Mefloquine preparation

Mefloquine is an antimalarial preparation that acts as a blood schizonticide. It is indicated in the treatment of mild to moderate malaria caused by mefloquine-susceptible strains of Plasmodium falciparum or P. vivax and prevention of malaria caused by P. falciparum or P. vivax. Patients with acute P. vivax need subsequent treatment with 9-ami-noquinolone to prevent relapse. 

Ethers, esters and carbonates of dihydroartemisinin have been prepared to obtain novel and more active derivatives [45]. After examination of the ethers, including the epimers at position 10, artemether (31 2, R = CH3) and arteether (31 3, R = CH2CH3), they were found to be about twice as active as artemisinin, but less active than dihydroartemisinin. Artemether has been isolated as a natural constituent of A. annua. Arteether was found to be 34 times more active than chloroquine against the W-2 (Indochina) clone of P. falciparum (normally resistant to chloroquine) and three times less active against the D-6 (Sierra Leone) clone (normally resistant to mefloquine). Artemether was two times more active and eight times more active than mefloquine against the W-2 and D-6 clones, respectively. Both artemether and arteether are more oil soluble than artemisinin and are currently in clinical trials. 

Mefloquine hydrochloride (lariam) is available for oral administration only. Tablets marketed in the U.S. contain 250 mg mefloquine hydrochloride, equivalent to 228 mg mefloquine base (this may vary in Canada and elsewhere). The dosing below is expressed in mg salt. Adults and children >45 kg body weight take 250 mg weekly starting 1-2 weeks before entering an endemic area and ending 4 weeks after leaving. Pediatric doses, taken by the same schedule, are 5 mg/kg for children up to 15 kg (may have to be prepared by a pharmacist) 62.5 mg (1/4 tablet) for 15-19 kg 125 mg (V2 tablet) for 20-30 kg 187.5 mg /k tablet) for 31 5 kg. Note Mefloquine is not recommended for children weighing <5 kg or individuals with a history of seizures, severe neuropsychiatric disturbances, sensitivity to quinoline antimalarials, or cardiac conduction abnormalities. 

Mefloquine is taken orally because parenteral preparations cause severe local reactions. The drug is well absorbed, a process enhanced by food. Probably owing to extensive enterogastric and enterohepatic circulation, plasma levels of mefloquine rise biphasically to peak in 17 hours. The drug is widely distributed, highly bound ( 98%) to plasma proteins, and slowly eliminated with a terminal 1 2 of 20 days. Several mefloquine metabolites are formed. Plasma levels of the inactive mefloquine 4-carboxylic acid exceed those of mefloquine itself and decline at about the same rate. Excretion is mainly by the fecal route 10% of mefloquine appears unchanged in the urine. 

Mefloquine hydrochloride is an interesting case of a compound that forms stoichiometric 1 1 solvates on cooling hot (50°C) saturated acetone solutions (Form B, acetone solvate 1 1), hot (50°C) saturated isopropanol (Form I, isopropanol solvate 1 1), and a nonstoichiometric ethanol solvate (2.12% ethanol) from hot (50°C) saturated ethanol. Form E, whose x-ray powder pattern does not change following heating to 80°C, in spite of a decrease in the ethanol level to 0.12%. Mefloquine hydrochloride can also be obtained in a nonsolvated form from hot (70°C) saturated acetonitrile (Form A) and as two hemihydrates from water (Forms D and C) prepared at room temperature and at30°C [82]. 

It is worth noting that the two optical isomers of ferroquine exist due to the planar chirality of the unsymmetrically 1,2-substituted ferrocene moiety. Both enantiomers were prepared by enzymatic resolution of an ester intermediate in >98% optical purity. Both isomers display similar activity in vitro " Although both enantiomers are less active than the racemate in vivo the (+)-enantiomer displays better curative effects than the optical antipode. This different behavior indicates different pharmacokinetics of the two enantiomers. Ferrocene derivatives of other antimalarial drugs like artemisinine, quinine, and mefloquine have also been tested, as well as various other chloroquine-derived organometallics. Moss and coworkers synthesized and tested chloroquine and ferroquine derivatives with other organometallic groups. 

Many ferrocene complexes derived from artemisinine 46 [126], quinine 47 and mefloquine 48 [127], chalcones 49 [128], ben2ylimidazolium 50 [129] and sugars 51 [130] have recently been prepared with an eye to their antimalarial properties (Scheme 3.19). 

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