Pyrimethamine

248.71

248.71

200-364-2

Z3614QOX8W

757306|3061

2811

DTXSID9021217

C788

Crystals|White scored tablets contains 25 mg pyrimethamine /Daraprim/

P01BD01|P - Antiparasitic products, insecticides and repellents

2933599090

77.8

2.7

Pyrimethamine is an odorless white crystalline powder. Tasteless. An antimalarial drug.

1.4±0.1 g/cm3

233.5 °C

491.5°C at 760 mmHg

176.6±30.7 °C

1.667

H2O: <0.01 g/100 mL at 21 ºC

0-6°C

1.32X10-8 mm Hg at 25 deg C (est)

LD50 oral in rat: 440mg/kg

7.34(at 20 °C)

Henry's Law constant = 1.08X10-10 atm-cu m/mol at 25 °C (est)

7.34 (at 20 °C)|pKa = 7.34 at 20 °C (conjugate acid)

155.8 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Hydroxyl radical reaction rate constant = 2.0X10-10 cu cm/molecule-sec at 25 °C (est)

Insoluble in water.

Amines, Phosphines, and Pyridines

PYRIMETHAMINE is sensitive to exposure to light (NTP, 1992). Neutralizes acids to form salts plus water in exothermic reactions. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides.

III

6.1(b)

3249

3

22-36

26

UV8140000

Xn

Stable, but light sensitive. Combustible. Incompatible with strong oxidizing agents.

P301 + P312 + P330

H302

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including pyrimethamine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.|Oral dosage form new animal drug. Sulfadiazine/pyrimethamine suspension. ... For the treatment of equine protozoal myeloencephalitis (EPM) caused by Sarcocystis neurona. Limitations: Do not use in horses intended for human consumption. Federal law restricts this drug to use by or on the order of a licensed veterinarian.|The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Pyrimethamine is included on this list.

Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)

|Warning|H302 (99.24%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 132 companies from 7 notifications to the ECHA C&L Inventory.

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids. SPILL: Increase, in the downwind direction, as necessary, the isolation distance shown above. FIRE: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2016)

SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should protect this material from exposure to light, and store it under ambient temperatures. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)

Although the clinical importance is unclear, mild hepatotoxicity has been reported in some patients receiving pyrimethamine and lorazepam concomitantly.|Although the clinical importance is unclear, p-aminobenzoic acid (PABA) reportedly interferes with the action of pyrimethamine and probably should not be used in patients receiving pyrimethamine.|An increased incidence and severity of adverse effects has been reported when chloroquine was used concomitantly with the fixed combination of sulfadoxine and pyrimethamine compared with use of the fixed combination alone. Sulfadoxine and pyrimethamine is compatible with quinine and with other anti-infectives.|Concomitant use of pyrimethamine or sulfadoxine and pyrimethamine with other antifolate agents (e.g., sulfonamides, co-trimoxazole, trimethoprim) is not recommended since such use may increase the risk of bone marrow suppression. If signs of folate deficiency develop, pyrimethamine or sulfadoxine and pyrimethamine should be discontinued and leucovorin administered (if necessary) until normal hematopoiesis is restored.|For more Interactions (Complete) data for Pyrimethamine (6 total), please visit the HSDB record page.

The fatal dose is variable, with the smallest reported fatal single dose being 375 mg.

LD50 Rat intraperitoneal 70 mg/kg|LD50 Mouse intraperitoneal 74 mg/kg|LD50 Mouse oral 92 mg/kg

