Short-term in vitro culture of Plasmodium vivax and P. ovale for drug-susceptibility testing.
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Animals↗
Biomedical subjects
L K Basco
Publications and source records attributed to L K Basco.
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↗
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↗
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↗
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↗
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↗
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↗
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↗
Halofantrine resistance in African countries.
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Adult↗
Antimalarial chemoprophylaxis for west Africa.
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Africa, Western↗
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↗
In vitro activity of cycloguanil against African isolates of Plasmodium falciparum.
The in vitro activity of cycloguanil was assessed against 86 African isolates of Plasmodium falciparum by a semi-micro assay system. A bimodal distribution of susceptibility patterns was observed, with 44% of the isolates being cycloguanil susceptible. Cycloguanil alone retains a high activity against the intraerythrocytic forms of some isolates and, together with its activity against the hepatic stages, may be useful for chemoprophylaxis when combined with chloroquine.
Animals↗
In vitro activity of monodesethylamodiaquine and amopyroquine against African isolates and clones of Plasmodium falciparum.
The in vitro activity of monodesethylamodiaquine and amopyroquine was evaluated against chloroquine-susceptible and chloroquine-resistant African clones of Plasmodium falciparum. The chloroquine-resistant clone (50% inhibitory concentration [IC50] = 1,630 nM) was 26 and 3.7 times less susceptible to monodesethylamodiaquine and amopyroquine, respectively, than the chloroquine-susceptible clone (IC50 = 36.5 nM). Cross-resistance patterns of chloroquine, monodesethylamodiaquine, and amopyroquine were determined against 62 African isolates of P. falciparum obtained from imported cases of malaria in France, using an isotopic semimicro drug susceptibility test. Chloroquine-resistant isolates (n = 38) were significantly less susceptible to both monodesethylamodiaquine (IC50 = 74.8 nM) and amopyroquine (IC50 = 18.9 nM), as compared with the 24 chloroquine-susceptible isolates (IC50 = 28.2 nM and 16.1 nM, respectively). A significant positive correlation was found between chloroquine and monodesethylamodiaquine (r = 0.903) and between chloroquine and amopyroquine (r = 0.371), indicating in vitro cross-resistance among these drugs. These in vitro results suggest that the clinical response to amodiaquine and amopyroquine needs to be closely monitored in Africa.
Aminoquinolines↗
In vitro activity of artemisinin derivatives against African isolates and clones of Plasmodium falciparum.
The in vitro activities of chloroquine, quinine, mefloquine, halofantrine, artemisinin, arteether, artemether, and artelinate were evaluated against African clones and isolates of Plasmodium falciparum, using an isotopic, semimicro, drug susceptibility test. The chloroquine-resistant FCM 29 clone was 1.6 and 6.2 times more susceptible to artemisinin when compared with the chloroquine-susceptible, mefloquine-, and halofantrine-resistant L-3 and L-16 clones, respectively. Cross-resistance patterns between the standard antimalarial drugs and artemisinin were determined against 36 African isolates of P. falciparum obtained from imported cases of malaria in France. Chloroquine-resistant isolates (n = 21) were significantly more susceptible to artemisinin (50% inhibitory concentration [IC50] 7.67 nM), arteether (IC50 3.88 nM), artemether (IC50 3.71 nM), and artelinate (IC50 3.46 nM), as compared with the 15 chloroquine-susceptible isolates (IC50 11.4, 5.66, 5.14, and 5.04 nM, respectively). Arteether, artemether, and artelinate were equally effective and twice as potent as artemisinin. A significant positive correlation was found between artemisinin and mefloquine (r = 0.424, P = 0.022), artemisinin and halofantrine (r = 0.569, P < 0.001), chloroquine and quinine (r = 0.651, P < 0.001), and mefloquine and halofantrine (r = 0.863, P < 0.001), suggesting in vitro cross-resistance among these drugs. The present in vitro findings require confirmation in clinical studies.
Animals↗
Evolution of chloroquine resistance in central and west Africa.
The evolution of in vitro chloroquine susceptibility of clinical isolates of Plasmodium falciparum obtained from travellers returning to France was studied between 1986 and 1991 using the isotopic semi-microtest. Based on the analysis of 1,147 interpretable tests on isolates originating from Central and West Africa, the study showed that the proportion of chloroquine-resistant falciparum malaria remained stable between 1986 and 1988 and has diminished between 1989 and 1991. The diminution of chloroquine-resistant imported malaria may be associated, at least in part, with a better compliance of French travellers with the recommendation to use either mefloquine or a combination of chloroquine and proguanil since 1989 and an increasing proportion of African immigrants who tend to neglect regular chemoprophylaxis during the visit to their countries. The reason for the stabilisation of chloroquine resistance is unknown, and this phenomenon may be temporary, necessitating a continuous surveillance of drug susceptibility.
Africa, Central↗
Chloroquine and proguanil prophylaxis in travellers to Kenya.
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Africa, Central↗
In vitro activity of pyronaridine against African strains of Plasmodium falciparum.
The in vitro activity of pyronaridine was determined and compared with the activity of monodesethylamodiaquine and amopyroquine against 31 clinical isolates and two clones of Plasmodium falciparum originating from Central and West Africa using a semi-micro drug susceptibility test. Pyronaridine and amopyroquine were 2.5 and four times less active, respectively, against the highly chloroquine-resistant clone, than against the chloroquine-susceptible clone but were equally active against chloroquine-susceptible and chloroquine-resistant clinical isolates. Compared with chloroquine-susceptible isolates, monodesethylamodiaquine was three times less active against chloroquine-resistant parasites. Pyronaridine is highly active against chloroquine-resistant strains of P. falciparum and may be a promising candidate for the treatment of resistant malaria.
Africa↗
In vitro activity of the enantiomers of mefloquine, halofantrine and enpiroline against Plasmodium falciparum.
The in vitro activity of the enantiomers of mefloquine, halofantrine and enpiroline was compared against chloroquine-resistant and -susceptible strains of Plasmodium falciparum using a semi-micro drug susceptibility test. For each strain, the corresponding enantiomers exhibited similar activities. The enantiomers of halofantrine were the most active against both susceptible and resistant strains, followed by the enantiomers of mefloquine and enpiroline.
Animals↗