This paper from the Malaria Research Division, Institute for Medical Research, Federation of Malaya, summarizes the results of studies on the suppression of malaria by synthetic drugs. Such studies began 25 years ago, and, in spite of interruptions in the work due to the Japanese invasion and due to banditry, studies are reported here on the effects of giving mepacrine in doses of 0.3 gm. once a week; proguanil in doses of 0.1 gm., 0.2 gm., 0.25 gm. and 0.3 gm. once a week; chloroquine in doses of 0.25 gm. once a week; and amodiaquin [camoquin] in dosos of 0.4 grn. base once a month. The populations upon whom the studies were made were labourers and their families-Tamils, Malays, and Javanese, on 3 estates in Selangor, and Negri Sembilan, Federation of Malaya, between December, 1946, and February, 1949. Each population was divided into 3 comparable sections, 2 of which received test drugs, while the third received a placebo and so formed a control group. Drugs were issued under the supervision of a Malaria Research Officer. Those people who developed fever wore supervised and treated by a hospital assistant resident on each estate. Thick blood films from such patients were studied. Parasite and spleen surveys were done every 3 months. Malaria transmission was assessed by the incidence of malaria in unprotected infants, who were not given suppressive drugs until after their first attack; and by the results of mosquito dissections. The commonest vectors woreA. letifer, A. maoulatus and A. umbrosus. The results of the tests of suppressivo drugs are shown in a series of tables, charts, and diagrams. Malarial transmission was considered light during the period of these trials. Chloroquino 0.25 gm. base once weekly proved the most effective drug in suppressing malarial attacks. There was little difference between proguanil in various doses, or between proguanil and mepacrine, but these two drugs were much cheaper than chloroquine or amodiaquin. All the drugs reduced the parasite and spleen rates. No significant toxic symptoms were observed with any of the drugs used. S. Bell.
A pharmacokinetic study with 12-hourly doses of 100 mg proguanil hydrochloride over 15 days has been conducted in six adult male Malaysian volunteers. Steady state for proguanil was established after the fourth dose on Day 2, for the active metabolite cycloguanil as from Day 3 inclusive. The steady state mean peak concentration of proguanil was 1201.6 +/- 132.4 nmol/l, the mean trough concentration 650.0 +/- 58.1 nmol/l. The corresponding values for cycloguanil were 317.0 +/- 44.4 nmol/l (mean peak) and 230.8 +/- 35.1 nmol/l (mean trough). The profiles and peak/trough ratios of proguanil and cycloguanil with 12-hourly dosing offer better prospects for protection against malaria than those obtained with 24-hourly doses of 200 mg proguanil hydrochloride, the current routine in malaria chemoprophylaxis.
During the early months of 1985 and 1986, 408 non-immune British soldiers undertook training in the jungles north of Kota Tinggi, in southern Malaysia. In this geographical location, where malaria transmission is now light, a combination of strict personal antimosquito measures plus proguanil 200 mg daily produced effective, safe protection, with only a single case of vivax malaria occurring. Given the limited malaria risk, however, the results of this study should be extrapolated only with caution to other areas of Malaysia.
Exposure of Plasmodium falciparum to increasing sublethal drug concentrations followed by drug treatment led to the development of many resistant parasites. Therefore, the susceptibility of these clones to the type II antifolate drugs, cycloguanil and pyrimethamine, before and after subculturing them in vitro for a period of 3 years, was studied.
Six clones were derived from each Plasmodium falciparum isolate obtained from Malaysia, Africa and Thailand and were characterized against type II antifolate drugs, cycloguanil and pyrimethamine using the modified in vitro microtechnique. Results showed that these isolates were of a heterogeneous population, with 50% inhibitory concentrations of Gombak A clones at 0.0151-0.1450 and 0.0068-0.1158 microM, Gambian clones at 0.0056-0.1792 and 0.0004-0.0068 microM and TGR clones at 0.0103-0.0703 and 0.0776-0.3205 microM against cycloguanil and pyrimethamine, respectively. All clones displayed similar susceptibilities as their parent isolates except A/D3, A/D5, A/G4 and A/H7 clones which were sensitive to cycloguanil at 0.0735, 0.0151, 0.0540 and 0.0254 microM but Gm/B2 clone was resistant at 0.1792 microM, respectively. However, A/D3, TGR/B4, TGR/B7, TGR/C4, TGR/C7 and TGR/H2 clones were resistant to pyrimethamine at 0.1158, 0.1070, 0.1632, 0.1580, 0.2409 and 0.3205 microM, respectively. Further results indicated that they were pure clones compared to their parent isolates as their drug susceptibility studies were statistically different (p < 0.05).
Six clones were derived from each Malaysian Plasmodium falciparum isolate and characterized for their susceptibilities against type II antifolate drugs, cycloguanil and pyrimethamine. Results showed that these isolates were of a heterogeneous population, with average IC50 values of Gombak C clones at 0.012-0.084 microM and 0.027-0.066 microM, ST 9 clones at 0.019-0.258 microM and 0.027-0.241 microM, ST 12 clones at 0.015-0.342 microM and 0.012-0.107 microM, ST 85 clones at 0.022-0.087 microM and 0.024-0.426 microM, and ST 148 clones at 0.027-0312 microM and 0.029-0.690 microM against cycloguanil and pyrimethamine, respectively. Generally, most of these clones displayed susceptibility patterns similar to their parent isolates except ST 9/A4, ST 9/A7, ST 9/B5, ST 9/D9, ST 9/D10, ST 148/A4, ST 148/A5, ST 148/A7, ST 148/F7, ST 148/F8 clones, which were sensitive at 0.027 microM, 0.019 microM, 0.022 microM, 0.063 microM, 0.037 microM, 0.031 microM, 0.042, microM, 0.042 microM, 0.062 microM, and 0.027 microM, whereas, ST 12/D7 clone was resistant at 0.342 microM, against cycloguanil respectively. However, ST 9/A4, ST 9/D8, ST 12/D5, ST 85/A5, ST 85/B3, ST 85/B4, ST 85/D3, ST 85/D7, ST 148/A6, and ST 148/A7 clones were resistant to pyrimethamine at 0.158 microM, 0.241 microM, 0.107 microM, 0.223 microM, 0.393 microM, 0.402 microM, 0.426 microM, 0.115 microM, 0.690 microM, and 0.520 microM, respectively.