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Pyrimethamine

Pyrimethamine
Systematic (IUPAC) name
5-(4-chlorophenyl)-6-ethyl- 2,4-pyrimidinediamine
Clinical data
Pronunciation
Trade names Daraprim
AHFS/Drugs.com
MedlinePlus
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability well-absorbed
Protein binding 87%
Metabolism Hepatic
Biological half-life 96 hours
Excretion Renal
Identifiers
CAS Registry Number  Y
ATC code P01
QP51 (combinations)
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  Y
ChEMBL  Y
PDB ligand ID CP6 (, )
Chemical data
Formula C12H13ClN4
Molecular mass 248.71 g/mol
 Y   

Pyrimethamine (trade name Daraprim) is a health system.[1]

Contents

  • History 1
  • Medical uses 2
    • Mechanism of resistance 2.1
  • Side effects 3
    • Contraindications 3.1
    • Interactions 3.2
  • Physicochemistry 4
  • Mechanism of action 5
  • Synthesis 6
  • Availability and price 7
  • References 8
  • External links 9

History

The Nobel Prize-winning American scientist Gertrude Elion developed the drug at Burroughs-Wellcome (now part of GlaxoSmithKline) to combat malaria.[2] Pyrimethamine has been available since 1953,[3] and is not subject to any unexpired patent.[4] In the United States the market for this product is quite small so no generic manufacturer has emerged. In 2010 GlaxoSmithKline sold the marketing rights for Daraprim to CorePharma and in 2015 the rights were bought by Turing Pharmaceuticals.[5]

Medical uses

Pyrimethamine is typically given with a sulfonamide and folinic acid:[6]

It is primarily active against Plasmodium falciparum, but also against Plasmodium vivax.[7] 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.[7] It has been used in the treatment of actinomycosis and isosporiasis, and for the treatment and prevention of Pneumocystis jirovecii pneumonia.

In 2011, researchers discovered that pyrimethamine can increase β-hexosaminidase activity, thus potentially slowing down the progression of late-onset Tay–Sachs disease.[8] It is being evaluated in clinical trials as a treatment for amyotrophic lateral sclerosis.[9]

Mechanism of resistance

Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce its effectiveness.[10] These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions.[11]

Side effects

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.[6]

Contraindications

Pyrimethamine is contraindicated in patients with:[6]

Interactions

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.[6]

Physicochemistry

It is a white, colourless, crystalline powder; it is practically insoluble in water and slightly soluble in ethanol, chloroform, and acetone.[7] It is unstable in the presence of air and light.[7] It is chemically a diaminopyrimidine derivative.[7]

Mechanism of action

Pyrimethamine interferes with tetrahydrofolic acid synthesis from folic acid by inhibiting the enzyme dihydrofolate reductase (DHFR).[12] Tetrahydrofolic acid is needed for DNA and RNA synthesis in many species, including protozoa.[12] It has also been found to reduce the expression of SOD1, a key protein involved in amyotrophic lateral sclerosis.[13][14]

Synthesis

Pyrimethamine synthesis.[15][16][17]

Condensation of p-chlorophenylacetonitrile with ethyl propionate in the presence of sodium methoxide gives the cyanoketone (3). Treatment with trimethyl orthoformate affords the methyl enol ether of that compound (4). Condensation with guanidine affords pyrimethamine (5).

Availability and price

In the United States, as of 2015, with Turing Pharmaceuticals' acquisition of the US marketing rights for Daraprim tablets,[18] Daraprim has become a single-source and specialty pharmacy item, and the cost of Daraprim has increased.[19] The cost of a monthly course for a person on 75 mg dose rose to about $75,000/month, from $13/tablet to $833/tablet,[20] or $750 per tablet.[21][22] 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.[19][23]

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."[24][25] As a result of the backlash, Shkreli hired a crisis public relations firm to help explain his fund's move.[26]

The price increase has been fiercely criticised by physician groups such as HIV Medicine Associates and Infectious Diseases Society of America.[27]

In India, over a dozen pharmaceutical companies manufacture and sell pyrimethamine tablets in India, and, multiple combinations of generic pyrimethamine are available for a price ranging from US$0.04–$0.10 each (3–7 rupees).[28][29][30][31]

In the UK, the same drug is available from GSK at a cost of US$20 (£13) for 30 tablets (approximately $0.66 each).[32]

As of September 2015, Daraprim imported directly from GSK UK is available for less than US$7 per tablet.[33]

In Brazil, the drug is available for R$0.07 a pill, or about US$0.02.[34]

In Canada, the drug was reportedly discontinued in 2013 but hospitals may make the drug in-house when it is needed.[35]

