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Biomedical subjects

J Le Bras

Publications and source records attributed to J Le Bras.

At least 55 records · Page 3Linked to original sources
PubMed1995

[The status of malaria chemoresistance in Africa].

Chloroquine resistance of Plasmodium falciparum in Africa emerged two decades ago. Today, this resistance is wide-spread to the whole african continent and other resistances have appeared since. Mechanisms of resistance to lysosomotropes and to antimetabolites are described here, as also the epidemiology of these resistances in 1994.

Africa↗
PubMed1994

Plasma concentrations of the enantiomers of halofantrine and its main metabolite in malaria patients.

The plasma concentrations of the enantiomers of halofantrine and its N-desbutyl metabolite in six patients with malaria were measured after oral administration of 3 x 750 mg doses of micronised, racemic halofantrine hydrochloride given at 6-hour intervals. Significant differences were observed between the plasma concentrations of the enantiomers both of halofantrine and its N-monodesbutyl metabolite. AUC(0)84h values were higher for (+)halofantrine (9917 micrograms.ml-1.h) than for (-)-halofantrine (6127 micrograms.ml-1.h). The clinical significance of these observations is not known. The isomers have equipotent activity in vitro but their relative toxicity has not yet been assessed.

Adult↗
PubMed1994

In vitro susceptibility of Cambodian isolates of Plasmodium falciparum to halofantrine, pyronaridine and artemisinin derivatives.

Multidrug-resistant Plasmodium falciparum is widespread in Cambodia. The in vitro susceptibilities of 14 Cambodian isolates to chloroquine, quinine, mefloquine, halofantrine, pyrimethamine, cycloguanil, pyronaridine, artemisinin, arteether, artemether and artelinate were studied using a semi-microtest on day 0 and after 15-30 days of culture. The culture-adapted isolates were all resistant to chloroquine, pyrimethamine and cycloguanil. The susceptibility to quinine was generally low. Three isolates were resistant to mefloquine. A comparison of susceptibility to cycloguanil, quinine, and mefloquine prior to and after culture adaptation showed a trend toward a higher resistance level in some isolates. Halofantrine, pyronaridine and artemisinin derivatives were highly active against the multidrug-resistant Cambodian isolates, with very similar 50% inhibitory concentrations (IC50). These results confirm the presence of multidrug-resistant P. falciparum isolates in Cambodia and indicate that quinine- and mefloquine-resistant populations of the parasite may already exist in the field. The high in vitro activities of halofantrine, pyronaridine and artemisinin derivatives indicate their potential usefulness for the treatment of multidrug-resistant malaria.

Adult↗
PubMed1994

In vitro activities of furoquinoline and acridone alkaloids against Plasmodium falciparum.

The in vitro activities of furo[2,3b]quinoline and acridone alkaloids against Plasmodium falciparum were evaluated by an isotopic semimicrotest. A pyran ring in the furoquinoline nucleus and 2-O-pyranoglycoside and 2-nitro substituents in the acridone nucleus improved the antimalarial activities of the compounds. These findings provide a clue for further chemical modifications.

Acridines↗
PubMed1994

In vitro activity of pyrimethamine, cycloguanil, and other antimalarial drugs against African isolates and clones of Plasmodium falciparum.

The in vitro activity of two dihydrofolate reductase (DHFR) inhibitors, pyrimethamine and cycloguanil, was evaluated against African clones and isolates of Plasmodium falciparum using an isotopic, semimicro drug susceptibility test. Three susceptibility levels (susceptible, intermediate, and resistant) were observed in the response of culture-adapted clones and strains to pyrimethamine (50% inhibitory concentration [IC50]) < 100, 100-2,000, and > 2,000 nM) and cycloguanil (IC50 < 50, 50-500, and > 500 nM). Based on these susceptibility levels, 73 and 68 of 96 fresh clinical isolates were susceptible to pyrimethamine (mean IC50 15.4 nM) and cycloguanil (mean IC50 11.1 nM), respectively. Thirteen and 18 isolates were resistant to pyrimethamine (mean IC50 9,440 nM) and cycloguanil (mean IC50 2,030 nM), respectively. A highly significant positive correlation was found between pyrimethamine and cycloguanil (r = 0.786), indicating in vitro cross-resistance between these antifolates. The spread of resistance to one of the DHFR inhibitors in Africa may compromise the utility of the other DHFR inhibitor.

Africa↗
PubMed1994

In vitro activity of bisquinoline WR268,668 against African clones and isolates of Plasmodium falciparum.