A bioassay of pyrimethamine, a prophylactic antimalarial, for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered pyrimethamine 5 days per week at one of two doses, either 200 or 400 ppm for the rats and either 500 or 1,000 ppm for the mice. The animals were administered the chemical for 78 weeks, then observed for 26 or 27 additional weeks. Matched controls consisted of 15 untreated rats and 15 untreated mice of each sex; pooled controls consisted of the matched controls combined with 30 untreated rats and 30 untreated mice from similar bioassays of two other test compounds. All surviving rats and mice were killed at 102-105 weeks. Mean body weights of the rats and mice fed diets containing pyrimethamine were slightly lower than those of the matched controls. Survival of the rats was not affected adversely by the chemical. In mice, survival rates of both dosed and matched- control males were low, with nearly two-thirds of the dosed and one-half of the control mice dying by week 52. Some of the deaths were associated with respiratory infections and may not have been related to administration of the chemical. Numbers of animals at risk in the dosed and control groups of female mice were adequate, however, for the development of late-appearing tumors. In rats of each sex, no neoplastic lesions were found at a statistically significant incidence in the groups fed the pyrimethamine as compared with control groups. An increased frequency of bone-marrow atrophy occurred in both male and female dosed groups. In male mice, the markedly decreased life spans may have prevented the observation of late-appearing tumors, since only two tumors were observed, one in a high-dose mouse and one in a low-dose mouse. In female mice, no neoplastic lesions were found at a statistically significant incidence in the groups fed the pyrimethamine as compared with control groups. It is concluded that under the conditions of this bioassay, pyrimethamine was not carcinogenic for male or female Fischer 344 rats or for female B6C3F1 mice. The carcinogenic potential of pyrimethamine for male B6C3F1 mice cannot be assessed by this bioassay, because of the markedly reduced life span.

Pyrimethamine should be used with caution in patients with impaired renal or hepatic function. The drug also should be used with caution in patients with possible folate deficiency, including patients with malabsorption syndrome, alcoholism, /and/ pregnancy.|Pyrimethamine ... is contraindicated in patients with megaloblastic anemia caused by folate deficiency.|Repeated prophylactic (prolonged) use of sulfadoxine and pyrimethamine is contraindicated in patients with renal or hepatic failure or with blood dyscrasias. The fixed-combination preparation also is contraindicated in patients with megaloblastic anemia caused by folate deficiency, in infants younger than 2 months of age, and for prophylaxis in pregnant women at term or nursing women.

87%

Pyrimethamine's production and use as an antimalarial and antiprotozoal drug(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), estimated Koc values of 1540 and 590(SRC), determined from a structure estimation method(2) and from a log Kow of 2.69(3) and a regression-derived equation(2) respectively, indicate that pyrimethamine is expected to have low mobility in soil(SRC). The pKa of pyrimethamine is 7.34(4), indicating that this compound will exist in cation form; in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Also, aromatic amines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group(6,7), suggesting that pyrimethamine may be immobile in some soils(SRC). Volatilization of pyrimethamine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.08X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Pyrimethamine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.32X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2).|AQUATIC FATE: Based on a classification scheme(1), estimated Koc values of 1540 and 590(SRC), determined from a structure estimation method(2) and from a log Kow of 2.69(3) and a regression-derived equation(2) respectively, indicate that pyrimethamine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 1.08X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(5), an estimated BCF of 28(SRC), from its log Kow and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Pyrimethamine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), pyrimethamine, which has an estimated vapor pressure of 1.32X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase pyrimethamine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2 hours(SRC), calculated from its rate constant of 2.0X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase pyrimethamine may be removed from the air by wet or dry deposition(SRC).

The rate constant for the vapor-phase reaction of pyrimethamine with photochemically-produced hydroxyl radicals has been estimated as 2.0X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 2 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Pyrimethamine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2).

An estimated BCF of 28 was calculated in fish for pyrimethamine(SRC), using a log Kow of 2.69(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The pKa of pyrimethamine is 7.34(1), indicating that this compound will exist partially in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(2). Because pyrimethamine ionizes in the environment, two estimated Koc values have been calculated(SRC). Using a structure estimation method based on molecular connectivity indices(3), the Koc of pyrimethamine can be estimated to be 1540(SRC). The Koc of pyrimethamine is estimated as 590(SRC), using a log Kow of 2.69(4) and a regression-derived equation(3). According to a classification scheme(5), these estimated Koc values suggest that pyrimethamine is expected to have low mobility in soil. Also, aromatic amines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group(6,7), suggesting that pyrimethamine may be immobile in some soils(SRC).

The Henry's Law constant for pyrimethamine is estimated as 1.08X10-10 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that pyrimethamine is expected to be essentially nonvolatile from water surfaces(2). Pyrimethamine's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to be an important fate process(SRC). Pyrimethamine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.32X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(1).

