Мефлохин

Описание

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.

Химические свойства

Off-White Solid

Использование

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.

Показания

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.

Всемирная организация здравоохранения(ВОЗ)

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.

Антимикробная активность

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.

Приобретенная устойчивость

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.

Фармацевтические приложения

A synthetic 4-quinolinemethanol, formulated as the hydrochloride for oral administration. It is slightly soluble in water.

Фармакокине?тика

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.

Клиническое использование

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.

Побочные эффекты

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.