The chemotherapy of malaria

Abstract

Malaria remains a formidable global problem. Although substantial progress has been made in efforts to combat and to eliminate this protozoan scourge, much remains to be done. This review dealing with the chemotherapy of malaria presents: a brief resume of historical aspects relating to the development of synthetic antimalarial drugs; a discussion of apposite considerations with respect to parasites that cause human malaria, classification of antimalarial drugs, and terminology; a summary of available information concerning the uses and effects of quinine and widely employed synthetic antimalarial drugs; a short account of certain other antimalarial agents, some developed recently, that are of considerable experimental interest; and a discussion of resistance of malaria parasites to drugs, with particular emphasis on recently detected parasites that are resistant to chloroquine and to other synthetic antimalarial drugs.

Relationships between chemical structures of 8-aminoquinolines and their capacities for radical cure of infections with Plasmodium cynomolgi in rhesus monkeys

“…16). Despite its limitations, which led to the current search for other curative agents, this drug has enjoyed widespread use for close to 20 years and, when it is or can be taken regularly at prescribed doses, has performed effectively (44,45). Yet, with respect to dose required for the same level of curative efficacy, primaquine is but twice as active as pamaquine and pentaquine and no more than one-and-one-half times as active as isopentaquine against P. vivax infections in human volunteers (1,3,17,19,22).…”

“…This would be true if lethality was the parameter of toxicity that determines tolerability of an 8-aminoquinoline for humans, but this, of course, is not the case. The concerns in humans are not with lethality, but with severe abdominal cramping, anorexia, and anemia associated with glucose-6-phosphate dehydrogenase deficiency, all of which occur, albeit with variable frequency depending upon the characteristics of the patient population, at doses of primaquine prescribed in curative, suppressivecurative, or prophylactic regimens and affect patient compliance with these schedules (44). The above manifestations of toxicity are not easily identified, or not possible to identify, in either rhesus monkeys or other experimental animals.…”

The use of a three compartment in vitro model to investigate the role of hepatic drug metabolism in drug‐induced blood dyscrasias.

“…Administration of primaquine is associated with a high incidence of red cell damage, in the form of methaemoglobinaemia and haemolysis, with rarer, idiosyncratic white cell abnormalities, such as granulocytopenia [14]. In the three compartment model, in which target cells are separated from the drug activating system, there was no detectable toxicity toward either white or red cells when either rat or human liver microsomes were used.…”

“…However, in contrast to dapsone, no red cell toxicity is observed during therapy with these drugs. Administration of primaquine is associated with both red cell toxicity, in the form of methaemoglobinaemia and haemolysis, especially in patients deficient in the enzyme glucose 6phosphate dehydrogenase, as well as rarer, idiosyncratic white cell toxicities such as granulocytopenia [14].…”