Cinchona bark was used in Europe for the treatment of fever as early as 1640. Only after Pelletier and Caventou isolated quinine from cinchona in 1820 did this alkaloid gain widespread acceptance as an antimalarial. Synthesis of new quinolines was stimulated by the interruption of quinine supplies during World Wars I and II and, after 1961, by the growing impact of drug-resistant falciparum malaria in several areas of the world. Among the most effective agents are those that share the double-ring structure of quinine.
Current analogs fall into three major groups: 4-aminoquinolines, 8-aminoquinolines, and 4-quinolinemethanols. Selective destruction of intracellular parasites results from ac-cumulation of the quinolines by parasitized host cells. Most of these agents appear to block nucleic acid synthesis by intercalation into double-stranded DNA. However, the failure of the 4-quinolinemethanols to intercalate indicates that other mechanisms, per-haps inhibition of heme polymerase, with the build up of toxic hemoglobin metabolites within the malarial parasite, are involved.
Quinine, 4-aminoquinolines, and 4-quinolinemethanols are preferentially concen-trated in parasitized erythrocytes and rapidly destroy the erythrocytic stage of the parasite that is responsible for the clinical manifestations of malaria. Thus, these agents can be used either prophylactically to suppress clinical illness should infection occur or thera-peutically to terminate an acute attack. They do not concentrate in tissue cells, and thus organisms sequestered in exoerythrocytic sites, particularly the liver, survive and may later reestablish erythrocytic infection and produce a clinical relapse. The 8-aminoquino-lines accumulate in tissue cells, destroy hepatic parasites, and effect a radical cure.
Chloroquine phosphate, a 4-aminoquinoline, is the most widely used of the blood schizonticidal drugs. In the doses used for long-term malarial prophylaxis, it has proven remarkably free of untoward effects. Primaquine phosphate, the 8-aminoquinoline used to eradicate persistent hepatic parasites, has toxic effects related to its oxidant activity. Methemoglobinemia and hemolytic anemia are particularly frequent in patients with glu-cose-6-phosphate dehydrogenase deficiency, because they are unable to generate suffi-cient quantities of the reduced form of nicotinamide adenine dinucleotide to respond to this oxidant stress. Typically, the anemia is severe in patients of Mediterranean and Far Eastern ancestry and mild in black patients.
Quinine is the most toxic of the quinolines and is currently used primarily to treat the strains of P. falciparum resistant to several blood schizonticidal agents that are spreading rapidly through Asia, Latin America, and Africa. Chloroquine resistance is the most fre-quent and worrisome, because suitable alternatives to this safe and highly effective agent are few. The mechanism of resistance is not clearly understood, but resistant organisms fail to accumulate chloroquine. Experimental reversal of resistance with calcium channel blockers suggests that the failure to accumulate this agent results from a rapid release mechanism. Quinidine, a less cardiotoxic optical isomer of quinine, is more readily available in the United States and is preferred to quinine when parenteral administration is required. Meflo-quine, a more recently developed oral 4-quinolinemethanol, originally displayed a high level of activity against most chloroquine-resistant parasites; however, mefloquine-resistant strains of P. falciparum are now widespread in Southeast Asia, and present, to a lesser de-gree, in South America. Resistant strains have recently been identified in Africa.
Phenanthrene methanols are not, in the strict sense, quinine analogs. Nevertheless, they are structurally similar to this group of agents and, together with them, were discov-ered to have antimalarial activity during the second World War. Halofantrine†, the most effective of the group, has only recently become available. In vitro and in vivo studies demonstrated that it is an effective blood schizonticide against both sensitive and mul-tidrug-resistant strains of P. falciparum. Its mechanism of action was originally thought to differ from that of quinine and mefloquine. Recently, mefloquine-resistant strains of P. falciparum have demonstrated decreased sensitivity to halofantrine, raising the possi-bility of cross-resistance between these two agents. Rarely, halofantrine has produced fa-tal heart arrhythmias, and it should not be given to patients with cardiac conduction abnormalities. It is otherwise well tolerated and appears to be free of teratogenicity. Oral absorption is both slow and erratic, reaching maximum concentrations in 5 to 7 hours; its half-life is relatively short (1 to 3 days). Clinical studies have demonstrated high failure rates when the drug is given in a single dose; cure rates with multiple-dose regimens, however, have been high.
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