides.[12] Central nervous system effects include ataxia, tremors, and seizures.[14] Hematologic side effects such as thrombocytopenia, leukopenia, and anemia can also occur.[14]

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.[9]

Mechanism of action[edit]

Pyrimethamine interferes with the regeneration of tetrahydrofolic acid from dihydrofolate by competitively inhibiting the enzyme dihydrofolate reductase.[15] Tetrahydrofolic acid is essential for DNA and RNA synthesis in many species, including protozoa.[15] Pyrimethamine has also been found to reduce the expression of SOD1, a key protein involved in amyotrophic lateral sclerosis.[16][17]

Other medications[edit]

Pyrimethamine is typically give with folinic acid and sulfadiazine.

Mechanism of resistance[edit]

Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce its effectiveness.[18] These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions.[19]

History[edit]

Synthesis of pyrimethamine typically begins with p-chlorophenylacetonitrile, which undergoes a condensation reaction with ethyl propionate ester; the product of this then reacts with diazomethane to form an enol ether, which reacts with free guanidine in a second condensation reaction.

Nobel Prize-winning American scientist Gertrude Elion developed the drug at Burroughs-Wellcome (now part of GlaxoSmithKline) to combat malaria.[20] Pyrimethamine has been available since 1953.[21] In 2010, GlaxoSmithKline sold the marketing rights for Daraprim to CorePharma. Impax Laboratories sought to buy CorePharma in 2014, and completed the acquisition, including Daraprim, in March 2015.[22] In August 2015, the rights were bought by Turing Pharmaceuticals.[23] Turing subsequently became known for a price hike controversy when it raised the price of a dose of the drug in the U.S. market from US$13.50 to US$750, a 5,500% increase.[24]

Availability and price[edit]

In the United States, as of 2015, with Turing Pharmaceuticals' acquisition of the US marketing rights for Daraprim tablets,[25] Daraprim has become a single-source and specialty pharmacy item, and the price of Daraprim has been increased.[26] The cost of a monthly course for a person on 75 mg dose rose to about $75,000/month, or $750 per tablet.[27][28] 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.[26][29] Presentations from Retrophin, a company formerly headed by Martin Shkreli, CEO of Turing, 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.[29]

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."[30][31] As a result of the backlash, Shkreli hired a crisis public relations firm to help explain his fund's move.[32] 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.[33] 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."[33]

The price increase has been fiercely criticised by physician groups such as HIV Medicine Associates and Infectious Diseases Society of America.[34]

In 2016, a group of high school students from Sydney Grammar supported by the University of Sydney prepared pyrimethamine as an illustration that the synthesis is comparatively easy and the price-hike unjustifiable. Shkreli said the schoolboys were not competition, likely because the necessary bioequivalence studies require a sample of the existing medication provided directly by the company, and not simply purchased from a pharmacy, which Turing could decline to provide.[35][36]

In India, over a dozen pharmaceutical companies manufacture and sell pyrimethamine tablets and, multiple combinations of generic pyrimethamine are available for a price ranging from US$0.04 to US$0.10 each (3–7 rupees).[37][38][39][8]

In the UK, the same drug is available from GSK at a cost of US$20 (£13) for 30 tablets (about $0.66 each).[40]

In Australia, the drug is available in most pharmacists at a cost of US$9.35 (A$12.99) for 50 tablets (around US$0.18 each).[41]

In Brazil, the drug is available for R$0.07 a pill, or about US$0.02.[42]

In Canada, the drug was reportedly discontinued in 2013, but hospitals may make the drug in-house when it is needed.[43] As of December 2015, Daraprim imported into Canada directly from GSK UK is available from an online pharmacy for US$2.20 per tablet.[44]

On October 22, 2015, Imprimis Pharmaceuticals announced it has made available compounded and customizable formulations of pyrimethamine and leucovorin in capsules to be taken by mouth starting as low as $99.00 for a 100-count bottle in the United States.[45]

Research[edit]

In 2011, researchers discovered that pyrimethamine can increase β-hexosaminidase activity, thus potentially slowing down the progression of late-onset Tay–Sachs disease.[46] It is being evaluated in clinical trials as a treatment for amyotrophic lateral sclerosis.[47]

See also[edit]

References[edit]