The in vitro activity of a new bisquinoline, WR268,668, was determined against chloroquine-susceptible and chloroquine-resistant African clones and isolates of Plasmodium falciparum using an isotopic semimicro drug susceptibility assay. The chloroquine-resistant clone (mean 50% inhibitory concentration [IC50] = 61.2 nM) was 11 times less susceptible to WR268,668 than the chloroquine-susceptible clone (IC50 = 5.75 nM). A similar result was obtained with fresh clinical isolates, with the chloroquine-susceptible isolates (IC50 = 5.36 nM, n = 11) being significantly (P < 0.05) more susceptible to WR268,668 than the chloroquine-resistant isolates (IC50 = 16.1 nM, n = 18). The compound WR268,668 exhibited a high activity against some moderately chloroquine-resistant isolates. There was a significant positive correlation between the in vitro responses to chloroquine and WR268,668 (r = 0.904, P < 0.05). Combinations of WR268,668 and desipramine, a chloroquine efflux inhibitor, showed that resistance to WR268,668 can be reversed against the chloroquine-resistant clone and that desipramine has no effect on the activity of WR268,668 against the chloroquine-susceptible clone. The results of the study indicate the presence of cross-resistance between chloroquine and WR268,668, and suggest that the basis of resistance to WR268,668 may be similar to that of other 4-aminoquinolines.

Africa↗
PubMed1994

Clinical efficacy and pharmacokinetics of micronized halofantrine for the treatment of acute uncomplicated falciparum malaria in nonimmune patients.

Twenty-eight nonimmune patients with acute uncomplicated falciparum malaria returning from subSaharan Africa were treated with a micronized formulation of halofantrine hydrochloride (three doses of 250 mg at 6-hr intervals) to investigate the drug's efficacy, tolerance, and pharmacokinetics. In vitro drug susceptibility patterns were determined by the isotopic semimicrotest. Twenty-four of 28 patients were cured. Two of the four patients experiencing recrudescence were associated with low absorption of the drug and parasites susceptible in vitro to halofantrine. The other two patients had adequate plasma concentrations of halofantrine and its main human metabolite, N-desbutylhalofantrine, but the isolates were also resistant in vitro to the drugs, suggesting drug resistance as the cause of treatment failure. Only mild, transitory side effects were noted. A wide interindividual variation in plasma concentrations of halofantrine and its metabolite was observed. Pharmacokinetic studies suggested that the micronized formulation of halofantrine hydrochloride may not increase drug absorption considerably. Further studies using higher doses or longer treatment periods are needed to ensure that adequate plasma concentrations of the drug are used.

Acute Disease↗
PubMed1994

In vitro reversal of chloroquine resistance with chlorpheniramine against African isolates of Plasmodium falciparum.

The in vitro chloroquine potentiating action of racemic chlorpheniramine was assessed by a semi-microtest against chloroquine-resistant African isolates of Plasmodium falciparum. At the chlorpheniramine concentrations of 312 and 625 nM, chloroquine resistance was reversed in 4 and 11 of 14 isolates, respectively, with a diminution of their 50% inhibitory concentration (IC50) values for chloroquine to below 100 nM. No effect was observed against the chloroquine-susceptible clone. The results of the study suggest that chlorpheniramine may be a promising chloroquine resistance modulator.

Africa↗
PubMed1994

In vitro activity of the enantiomers of N-desbutyl derivative of halofantrine.

The in vitro activity of the enantiomers of N-desbutylhalofantrine, the major human metabolite of halofantrine, was compared using the semi-microtest against the multidrug-resistant Plasmodium falciparum FCM 29/Cameroon clone. The mean 50% inhibitory concentration (IC50) values (+/- standard deviation) of the enantiomers were equivalent (2.07 +/- 0.41 and 1.70 +/- 0.33 nmol/L). The enantiomers of the metabolite of halofantrine, as well as those of the parent compound, have the same antimalarial activity. Since (+)-halofantrine and enantiomer-1 of the metabolite attain higher plasma concentrations in man, our study suggests that these enantiomers may be more active in vivo.

Animals↗
PubMed1993

In vitro activity of chloroquine and quinine in combination with desferrioxamine against Plasmodium falciparum.

The activity of chloroquine and quinine, alone and in combination with desferrioxamine (7 mumol/liter), was evaluated in vitro against susceptible and resistant clones of Plasmodium falciparum by a semimicroassay system. The addition of desferrioxamine had no effect on the activity of chloroquine against both clones. Desferrioxamine had no effect on the activity of quinine against the susceptible clone but had slightly enhanced quinine action against the resistant clone. Further development of desferrioxamine as an antimalarial drug may be of limited interest.

Animals↗