The concentration of chloroquine, dapsone and pyrimethamine in plasma and milk were measured following the coadministration of a single dose of chloroquine and Maloprim to lactating women. The milk to plasma area under the concentration-time curve (AUC) ratio ranged from 1.96 to 4.26 for chloroquine, 0.22 to 0.45 for dapsone and 0.46 to 0.66 for pyrimethamine. Assuming a daily milk ingestion of 1 l by the infant, the maximum percentage of the maternal dose for chloroquine, dapsone and pyrimethamine in milk was 4.2%, 14.3% and 45.6%, respectively, over a 9 day period.|Pyrimethamine was detected in raw bovine milk samples collected in Spain at a concentration of 0.15 ug/kg(1) and in whole milk samples at a concentration of 0.21 ug/kg; concentrations in skim milk samples ranged from 0.07-0.17 ug/kg(1).|Pyrimethamine is excreted into milk. It is estimated that approximately 3-4 mg of the drug would be ingested by a nursing infant over the first 48-hour period following administration of a single 75-mg oral dose to the mother.

Occupational exposure to pyrimethamine may occur through contact with this compound at workplaces where pyrimethamine is produced or used. The general population will be exposed through ingestion of pyrimethamine's use as an antimalarial and antiprotozoal drug. Monitoring data indicate that the general population may be exposed to pyrimethamine via ingestion of bovine milk containing pyrimethamine. (SRC)

For the treatment of toxoplasmosis and acute malaria; For the prevention of malaria in areas non-resistant to pyrimethamine|FDA Label

Although pyrimethamine has been used alone for suppression or chemoprophylaxis of malaria in travelers, the drug is no longer recommended by the US Centers for Disease Control and Prevention (CDC) or other experts for prevention of malaria. The manufacturer states that pyrimethamine should only be used for suppression or chemoprophylaxis of malaria caused by Plasmodium known to be susceptible to the drug. However, resistance to pyrimethamine is prevalent worldwide and the drug alone is not a suitable chemoprophylaxis regimen for travelers to most areas of the world. /Included in US product labeling/|Pyrimethamine is used in conjunction with sulfadiazine or, alternatively, clindamycin, atovaquone, or azithromycin for the treatment of toxoplasmosis caused by Toxoplasma gondii. /Included in US product labeling/|Oral or parenteral leucovorin is used with pyrimethamine in these regimens to prevent pyrimethamine-induced adverse hematologic effects. /Included in US product labeling/|Although co-trimoxazole generally is considered the drug of choice for the treatment of GI infections caused by Isospora belli, pyrimethamine has been used for the treatment of isosporiasis in some patients (e.g., HIV-infected patients) when co-trimoxazole was contraindicated, including those with sulfonamide sensitivity. /NOT included in US product labeling/|For more Therapeutic Uses (Complete) data for Pyrimethamine (16 total), please visit the HSDB record page.

High dosages of pyrimethamine may result in adverse nervous system effects including ataxia, tremors, seizures, and respiratory failure. Headache, light-headedness, insomnia, depression, malaise, fatigue, and irritability have been reported rarely with pyrimethamine. Reversible hyperesthesia has been reported rarely with sulfadoxine and pyrimethamine. Other adverse nervous system effects reported with sulfonamides or pyrimethamine include peripheral neuritis, hallucinations, tinnitus, vertigo, muscle weakness, nervousness, and polyneuritis.|Sensitivity reactions, occasionally severe (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, anaphylaxis) have been reported with pyrimethamine, especially when the drug was used with a sulfonamide. Severe, sometimes fatal, hypersensitivity reactions have occurred with the fixed-combination preparation of sulfadoxine and pyrimethamine. In most reported cases, fatalities resulted from severe cutaneous reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Pulmonary hypersensitivity reactions and a fatal reaction involving the skin, liver, and kidneys also have been reported. Fatal hepatitis also has been reported with the fixed-combination drug.|Severe reactions to sulfadoxine and pyrimethamine have occurred in travelers who received 2-9 doses of the drug for prophylaxis of malaria, but have not been reported to date following a single dose of the drug such as that used in the treatment of malaria. It is estimated that the incidence of severe cutaneous adverse reactions ranges from 1/8000 to 1/5000 and that the incidence of fatal cutaneous reactions ranges from 1/25,000 to 1/11,000 in US travelers receiving chemoprophylaxis with sulfadoxine and pyrimethamine.|Anorexia, abdominal cramps, diarrhea, and vomiting may occur with high dosages of pyrimethamine. Anorexia and vomiting may be minimized by reducing dosage of pyrimethamine or by administering the drug with meals. Atrophic glossitis or gastritis also has been reported with high dosages of pyrimethamine. Other adverse GI effects reported with sulfonamides or with pyrimethamine include stomatitis, nausea, abdominal pain, and feeling of fullness.|For more Drug Warnings (Complete) data for Pyrimethamine (21 total), please visit the HSDB record page.

