MEFLOQUINE

Absorption

Mefloquine is readily absorbed from the gastrointestinal tract; food significantly increases absorption and increases bioavailability by 40%. The bioavailability of tablets compared with the oral solution preparation of mefloquine is over 85%. Cmax is achieved in 6 to 24 hours in healthy volunteers after a single dose. Average blood concentrations range between 50 to 110 ng/ml/mg/kg. A weekly dose of 250 mg leads to steady-state plasma concentrations of 1000 to 2000 μg/L, after 7 to 10 weeks of administration.

Toxicity

The oral TDLO of mefloquine in humans is 11 mg/kg/2W (intermittent) and 880 mg/kg in the rat. Intraperitoneal LD50 in the rat is 130 mg/kg. Symptoms of an overdose with mefloquine may manifest as a worsening of adverse effects. In the case of an overdose, symptomatic and supportive care should be provided. There is no known antidote for an overdose with mefloquine. Monitor cardiac function by ECG, follow neuropsychiatric status for at least 24 hours, and provide treatment as required.

Description

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.

Chemical properties

Off-White Solid

Originator

Lariam,Roche Pharmaceuticals,Switz.

The Uses of MEFLOQUINE

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.

The Uses of MEFLOQUINE

Mefloquine is an analog of quinine, and it differs from it in that the side chain at C4 of the quinoline ring contains a piperidine fragment instead of a quinuclidine fragment, and positions C2 and C8 are substituted with trifluoromethyl groups. This antimalarial drug was created to treat and prevent chloroquine resistance of malarial forms caused by P. falciparum. It is not clinically active against exoerythrocyte forms of P. vivax, although it is extremely active against blood schizontosides P. vivax and P. falciparum. It is intended to be used for treating weak and moderate forms of malaria caused by the indicated plasmodia. A synonym of this drug is lariam.

Background

Malaria is a protozoan disease that places an enormous burden on human health in endemic areas around the world. The 2020 World Health Organization malaria report indicates a 60% decrease in the global malaria fatality rate between 2000 to 2019. Despite this, malaria remains a significant cause of morbidity and mortality; 90% of deaths from malaria occur in Africa. Individuals at the highest risk for malaria are those in disease na?ve populations, children under age 5, refugees in Central and Eastern Africa, nonimmune civilian and military travelers, pregnant women, and immigrants traveling to their place of origin.
Mefloquine, commonly known as Lariam, is an antimalarial drug used for the prevention and treatment of malaria caused by infection with Plasmodium vivax and Plasmodium falciparum. The drug was initially discovered by the Walter Reed Army Institute of Research (WRAIR) during a malaria drug discovery program between 1963 until 1976. It was approved by the FDA in 1989, and was first marketed by Hoffman Laroche. This drug has been the subject of widespread controversy due to concerns regarding neurotoxic effects; product information warns of potential serious neuropsychiatric effects.

Indications

Mefloquine is indicated for the treatment of mild to moderate cases of malaria caused by Plasmodium falciparum and Plasmodium vivax. It is effective against chloroquine-resistant forms of Plasmodium falciparum. Mefloquine is also indicated for the prophylaxis of malaria caused by Plasmodium falciparum and Plasmodium vivax, including chloroquine-resistant forms of Plasmodium falciparum.

Indications

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.

Definition

ChEBI: (-)-(11S,2'R)-erythro-mefloquine is an optically active form of [2,8-bis(trifluoromethyl)quinolin-4-yl]-(2-piperidyl)methanol having (-)-(11S,2'R)-erythro-configuration. An antimalarial agent, used in racemic form, which acts as a blood schizonticide; its mechanism of action is unknown. It has a role as an antimalarial. It is an enantiomer of a (+)-(11R,2'S)-erythro-mefloquine.

