Studies on the Chemotherapy of the Human Malarias. X. The Suppressive Antimalarial Effect of Paludrine 12

Abstract

Paludrine, N1-p-chlorphenyl-N5-isopropylbiguanide acetate, was found by British workers to be ;he most active antimalarial of a series of synthetic guanidines and biguanidines (1, 2). It possesses high activity against the erythrocytic asexual parasites of both vivax and falciparum malaria and is practically non-toxic at therapeutic doses (3, 4). Previous study of the compound has included extensive prophylactic, curative and suppressive trials by the Australian Malarial Unit at Cairns in experimental sporozoite and trophozoite induced vivax and falciparum malaria (5) and curative trials in naturally acquired relapsing Southwest Pacific vivax malaria (6). The drug has a prophylactic action in falciparum malaria which is complete in single doses as low as 25 mgm. The prophylactic action in vivax malaria is less definite, although the incubation periods of patients in the Cairns studies were systematically prolonged, and subinoculations from infected patients showed that this was due to an effect upon the initial tissue phase (cf. 7) of the disease. It is also effective in the treatment of clinical attacks of malaria, being curative in falciparum but not in vivax malaria. The response of fever and symptoms in each infection is somewhat less prompt

Mechanisms of Resistance of Malaria Parasites to Antifolates

“…Clyde and Shute (1957) found incomplete cross-resistance between pyrimethamine and proguanil, and Peters (1975) found the same between the sulfonamides and sulfones. Multidrug resistance was described by Earle et al (1948) in a Central American strain resistant to proguanil, mepacrine, and quinine. These findings largely have been proved accurate.…”

“…The DHFR and DHPS inhibitors are inherently less active against P. vivax, P. malariae, and P. ovale than against P. falciparum (Coggeshall et al, 1941;Earle et al, 1948;Laing, 1968b). For example, the Chesson strain of P. vivax was not inhibited by 1 g of dapsone daily for 10 days and both sulfadoxine and sulfalene were incapable of effecting a radical cure of the same strain (Martin and Arnold, 1969).…”

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

“…James et alii (1932) first demonstrated that his Rome strain of P. falciparum required eight times as much quinine for its therapeutic control as an Indian strain of the same species. 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.…”

Summary of Antimalarial Drugs

“…In P. falciparum infections, chlorguanide acts as a causative prophylactic (61,62) and usually cures (61,63). Some strains of P. falciparum show resistance to the drug (21, 62, 64, 65,66,67) to a degree which has prompted the suggestion (62) that a more rapidly effective drug such as quinacrine be used for first day of treatment and that 0.1 gram of chlorguanide be taken daily for 6 weeks after therapy.…”

“…All parasites are not eradicated, so that infections appear after suppression is discontinued. It alleviates acute attacks of vivax malaria over a wide dosage range (34,61,65,68,69,70) but this effect is often relatively slow. Relapses of P. vivax occur at about the same rate and time as after quinacrine (61,68,69,70,71,72,73).…”