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
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
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.
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