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Pyrimethamine

Pharmacology and mechanism of action Preparations Antiprotozoal veterinary drug Role and purpose Pharmacokinetics Side effects Precautions Medicine interactions Dosage References
Pyrimethamine
Pyrimethamine structure
CAS No.
58-14-0
Chemical Name:
Pyrimethamine
Synonyms
wr2978;RP 4753;WR 2978;bw50-63;Malacid;Malocid;nsc3061;4753r.p.;Tindurin;BW 50-63
CBNumber:
CB8461315
Molecular Formula:
C12H13ClN4
Formula Weight:
248.71
MOL File:
58-14-0.mol

Pyrimethamine Properties

Melting point:
233-234°C
Boiling point:
393.35°C (rough estimate)
Density 
1.2171 (rough estimate)
refractive index 
1.6110 (estimate)
storage temp. 
0-6°C
solubility 
Prepare the solution immediately before use. Dissolve 0.25 g in a mixture of 1 volume of methanol R and 3 volumes of methylene chloride R and dilute to 10 mL with the same mixture of solvents. The solution is clear (2.2.1) and not more intensely coloured than reference solution BY6 (2.2.2, Method II).
form 
neat
pka
pKa 7(t=20.0) (Uncertain)
Water Solubility 
<0.01 g/100 mL at 21 ºC
λmax
276nm(lit.)
Merck 
14,7985
BRN 
219864
Stability:
Stable, but light sensitive. Combustible. Incompatible with strong oxidizing agents.
CAS DataBase Reference
58-14-0(CAS DataBase Reference)
NIST Chemistry Reference
Pyrimethamine(58-14-0)
EPA Substance Registry System
2,4-Pyrimidinediamine, 5-(4-chlorophenyl)-6-ethyl- (58-14-0)
SAFETY
  • Risk and Safety Statements
  • Hazard and Precautionary Statements (GHS)
Hazard Codes  Xn
Risk Statements  22-36
Safety Statements  26
RIDADR  3249
WGK Germany  3
RTECS  UV8140000
HazardClass  6.1(b)
PackingGroup  III
HS Code  29335990
Symbol(GHS):
Signal word: Warning
Hazard statements:
Code Hazard statements Hazard class Category Signal word Pictogram P-Codes
H302 Harmful if swallowed Acute toxicity,oral Category 4 Warning P264, P270, P301+P312, P330, P501
Precautionary statements:

Pyrimethamine price More Price(9)

Manufacturer Product number Product description CAS number Packaging Price Updated Buy
Sigma-Aldrich 46706 Pyrimethamine VETRANAL 58-14-0 250mg $58.2 2018-11-20 Buy
Sigma-Aldrich 1589007 Pyrimethamine United States Pharmacopeia (USP) Reference Standard 58-14-0 200mg $352.8 2018-11-20 Buy
TCI Chemical P2037 Pyrimethamine >98.0%(HPLC)(T) 58-14-0 1g $39 2018-11-22 Buy
TCI Chemical P2037 Pyrimethamine >98.0%(HPLC)(T) 58-14-0 5g $125 2018-11-22 Buy
Cayman Chemical 16472 Pyrimethamine ≥98% 58-14-0 10mg $25 2018-11-13 Buy

Pyrimethamine Chemical Properties,Uses,Production

Pharmacology and mechanism of action

Pyrimethamine is a diaminopyrimidine which is structurally related to trimethoprim. It is effective against erythrocytic stage of Plasmodium (P) falciparum and less so against P. vivax, P. ovale and P. malariae. Pyrimethamine also inhibits the sporogony in the mosquito, resulting in a decrease of transmission of the infection within the community [1].
The mechanism of action of pyrimethamine is related to its inhibition of dihydrofolic reductase necessary for the folic acid synthesis in the parasite. Pyrimethamine acts slowly and is not recommended as monotherapy for acute malaria attacks. Resistance to pyrimethamine developed soon when the drug was used on a large scale as monoprophylaxis [1]. In resistant strains, the enzyme dihydrofolic reductase binds to pyrimethamine several hundred times less than in sensitive strains [2]. This high grade resistance is probably a onestep mutation and cannot be overcome by increasing the dose. However, when combined with long-acting sulphonomides (sulphadoxine), the effect of pyrimethamine is potentiated and the risk of developing resistant strains is far less.
 

Preparations

Pyrimethamine combined with sulphadoxine.
 
• Fansidar® (Roche). Tablets (pyrimethamine 25 mg plus sulphadoxine 500 mg). Solution for intramuscular injection (pyrimethamine 10 mg/ml and sulphadoxine 200 mg/ml).
 

