Pyrimethamine, sold under the brand name Daraprim among others, is a medication used with

leucovorin Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to tr ...

(leucovorin is used to decrease side effects of pyrimethamine; it does not have intrinsic anti-parasitic activity) to treat the parasitic diseases

toxoplasmosis Toxoplasmosis is a parasitic disease caused by ''Toxoplasma gondii'', an apicomplexan. Infections with toxoplasmosis are associated with a variety of neuropsychiatric and behavioral conditions. Occasionally, people may have a few weeks or months ...

and

cystoisosporiasis Isosporiasis, also known as cystoisosporiasis, is a human intestinal disease caused by the parasite ''Cystoisospora belli'' (previously known as ''Isospora belli''). It is found worldwide, especially in tropical and subtropical areas. Infection of ...

. It is also used with

dapsone Dapsone, also known as 4,4'-sulfonyldianiline (SDA) or diaminodiphenyl sulfone (DDS), is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is a second-line medication for the treatment a ...

as a second-line option to prevent ''Pneumocystis jiroveci'' pneumonia in people with

HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...

. It was previously used for

malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...

but is no longer recommended due to resistance. Pyrimethamine is taken by mouth. Common side effects include gastrointestinal upset, severe

allergic reactions Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

, and

bone marrow suppression Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity ( leukocytes), carrying oxygen ( erythrocytes), and/or those responsible for normal blood clotting ...

. It should not be used by people with

folate deficiency Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. Signs of folate deficiency are often subtle. A low number of red blood cells (anemia) is a late finding in folate deficiency and folate ...

that has resulted in

anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...

. 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. Pyrimethamine is classified as a

folic acid antagonist Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine ...

. It works by inhibiting

folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...

metabolism and therefore the making of DNA. Pyrimethamine was discovered in 1952 and came into medical use in 1953. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...

. It was approved as a

generic Generic or generics may refer to: In business * Generic term, a common name used for a range or class of similar things not protected by trademark * Generic brand, a brand for a product that does not have an associated brand or trademark, other ...

in the United States in February 2020.

Medical uses

Pyrimethamine is typically given with a

sulfonamide In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactive. ...

and

folinic acid Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to ...

. It is used for the treatment of toxoplasmosis,

actinomycosis Actinomycosis is a rare infectious bacterial disease caused by ''Actinomyces'' species. The name refers to ray-like appearance of the organisms in the granules. About 70% of infections are due to either '' Actinomyces israelii'' or '' A. gerencser ...

, and

isosporiasis Isosporiasis, also known as cystoisosporiasis, is a human intestinal disease caused by the parasite ''Cystoisospora belli'' (previously known as ''Isospora belli''). It is found worldwide, especially in tropical and subtropical areas. Infection of ...

, and for the treatment and prevention of ''

Pneumocystis jirovecii ''Pneumocystis jirovecii'' (previously ''P. carinii'') is a yeast-like fungus of the genus ''Pneumocystis''. The causative organism of ''Pneumocystis'' pneumonia, it is an important human pathogen, particularly among immunocompromised hosts. Pr ...

'' pneumonia.

Toxoplasmosis

Pyrimethamine is also used in combination with sulfadiazine to treat active

. The two drugs bind the same enzymatic targets as the drugs

trimethoprim Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for ''Pneumocystis'' pneumonia in peop ...

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. To date, not enough evidence on its risks in pregnancy or its effects on the fetus is available.

Malaria

It is primarily active against ''

Plasmodium falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...

'', but also against ''

Plasmodium vivax ''Plasmodium vivax'' is a protozoal parasite and a human pathogen. This parasite is the most frequent and widely distributed cause of recurring malaria. Although it is less virulent than ''Plasmodium falciparum'', the deadliest of the five huma ...

''. 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 Sulfadoxine/pyrimethamine, sold under the brand name Fansidar, is a combination medication used to treat malaria. It contains sulfadoxine (a sulfonamide) and pyrimethamine (an antiprotozoal). For the treatment of malaria it is typically used a ...

, though resistance to this combination is increasing.

Contraindications

Pyrimethamine is contraindicated in people with folate-deficiency anaemia.

Side effects

When higher doses are used, as in the treatment of toxoplasmosis, pyrimethamine can cause gastrointestinal symptoms such as nausea, vomiting,

glossitis Glossitis can mean soreness of the tongue, or more usually inflammation with depapillation of the dorsal surface of the tongue (loss of the lingual papillae), leaving a smooth and erythematous (reddened) surface, (sometimes specifically termed atro ...

, anorexia, and diarrhea. A rash, which can be indicative of a hypersensitivity reaction, is also seen, particularly in combination with sulfonamides. Central nervous system effects include ataxia, tremors, and seizures. Hematologic side effects such as

thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...

leukopenia Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...

, and anemia can also occur.

Interactions

Other antifolate agents such as

methotrexate Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...

and

may potentiate the antifolate actions of pyrimethamine, leading to potential folate deficiency, anaemia, and other

blood dyscrasia In medicine, both ancient and modern, a dyscrasia is any of various disorders. The word has ancient Greek roots meaning "bad mixture". The concept of dyscrasia was developed by the Greek physician Galen (129–216 AD), who elaborated a model of h ...

Mechanism of action

Pyrimethamine interferes with the regeneration of

tetrahydrofolic acid Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative. Metabolism Human synthesis Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate. It is conv ...

from

dihydrofolate Dihydrofolic acid (conjugate base dihydrofolate) (DHF) is a folic acid (vitamin B9, vitamin B9) derivative which is converted to tetrahydrofolic acid by dihydrofolate reductase. Since tetrahydrofolate is needed to make both purines and pyrimidine ...

by competitively inhibiting the enzyme dihydrofolate reductase. Tetrahydrofolic acid is essential for DNA and

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

synthesis in many species, including protozoa. It has also been found to reduce the expression of

SOD1 Superoxide dismutase u-Zn'' also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the ''SOD1'' gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, fam ...

