Activity of benflumetol and its enantiomers in fresh isolates of Plasmodium falciparum from East Africa.

Benflumetol, a novel antimalarial compound belonging to the fluorenes (2,3-benzindenes), has high blood schizontocidal activity, in vitro and in vivo, against mammalian plasmodia, including chloroquine-resistant Plasmodium falciparum. Due to its molecular structure benflumetol occurs in the dextrorotatory and the laevorotatory form. Normal synthesis yields the racemate of both enantiomers. Enantiomers of some antimalarial drugs possess different specific activity. It was therefore of interest to compare the response of P. falciparum to the enantiomers and the racemate of benflumetol in a variety of fresh, natural isolates. Measuring the concentration-specific inhibition of schizont maturation, the parallel investigation of 29 isolates produced no evidence of substantial activity differences between (+)-benflumetol, (-)-benflumetol and racemic benflumetol, the mean EC-50 values being 8.87, 9.71 and 12.44 nmol/l blood-medium-mixture, respectively.

Antimalarial activity of Tanzanian medicinal plants.

Tanzanian medicinal plants were extracted and tested for in vitro antimalarial activity, using the multidrug resistant K1 strain of Plasmodium falciparum. Of 49 plants investigated, extracts of three plants were found to have an IC50 between 5-10 micrograms/ml, extracts of 18 other plants showed an IC50 between 10 and 50 micrograms/ml, all others were less active. The three most active extracts were obtained from the tubers of Cyperus rotundus L. (Cyperaceae), the rootbark of Hoslundia opposita Vahl. (Labiatae), and the rootbark of Lantana camara L. (Verbenaceae).

Antimalarial compounds containing an alpha,beta-unsaturated carbonyl moiety from Tanzanian medicinal plants.

Pure compounds were isolated from plant extracts with antimalarial activity. The extracts were obtained from the tubers of Cyperus rotundus L. (Cyperaceae), the rootbark of Zanthoxylum gilletii (De Wild) Waterm. (Rutaceae), and the rootbark of Margaritaria discoidea (Baill.) Webster (Euphorbiaceae). The most active compounds included (IC50 within brackets): alpha-cyperone (1) (5.5 micrograms/ml), N-isobutyldeca-2,4-dienamide (2) (5.4 micrograms/ml), and securinine (3) (5.4 micrograms/ml). A mixture of autoxidation products of beta-selinene was found to be the most active antimalarial substances obtained from C. rotundus (5.6 micrograms/ml.

The in vitro response of Plasmodium falciparum to amodiaquine, quinine and quinidine in Tanga region, Tanzania.

The in vitro response of P. falciparum to amodiaquine, quinine and quinidine was assessed in Tanga region where chloroquine resistance is established, to determine baseline susceptibility levels which could guide health care deliverers on the suitability of these drugs for the treatment of falciparum malaria in the areas studied. Amodiaquine resistance was observed in all of the three areas. 16.7%, 24.0% and 14.7% of successful in vitro tests showed resistance to amodiaquine in Korogwe, Muheza and Tanga respectively. The in vitro response to quinine and quinidine showed that P. falciparum strains in the three areas are very sensitive to the two drugs. Only 1.9%, 4.5% and 1.4% of successful quinine tests showed resitance in Korogwe, Muheza and Tanga respectively. Quinidine showed activity which is twice higher than that of quinine and only 1 isolate in Tanga showed resistance response to quinidine.

Low resistance of Plasmodium falciparum to mefloquine in Tanga region, Tanzania.

Studies were undertaken in the towns of Muheza, Korogwe and Tanga in Tanga region, north-eastern Tanzania in 1986 to assess the sensitivity of Plasmodium falciparum to mefloquine using an in vitro microtechnique. Successful tests were achieved on 29, 40 and 118 isolates from Korogwe, Muheza and Tanga respectively. The mean minimum inhibitory concentrations (logometric) were 0.52, 0.50 and 0.59 mumol per litre of blood for Korogwe, Muheza and Tanga respectively. Six isolates, 2 from Muheza and 4 from Tanga, showed resistance to mefloquine, having minimum inhibitory concentrations greater than 3.2 mumol per litre of blood. The chloroquine and mefloquine sensitivities of the isolates which showed mefloquine resistance were determined.

