<i>In vitro</i> activities of ferrochloroquine against 55 Senegalese isolates of <i>Plasmodium falciparum</i> in comparison with those of standard antimalarial drugs

Pradines, Bruno; Tall, Adama; Rogier, Christophe; Spiegel, André; Mosnier, Joël; Marrama, Laurence; Fusaı̈, Thierry; Millet, Pascal; Panconi, E.; Trape, Jean François; Parzy, Daniel

doi:10.1046/j.1365-3156.2002.00848.x

Cited by 64 publications

(61 citation statements)

References 32 publications

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“…In all these studies, LM activity was high, with IC 50 s of Ͻ30 nM for more than 95% of isolates (1, 4, 16, 21, 25, 26). In our study, we observed a higher LM IC 50 range, and IC 50 s of Ͼ200 nM for some isolates, findings similar to those of a report from Senegal (27).…”

Section: Discussionsupporting

confidence: 92%

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

Mwai

Kiara

Abdi

et al. 2009

Antimicrob Agents Chemother

150

156

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We have analyzed the in vitro chemosensitivity profiles of 115 Kenyan isolates for chloroquine (CQ), piperaquine, lumefantrine (LM), and dihydroartemisinin in association with polymorphisms in pfcrt at codon 76 and pfmdr1 at codon 86, as well as with variations of the copy number of pfmdr1. The median drug concentrations that inhibit 50% of parasite growth (IC 50 s) were 41 nM (interquartile range [IQR], 18 to 73 nM), 50 nM (IQR, 29 to 96 nM), 32 nM (IQR, 17 to 46 nM), and 2 nM (IQR, 1 to 3 nM) for CQ, LM, piperaquine, and dihydroartemisinin, respectively. The activity of CQ correlated inversely with that of LM (r 2 ‫؍‬ ؊0.26; P ‫؍‬ 0.02). Interestingly, parasites for which LM IC 50 s were higher were wild type for pfcrt-76 and pfmdr1-86. All isolates had one pfmdr1 copy. Thus, the decrease in LM activity is associated with the selection of wild-type pfcrt-76 and pfmdr1-86 parasites, a feature that accounts for the inverse relationship between CQ and LM. Therefore, the use of LM-artemether is likely to lead to the selection of more CQ-susceptible parasites.Chemotherapy is still the main approach for the control of malaria, and current strategies for malaria treatment rely on the use of combinations of drugs that include artemisinin compounds. Although this strategy is designed to reduce the chance of resistance emerging, there is considerable concern that this will inevitably occur.For instance, the combination of lumefantrine (LM) and artemether (ATM), known as Coartem, has become the firstline treatment for malaria in many African countries, including Kenya (19). ATM is converted in vivo to dihydroartemisinin (DHA). Emerging reports indicate that the use of LM (in Coartem) selects for parasites that show increased tolerance to Coartem, and these parasites select for a wild-type pfmdr1 genotype or show increased copy numbers of pfmdr1, a gene associated with chloroquine (CQ) and mefloquine (MFQ) resistance (7,13,15,20,36,38). Thus, there is concern that resistance to LM could emerge rapidly. On the other hand, recent reports from Southeast Asia indicate that resistance to artemisinin derivatives is increasing, threatening the concept of artemisinin-based combinations (8).Another combination, piperaquine (PQ) and DHA, known as Artekin, is undergoing clinical evaluation (17,39,42). This drug is efficacious, safe, and affordable and thus is likely to become an alternative to Coartem. PQ is a bisquinoline derivative consisting of two linked CQ molecules. Although reports indicate that PQ retains potency against CQ-resistant parasites (3), there is concern that PQ could become less susceptible against a backdrop of high CQ resistance (17,22).In this paper, we sought to analyze the in vitro activities of the antimalarials LM, DHA, and PQ in relation to polymorphisms in pfcrt at codon 76 (pfcrt-76) and in pfmdr1 at codon 86 (pfmdr1-86) and in relation to pfmdr1 copy number variations in Kenyan isolates. We used CQ as a reference drug. MATERIALS AND METHODSCQ was purchased from Sigma Chemical Co. (Poole, Dorset, United...

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Section: Discussionsupporting

confidence: 92%

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

Mwai

Kiara

Abdi

et al. 2009

Antimicrob Agents Chemother

150

156

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“…In this study, we demonstrated in vitro crossresistance between dihydroartemisinin and mefloquine or lumefantine. The in vitro cross-resistance between lumefantrine and artemisinin derivatives has been observed previously (32). However, no in vitro resistance to both lumefantrine and dihydroartemisinin, monodesethylamodiquine and dihydroartemisinin, or atovaquine and proguanil was demonstrated.…”

Section: Discussionsupporting

confidence: 56%

Prevalence of In Vitro Resistance to Eleven Standard or New Antimalarial Drugs among Plasmodium falciparum Isolates from Pointe-Noire, Republic of the Congo