Antiprotozoal veterinary drug

Pyrimethamine is a widely used broad-spectrum antiprotozoal veterinary medicine. In addition to this, pyrimethamine can also be applied to the breeding of the aquatic product and is also capable of enhancing the disease resistance capability of aquaculture fish. However, pyrimethamine has significant side effects with being used in excess amount being able to cause damage to the reproductive system of livestock and poultry, and is also difficult for recovery. Pyrimethamine has inhibitory effect on the primary exo-erythrocytic stage of Plasmodium falciparum and vivax malaria, and is a good preventive medicine. Although it has no significant effects on the malaria gametocyte but when the drug-containing blood enters into the mosquito body, it can affect the development of gametocytes inside mosquitoes, thus being able to interrupt the transmission. The mechanism of action is to inhibit the dihydrofolate reductase and affect the utilization of folate, causing reduction of the nucleic acid synthesis and inhibiting the malaria parasite reproduction. Meanwhile pyrimethamine and chloroquine, through lowering the level of oxidative stress and apoptosis, can exert protective effect on the placental pathology after the infection of malaria and can also reduce the proportion of infected red cells in the blood, therefore being able to achieving a excellent therapeutic effect on malaria. It also has enrichment effect in aquatic body. Upon going beyond a certain range, it can cause hemolytic anemia after being eaten and even has direct toxicity on the central nervous system.
This product is mainly used for the prevention of malaria and can also be used for the treatment of toxoplasmosis. It has inhibitory effects on the primary exo-erythrocytic stage of some kinds of Plasmodium falciparum and vivax malaria and is a good preventive medicine. Owing to its slow excretion rate, it has a long-lasting effect with the preventive effect of one-time medication being able to be maintained for more than 1 week. Although this product has no significant effects on the malaria gametocyte but when the drug-containing blood is inhaled into the mosquito body, it can affect the development of gametocytes inside mosquitoes, thus being able to interrupt the transmission. Because of its effect on inhibiting the exo-erythrocytic stage of Plasmodium, it is usually used in combination with primaquine for the prevention of recurrence.
This product appears as white crystalline powder; it is odorless and tasteless. It is insoluble in water, slightly soluble in ethanol, chloroform and acetone and soluble in dilute acid. It has a melting point of 232~235 ℃.

Figure 1 is a structural formula of pyrimethamine

Role and purpose

This product can inhibit dihydrofolate reductase, causing failure of the conversion from dihydrofolate into tetrahydrofolate, resulting in decreased synthesis of nucleic acid, so that the parasite propagation is inhibited. It is mainly used for the prevention of malaria, it can also be combined with primaquine to prevent relapse of malaria.

Pharmacokinetics

After oral administration, gastrointestinal absorption is complete but very slow with the blood concentration reaching peak after four hours. Plasma protein has a binding rate of 80%. It is mainly distributed in tissues such as liver, lung, kidney and other tissues as well as in milk. The half-life is about 90 hours with only 10% to 20% of the prototype drug being excreted through the urine at 5 to 7 days after administration. The effective concentration of the blood can be maintained for two weeks. Therefore, single-time medication can has its preventive effect be maintained for more than 1 week.

Side effects

1. Upon administration of high dose can cause acute poisoning symptoms such as fatigue, nausea, vomiting, abdominal pain, fever, cyanosis, jaundice, splenomegaly, etc. Upon this condition, drug administration should be promptly discontinued and the patients should be subject to gastric lavage, rehydration and symptomatic treatment. Because of the sweet taste of this product, it is more prone for children to be subject to mistakenly administration and poisoning, special attention should be paid.
2. Long-term administration can interfere with the in vivo utilization of folic acid, producing megaloblastic anemia. Therefore, the patients should be subject to regularly monitoring of blood. If the above issue happens, we should treat with leucovorin.

Precautions

1. Lactating women and patients of renal dysfunction should take with caution. Pregnant women in early phase should be disabled. Children less than 1 year of age should not use.
2. This product has slightly fragrance without bitter taste and should be protected from the reach of children whose mistaken administration can lead to poisoning, convulsions (Children under age 6 who takes 50~100mg can get poisoning and die). Barbiturates can confront its role in the central excitability.
3. This product, after single-time overdose of long-term continuous administration can cause bone marrow suppression and gastrointestinal function inhibition, resulting in megaloblastic anemia and leukopenia with timely withdrawal leading to self-healing. Giving formylation CF may alleviate the bone marrow function.
4. Adults, after single dose administration of 150~200mg have the risk of poisoning. It often occurs of nausea, vomiting, headache, dizziness and other symptoms within 1 to 5 hours with convulsions and coma occurring in severe cases. Children under 6 years of age can die upon administration at draught of 50~100mg and get poisoning and die, it should be given attention. First aid measures: apply gastric lavage, vomiting; drink a lot of sugar or 10% carrot juice. The patients can further subject to administration of the glucose infusion and diuretics. Patients of spasms and convulsions should be subject to infusion of thiopental.
5. Patients of renal damage, unconsciousness, 6-GPD deficiency and giant cell anemia should take with caution.
This information is edited by Xiongfeng Dai from Chemicalbook.

Medicine interactions

Being used in combination with dihydrofolate synthetase inhibitors (such as sulfadoxine or dapsone) can double block the folate metabolism of malaria parasite and enhance its performance, delay or prevent the emergence of drug-resistant strains of insects. It can’t be used in combination with other kinds of dihydrofolate reductase inhibitor because it can enhance the toxicity.

