メフロキン 化學(xué)特性,用途語(yǔ),生産方法
用途
抗原蟲(chóng)薬抗マラリア薬
効能
抗マラリア薬
説明
Mefloquine, which was synthesized with the intent of blocking the site of metabolism in quinine
with the chemically stable CF3 group, exists as four optical isomers of nearly equal activity. The
drug is active against chloroquine-resistant strains of plasmodium, yet cross-resistance is not
uncommon. Metabolism is cited as the possible mechanism of resistance. Mefloquine is slowly
metabolized through CYP3A4 oxidation to its major inactive metabolite, carboxymefloquine. Most of the parent drug is excreted unchanged into the urine. Its coadministration with
CYP3A4 inhibitors (e.g., ketoconazole) has increased the area under the curve for mefloquine by
inhibiting its metabolism to carboxymefloquine.
化學(xué)的特性
Off-White Solid
使用
Labelled quinoline methanol antimalarial agent.
Mefloquine is also a 4-aminoquinoline. It is a blood schizonticide active against the asexual stages of all malaria parasites. Mefloquine is currently the prophylactic agent of choice for short-term travellers. Resistance of P. falciparum against mefloquine has occurred in South-East Asia. Only an oral formulation of mefloquine exists because of intense local irritation with parenteral use. It is well absorbed orally and notwithstanding a high protein binding of about 98% it is distributed throughout the body. Mefloquine is metabolized in the liver and eliminated slowly, mainly in bile and faeces with an elimination half-life of 10–30 days. Adverse effects include gastrointestinal pain and other disturbances and also, sinus bradycardia. More serious are CNS effects like dizziness and vertigo and more rarely neuropsychiatric disturbances, seizures.
適応癥
Mefloquine (Lariam) is a 4-quinolinemethanol derivative
used both prophylactically and acutely against resistant
P. falciparum malaria. It is ineffective against the
liver stage of P. vivax malaria.
While its detailed mechanism of action is unknown,
it is an effective blood schizonticide; that is, it acts
against the form of the parasite responsible for clinical
symptoms. Orally administered mefloquine is well absorbed
and has an absorption half-life of about 2 hours;
the elimination half-life is 2 to 3 weeks. Among its side
effects are vertigo, visual alterations, vomiting, and such
CNS disturbances as psychosis, hallucinations, confusion,
anxiety, and depression. It should not be used concurrently
with compounds known to alter cardiac conduction
or prophylactically in patients operating
dangerous machinery. It should not used to treat severe
malaria, as there is no intravenous formulation.
世界保健機(jī)関（WHO）
Mefloquine was developed in response to proliferation of multidrug
resistant strains of Plasmodium falciparum, and has been widely used since
the early 1980s. Provided the drug is used appropriately, the risks associated with
its prophylactic use are clearly outweighed by the benefits. Mefloquine is listed in
the WHO Model List of Essential Drugs.
抗菌性
Mefloquine is a lipophilic drug with a high affinity to membranes.
A concentration of 10–40 nm has rapid dose-related
activity against erythrocytic stages of Plasmodium spp.,
including strains resistant to chloroquine, sulfonamides and
pyrimethamine. The C-11 (hydroxy) enantiomers have equal
antimalarial activity. It also exhibits activity against bacteria
(including methicillin-resistant Staphylococcus aureus), and
some fungi and helminths.
獲得抵抗性
Resistance in P. falciparum is widespread in South East Asia
where high-grade resistance was found in 15% of patients and
low-grade resistance in about 50%. There is cross-resistance
with quinine and halofantrine, and an inverse relationship
with chloroquine resistance has been reported. The molecular
basis of resistance remains unclear but polymorphisms
of the pfmdr1 gene, associated with chloroquine resistance,
led to increased sensitivity to mefloquine. Resistant strains of
P. falciparum appeared in Africa before the drug was used in
that continent, perhaps because of quinine abuse or intrinsic
resistance. In South East Asia, declining response rates to
combination therapy with mefloquine and artesunate are
reported.
応用例（製薬）
A synthetic 4-quinolinemethanol, formulated as the hydrochloride
for oral administration. It is slightly soluble in water.
薬物動(dòng)態(tài)學(xué)
Oral absorption: 70–80%
C
max 1 g oral: 1 mg/L after 2–12 h
Plasma half-life: 20 days
Volume of distribution: 16–25 L/kg
Plasma protein binding: 98%
Mefloquine is concentrated two- to five-fold in erythrocytes.
The major metabolites do not have antimalarial activity.
Pregnant women require larger doses than non-pregnant
women to achieve comparable blood levels. It is predominantly
excreted in the bile. Less than 10% is excreted in urine.
臨床応用
Antimalarial prophylaxis in areas of chloroquine resistance
Treatment of uncomplicated multidrug-resistant malaria
A mefloquine–artesunate co-formulation is available.
Mefloquine has been used for the treatment of cutaneous
leishmaniasis in South America.
副作用
At prophylactic doses risks of serious toxicity are about 1 in
10 000, similar to chloroquine. Doses used in therapy are
more commonly associated with nausea, dizziness, fatigue,
mental confusion and sleep loss. Psychosis, encephalopathy
and convulsions are seen in about 1 in 1200–1700 patients.
Mefloquine(+), the enantiomer with potential lower toxicity,
is currently in development.
メフロキン 上流と下流の製品情報(bào)
原材料
準(zhǔn)備製品