Pyrimethamine

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Pyrimethamine
Pyrimethamine2DACS.svg
Pyrimethamine-3D-balls.png
Clinical data
Pronunciation/ˌpɪrɪˈmɛθəmɪn/
Trade namesDaraprim, others
AHFS/Drugs.comMonograph
MedlinePlusa601050
License data
Pregnancy
category
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailabilitywell-absorbed
Protein binding87%
MetabolismLiver
Elimination half-life96 hours
ExcretionKidney
Identifiers
  • 5-(4-chlorophenyl)-6-ethyl- 2,4-pyrimidinediamine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.000.331 Edit this at Wikidata
Chemical and physical data
FormulaC12H13ClN4
Molar mass248.71 g·mol−1
3D model (JSmol)
Melting point233 to 234 °C (451 to 453 °F)
  • 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, sold under the brand name Daraprim among others, is a medication used with leucovorin (leucovorin is used to decrease side effects of pyrimethamine; it does not have intrinsic anti-parasitic activity) to treat the parasitic diseases toxoplasmosis and cystoisosporiasis.[3][4] It is also used with dapsone as a second-line option to prevent Pneumocystis jiroveci pneumonia in people with HIV/AIDS.[3] It was previously used for malaria but is no longer recommended due to resistance.[3] Pyrimethamine is taken by mouth.[3]

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

Pyrimethamine was discovered in 1952 and came into medical use in 1953.[3][5] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[6] It was approved as a generic in the United States in February 2020.[7]

Medical uses[edit]

Pyrimethamine is typically given with a sulfonamide and folinic acid.[8]

It is used for the treatment of toxoplasmosis, actinomycosis, and isosporiasis, and for the treatment and prevention of Pneumocystis jirovecii pneumonia.[3]

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.[citation needed]

Pyrimethamine has also been used in several trials to treat retinochoroiditis.[9]

Pregnancy consideration[edit]

Pyrimethamine is labeled as pregnancy category C in the United States.[1][10] To date, not enough evidence on its risks in pregnancy or its effects on the fetus is available.[10][11]

Malaria[edit]

It is primarily active against Plasmodium falciparum, but also against Plasmodium vivax.[12] 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.[12]

Contraindications[edit]

Pyrimethamine is contraindicated in people with folate-deficiency anaemia.[8]

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.[11][13] A rash, which can be indicative of a hypersensitivity reaction, is also seen, particularly in combination with sulfonamides.[11] Central nervous system effects include ataxia, tremors, and seizures.[13] Hematologic side effects such as thrombocytopenia, leukopenia, and anemia can also occur.[13]

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.[8]

Mechanism of action[edit]

Pyrimethamine interferes with the regeneration of tetrahydrofolic acid from dihydrofolate by competitively inhibiting the enzyme dihydrofolate reductase.[14] Tetrahydrofolic acid is essential for DNA and RNA synthesis in many species, including protozoa.[14] It has also been found to reduce the expression of SOD1, a key protein involved in amyotrophic lateral sclerosis.[15][16]

Other medications[edit]

Pyrimethamine is typically given with folinic acid and sulfadiazine.[10]

Mechanism of resistance[edit]

Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce its effectiveness.[17] These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions.[18]

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.[19] Pyrimethamine has been available since 1953.[20] 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.[21] In August 2015, the rights were bought by Turing Pharmaceuticals.[22] Turing subsequently became infamous 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.[23]

Society and culture[edit]

Economics[edit]

In the United States in 2015, Turing Pharmaceuticals was criticized for increasing the price 50-fold, from US$13.50 to $750 a tablet,[24] leading to a cost of $75,000 for a course of treatment reported at one hospital.[25]

United States[edit]

In the United States, in 2015, with Turing Pharmaceuticals' acquisition of the US marketing rights for Daraprim tablets,[26] Daraprim became a single-source and specialty pharmacy item, and the price was increased.[27] The cost of a monthly course for a person on 75 mg dose rose to about $75,000/month at one hospital, or $750 per tablet while it was previously priced at 13.50.[28]

Outpatients could no longer obtain the medication from a community pharmacy, but only through a single dispensing pharmacy, Walgreens Specialty Pharmacy, and institutions could no longer order from their general wholesaler, but had to set up an account with the Daraprim Direct program.[27][29] Presentations from Retrophin, a company formerly headed by Martin Shkreli, CEO of Turing, from which Turing acquired the rights to Daraprim, suggested 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]

