Correlation of in vivo‐resistance to chloroquine and allelic polymorphisms in Plasmodium falciparum isolates from Uganda
Thomas Paul Franz FlüeckTomáš Jelı́nekA. H. D. KilianI. S. AdaguG. KabagambeFrank von SonnenburgDavid C. Warhurst
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Summary The efficacy of chloroquine in the treatment of uncomplicated falciparum malaria in Africa is heavily compromised by high levels of drug resistance. The occurrence of active site mutations in the Plasmodium falciparum multi drug resistance‐gene 1 ( pfmdr1 ) has been associated with development of resistance to chloroquine. This study investigates the occurrence of several mutations at codons 86, 1042 and 1246 of the pfmdr1 ‐gene in infected blood samples taken from Ugandan children before treatment with chloroquine and their relationship to clinical and parasitological resistance. Even though a clear association of CQR to one certain pfmdr1 single point mutation could not be substantiated, the frequency of resistance was consistently higher for samples revealing any of the mutations than among wild type samples, and 90% of the clinically resistant samples did present a mutation. Thus detection of these allelic pfmdr1 polymorphisms is not a decisive factor for prediction of clinical chloroquine resistance, but an interplay of the different mutations with unknown cofactors is to be assumed and the possible role of other genetic alterations remains to be investigated.Cite
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The response in vitro of Plasmodium falciparum to chloroquine, mefloquine and quinine was studied in a hyperendemic peri-urban area of Accra, Ghana, during the fourth quarter of 1991, yielding a total of 159 valid tests. Schizont maturation in drug-free controls and effective chloroquine concentrations were strongly correlated. This was not seen with mefloquine or quinine. Higher mean parasitaemia in untreated oligo-symptomatic carriers of overtly chloroquine-resistant P. falciparum than in carriers of more sensitive parasites was another indication of higher viability and biological advantage of chloroquine-resistant P. falciparum that may conceivably have clinical implications.
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The antimalarial activity of four chloroquine derivatives has been assessed in vitro by the Trager and Jensen technique against the strain of Plasmodium falciparum FCC, 2spp. Monodesethyl-chloroquine possessed a significant activity, reducing the parasitaemia to 5% with 2 nM ml−1 (base). The hydroxy-metabolite showed a slight activity, reducing the parasitaemia to 39·5% with 2 nM ml−1 (base). No activity was found with the amino-metabolite and the pyrrolidinyl chemical derivative. The antimalarial activity of monodesethyl-chloroquine should be considered for pharmacokinetics and for optimizing chloroquine treatments.
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Four cases of Plasmodium falciparum malaria are presented. These cases are typical of chloroquine resistant malaria, with their pattern of 'breakthrough' malaria despite chloroquine prophylaxis, absence of response to therapeutic doses of chloroquine and recrudescence of the malarial parasites. These cases should alert physicians in other parts of the world, who may have to treat travelers from Central and West Africa, and particularly from the Ivory Coast, to the possibility that the malaria contracted in these areas may be chloroquine-resistant. The most effective drug in these cases appears to be a combination of sulphadoxine and pyrimethamine.
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The in vivo and in vitro response of Plasmodium falciparum to chloroquine was conducted in Ankazobe, a village located in the high plateau area. These studies confirmed the low level of chloroquine-resistance. The in vivo data indicate the absence of increase resistance during the 2 years study. Chloroquine is still the drug of choice for the treatment of malaria attack in this area.
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Polymorphism in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo, and 3-iodo) against chloroquine-susceptible and -resistant P. falciparum. All three derivatives inhibited the proliferation of P. falciparum; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant P. falciparum.
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With the test in vivo and the bleeding dosage of chloroquine, authors report the rate of resistance of chloroquine to Plasmodium falciparum. 2.3% of Plasmodium falciparum in Kinshasa are resistant to chloroquine.
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Glucose stimulates the high-affinity processes of chloroquine and amodiaquin accumulation in owl monkey erythrocytes infected with a chloroquine-susceptible strain of Plasmodium falciparum . Although these erythrocytes have greater ability to accumulate amodiaquin than chloroquine, glucose has relatively less effect on amodiaquin accumulation than on chloroquine accumulation. In contrast to these findings with chloroquine-susceptible P. falciparum , glucose stimulates amodiaquin but not chloroquine accumulation in erythrocytes infected with chloroquine-resistant P. falciparum . This lack of function of a substrate-dependent component of chloroquine accumulation distinguishes chloroquine-resistant from chloroquine-susceptible P. falciparum .
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