ハロファントリン 化学特性,用途語,生産方法
効能
抗マラリア薬
説明
Halofantrine is an orally-active blood schizonticide reportedly highly effective in the
treatment of fulcipurum malaria and other types of parasitemia. Cure rate is claimed to be
over 95%.
世界保健機関（WHO）
Halofantrine is an antimalarial introduced to medicine in 1982. It
should be reserved for use in areas where multiple drug-resistant falciparum
malaria is prevalent. Cases of serious cardiotoxicity have been reported.
抗菌性
It inhibits erythrocytic stages of chloroquine-sensitive and
chloroquine-resistant P. falciparum and other Plasmodium spp.
in vitro at concentrations of 0.4–4.0 mg/L. It is more active
than mefloquine and the combination of proguanil and atovaquone
against P. falciparum, but less effective than mefloquine
or chloroquine against P. vivax.
獲得抵抗性
Resistance in P. falciparum has been reported in Central and
West Africa, where it has been used widely. Cross-resistance
with mefloquine has been reported in Thailand, where it has
not been used.
一般的な説明
Structurally, halofantrine differs from allother antimalarial drugs. It is a good example of drug designthat incorporates bioisosteric principles as evidenced by thetrifluromethyl moiety. Halofantrine is a schizonticide and has no affect on the sporozoite, gametocyte,or hepatic stages. Both the parent compound and Ndesbutylmetabolite are equally active in vitro. Halfantrine’sspecific mechanism of action against the parasite is notknown. There is contradictory evidence that its mechanismranges from requiring heme to disrupting the mitochondria.There is a prominent warning that halfantrine can affectnerve conduction in cardiac tissue.
応用例（製薬）
A phenanthrene methanol, formulated as the hydrochloride
for oral administration. Parenteral formulations are not
available. The enantiomers have equivalent activity in vitro.
Aqueous solubility is extremely low.
薬物動態学
Absorption shows high intra- and inter-subject variability
and depends on co-administration with fats. Bioavailability is
increased more than six-fold after a fatty meal or by lipidbased
formulations. Bioavailability is significantly lower in
patients with malaria than in healthy individuals. Peak plasma
levels are variable and occur 3–6 h after administration.
Unlike many other antimalarials, halofantrine is not concentrated
by infected or uninfected erythrocytes. Distribution to
lipoproteins is stereo-selective. About 20–30% of the dose is
metabolized to an N-desbutyl derivative by cytochrome P
450
(CYP) 3A4 and 3A5. The elimination half-life of the parent
drug is generally 1–2 days and that of the metabolite 3 days.
Little unchanged drug is excreted in urine.
臨床応用
Treatment of multidrug-resistant falciparum malaria
Its use has been questioned due to the existence of safer
alternatives.
副作用
Abdominal pain, diarrhea and pruritus are the most frequent.
High doses (24 mg/kg) induce prolongation of the PR and
QTc intervals; this is not stereo-selective. There are individual
reports of fatal cardiac arrest and torsade de pointes.
To reduce the risk of cardiac toxicity it should be taken on
an empty stomach. It should not be administered with other
antimalarials that have the potency to induce cardiac arrhythmias
(mefloquine, chloroquine, quinine). Halofantrine has
also been associated with intravascular hemolysis.
代謝
Halofantrine is considered to be an alternative drug for treatment of both chloroquine-sensitive
and chloroquine-resistant Plasmodium falci parum malaria, but its efficacy in mefloquine-resistant
malaria may be questionable. The drug is metabolized via N-dealkylation to desbutylhalofantrine
by CYP3A4. The metabolite appears to be several-fold more active than the
administered drug.
ハロファントリン 上流と下流の製品情報
原材料
準備製品