The concentration of chloroquine, dapsone and pyrimethamine in plasma and milk were measured following the coadministration of a single dose of chloroquine and Maloprim to lactating women. The milk to plasma area under the concentration-time curve (AUC) ratio ranged from 1.96 to 4.26 for chloroquine, 0.22 to 0.45 for dapsone and 0.46 to 0.66 for pyrimethamine. Assuming a daily milk ingestion of 1 l by the infant, the maximum percentage of the maternal dose for chloroquine, dapsone and pyrimethamine in milk was 4.2%, 14.3% and 45.6%, respectively, over a 9 day period.|The fatal dose is variable, with the smallest reported fatal single dose being 375 mg.

Resistance to pyrimethamine can be readily induced in plasmodia and occurs frequently in areas where pyrimethamine has been widely used. Resistance to pyrimethamine has been reported in Plasmodium vivax, P. malariae, and P. falciparum malaria. Pyrimethamine-resistant P. falciparum also may be cross resistant to chloroquine and hydroxychloroquine. Pyrimethamine-resistant and/or chloroquine-resistant P. falciparum may be susceptible to sulfadoxine and pyrimethamine; however, P. falciparum resistant to both chloroquine and the combination of sulfadoxine and pyrimethamine is widespread in Thailand, Burma, Cambodia, the Amazon basin area of South America, and, increasingly, parts of East Africa. Resistance to sulfadoxine and pyrimethamine also has been reported in Southeast Asia, Bangladesh, and Oceania.

Pyrimethamine is an antiparasitic compound commonly used as an adjunct in the treatment of uncomplicated, chloroquine resistant, P. falciparum malaria. Pyrimethamine is a folic acid antagonist and the rationale for its therapeutic action is based on the differential requirement between host and parasite for nucleic acid precursors involved in growth. This activity is highly selective against plasmodia and Toxoplasma gondii. Pyrimethamine possesses blood schizonticidal and some tissue schizonticidal activity against malaria parasites of humans. However, the 4-amino-quinoline compounds are more effective against the erythrocytic schizonts. It does not destroy gametocytes, but arrests sporogony in the mosquito. The action of pyrimethamine against Toxoplasma gondii is greatly enhanced when used in conjunction with sulfonamides.

Inhibitors of the enzyme, dihydrofolate reductase (TETRAHYDROFOLATE DEHYDROGENASE), which converts dihydrofolate (FH2) to tetrahydrofolate (FH4). They are frequently used in cancer chemotherapy. (From AMA, Drug Evaluations Annual, 1994, p2033) (See all compounds classified as Folic Acid Antagonists.)|Agents used in the treatment of malaria. They are usually classified on the basis of their action against plasmodia at different stages in their life cycle in the human. (From AMA, Drug Evaluations Annual, 1992, p1585) (See all compounds classified as Antimalarials.)|Substances that are destructive to protozoans. (See all compounds classified as Antiprotozoal Agents.)

