Studies on a West African strain of plasmodium falciparum II. The efficacy of paludrine (proguanil) as a therapeutic agent

Mechanisms of Resistance of Malaria Parasites to Antifolates

“…Proguanil. Early reports on the use of proguanil (Paludrine) for both prophylaxis and treatment were very encouraging (Maegraith et al, 1945(Maegraith et al, , 1946Jones et al, 1948;Seaton and Lourie, 1949), despite a slower schizontocidal action (defined as activity against any asexual blood stage parasite, not only schizonts) compared with quinine or mepacrine (Covell et al, 1949). Thereafter, when proguanil was used in the late 1940s and the early 1950s as prophylaxis for plantation workers in Southeast Asia and elsewhere, it provided an opportunity for widespread drug selection pressure on the parasite and the subsequent development of resistance to this drug.…”

“…followed from these early observations. Covell et al (1949) described a proguanil-resistant isolate from Nigeria and MECHANISMS OF RESISTANCE OF MALARIA PARASITES TO ANTIFOLATES suggested that resistance, as seen in the Lagos and Malayan strains, was an acquired trait. Clyde and Shute (1957) found incomplete cross-resistance between pyrimethamine and proguanil, and Peters (1975) found the same between the sulfonamides and sulfones.…”

“…Once again, the allele containing A16V and S108T was found in only one isolate (FCR3). This second group proposed that these mutations arose independently, i.e., that pyrimethamine resistance was an acquired trait, a supposition first put forth by Covell in 1949(Covell et al, 1949.…”

The Chemoprophylaxis and Chemotherapy of Malaria in Man With Special Reference to the Life Cycle

“…Similarly, the Costa strain of P. falciparum proved more refractory than the McClendon strain (Earle, Berliner et alii, 1948). Covell et alii (1949) found that a West African strain of P. falciparum was more refractory to the schizonticidal action of proguanil than the New Guinea strain of the same species studied at Cairns by Fairley et alii (1946) ; no difference, however, was noted in its action as a causal prophylactic.…”

“…Actually in the naturally occurring so-called resistant strains of parasites so far studied in man, there is evidence of decreased sensitivity of the asexual parasites to the schizonticidal action of " Paludrine ", but not of increased resistance of pre-erythrocytic parasites to this drug. Covell et alii (1949) also investigated the causal prophylactic action of proguanil in general paralytics infected with the West African strain of P. f alciparum already referred to, which was relatively insensitive to the schizonticidal action of the drug. They found, however, even with this strain, that complete protection was afforded and malaria prevented by proguanil when given in doses of (1) 50 to IOO milligrammes daily, (2) IOO milligrammes twice a week at intervals of three to four days, or (3) 300 milligrammes once weekly.…”