On October 22, 2015, Imprimis Pharmaceuticals announced it has made available a formulation of Pyrimethamine and Leucovorin in oral capsules starting as low as $99.00 for a 100 count bottle. [36]

References

  1. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  2. ^ "Gertrude Elion". 
  3. ^ Ariana Eunjung Cha (2015-09-22). "CEO who raised price of old pill more than $700 calls journalist a 'moron' for asking why".  
  4. ^ FDA AccessData entry for Pyrimethamine, accessed September 24, 2015
  5. ^ John LaMattina (2015-09-21). "Here's A Way For Pharma To Prevent Outrageous Generic Price Increases -- And Help Its Reputation".  
  6. ^ a b c d Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust.  
  7. ^ a b c d e Brayfield, A, ed. (13 December 2013). "Pyrimethamine". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 12 April 2014. 
  8. ^ 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.  
  9. ^ "Pyrimethamine ALS trial". 
  10. ^ Gatton M.L.; et al. (2004). "Plasmodium falciparum"Evolution of resistance to sulfadoxine-pyrimethamine in . Antimicrob Agents Chemother 48 (6): 2116–23.  
  11. ^ 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.  
  12. ^ a b "PRODUCT INFORMATION DARAPRIM TABLETS". TGA eBusiness Services. Aspen Pharmacare Australia Pty Ltd. 5 December 2011. p. 1. Retrieved 12 April 2014. 
  13. ^ 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.  
  14. ^ 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.  
  15. ^ Russell, P. B.; Hitchings, G. H. (1951). "2,4-Diaminopyrimidines as Antimalarials. III. 5-Aryl Derivatives". Journal of the American Chemical Society 73 (8): 3763.  
  16. ^ 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 Berichte 87 (3): 435.  
  17. ^ DE 2258238  U.S. Patent 2,576,939 U.S. Patent 2,602,794 U.S. Patent 2,680,740
  18. ^ Turing Pharmaceuticals AG Turing Pharmaceuticals AG Acquires U.S. Marketing Rights to DARAPRIM® (pyrimethamine) 10 August 2015, PR Newswire Association LLC
  19. ^ a b Monica V. Mahoney New Pyrimethamine Dispensing Program: What Pharmacists Should Know PharmacyTimes, July 17, 2015
  20. ^ Daraprim Prices, GoodRx, Inc. accessed 9 September 2015, quote: 60x 25 mg tablets varied between US$45,615.80 and US$49,226.25.
  21. ^ ANDREW POLLACK (20 September 2015). "Drug Goes From $13.50 a Tablet to $750, Overnight". Retrieved 21 September 2015. 
  22. ^ "'"WATCH: Ex-hedge funder who hiked AIDS pill cost by 5,500 percent says drug 'still underpriced. RawStory.com. Retrieved 22 September 2015. 
  23. ^ "The Most Unconscionable Drug Price Hike I Have Yet Seen", by Derek Lowe, September 11, 2014, In the Pipeline.
  24. ^ Ramsey, Lydia (22 Sep 2015). "A pharma CEO tried to defend his decision to jack up the price of a critical drug by 5,000% — and it backfired". Business Insider. 
  25. ^ Reuters (22 Sep 2015). "Company hikes price of popular drug". Reuters. 
  26. ^ Tannahill, Jason (9 Oct 2015). "PR Man Allan Ripp Representing The “Most Hated Man in America”". EverythingPR. 
  27. ^ http://www.hivma.org/uploadedFiles/HIVMA/HomePageContent/PyrimethamineLetterFINAL.pdf
  28. ^ "MEDLINE INDIA - SULFADOXINE WITH PYRIMETHAMINE". www.medlineindia.com. Retrieved 2015-09-22. 
  29. ^ "It is Cheaper for an American patient to fly out to India and buy a year's supply of the medication than buy a single Daraprim tablet in the US". 
  30. ^ "There is no reason why the United States cannot have as vigorous a market in generic pharmaceuticals as does India". 
  31. ^ "High Drug Prices: Should We Blame Pharma Or The FDA?". 
  32. ^ "What's a fair price for a drug? - BBC News". www.bbc.com. Retrieved 2015-09-23. 
  33. ^ "Daraprim 25mg and/or Equivalents". Retrieved 2015-09-28. 
  34. ^ "Remédio que teve aumento de 5.000% nos EUA custa R$ 0,07 no Brasil (e não vai aumentar)". brasilpost.com.br. Retrieved 2015-09-23. 
  35. ^ "Turing CEO to roll back 5,000% price hike for Daraprim pills". 
  36. ^ "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. 

External links

  • Daraprim – Package insert (PDF file)
  • Fansidar – sulfadoxine and pyrimethamine
  • Pyrimethamine page on GoodRx.com drug price transparency web site
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