Well absorbed with peak levels occurring between 2 to 6 hours following administration|The concentration of chloroquine, dapsone and pyrimethamine in plasma and milk were measured following the coadministration of a single dose of chloroquine and Maloprim to lactating women. The milk to plasma area under the concentration-time curve (AUC) ratio ranged from 1.96 to 4.26 for chloroquine, 0.22 to 0.45 for dapsone and 0.46 to 0.66 for pyrimethamine. Assuming a daily milk ingestion of 1 l by the infant, the maximum percentage of the maternal dose for chloroquine, dapsone and pyrimethamine in milk was 4.2%, 14.3% and 45.6%, respectively, over a 9 day period.|Pyrimethamine is excreted into milk. It is estimated that approximately 3-4 mg of the drug would be ingested by a nursing infant over the first 48-hour period following administration of a single 75-mg oral dose to the mother.|In this study, the kinetics of pyrimethamine elimination via the urine was investigated. The experiments were carried out on six healthy male volunteers aged 23-32 years. The drug was administered orally (p.o.) in a single dose at three different concentrations i.e.: 50, 75 and 100 mg. The concentration of the drug in the urine was determined via the modified method of Bonini et al. and Garber et al. It was found that 13.4 +/- 1.3% of the dose eliminated via the urine was in unchanged form. The process of pyrimethamine elimination may be described according to an open kinetic two-compartmental model: the formula showing the course of pyrimethamine elimination over time has been given. Several examples of the quantitative exposure test have been proposed, which allow the calculation of the drug dose absorbed and thus the degree of toxicity to be determined. This test can also be useful in a controlled clinical setting.|A pharmacokinetic study of pyrimethamine was carried out in 4- (103-115 g) and 12-week-old (260-280 g) white male Wistar rats fed a standard diet containing 24% protein, and a low-protein diet containing 8% protein. After intragastric administration of the drug in a single dose of 40 mg/kg body weight, the concentrations of pyrimethamine in the blood were determined at different time points from 15 min to 20 hours post-dose. On the basis of the results obtained, a number of parameters characterizing the course of absorption and elimination of the drug from the blood were calculated. The majority of parameters were dependent on both age and type of diet. The greatest bioavailability was observed in the 4-week-old rats: for the animals fed the low-protein diet, the area under the concentration-time curve (AUC) amounted to 593.0 and for those on the standard diet the AUC was 503.1. In the older rats, this parameter was 339.3 and 228.1 respectively. The k(e) values were lower in the younger rats (i.e. 0.0121 hr(-1) and 0.0135 h(-1)) than in the older animals (i.e. 0.0164 h(-1) and 0.0193 hr(-1) respectively). The elimination half-life (t1/2) was higher in the 4-week-old rats (i.e. 57.1 hr; 8% protein, and 51.2 hr; 24% protein) than in the 12-week-old animals (i.e. 42.4 hr; 8% protein, and 36.0 hr; 24% protein).|For more Absorption, Distribution and Excretion (Complete) data for Pyrimethamine (10 total), please visit the HSDB record page.

Hepatic|Pyrimethamine is metabolized to several unidentified metabolites. About 5% of a dose of sulfadoxine is present in plasma as an acetylated metabolite and about 2-3% is present as the glucuronide.

96 hours|Pyrimethamine reportedly has an average plasma half-life of 111 hours (range: 54-148 hours). The plasma half-life of sulfadoxine reportedly averages 169 hours (range: 100-231 hours).|To determine pyrimethamine levels in sera, cerebrospinal fluid, and ventricular fluid in infants, specimens were examined from 37 infants, ages 10 days to 1.5 yr, receiving pyrimethamine 1 mg/kg of body weight daily for 2 months followed by the same dosage each Monday, Wednesday, and Friday for treatment of suspect or proven congenital toxoplasmosis. The pyrimethamine half-life obtained from serum of 9 babies was 64 hr, which was significantly different than for 2 infants taking phenobarbital (33 hr).|A pharmacokinetic study of pyrimethamine was carried out in 4- (103-115 g) and 12-week-old (260-280 g) white male Wistar rats fed a standard diet containing 24% protein, and a low-protein diet containing 8% protein. After intragastric administration of the drug in a single dose of 40 mg/kg body weight, the concentrations of pyrimethamine in the blood were determined at different time points from 15 min to 20 hours post-dose...The elimination half-life (t1/2) was higher in the 4-week-old rats (i.e. 57.1 hr; 8% protein, and 51.2 hr; 24% protein) than in the 12-week-old animals (i.e. 42.4 hr; 8% protein, and 36.0 hr; 24% protein).