Pradines

Hovette²,

Fusaı̈

et al. 2006

J Clin Microbiol

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We determined the level of in vitro resistance of Plasmodium falciparum parasites to standard antimalarial drugs, such as chloroquine, quinine, amodiaquine, halofantrine, mefloquine, cycloguanil, and pyrimethamine, and to new compounds, such as dihydroartemisinin, doxycycline, atovaquone, and lumefantrine. The in vitro resistance to chloroquine reached 75.5%. Twenty-eight percent of the isolates were intermediate or had reduced susceptibility to quinine. Seventy-six percent and 96% of the tested isolates showed in vitro resistance or intermediate susceptibilities to cycloguanil and pyrimethamine, respectively. Only 2% of the parasites demonstrated in vitro resistance to monodesethylamodiaquine. No resistance was shown with halofantrine, lumefantrine, dihydroartemisinin, or atovaquone. Halofantrine, mefloquine, and lumefantrine demonstrated high correlation. No cross-resistance was identified between responses to monodesethyl-amodiaquine, dihydroartemisinin, atovaquone, and cycloguanil. Since the level of chloroquine resistance in vitro exceed an unacceptable upper limit, high rates of in vitro resistance to pyrimethamine and cycloguanil and diminution of the susceptibility to quinine, antimalarial drugs used in combination, such as amodiaquine, artemisinin derivatives, mefloquine, lumefantrine, or atovaquone, seem to be appropriate alternatives for the first line of treatment of acute, uncomplicated P. falciparum malaria.

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“…The results of this study seem to indicate a difference in the modes of action of AQ and DAQ, highlighting the crucial role of very low AQ concentrations in the potentiation of DAQ activity. This phenomenon is apparently not unique to AQ and DAQ; similar interactions have been observed recently between chloroquine with its metabolite (15), among diastereomers of the Cinchona alkaloids in vitro (10,34), and between ␤-artemether and lumefantrine (21,24).…”

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confidence: 70%

Synergism between Amodiaquine and Its Major Metabolite, Desethylamodiaquine, against Plasmodium falciparum In Vitro

Mariga

Gil

Sisowath

et al. 2004

Antimicrob Agents Chemother

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The in vitro activity of the prodrug amodiaquine and its metabolite monodesethyl-amodiaquine has been studied for three strains of Plasmodium falciparum: LS-2, LS-3, and LS-1. Both compounds showed significant activity against all three strains; the activity of amodiaquine was slightly higher than that of the metabolite. By use of a checkerboard design, interaction studies with both compounds yielded evidence of significant synergism; means of the sums of the fractional inhibitory concentrations were 0.0392 to 0.0746 for strain LS-2, 0.1567 to 0.3102 for strain LS-3, and 0.025 to 0.3369 for strain LS-1. In further investigations, the interaction of amodiaquine with monodesethyl-amodiaquine was tested at clinically relevant concentrations of both compounds. In these studies, involving amodiaquine at picomolar and femtomolar concentrations, the compound was found to exert high potentiating activity on monodesethyl-amodiaquine. This interaction produced mean ratios of observed to expected activity of 0.0505 to 0.0642 for strain LS-2, 0.0882 to 0.3820 for strain LS-3, and 0.0752 to 0.2924 for strain LS-1. The synergistic activity was most marked at monodesethyl-amodiaquine/ amodiaquine ratios up to 100,000:1 but was still evident at higher ratios.The widespread increase of resistance to chloroquine in Plasmodium falciparum has resulted in renewed interest in amodiaquine (AQ) as a replacement for chloroquine in the treatment of malaria, especially in sub-Saharan Africa. Although AQ belongs to the same chemical class of compounds as chloroquine, the 4-aminoquinolines, this drug often shows adequate clinical-parasitological efficacy in chloroquine-resistant infections. Furthermore, adverse reactions reported previously, such as agranulocytosis (14) and hepatitis (20), were mainly associated with the prophylactic use of AQ, and more recent reports show that therapeutic regimens are well tolerated (22). Therefore, the World Health Organization has again listed AQ as a drug for treatment of chloroquine-resistant falciparum malaria (40).During and after absorption, orally administered AQ is rapidly metabolized to desethylamodiaquine (DAQ) and other derivatives of lesser antimalarial significance (9). Clinically, the antimalarial activity of AQ is exerted mainly through DAQ (37). Earlier in vitro studies indicated that DAQ and AQ have equal activity against P. falciparum (8). Other observations suggest that the two compounds possess independent modes of action (7,27). However, recent comparative in vitro studies with fresh isolates of P. falciparum showed a significant correlation between the activities of the two compounds that indicates similarities in the way they act against the parasite (12).Chloroquine-resistant falciparum malaria on the African continent was first detected in Kenya and Tanzania. During the past 2 decades it has extended to practically all parts of tropical Africa (32,39). AQ has been shown to maintain high efficacy in the areas of malaria endemicity in the continent where chloroquine resistance is st...

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In vitro activities of ferrochloroquine against 55 Senegalese isolates of Plasmodium falciparum in comparison with those of standard antimalarial drugs

Cited by 64 publications

References 32 publications

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

Prevalence of In Vitro Resistance to Eleven Standard or New Antimalarial Drugs among Plasmodium falciparum Isolates from Pointe-Noire, Republic of the Congo

Synergism between Amodiaquine and Its Major Metabolite, Desethylamodiaquine, against Plasmodium falciparum In Vitro

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