Serial studies on the evolution of drug resistance in malaria in an area of east Africa: findings from 1979 up to 1986.

Observations, previously reported for 1979-82, have been continued up to 1986 on the development of drug resistance in P. falciparum in the North Mara area of Tanzania, where a chloroquine chemosuppression campaign was attempted from 1977 to 1982. The WHO micro in-vitro test for chloroquine and other drugs was used. Because of the large number of tests done, each test was characterized by the mean minimum inhibitory concentrations (MIC) of drug needed to prevent schizont development instead of counting the numbers of schizonts. The MIC for chloroquine has risen progressively each year but changes in the findings of in-vivo tests were less dramatic possibly due to the effects of immunity. Resistance to amodiaquine has followed that to chloroquine at a lower level, and in the last years the MIC for quinine has risen. Sporadic resistance to mefloquine was found and, by in-vivo test, to sulphadoxine-pyrimethamine. Possible factors in the evolution of drug resistance are discussed together with implications for the future.

Serial studies on the evolution of chloroquine resistance in an area of East Africa receiving intermittent malaria chemosuppression.

Serial in vitro and in vivo tests for chloroquine sensitivity of Plasmodium falciparum were carried out from 1979 to 1982 in an area of E. Africa where chemosuppression with chloroquine had been attempted since 1977. Within 1(1/2) years there were signs of a decreasing drug response. Chloroquine resistance was first detected in 1981 and this increased markedly in 1982. Other contributory causes for the rise of parasite rates in children were possibly a decline in the efficiency of the drug distribution system and also immunological factors. Evidence of resistance to pyrimethamine was also found. Observations were made of the heterogeneity of the parasites' responses with emerging resistance. Implications for the future are discussed.

In vivo and in vitro assessment of the sensitivity of Plasmodium falciparum to chloroquine in four districts of Tanga region, Tanzania.

The sensitivity of Plasmodium falciparum to chloroquine was tested in Muheza, Pangani, Tanga and Korogwe districts in north-eastern Tanzania by applying both in vivo and in vitro tests in schoolchildren. A total dose of 25 mg chloroquine base/kg body-weight given over a period of three days (10 mg/kg on days 0 and one; and 5 mg/kg on day 2) failed to clear asexual parasites from the peripheral blood by day 7 in 12.5% of the children tested at Muheza, 5.9% at Pangani, 31.8% at Tanga, and 39.5% at Korogwe. In vitro micro tests were successfully carried out on 44 isolates at Muheza, 29 isolates at Pangani, 45 isolates at Tanga and 44 isolates at Korogwe. Schizont maturation at chloroquine concentrations of 1.14 mu mol/litre of blood and above, an indication of drug resistance, was observed in 20.5% of the isolates at Muheza, 41.4% at Pangani, 51.1% at Tanga and 45.5% at Korogwe. In vivo and in vitro results of the tests for resistance have been compared.

In vivo assessment of the sensitivity of Plasmodium falciparum to sulphadoxine/pyrimethamine combination (Fansidar) in six localities in Tanzania where chloroquine-resistant P. falciparum has been detected.

The sensitivity of Plasmodium falciparum strains to Fansidar (500 mg sulphadoxine/25 mg pyrimethamine) was tested in vivo in six localities in the United Republic of Tanzania where chloroquine-resistant P. falciparum strains have been demonstrated by both in vivo and in vitro tests. Single doses as recommended by the manufacturers achieved 100% clearance of parasitaemia in five localities with mean clearance period of between 2.2 and 2.9 days. In one locality (Gonja) the recommended dose failed to clear parasitaemia in two of the 38 cases (5.3%) within seven days. The possibility of using this drug combination for the treatment of chloroquine-resistant P. falciparum strains in the United Republic of Tanzania is discussed.