  1. ^ a b c d e "Pyrimethamine". The American Society of Health-System Pharmacists. Retrieved 2 December 2016. 
  2. ^ a b Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 54. ISBN 9781284057560. 
  3. ^ "Pyrimethamine (Daraprim) Use During Pregnancy". www.drugs.com. Retrieved 3 December 2016. 
  4. ^ Sylvie, Manguin; Pierre, Carnevale; Jean, Mouchet (2008). Biodiversity of Malaria in the world. John Libbey Eurotext. p. 6. ISBN 9782742009633. 
  5. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  6. ^ Mullin, Emily. "Turing Pharma Says Daraprim Availability Will Be Unaffected By Shkreli Arrest". Forbes. Retrieved 2016-11-10. 
  7. ^ Alpern, JD; Song, J; Stauffer, WM (19 May 2016). "Essential Medicines in the United States--Why Access Is Diminishing.". The New England journal of medicine. 374 (20): 1904–7. PMID 27192669. 
  8. ^ a b "High Drug Prices: Should We Blame Pharma Or The FDA?". 29 September 2015. 
  9. ^ a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. 
  10. ^ Pradhan E, Bhandari S, Gilbert RE, Stanford M (2016). "Antibiotics versus no treatment for toxoplasma retinochoroiditis". Cochrane Database Syst Rev. 5: CD002218. doi:10.1002/14651858.CD002218.pub2. PMID 27198629. 
  11. ^ a b "Daraprim - FDA prescribing information, side effects and uses". www.drugs.com. Retrieved 2016-11-07. 
  12. ^ a b c "Pyrimethamine | FDA Label - Tablet | AIDSinfo". AIDSinfo. Retrieved 2016-11-07. 
  13. ^ a b Brayfield, A, ed. (13 December 2013). "Pyrimethamine". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 12 April 2014. 
  14. ^ a b c "Daraprim Side Effects in Detail - Drugs.com". www.drugs.com. Retrieved 2016-11-07. 
  15. ^ a b "PRODUCT INFORMATION DARAPRIM TABLETS". TGA eBusiness Services. Aspen Pharmacare Australia Pty Ltd. 5 December 2011. p. 1. Retrieved 12 April 2014. 
  16. ^ 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 3678841Freely accessible. PMID 23766784. 
  17. ^ 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. 
  18. ^ 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 415611Freely accessible. PMID 15155209. 
  19. ^ 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. 
  20. ^ Vasudevan, D.M.; Sreekumari, S.; Vaidyanathan, Kannan (2013). Textbook of Biochemistry for Medical Students. JP Medical Ltd. p. 491. ISBN 9789350905302. OCLC 843532694. Retrieved January 15, 2016. 
  21. ^ Ariana Eunjung Cha (2015-09-22). "CEO who raised price of old pill more than $700 calls journalist a 'moron' for asking why". The Washington Post. 
  22. ^ Pollack, Andrew (20 September 2015). "Drug Goes From $13.50 a Tablet to $750, Overnight". New York Times. Retrieved 17 December 2015. 
  23. ^ John LaMattina (2015-09-21). "Here's A Way For Pharma To Prevent Outrageous Generic Price Increases -- And Help Its Reputation". Forbes. 
  24. ^ Kliff, Sarah (September 22, 2015). "Vox Explainers: A Drug Company Raised a Pill's Price 5,500 Percent Because, in America, It Can". Vox (online). Retrieved December 9, 2015. 
  25. ^ Turing Pharmaceuticals AG Turing Pharmaceuticals AG Acquires U.S. Marketing Rights to DARAPRIM® (pyrimethamine) 10 August 2015, PR Newswire Association LLC
  26. ^ a b Monica V. Mahoney New Pyrimethamine Dispensing Program: What Pharmacists Should Know PharmacyTimes, July 17, 2015
  27. ^ ANDREW POLLACK (20 September 2015). "Drug Goes From $13.50 a Tablet to $750, Overnight". Retrieved 21 September 2015. 
  28. ^ "WATCH: Ex-hedge funder who hiked AIDS pill cost by 5,500 percent says drug 'still underpriced'". RawStory.com. Retrieved 22 September 2015. 
  29. ^ a b "The Most Unconscionable Drug Price Hike I Have Yet Seen", by Derek Lowe, September 11, 2014, In the Pipeline.
  30. ^ Ramsey, Lydia (22 Sep 2015). "A pharma CEO tried to defend his decision to jack up the price of a critical drug by 5,000% — and it backfired". Business Insider. 
  31. ^ Reuters (22 Sep 2015). "Company hikes price of popular drug". Reuters. 
  32. ^ Tannahill, Jason (9 Oct 2015). "PR Man Allan Ripp Representing The "Most Hated Man in America"". EverythingPR. 
  33. ^ a b Pollack, Andrew (24 November 2015). "Turing Refuses to Lower List Price of Toxoplasmosis Drug". New York Times. Retrieved 25 November 2015. 
  34. ^ http://www.hivma.org/uploadedFiles/HIVMA/HomePageContent/PyrimethamineLetterFINAL.pdf
  35. ^ Davey, Melissa (December 1, 2016). "Australian students recreate Martin Shkreli price-hike drug in school lab". The Guardian. Retrieved December 1, 2016. 
  36. ^ Dunlop, Greg (1 December 2016). "Australian boys recreate life-saving drug". BBC News. Retrieved 1 December 2016. 
  37. ^ "MEDLINE INDIA - SULFADOXINE WITH PYRIMETHAMINE". www.medlineindia.com. Retrieved 2015-09-22. 
  38. ^ "It is Cheaper for an American patient to fly out to India and buy a year's supply of the medication than buy a single Daraprim tablet in the US". 
  39. ^ "There is no reason why the United States cannot have as vigorous a market in generic pharmaceuticals as does India". 
  40. ^ "What's a fair price for a drug?". BBC News. Retrieved 2015-09-23. 
  41. ^ "Chemist Warehouse". www.chemistwarehouse.com.au. Retrieved 2015-12-12. 
  42. ^ "Remédio que teve aumento de 5.000% nos EUA custa R$ 0,07 no Brasil (e não vai aumentar)". brasilpost.com.br. Retrieved 2015-09-23. 
  43. ^ "Turing CEO to roll back 5,000% price hike for Daraprim pills". 
  44. ^ "Daraprim 25mg and/or Equivalents". Retrieved 2015-12-18. 
  45. ^ "Imprimis Pharmaceuticals to Make Compounded and Customizable Formulation of Pyrimethamine and Leucovorin Available for Physicians to Prescribe for their Patients as an Alternative to Daraprim® - Oct 22, 2015". imprimispharma.investorroom.com. Retrieved 2015-10-23. 
  46. ^ 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. 
  47. ^ "Pyrimethamine ALS trial". 

External links[edit]