Dosage

Prophylaxis: start administration at 1 to 2 weeks before entering into the affected area. It is generally recommended to keep administration to until 6 to 8 weeks after leaving the affected areas once per week and 25 mg per time. Children take once per week with 0.9 mg/kg per time with the highest dose limited for adults.
For Plasmodium falciparum caused chloroquine-resistant strains: take 50 mg daily with 2 times. For children, take 0.3 mg/kg at 3 times per day with the course of three days.
Toxoplasmosis: Daily 50~100 mg, administrate at draught at a dose of 25 mg after 1 to 3 days with a course of 4 to 6 weeks. For children, take 1 mg/kg with 2 times. After 1-3 days, change to 0.5 mg/kg daily at 2 times with a course of 4 to 6 weeks.

References

1. Black RH, Canfield CJ, Clyde DF, Peters W, Wernsdorfer WH (1986). Chemotherapy of Malaria, 2nd edn, edited by L.J.Bruce-Chwatt. (Geneva: World Health Organization), pp. 77–80.
2. The biology of malaria parasites. Technical Report Series no 743 (1987). (Geneva: World Health Organization).
3. Friman G, Nyström-Rosander C, Jonsell G, Björkman A, Svendsrup B (1985). Agranulocytosis associated with malaria prophylaxis with Maloprim. BMJ, 286, 1244–1245.
4. Pyrimethamine. Therapeutic Drugs, edited by Sir Colin Dollery (1991), (London: Churchill Livingstone), pp. P314–P317.

Chemical Properties

White Solid

Uses

For the treatment of toxoplasmosis and acute malaria; For the prevention of malaria in areas non-resistant to pyrimethamine.
Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum malaria with pyrimethamine alone is therefore not recommended. Most strains of Plasmodium vivax have remained sensitive. Pyrimethamine is also used in combination with a sulfonamide for the treatment of Toxoplasmosis. It is slowly absorbed from the gastrointestinal tract with peak plasma levels 4–6 hours after dosing. Pyrimethamine is bound to plasma proteins and is extensively metabolized before excretion. Its elimination half-life is 3–5 days.

Uses

Dihydrofolate reductase inhibitor; generally used in combination with other antimicrobial agents. Antiprotozoal (Toxoplasma); antimalarial

Definition

ChEBI: An aminopyrimidine that is pyrimidine-2,4-diamine which is substituted at position 5 by a p-chlorophenyl group and at position 6 by an ethyl group. It is a folic acid antagonist used as an antimalarial or with a sulfonamide to treat toxoplasmo is.

brand name

Daraprim (GlaxoSmithKline).

General Description

Odorless white crystalline powder. Tasteless. An antimalarial drug.

Air & Water Reactions

Pyrimethamine is a diaminopyrimidine which is structurally related to trimethoprim. It is effective against erythrocytic stage of Plasmodium (P) falciparum and less so against P. vivax, P. ovale and P. malariae. Pyrimethamine also inhibits the sporogony in the mosquito, resulting in a decrease of transmission of the infection within the community[1].
The mechanism of action of pyrimethamine is related to its inhibition of dihydrofolic reductase necessary for the folic acid synthesis in the parasite. Pyrimethamine acts slowly and is not recommended as monotherapy for acute malaria attacks. Resistance to pyrimethamine developed soon when the drug was used on a large scale as monoprophylaxis [1]. In resistant strains, the enzyme dihydrofolic reductase binds to pyrimethamine several hundred times less than in sensitive strains [2]. This high grade resistance is probably a onestep mutation and cannot be overcome by increasing the dose. However, when combined with long-acting sulphonomides (sulphadoxine), the effect of pyrimethamine is potentiated and the risk of developing resistant strains is far less.
 

Reactivity Profile

Pyrimethamine together with sulphadoxine (Fansidar) is used in the treatment of P. falciparum malaria (cf. Sulphadoxine: Indications). Pyrimethamine is also valuable in the treatment of toxoplasmosis.

Fire Hazard

Pyrimethamine in combination with sulphadoxine (Fansidar) can cause severe cutaneous adverse reactions (cf. Sulphadoxine: Side effects). Agranulocytosis occurs quite frequently (1/2000) and fatalities have been reported when pyrimethamine is combined with dapsone [3]. When given alone, life-threatening adverse reactions are very rare and the drug is generally well tolerated. Megaloblastic anaemia may, however, occur during long-term treatment with high doses (i.e. for toxoplasmosis) and can be prevented by folinic acid supplementation [4].

Biological Activity

During long-term treatment with high doses, folinic acid supplement is usually given.

Safety Profile

Poison by ingestion, subcutaneous, and intraperitoneal routes. Experimental teratogenic and reproductive effects. Questionable carcinogen. Human mutation data reported. When heated to decomposition it emits very toxic fumes of Cland NOx. Used as an antimalarial drug for humans and to treat toxoplasmosis in hogs.

Pyrimethamine Preparation Products And Raw materials

Raw materials

Preparation Products


Pyrimethamine Suppliers

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View Lastest Price from Pyrimethamine manufacturers

Image Release date Product Price Min. Order Purity Supply Ability Manufacturer
2018-12-21 Pyrimethamine
58-14-0
US $8.00 / kg 1kg 99% 10MT career henan chemical co

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