Manufacturing Process

The first method of synthesis of 2,8-bis(trifluoromethyl)-4-quinolinyl-2- pyridinylmethanone
N-Methoxy-N-methyl-2,8-bis(trifluoromethyl)-quinoline-4-carboxamide was prepared using synthetic methodology reported by Thiesen et al (J. Org. Chem. 1988, 53, 2374). To a suspension of 12.5 g (40.4 mmol) 2,8- bis(trifluoromethyl)quinoline-4-carboxylic acid (was prepared by the method of Hickmann et al. (U.S. Patent No. 4,327,215)) in 200 ml CH2Cl2 was added 1,1'-carbonyldiimidazole (7.3 g, 45 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.25 g, 45 mmol). The resulting deep red solution was stirred overnight, then poured into dilute hydrochloric acid (0.25 M, 200 ml). The organic phase was separated, and washed with dilute sodium hydroxide and brine, and dried (MgSO4). The solvents was evaporated to leave a viscous brown oil, which was filtered through a pad of silica gel using ethyl acetatehexane (1:1) as eluent to give N-methoxy-N-methyl-2,8-bis(trifluoromethyl)- quinoline-4-carboxamide as a yellowish oil, 14.3 g (98%), which solidified on standing. This material was broken up under hexane to afford the product as a solid, melting point 93-95°C. Analysis of this material by HPLC showed it to be >99.8% pure.
To a solution of the N-methoxy-N-methyl-2,8-bis(trifluoromethyl)-quinoline-4- carboxamide amide (10 g, 28.4 mmol) in anhydrous ether (100 ml) was added a solution of 2-pyridyl lithium (Pinder et al (J. Med. Chem. 1968, 11, 267)) [formed by addition of 2-bromopyridine (3.3 ml, 34.6 mmol) to a solution of butyl lithium (29.7 ml of a commercial 1.6 M solution, diluted with an equal quantity of ether) at -78°C] at -78°C. Analysis of the reaction by TLC after 10 min showed that no starting material remained. The reaction was allowed to warm to room temperature, then poured into aqueous ammonium acetate, and extracted with ether, the combined organic layers washed with brine and dried (MgSO4). Filtration through a pad of silica gel using ethyl acetate-hexane (1:1) afforded 9.0 g (84%) of the crude 2,8- bis(trifluoromethyl)-4-quinolinyl-2-pyridinylmethanone. This was recrystallised from isopropyl alcohol to give the product as colourless needles, identical to that described in the literature (Hickmann et al.; Pinder et al.; Ohnmacht et al.; and Adam et al. (Tetrahedron 1991, 36, 7609)).
The second method of synthesis of 2,8-bis(trifluoromethyl)-4-quinolinyl-2- pyridinylmethanone
In a round bottom flask (100 ml) were placed 4-chloro-2,8- bis(trifluoromethyl)quinoline (0.0385 mole, 11.52 g), 2-pyridylacetonitrile (0.0423 mole, 5.0 g), benzyltriethylammonium chloride (0.26 g, 3 mole %), THF (35 ml) and aq NaOH (20 N, 9.63 ml, 0.192 moles). On stirring the colour of the solution became cherry red. The reaction temperature was increased to 5-0°C and stirred for further 1 hour. Monitoring of the reaction mixture by thin layer chromatography (TLC) or gas liquid chromatography (GLC) indicated complete consumption of 4-chloroquinoline to give nitrile. The reaction temperature was lowered to 20-25°C followed by addition of 30% H2O2 (13 ml, 0.1154 moles). TLC and GLC monitoring indicated complete conversion of nitrile compound to 2,8-bis(trifluoromethyl)-4-quinolinyl-2- pyridinylmethanone. Reaction mixture was cooled to 0-5°C and neutralized by ortho-phosphoric acid (85% aq, 4.5 ml). THF was distilled off, followed by addition of water (30 ml) and extraction with toluene. The crude product was crystallized from isopropanol to obtain 2,8-bis(trifluoromethyl)-4-quinolinyl]-2- pyridinylmethanone. Yield = 13.17 g (92%), melting point 123°C.

brand name

Lariam (Roche).

Therapeutic Function

Antimalarial

World Health Organization (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.

Antimicrobial activity

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.

Acquired resistance

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.

Pharmaceutical Applications

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

Pharmacokinetics

Sporozoites located in the salivary glands of mosquitoes infected with malaria parasites are introduced into the bloodstream of a human host during mosquito feeding. These sporozoites rapidly invade the liver, where they mature into liver-stage schizonts, rupturing and releasing 2,000 - 40,000 merozoites that invade red blood cells. Mefloquine is an antimalarial drug acting as a blood schizonticide, preventing and treating malaria.

Pharmacokinetics

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.

Clinical Use

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.

Side Effects

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.

Synthesis

Mefloquine, D,L-erythro-α-2-piperidyl-2,8-bis-(trifluoromethyl)-4-quinolinmethanol (37.1.1.53), is made in various ways from 2-trifluoromethylaniline. According to the first method, heterocyclization of the reaction product 2-trifluoromethylaniline with trifluoroacetoacetic ester gives 2,8-bis-(trifluoromethyl)-4-hydroxyquinoline (37.1.1.48). Reacting the product with phosphorus tribromide replaces the hydroxyl group in the fourth position of the quinoline ring with a bromine atom, giving 2,8-bis-(trifluoromethyl)-4-bromoquinoline (37.1.1.49). Reaction of the last with butyllithium gives a organolithium derivative—2,8- bis-(trifluoromethyl)-4-lithiumquinoline (37.1.1.50). Reacting this with carbon dioxide makes 2,8-bis-(trifluoromethyl)-4-quinolincarboxylic acid (37.1.1.51). Interaction of the resulting acid with 2-lithiumpyridine gives the ketone (37.1.1.52). Reducing both the keto group and the pyridine ring with hydrogen using a platinum catalyst gives the desired mefloquine.

The second way of making mefloquine is from 2,8-bis-(trifluoromethyl)-4-lithiumquiniline described above (37.1.1.50), which is reacted with 2-formylpyridine to make α-2-pyridyl-2,8-bis-(trifluoromethyl)-4-methanolquinoline (37.1.1.54). The pyridiyl group in this compound is also reduced as described above, resulting in the formation of the desired mefloquine.
Finally, the third way of making mefloquine also begins with 2-trifluoromethylaniline, except in this case it is reacted with chloralhydrate and hydroxylamine to make isonitrosoacetyl(2-trifluoromethyl)anilide (37.1.1.55), which when heated in the presence of sulfuric acid cyclizes to 7-trifluoromethylisatine (37.1.1.56) (Sandmeyer reaction). The resulting 7-trifluoromethylisatine (37.1.1.56) is then reacted with 1,1,1-trifluoroacetone in the presence of a base in a Friedlaender reaction conditions to make 2,8-bis-(trifluoromethyl)-4-quinoline carboxylic acid described above (37.1.1.51). Reacting this with lithium hydroxide turns it into a lithium salt, which is reacted with a Grignard reagent, 2-magnesiumbromopyridine (made from 2-bromopyridine and magnesium). The resulting ketone (37.1.1.52) is again reduced with a platinum catalyst to make the desired mefloquine.

Metabolism

Mefloquine is heavily metabolized in the liver by the CYP3A4 enzyme. Two metabolites have been identified; the main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, which inactive against plasmodium falciparum. The second metabolite, an alcohol, is found in small quantities.