Three persons were experimentally inoculated with malaria by means of Anopheles ludlowi reared from larvae and infected with a pure strain of subtertian plasmodium (Plasmodium falciparum), thus proving that there exists no mechanical impediment or obstacle to the free exit of sporozoites from the salivary ducts or proboscis. In the dissection of infected mosquitoes there were no evidences of degenerated zygotes. Sporozoites appeared promptly in the salivary glands (9 to 12 days). Inoculation occurred with ease either in an interrupted feeding or after mosquitoes had been fed twice previously. The period of incubation was 14 and 18 days. The clinical manifestations were more severe in the subject that had never been infected with malaria previously, while the splenic enlargement was most pronounced in the subject infected after a long interval of freedom from malaria. In a third subject already suffering from tertian malaria there was only the slightest evidence of physical illness elicited by the superimposed subtertian infection; his temperature, however, became duly elevated. The type of febrile reaction in the two uncomplicated cases was at first tertian, becoming quotidian later, and this phenomenon in a pure strain leads strongly to the supposition that Plasmodium falciparum possesses inherently both tertian (or subtertian) and quotidian tendencies, as well as its well known tendencies to cause fever of the irregularly remittent or continued type. The creation of a specific plasmodium to account for clinical forms of aestivo-autumnal or subtertian malaria having a quotidian periodidty is probably unwarranted. In consideration of the facility with which this species can be infected and man inoculated experimentally, the occurrence of naturally infected wild specimens, and the positive epidemiological evidence, there should no longer exist in the minds of sanitarians any doubt as to its being a malarial carrier. Operations against this species can therefore be recommended without reservation and should be carried out without delay.
A letter from Drs. G. I. Robertson, D. G. Davey, and Sir Hamilton Fairley (December 6, 1952, p. 1255) reported that a proguanil-resistant strain of Plasmodium falciparum from Malaya had proved to be resistant also to pyrimethamine (" daraprim "). Proguanil-resistance in Malayan strains of P. falciparum has been recognized since 19491; and if a true cross-resistance exists, this might-as implied by Dr. J. S. K. Boyd (February 7, p. 337)-go far to explain the pyrimethamine failures described in our paper (January 31, p. 253). Proguanil has been so widely used throughout Malaya for the past six years that there can be few strains of parasite which have not yet come into contact with it; thus there is little chance of deciding now how the "parent" strains (without previous contact with proguanil) might have responded to pyrimethamine. We have not, however, been able to confirm that there is any consistent cross-resistance between these two drugs in naturally acquired falciparum malaria since pyrimethamine was first used in Malaya in 1951. Pyrimethamine failures have been successfully treated with normal doses of proguanil, and proguanilresistant infections have responded readily to pyrimethamine. In some of these cases an interval of several days was allowed to elapse between treatments, so the possibility of a combined action of the two drugs should have 'been small. We consider that these apparently conflicting results can best be explained by assuming that some present-day strains of P. falciparum in Malaya possess a " natural" resistance to pyrimethamine, whether or not any particular strain is also demonstrably resistant to proguanil. With this species of parasite, a true cross-resistance has still to be proved. REFERENCE 1 British Medical Journal, 1950. 1, 147.
In view of the problems caused by the chloroquine-resistance of some strains of Plasmodium falciparum, the authors have investigated the effectiveness of diaphenylsulfone against two such resistant strains, from Malaya and Viet-Nam. They found that diaphenylsulfone given during acute attacks of malaria had a blood schizontocidal activity against the Malayan resistant strain but was not rapidly effective in terminating acute attacks in non-immune persons, and that, when the drug was given prophylactically in relatively small doses, it was substantially effective in preventing patency of mosquito-induced infection with the same strain. The protective effect of diaphenylsulfone is that of a clinical prophylactic or suppressive drug; it does not appear to be a true causal prophylactic. It was also found that the protective effect is vitiated by the concurrent administration of paraaminobenzoic acid.These studies indicate a need for further assessment of the antimalarial value of sulfones and sulfonamides, both alone and in combination with other drugs, for prevention and cure.