Pyrimethamine inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver.|Pyrimethamine is an antimalarial drug that has also been used successfully to treat autoimmune diseases such as lymphoproliferative syndrome. In this work, the effect of pyrimethamine (PYR) on the production of free radicals in malaria-infected mice was studied to better understand the drug's immunomodulatory properties. BALB/c and CBA/Ca mice were infected with Plasmodium yoelii 17XL. Seven days after infection, mice were treated with PYR or vehicle and sacrificed 24h later. Treatment with PYR increased superoxide dismutase and glutathione peroxidase activities in erythrocytes and the liver, augmented the levels of nitric oxide in the serum, and upregulated mRNA levels of superoxide dismutase, glutathione peroxidase, catalase, and iNOS in the spleen. In addition, PYR increased lipoperoxidation and protein carbonylation in infected mice. Our results indicate that P. yoelii 17XL reduces oxidative stress in infected cells, while PYR induces it, which is associated with increased parasite elimination. Thus, it is possible that oxidative stress generated by pyrimethamine is also involved in its immunomodulatory mechanism of action.|Co-infection of human immunodeficiency virus (HIV) with malaria is one of the pandemic problems in Africa and parts of Asia. Here we investigated the impact of pyrimethamine (PYR) and two other clinical anti-malarial drugs (chloroquine [CQ] or artemisinin [ART]) on HIV-1 replication. Peripheral blood mononuclear cells (PBMCs) or MT-2 cells were infected with HIV(NL4.3) strain and treated with different concentrations of the anti-malarial drugs. HIV-1 replication was measured using p24 ELISA. We show that 10 uM CQ and ART inhibited HIV-1 replication by 76% and 60% in PBMCs, respectively, but not in MT-2 cells. In contrast, 10 uM PYR enhanced HIV-1 replication in MT-2 cells by >10-fold. A series of molecular mechanism studies revealed that PYR increased intracellular HIV gag proteins without affecting the promoter or the reverse transcriptase activity. The effect of PYR was independent of HTLV-1 produced by MT-2 cells. Of interest, PYR treatment led to S-phase accumulation and increased AZT and d4T antiviral activity by ~ 4-fold. Taken together, we show that PYR significantly enhances HIV-1 replication by affecting the cellular machinery. Our results could be relevant for the management of malaria and HIV particularly in regions where HIV-1 and malaria epidemics overlap.|Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder mostly caused by mutations in PKD1, encoding polycystin-1 (PC1). The disease is characterized by development and growth of epithelium-lined cyst in both kidneys, often leading to renal failure. There is no specific treatment for this disease. Here, we report a sustained activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in ischemic injured and uninjured Pkd1 knockout polycystic kidneys and in human ADPKD kidneys. Through a chemical library screen, we identified the anti-parasitic compound pyrimethamine as an inhibitor of STAT3 function. Treatment with pyrimethamine decreases cell proliferation in human ADPKD cells and blocks renal cyst formation in an adult and a neonatal PKD mouse model. Moreover, we demonstrated that a specific STAT3 inhibitor, S3I-201, reduces cyst formation and growth in a neonatal PKD mouse model. Our results suggest that PC1 acts as a negative regulator of STAT3 and that blocking STAT3 signaling with pyrimethamine or similar drugs may be an attractive therapy for human ADPKD.|The unresponsiveness of metastatic melanoma to conventional chemotherapeutic and biological agents is largely due to the development of resistance to apoptosis. Pyrimethamine belongs to the group of antifolate drugs, and in addition to antiprotozoan effects, it exerts a strong proapoptotic activity, which we recently characterized in human T lymphocytes. However, no data regarding pyrimethamine anticancer activity are available thus far. To this end, we examined the in vitro effects of pyrimethamine on apoptosis, cell cycle distribution, and cell proliferation of human metastatic melanoma cell lines. The in vivo antitumor potential of pyrimethamine was evaluated in a severe combined immunodeficiency (SCID) mouse xenotransplantation model. Our data indicate that pyrimethamine, when used at a clinically relevant concentration, induced apoptosis in metastatic melanoma cells via the activation of the cathepsin B and the caspase cascade (i.e., caspase-8 and caspase-9) and subsequent mitochondrial depolarization. This occurred independently from CD95/Fas engagement. Moreover, pyrimethamine induced a marked inhibition of cell growth and an S-phase cell cycle arrest. Results obtained in SCID mice, injected s.c. with metastatic melanoma cells and treated with pyrimethamine, indicated a significant inhibitory effect on tumor growth. In conclusion, our results suggest that pyrimethamine-induced apoptosis may be considered as a multifaceted process, in which different inducers or regulators of apoptosis are simultaneously implicated, thus permitting death defects of melanoma cells to be bypassed or overcome. On these bases, we hypothesize that pyrimethamine could represent an interesting candidate for the treatment of metastatic melanoma.|Pyrimethamine is a folic acid antagonist and has a mechanism of action similar to that of trimethoprim. By binding to and reversibly inhibiting dihydrofolate reductase, pyrimethamine inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid (folinic acid). Pyrimethamine interferes with the synthesis of tetrahydrofolic acid in malarial parasites at a point immediately succeeding that where sulfonamides act. Sulfadoxine, like other sulfonamides, is a structural analog of p-aminobenzoic acid (PABA) and competitively inhibits dihydrofolic acid synthesis which is necessary for the conversion of PABA to folic acid. The combination of sulfadoxine and pyrimethamine results in a synergistic action against susceptible plasmodia.

