Antimalarial agents resistance

Stepniewska K, White NJ Pharmacokinetic determinants of the window of selection for antimalarial drug resistance. Antimicrob Agents Chemother 2008 52 1589. 

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. 

Krogstad DJ, Schlesinger PH, Herwaldt BL (1988) Antimalarial agents mechanism of chloroquine resistance. Antimicrob Agents Chemother 32 799-801... 

Vinyl-l,2,4-Trioxyspiro antimalarial agents, (I), prepared by Singh (2) were effective in treating multidrug-resistant malaria strains. 

The results of the repository antimalarial studies with CI-679 indicate that the drug is worthy of consideration for use as a repository antimalarial agent in drug-resistant malaria either alone or in combination with a long-acting sulfone such as DADDS or PSBA (vide supra). 

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. 

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