Mefloquine antimalarial agent

Of industrial significance are ethyl 4,4,4-trifluoroacetoacetate [372-31-6] methyl 4,4,4-trifluoroacetoacetate, and isopropyl 4,4,4-trifluoroacetoacetate for the production of herbicides (eg, Monsanto s Dimension) and antimalarial agents such as Roche s Mefloquin [51773-92-3] as weU as ethyl 4,4,4-trichloroacetoacetate [3702-98-5] for the production of pharmaceuticals. 

Clinical Use. Mefloquine (Lariam) has emerged as one of the most important antimalarial agents.61 This drug is especially important in the prevention and treatment of malaria that is resistant to traditional antimalarial drugs such as chloroquine and quinine.50 Mefloquine is often the drug of choice for antimalarial prophylaxis, especially in areas of the world where chloroquine-resistant strains of malaria are common.23 Mefloquine can be used alone, but combining this... 

Following the development of synthetic antimalarial agents, such as chloroquine and mefloquine, the use of Cinchona alkaloid quinine declined. However, with the emergence of chloroquine-resistant and multiple-drug-resistant strains of malarial parasites, its use has become firmly reestablished. Quinine is the drug of choice for severe chloroquine-resistant malaria due to Plasmodium falciparum. In the U.S., the related alkaloid quinidine is recommended because of its wide availability and use as an antiarrhythmic agent. In many clinics in the tropics, quinine is the only effective treatment for severe malaria unfortunately, decreasing sensitivity of P. falciparum to quinine has already been reported from Southeast Asia. 

Phillips-Howard PA, Steffen R, Kerr L, Vanhauwere B, Schildknecht J, Fuchs E, Edwards R. Safety of mefloquine and other antimalarial agents in the first trimester of pregnancy. J Travel Med 1998 5(3) 121-6. 

Schwartz E, Regev-Yochay G. Primaquine as prophylaxis for malaria for nonimmune travelers A comparison with mefloquine and doxycycline. Clin Infect Dis I999 29(6) 1502-6. Lobel HO, Coyne PE, Rosenthal PJ. Drug overdoses with antimalarial agents prescribing and dispensing errors. JAMA 1998 280(17) 1483. 

Other chiral phosphine/transition metal complexes catalyze the hydrogenation of a-pyridyl ketones (to biologicaly active amino alcohols like (/ ,S)-Mefloquine, an antimalarial agent (Hoffmann-La Roche [30]) or of a-benzamide ketones to... 

Aubry A. F., Gimenez, F., Farinotti, R., Wainer, 1. W. Enantioselective chromatography of the antimalarial agents chloro-quine, mefloquine, and enpiroline on a al-acid glycoprotein chiral stationary phase Evidence for a multiple-site chiral recognition mechanism. Chirality, 1992, 4, 30-35. 

Figure 25.4 Antimalarial agents drugs (chloroquine, mefloquin, and pyrimethamine) in the market and clinical candidates (GNF-156 and NITD-609).

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic dmgs came this century when the two World Wars intermpted the supply of cinchona bark to the combatants. A stmcturally related 4-quinolinemethanol is mefloquine (65, Lariam [51773-92-3]) which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this dmg such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

VLa.2,6. Other antimalarials. Doxycydine (see Section ILb) is a useful and effective short-term prophylactic agent for travellers to chloroquine-resistant areas and can be used as an alternative when mefloquine or proguanil is unavailable or mefloquine is contraindicated. In combination with quinine also tetracycline is used as an antimalarial. 

Mefloquine is effective in treating most falciparum malaria. The drug is not appropriate for treating individuals with severe or complicated malaria, since quinine, quinidine, and artemisinins are more rapidly active, and since drug resistance is less likely with those agents. The combination of artesunate plus mefloquine showed excellent antimalarial efficacy in regions of Southeast Asia with some resistance to mefloquine, and this regimen is now one of the combination therapies recommended by the WHO for the treatment of uncomplicated falciparum malaria (Table 52-4). Artesunate-mefloquine is the first-line therapy for uncomplicated malaria in a number of countries in Asia and South America. 

In the last few years, variations on the basic stracmre have been launched in combination with other antimalarials (usually variations on the chloroquine structure) such as dihydroartemismin and piperaquine phosphate (Artekin), artemether and lumefantrine (Coartem), artesunate/mefloquine (Artequin) and artesunate, sulfamethoxypyrazine, and pyrimethamine (Co-Arinate). Currently, there is another fixed dose combination with an artemisinin derivative in clinical trials, pyronaridine/artesunate (Pyramax in Phase III). However, the tri-oxo scaffold system in artemisinins has led to the synthesis of not only artemisinin variations but to totally synthetic molecules with the trioxane moiety included, such as arterolane tosylate (81). This compound is in Phase II trials as a single agent under Ranbaxy and is in Phase I trials in combination with piperaquine phosphate, also under Ranbaxy. 

Miscellaneous compounds of pharmacological interest have been shown to inhibit aromatase in vitro, including the antimalarial drug mefloquine, [138], the oral hypoglycaemic agent, tolbutamide [139], and nicotine, its metabolite cotinine, and anabasine, all of which are found in tobacco [140]. These effects probably have little clinical relevance, although the latter three compounds may account for the reduced urinary [141] and plasma [142] oestrogen concentrations found in smokers [140],... 

Describe the pharmacodynamic and pharmacokinetic properties of the major antimalarial drugs (chloroquine, mefloquine, quinine, primaquine, and the antifolate agents). 

---