SYMPTOMS: Symptoms of exposure to this compound include megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia, atrophic glossitis, vomiting, convulsions, respiratory failure and death. Chronic exposure may cause depression of hemopoiesis due to interference in the metabolism of folic acid. Skin rashes may also occur. ACUTE/CHRONIC HAZARDS: When heated to decomposition this compound emits toxic fumes of chlorine and nitrogen oxides. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Generally, the induction of vomiting is NOT recommended outside of a physician's care due to the risk of aspirating the chemical into the victim's lungs. However, if the victim is conscious and not convulsing and if medical help is not readily available, consider the risk of inducing vomiting because of the high toxicity of the chemical ingested. Ipecac syrup or salt water may be used in such an emergency. IMMEDIATELY transport the victim to a hospital. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

There is no specific antidote to acute pyrimethamine poisoning. In the event of overdosage, symptomatic and supportive measures should be employed. Gastric lavage is recommended and is effective if carried out very soon after drug ingestion. Parenteral diazepam may be used to control convulsions. Folinic acid should also be administered within 2 hours of drug ingestion to be most effective in counteracting the effects on the hematopoietic system. Due to the long half-life of pyrimethamine, daily monitoring of peripheral blood counts is recommended for up to several weeks after the overdose until normal hematologic values are restored.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ Following the ingestion of 300 mg or more of pyrimethamine, gastrointestinal and/or central nervous system signs may be present, including convulsions. The initial symptoms are usually gastrointestinal and may include abdominal pain, nausea, severe and repeated vomiting, possibly including hematemesis. Central nervous system toxicity may be manifest by initial excitability, generalized and prolonged convulsions which may be followed by respiratory depression, circulatory collapse, and death within a few hours. Neurological symptoms appear rapidly (30 minutes to 2 hours after drug ingestion), suggesting that in gross overdosage pyrimethamine has a direct toxic effect on the central nervous system.|/CASE REPORTS/ There have been at least 2 reports of cancer associated with long-term use of pyrimethamine for the treatment of toxoplasmosis; one 51-year-old woman developed chronic granulocytic leukemia after receiving the drug for 2 years and one 56-year-old patient developed reticulum cell sarcoma after receiving the drug for 14 months.|/CASE REPORTS/ Toxoplasmosis is one of the life-threatening infections that can occur after hematopoietic stem cell transplantation (HSCT) and also solid organ transplantation. The standard treatment for toxoplasmosis is combination therapy with pyrimethamine and sulfadiazine, both of which inhibit folate metabolism. Therefore, therapy with these agents could result in marrow toxicity including megaloblastic anemia or pancytopenia, which is reversible or preventable with folate supplementation. Transplant-associated microangiopathy (TAM) is another situation where folate is required to compensate for increased erythropoiesis due to hemolysis after allogeneic HSCT. Here, we report a case of severe marrow toxicity manifesting as pancytopenia due to low-dose pyrimethamine, which was triggered by TAM after HSCT.|/CASE REPORTS/ Curative treatment of congenital toxoplasmosis is based on the association of pyrimethamine and sulfonamide. There is currently no pediatric galenic formulation. /The investigators/ report the case of a newborn child affected by asymptomatic congenital toxoplasmosis who received an overdose of pyrimethamine. The patient received a dose of pyrimethamine 4 times, equal to 100 times the recommended dose, due to an error in the prescription. He had partial seizures 48 h after the last medicinal absorption. /The investigators/ noted a lack of appetite and vomiting, with a favorable progression in 5 days. Blood analysis showed isolated, spontaneously regressive moderate cholestasis.|For more Human Toxicity Excerpts (Complete) data for Pyrimethamine (11 total), please visit the HSDB record page.

Chloridin

Daraprim Oral Tablets 25 mg, manufactured by GlaxoSmithKline

Pyrimethamine has been determined in animal feed by gas chromatography with electron capture detection. ... It can be determined in pharmaceutical products by nuclear magnetic resonance spectroscopy.

Gas chromatography with both electron capture and mass spectrometry detection have been used for its determination in tissues, with a detection 0.1 mg/kg.|LC-MS determination in plasma.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals -> Animal Drugs -> Approved in Taiwan