プログアニル 化学特性,用途語,生産方法
効能
抗マラリア薬
説明
Chloroguanide is active with respect to exoerythrocyte and erythrocyte forms of
plasmodia. It is most beneficial for suppressive therapy. It is used for preventing malaria,
and it should be started 2 weeks before entering a malarial zone and should be taken
for 8 weeks. Synonyms of this drug are biguanide, bigunal, paludrine, proguanil, and
others.
使用
Proguanil is medicaments; used in preparation of pyrrolecarboxamide derivatives as anti-malarial agents.
適応症
Chloroguanide hydrochloride (Paludrine) is activated
to a triazine metabolite, cycloguanil, which also interferes
with parasite folic acid synthesis. It is a dihydrofolate
reductase inhibitor that is used for the prophylaxis
of malaria caused by all susceptible strains of plasmodia.
Chloroguanide is rapidly absorbed from the gastrointestinal
tract. Peak plasma levels occur 2 to 4 hours
after oral administration, and the drug is excreted in the
urine with an elimination half-life of 12 to 21 hours. Its
side effects and spectrum of antimalarial activity are
quite similar to those of pyrimethamine.The conversion
of chloroguanide to the active metabolite is decreased
in pregnancy and also as a result of genetic polymorphism
in 3% of whites and Africans and 20% of Asians.
定義
ChEBI: A biguanide compound which has isopropyl and p-chlorophenyl substituents on the terminal N atoms. A prophylactic antimalarial drug, it works by inhibiting the enzyme dihydrofolate reductase, which is involved in the reproduction of the malaria
parasites Plasmodium falciparum and P. vivax within the red blood cells.
抗菌性
Proguanil has low antiplasmodial action, but useful activity is
attributable to the metabolite cycloguanil, which inhibits the
early erythrocytic stages of all four Plasmodium spp. that cause
human malaria and the primary hepatic stage of P. falciparum.
Proguanil acts synergistically with atovaquone and probably
enhances its effect on mitochondrial membrane charge.
獲得抵抗性
Resistance of P. falciparum associated with point mutations
of dihydrofolate reductase has been reported worldwide.
Resistance in P. vivax and P. malariae has been reported in
South East Asia. Cross-resistance with pyrimethamine is not
absolute, because differential resistance can arise from different
point mutations on the dihydrofolate reductase gene.
応用例（製薬）
A synthetic arylbiguanide, formulated as the hydrochloride
for oral use. It is slightly soluble in water.
薬物動態学
Oral absorption: >90%
C
max 100 mg oral: 0.4 mg/L after 2–4 h
Plasma half-life: 10 h
Plasma protein binding: 75%
Oral absorption is slow. It is 75% protein bound and is concentrated
10- to 15-fold by erythrocytes. About 20% of the
drug is metabolized to dihydrotriazene derivatives, most
importantly cycloguanil,by hepatic cytochrome P
450 processes.
Cycloguanil is detectable 2 h after administration of
proguanil. High proportions of ‘non-metabolizers’ have been
identified in Japan and Kenya, indicating another source of
resistance. About 60% of the dose is excreted in the urine.
臨床応用
Antimalarial prophylaxis (usually in combination with chloroquine)
Treatment and prophylaxis for drug-resistant falciparum malaria (in
combination with atovaquone)
副作用
It is well tolerated at recommended doses. Gastrointestinal and
renal effects have been reported at doses exceeding 600 mg
per day.
安全性プロファイル
Poison by ingestion,
intravenous, and intraperitoneal routes.
Experimental reproductive effects. When
heated to decomposition it emits toxic
fumes of Cland NOx.
プログアニル 上流と下流の製品情報
原材料
準備製品