Shkreli 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 24 November 2015, "that it would not reduce the list price of that drug after all", but they would offer patient assistance programs.[33] 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 was criticized 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. His team produced 3.7 g for US$20, which would have been worth between US$35,000 and US$110,000 in the United States at the time.[35] 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.[36][37] Nonetheless, the students' work was featured in The Guardian[36] and Time magazine,[38] and on ABC Australia,[35] the BBC,[37] and CNN.[39]

On 22 October 2015, Imprimis Pharmaceuticals announced it had 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.[40] Pyrimethamine was approved as a generic in the United States in February 2020.[7]

Other countries[edit]

In India, over a dozen manufacturers 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).[41][42][43][44]

In the UK, the same drug is available from GSK at a cost of US$20 (£13) for 30 tablets (about $0.66 each).[45]

In Australia, the drug is available in most pharmacies at a cost of US$9.35 (A$12.99) for 50 tablets (around US$0.18 each).[46]

In Brazil, the drug is available for R$0.07 a pill, or about US$0.02.[47]

In Canada, the drug was reportedly discontinued in 2013, but hospitals may make the drug in-house when it is needed.[48] As of December 2015, Daraprim imported into Canada directly from GSK UK is available from an online pharmacy for US$2.20 per tablet.[49]

In Switzerland, the drug is available for US$9.45 (CHF9.05) for 30 tablets (around US$0.32 a piece).[50]

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.[51] It is being evaluated in clinical trials as a treatment for amyotrophic lateral sclerosis.[52]

See also[edit]

References[edit]

