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外観
白色～わずかにうすい褐色, 結晶～粉末
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溶解性
酢酸に溶け、水にほとんど溶けない。
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解説
ピリメサミン，化学的に合成される。結晶性。融点 233～234℃。水に不溶。エチルアルコールにわずかに可溶。
ブリタニカ国際大百科事典 小項目事典 ブリタニカ
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用途
抗マラリア薬で，葉酸と拮抗作用をもつ。副作用は貧血。
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効能
抗マラリア薬
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化学的特性
White Solid
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使用
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.
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定義
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.
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適応症
Pyrimethamine (Daraprim) is the best of a number of 2,4-
diaminopyrimidines that were synthesized as potential
antimalarial and antibacterial compounds. Trimethoprim
(Proloprim) is a closely related compound.
Pyrimethamine is well absorbed after oral administration,
with peak plasma levels occurring within 3 to 7
hours. An initial loading dose to saturate nonspecific
binding sites is not required, as it is with chloroquine.
However, the drug binds to tissues, and therefore, its
rate of renal excretion is slow. Pyrimethamine has a
half-life of about 4 days. Although the drug does undergo
some metabolic alterations, the metabolites
formed have not been totally identified.
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一般的な説明
Odorless white crystalline powder. Tasteless. An antimalarial drug.
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空気と水の反応
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.
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反応プロフィール
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.
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火災危険
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].
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生物活性
During long-term treatment with high doses, folinic acid supplement is usually given.
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作用機序
The combination of pyrimethamine with a long-acting sulfonamide, sulfadoxine, which
blocks dihydrofolate synthesis by blocking incorporation of PABA into the dihydrofolate, is called
Fansidar, which produces sequential blockage of tetrahydrofolate synthesis similar to that reported
for treatment of bacterial infections. Plasmodium enzymes catalyzing folic acid
synthesis differ from those enzymes found in other organisms. A single bifunctional protein present
in Plasmodium sp. catalyzes the phosphorylation of 6-hydroxymethyl-7,8-hydropterin
(a pyrophosphokinase) and the incorporation of PABA into dihydropteroic acid. A second
bifunctional enzyme catalyzes the reduction of dihydropteroic acid and thymidylic acid synthesis.
As a result, the drug combination (Fansidar) appears to have improved drug-mediated disruption of
folic acid in Plasmodium sp.. This combination has been used with quinine for the
treatment and prevention of chloroquine-resistant malaria (Plasmodium falciparum, Plasmodium
ovale, Plasmodium vivax, and Plasmodium malaria). The combination therapy (Fansidar) has the
added advantage of being inexpensive, which is essential for successful therapy in developing
countries. When used on its own, pyrimethamine is a blood schizonticide without effects on the
tissue stage of the disease.
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臨床応用
Pyrimethamine has been recommended for prophylactic
use against all susceptible strains of plasmodia;
however, it should not be used as the sole therapeutic
agent for treating acute malarial attacks. As mentioned
previously, sulfonamides should always be coadministered
with pyrimethamine (or trimethoprim), since the
combined antimalarial activity of the two drugs is significantly
greater than when either drug is used alone.
Also, resistance develops more slowly when they are
used in combination. Sulfonamides exert little or no effect
on the blood stages of P. vivax, and resistance to the
dihydrofolate reductase inhibitors is widespread.
In addition to its antimalarial effects, pyrimethamine
is indicated (in combination with a sulfonamide) for the
treatment of toxoplasmosis.The dosage required is 10 to
20 times higher than that employed in malarial infections.
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副作用
Relatively few side effects are associated with the
usual antimalarial dosages. However, signs of toxicity are
evident at higher dosages, particularly those used in the
management of toxoplasmosis. Many of these reactions
reflect the interference of pyrimethamine with host folic
acid metabolism, especially that occurring in rapidly dividing
cells. Toxic symptoms include anorexia, vomiting,
anemia, leukopenia, thrombocytopenia, and atrophic
glossitis. CNS stimulation, including convulsions, may follow
an acute overdose.The side effects associated with the
pyrimethamine–sulfadoxine combination include those
associated with the sulfonamide and pyrimethamine
alone. In addition, there is evidence of a greater incidence
of allergic reactions, particularly toxic epidermal necrolysis
and Stevens-Johnson syndrome, with the combination.
This carries an estimated mortality of 1:11,000 to 1:25,000
when used as a chemoprophylactic.
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安全性プロファイル
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.
