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.[ It was previously used for malaria but is no longer recommended due to resistance.][ Pyrimethamine is taken by mouth.]
Common side effects include gastrointestinal upset, severe allergic reactions, and bone marrow suppression.[ It should not be used by people with folate deficiency that has resulted in anemia.][ There is concern that it may increase the risk of cancer.][ While occasionally used in pregnancy it is unclear if pyrimethamine is safe for the baby.][ It works by inhibiting folic acid metabolism and therefore the making of DNA.][
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Pyrimethamine was discovered in 1952 and came into medical use in 1953.
Medical uses
Pyrimethamine is typically given with a sulfonamide and folinic acid.
It is used for the treatment of toxoplasmosis, actinomycosis, and isosporiasis, and for the treatment and prevention of Pneumocystis jirovecii pneumonia.[
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Toxoplasmosis
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.
Pregnancy consideration
Pyrimethamine is labeled as pregnancy category C in the United States.
Malaria
It is primarily active against Plasmodium falciparum, but also against Plasmodium vivax.[
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Contraindications
Pyrimethamine is contraindicated in people with folate-deficiency anaemia.[
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Side effects
When higher doses are used, as in the treatment of toxoplasmosis, pyrimethamine can cause gastrointestinal symptoms such as nausea, vomiting, glossitis, anorexia, and diarrhea.
Interactions
Other antifolate agents such as methotrexate and trimethoprim may potentiate the antifolate actions of pyrimethamine, leading to potential folate deficiency, anaemia, and other .[
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Mechanism of action
Pyrimethamine interferes with the regeneration of tetrahydrofolic acid from dihydrofolate by competitively inhibiting the enzyme dihydrofolate reductase.[ It has also been found to reduce the expression of SOD1, a key protein involved in amyotrophic lateral sclerosis.]
Other medications
Pyrimethamine is typically given with folinic acid and sulfadiazine.
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Sulfonamides (e.g. sulfadiazine) 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.
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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.
Mechanism of resistance
Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce its effectiveness.
History
Nobel Prize-winning American scientist Gertrude Elion developed the drug at Burroughs-Wellcome (now part of GlaxoSmithKline) to combat malaria.
Society and culture
Economics
In the United States in 2015, Turing Pharmaceuticals was criticized for increasing the price 50-fold, from US$13.50 to $750 a tablet,
United States
In the United States, in 2015, with Turing Pharmaceuticals' acquisition of the US marketing rights for Daraprim tablets,
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.[
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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."
The price increase was criticized by physician groups such as HIV Medicine Associates and Infectious Diseases Society of America.
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.
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 for a 100-count bottle in the United States.
In January 2020, the FTC filed a case against Vyera "alleging an elaborate anticompetitive scheme to preserve a monopoly for the life-saving drug, Daraprim".
Other countries
In India, multiple combinations of generic pyrimethamine are available for a price ranging from US$0.04 to US$0.10 each (3–7 rupees).
In the UK, the same drug is available from GlaxoSmithKline at a cost of US$20 (£13) for 30 tablets (about $0.66 each).
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).
In Brazil, the drug is available for R$0.07 a pill, or about US$0.02.
In Switzerland, the drug is available for US$9.45 (CHF9.05) for 30 tablets (around US$0.32 a piece).
Research
In 2011, researchers discovered that pyrimethamine can increase β-hexosaminidase activity, thus potentially slowing down the progression of late-onset Tay–Sachs disease.
See also
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Sulfadoxine/pyrimethamine
External links