  1. ^ a b c "Pyrimethamine (Daraprim) Use During Pregnancy". Drugs.com. 31 July 2019. Retrieved 28 February 2020.
  2. ^ "Daraprim Tablets – Summary of Product Characteristics (SmPC)". (emc). 19 February 2020. Retrieved 28 February 2020.
  3. ^ a b c d e f g h i j k "Pyrimethamine". The American Society of Health-System Pharmacists. Archived from the original on 2 December 2016. Retrieved 2 December 2016.
  4. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 54. ISBN 9781284057560.
  5. ^ Sylvie, Manguin; Pierre, Carnevale; Jean, Mouchet (2008). Biodiversity of Malaria in the world. John Libbey Eurotext. p. 6. ISBN 9782742009633.
  6. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ^ a b "FDA Approves First Generic of Daraprim". U.S. Food and Drug Administration (FDA) (Press release). 28 February 2020. Retrieved 28 February 2020.
  8. ^ 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.
  9. ^ Pradhan E, Bhandari S, Gilbert RE, Stanford M (2016). "Antibiotics versus no treatment for toxoplasma retinochoroiditis" (PDF). Cochrane Database Syst Rev. 5 (5): CD002218. doi:10.1002/14651858.CD002218.pub2. PMC 7100541. PMID 27198629.
  10. ^ a b c "Daraprim- pyrimethamine tablet". DailyMed. 31 August 2017. Retrieved 28 February 2020.
  11. ^ a b c "Pyrimethamine | FDA Label - Tablet | AIDSinfo". AIDSinfo. Archived from the original on 18 January 2017. Retrieved 7 November 2016.
  12. ^ a b Brayfield, A, ed. (13 December 2013). "Pyrimethamine". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 12 April 2014.
  13. ^ a b c "Daraprim Side Effects in Detail - Drugs.com". www.drugs.com. Archived from the original on 8 November 2016. Retrieved 7 November 2016.
  14. ^ a b "Product Information Daraprim Tablets". TGA eBusiness Services. Aspen Pharmacare Australia Pty Ltd. 5 December 2011. p. 1. Archived from the original on 5 October 2016. Retrieved 12 April 2014.
  15. ^ 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. Archived (PDF) from the original on 13 April 2014.
  16. ^ 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. S2CID 39846211.
  17. ^ 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.
  18. ^ 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.
  19. ^ Vasudevan, D.M.; Sreekumari, S.; Vaidyanathan, Kannan (2013). Textbook of Biochemistry for Medical Students. JP Medical Ltd. p. 491. ISBN 9789350905302. OCLC 843532694. Archived from the original on 8 September 2017. Retrieved 15 January 2016.
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  22. ^ John LaMattina (21 September 2015). "Here's A Way For Pharma To Prevent Outrageous Generic Price Increases – And Help Its Reputation". Forbes. Archived from the original on 23 September 2015.
  23. ^ Kliff, Sarah (22 September 2015). "Vox Explainers: A Drug Company Raised a Pill's Price 5,500 Percent Because, in America, It Can". Vox. Archived from the original on 10 December 2015. Retrieved 9 December 2015.
  24. ^ Pollack, Andrew (20 September 2015). "Drug Goes From $13.50 a Tablet to $750, Overnight". The New York Times. Retrieved 31 March 2020. Turing immediately raised the price to $750 a tablet from $13.50, bringing the annual cost of treatment for some patients to hundreds of thousands of dollars.
  25. ^ 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): 1904–07. doi:10.1056/nejmp1601559. PMID 27192669. Heavy scrutiny followed, and although Turing agreed to reduce the price, the drug remains prohibitively expensive for many patients. Recently, at our hospital, an immigrant patient with a new diagnosis of HIV– AIDS and toxoplasmosis couldn’t receive first-line therapy because of cost: the price for 100 pills was $75,000.
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  27. ^ a b Monica V. Mahoney New Pyrimethamine Dispensing Program: What Pharmacists Should Know Archived 2015-09-06 at the Wayback Machine PharmacyTimes, 17 July 2015
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  29. ^ a b "The Most Unconscionable Drug Price Hike I Have Yet Seen" Archived 2016-06-07 at the Wayback Machine, by Derek Lowe, 11 September 2014, In the Pipeline.
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  33. ^ a b Pollack, Andrew (24 November 2015). "Turing Refuses to Lower List Price of Toxoplasmosis Drug". New York Times. Archived from the original on 8 September 2017. Retrieved 25 November 2015.
  34. ^ "Archived copy" (PDF). Archived (PDF) from the original on 23 September 2015. Retrieved 23 September 2015.CS1 maint: archived copy as title (link)
  35. ^ a b Hunjan, Raveen (30 November 2016). "Daraprim drug's key ingredient recreated by high school students in Sydney for just $20". ABC News. Retrieved 23 April 2019.
  36. ^ a b Davey, Melissa (1 December 2016). "Australian students recreate Martin Shkreli price-hike drug in school lab". The Guardian. Archived from the original on 1 December 2016. Retrieved 1 December 2016.
  37. ^ a b Dunlop, Greg (1 December 2016). "Australian boys recreate life-saving drug". BBC News. Archived from the original on 1 December 2016. Retrieved 1 December 2016.
  38. ^ Lui, Kevin (2 December 2016). "Watch Martin Shkreli Respond to the School Kids Who Recreated His Drug for $2 a Dose". Time. Retrieved 23 April 2019.
  39. ^ Roberts, Elizabeth (1 December 2016). "'Pharma Bro' Martin Shkreli meets his match in a group of Australian schoolboys". CNN. Retrieved 23 April 2019.
  40. ^ "Express Scripts, Imprimis to offer $1 Daraprim alternative". December 2015.
  41. ^ "High Drug Prices: Should We Blame Pharma Or The FDA?". 29 September 2015. Archived from the original on 30 September 2015.
  42. ^ "Medline India – Sulfadoxine with Pyrimethamine". www.medlineindia.com. Archived from the original on 24 September 2015. Retrieved 22 September 2015.
  43. ^ "It is Cheaper for an American patient to fly out to India and buy a year's supply of the medication than buy a single Daraprim tablet in the US". 25 September 2015. Archived from the original on 28 September 2015.
  44. ^ "There is no reason why the United States cannot have as vigorous a market in generic pharmaceuticals as does India". 24 September 2015. Archived from the original on 6 October 2015.
  45. ^ "What's a fair price for a drug?". BBC News. 22 September 2015. Archived from the original on 24 September 2015. Retrieved 23 September 2015.
  46. ^ "Chemist Warehouse". www.chemistwarehouse.com.au. Archived from the original on 22 December 2015. Retrieved 12 December 2015.
  47. ^ "Remédio que teve aumento de 5.000% nos EUA custa R$ 0,07 no Brasil (e não vai aumentar)". brasilpost.com.br. Archived from the original on 25 September 2015. Retrieved 23 September 2015.
  48. ^ "Turing CEO to roll back 5,000% price hike for Daraprim pills". 22 September 2015. Archived from the original on 25 September 2015.
  49. ^ "Daraprim 25mg and/or Equivalents". Retrieved 18 December 2015.
  50. ^ "Swiss Compendium information about Daraprim". compendium.ch. Retrieved 1 September 2017.
  51. ^ 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.
  52. ^ "Pyrimethamine ALS trial". Archived from the original on 19 October 2012.

External links[edit]

  • "Pyrimethamine". Drug Information Portal. U.S. National Library of Medicine.