, a key protein involved in amyotrophic lateral sclerosis.

Other medications

Pyrimethamine is typically given with folinic acid and sulfadiazine. *

Sulfonamide In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactive. ...

s (e.g. sulfadiazine) inhibit

dihydropteroate synthetase Dihydropteroate synthase is an enzyme classified under . It produces dihydropteroate in bacteria, but it is not expressed in most eukaryotes including humans. This makes it a useful target for sulfonamide antibiotics, which compete with the PA ...

, an enzyme that participates in folic acid synthesis from

para-aminobenzoic acid 4-Aminobenzoic acid (also known as ''para''-aminobenzoic acid or PABA because the two functional groups are attached to the benzene ring across from one another in the ''para'' position) is an organic compound with the formula H2NC6H4CO2H. PABA i ...

. Hence, sulfonamides work synergistically with pyrimethamine by blocking a different enzyme needed for folic acid synthesis. *

Folinic acid Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to ...

(leucovorin) is a folic acid derivative converted to

tetrahydrofolate Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative. Metabolism Human synthesis Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate. It is co ...

, the primary active form of folic acid, ''in vivo'', without relying on dihydrofolate reductase. Folinic acid reduces side effects related to

in the patient.

Mechanism of resistance

Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce its effectiveness. These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of

hydrogen bonds In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...

and

steric Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...

interactions.

History

Nobel Prize The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel's will of 1895, are awarded to "those who, during the preceding year, have conferred the greatest benefit to humankind." Alfr ...

-winning American scientist

Gertrude Elion Gertrude "Trudy" Belle Elion (January 23, 1918 – February 21, 1999) was an American biochemist and pharmacologist, who shared the 1988 Nobel Prize in Physiology or Medicine with George H. Hitchings and Sir James Black for their use of innovat ...

developed the drug at Burroughs-Wellcome (now part of GlaxoSmithKline) to combat malaria. Pyrimethamine has been available since 1953. In 2010,

GlaxoSmithKline GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the ten ...

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. In August 2015, the rights were bought by

Turing Pharmaceuticals Vyera Pharmaceuticals (formerly Turing Pharmaceuticals) is a pharmaceutical company incorporated in Zug, Switzerland, with offices in New York City. The company started to do business in the US as Vyera Pharmaceuticals in September 2017. The com ...

. 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.

Society and culture

Economics

In the United States in 2015,

was criticized for increasing the price 50-fold, from US$13.50 to $750 a tablet, leading to a cost of $75,000 for a course of treatment reported at one hospital.

United States

In the United States, in 2015, with Turing Pharmaceuticals' acquisition of the US marketing rights for Daraprim tablets, Daraprim became a single-source and specialty pharmacy item, and the price was increased.Monica V. Mahone
New Pyrimethamine Dispensing Program: What Pharmacists Should Know
PharmacyTimes, 17 July 2015 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. 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."The Most Unconscionable Drug Price Hike I Have Yet Seen"
, by Derek Lowe, 11 September 2014, In the Pipeline. Presentations from

Retrophin Martin Shkreli (; born March 17, 1983) is an American former hedge fund manager. Shkreli is the co-founder of the hedge funds Elea Capital, MSMB Capital Management, and MSMB Healthcare; the co-founder and former chief executive officer (CEO) of ...

, a company formerly headed by

Martin Shkreli Martin Shkreli (; born March 17, 1983) is an American former hedge fund manager. Shkreli is the co-founder of the hedge funds Elea Capital, MSMB Capital Management, and MSMB Healthcare; the co-founder and former chief executive officer (CEO) of ...

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

New York Times ''The New York Times'' (''the Times'', ''NYT'', or the Gray Lady) is a daily newspaper based in New York City with a worldwide readership reported in 2020 to comprise a declining 840,000 paid print subscribers, and a growing 6 million paid d ...

'' 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." The price increase was criticized by physician groups such as HIV Medicine Associates and

Infectious Diseases Society of America The Infectious Diseases Society of America (IDSA) is a medical association representing physicians, scientists and other health care professionals who specialize in infectious diseases. It was founded in 1963 and is based in Arlington, Virginia. ...

. In 2016, a group of high school students from Sydney Grammar supported by the

University of Sydney The University of Sydney (USYD), also known as Sydney University, or informally Sydney Uni, is a public research university located in Sydney, Australia. Founded in 1850, it is the oldest university in Australia and is one of the country's si ...

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 The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...

at the time. 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. Nonetheless, the students' work was featured in ''

The Guardian ''The Guardian'' is a British daily newspaper. It was founded in 1821 as ''The Manchester Guardian'', and changed its name in 1959. Along with its sister papers ''The Observer'' and ''The Guardian Weekly'', ''The Guardian'' is part of the Gu ...

'' and ''

Time Time is the continued sequence of existence and events that occurs in an apparently irreversible succession from the past, through the present, into the future. It is a component quantity of various measurements used to sequence events, to ...

'' magazine, and on

ABC Australia The Australian Broadcasting Corporation (ABC) is the national broadcaster of Australia. It is principally funded by direct grants from the Australian Government and is administered by a government-appointed board. The ABC is a publicly-owned ...

, the

BBC #REDIRECT BBC #REDIRECT BBC Here i going to introduce about the best teacher of my life b BALAJI sir. He is the precious gift that I got befor 2yrs . How has helped and thought all the concept and made my success in the 10th board exam. ...

...