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.
Chloroquine resistance is a well established entity in South East Asia, and presents a problem of increasing importance. Strains of P. falciparum resistant to chloroquine have also been found to be resistant to amodiaquine and a combination of pyrimethamine and sulphadoxine. Knowledge of the drug sensitivity of the strains of malaria parasite in a given locality is important so that the right choice of drugs can be made in treatment of the disease. The treatment of chloroquine resistant malaria in West Malaysia is a subject of another paper but suffice it to say that increased doses of chloroquine have still been found to be effective in treating many cases of falciparum malaria from areas of chloroquine resistance.
Chloroquine pressure was applied over a 22 month period on a somewhat isolated, malarious rubber estate by examination of residents at 4-week intervals and treatment of parasitaemias with chloroquine. During this time the monthly attack rate for P. falciparum rose four-fold to an average of nearly 18% per month, while that of P. vivax remained relatively constant at about 8%. Eight in vivo chloroquine resistance studies, which allowed both detection of late recrudescing R-I resistance and estimation of the risk of reinfection, showed an apparent rise in the drug resistance rate, from 12% to 20% prior to the study to the range of 40-50%. Virtually all resistance encountered was R-I in nature. There was no convincing evidence of chloroquine resistance among 148 tested P. vivax infections.
In vivo chloroquine resistance surveys, which allowed for detection of late recrudescing RI resistance, were conducted in three regions of Peninsular Malaysia, which were previously not recognized as having appreciable drug resistance. Among the 485 Plasmodium falciparum infections tested resistance rates ranged locally from 20% to 67% in those with parasitaemias over 1,000 per mm3, and 5% to 59% in all parasitaemias. The region found to have the most serious resistance was western Pahang. In one study a combination of chloroquine and pyrimethamine proved no more efficacious than chloroquine alone. Most of the resistance encountered was the late recrudescing RI type. There was no apparent correlation between drug resistance and Anopheles balabacensis as this species was not found despite intensive collections in two of the three main regions. There was no evidence of resistance among the 222 P. vivax and 35 P. malariae infections also tested.
The status of P. falciparum resistance to chloroquine in Sabah, Malaysia were not know until 1971-1972. Several in-vivo and on in-vivo studies were conducted from 971-1975, and the result showed 51% out of total 57 cases studied were resistant to chloroquine. The latest in-vitro study (collaborative with WHO) started in July 1978, to continue till 1980, to cover the whole State. The preliminary result shows 65 cases (85%) out of a total 76 successful tests are resistant to chloroquine. On the basis of this preliminary result, the radical treatment for P. falciparum infection was changed from chloroquine to Fansidar from June 1979 throughout the State.
A report was made of 4 cases of chloroquine resistant Plasmodium falciparum infections. The infections, detected in Jakarta, were imported from Kotabumi, Tanjung Karang, the Island of Pidada in the Lampung Province and from Pangkalpinang on the Island Bangka in the Province of South Sumatra. Treatment with courses of 1500 mg chloroquine base and with increased dosages up to 2250 mg base failed to cure the patients. The chloroquine sensitivity test in vitro was carried out in 3 patients, which showed that the Plasmodium falciparum strains were resistant to chloroquine at the R I level. The strains appeared to be similar to the Malaya Camp strain. In vivo observations revealed that the parasites were resistant at the R I level with a delayed recrudescence. The chloroquine resistant falciparum malaria cases, acquired in South Sumatra, may therefore be regarded as the first reported cases from a focus outside the already known two foci in Indonesia, namely East Kalimantan and Irian Jaya. It may be expected that chloroquine resistant Plasmodium falciparum will be encountered in other parts of Indonesia in the near future. The use of a combination of sulfadoxine and pyrimethamine should not be recommended in Indonesia because chloroquine is still considered the drug of choice against all malaria infections in Indonesia.
Doxycycline in a single dose was found to be a valuable drug in the treatment of chloroquine-resistant falciparum malaria. It was less effective in a single daily dose of 4 mg/kg body-weight for four days, when it cured only five out of nine patients, while a dosage of 4 mg/kg body-weight for seven days cured 23 out of 26 patients.