Reversal of mefloquine resistance with penfluridol in isolates of Plasmodium falciparum from south-west Nigeria

Oduola, A. M. J.; Omitowoju, G.O.; Gerena, Lucia; Kyle, Dennis E.; Milhous, Wilbur K.; Sowunmi, A.; Salako, L.A.

doi:10.1016/0035-9203(93)90434-r

Cited by 50 publications

(22 citation statements)

References 20 publications

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“…In contrast to verapamil, penfluridol shows no effect on CQ sensitivity. 33 The mechanistic basis for the effects seen with penfluridol, the reasons it is not effective in all isolates exhibiting reduced susceptibility, and the clinical relevance remain to be addressed.…”

Section: Discussionmentioning

confidence: 99%

“…Sensitivity to antimalarial drugs (CQ, QN, MQ, and HF) in the presence and absence of fixed concentration of chemosensitizers (verapamil [5 M] was used as an agent that can reverse resistance to CQ and QN while penfluridol [1 M] was used as an agent reported to selectively enhance sensitivity to MQ in resistant isolates of P. falciparum 33 ) were determined by measurement of 3 H-hypoxanthine incorporation into parasite nucleic acids as previously described. 34 The concentration of drug that inhibits parasite growth by 50% (IC 50 ) was determined from the log dose/response relationship as fitted by GRAFIT (Erithacus Software, Kent, United Kingdom).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Phenotypic and genotypic characteristics of recently adapted isolates of Plasmodium falciparum from Thailand.

Mungthin¹,

Bray²,

Ward³

1999

Am J Trop Med Hyg

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Abstract. The drug sensitivity characteristics and Plasmodium falciparum pfmdr1 status of five isolates of P. falciparum recently isolated from patients presenting for treatment from the Thailand/Myanmar border have been investigated. The aim of the study was to avoid the criticisms of some earlier studies by focusing on newly collected isolates from a specific geographic location. Three of the isolates studied exhibited clear resistance to chloroquine similar to that observed in the K1 Thai standard isolate obtained in the 1970s, and the other two isolates were of intermediate sensitivity to chloroquine with concentrations of drug that inhibit parasite growth by 50% of 50 and 43 nmol. The sensitivity of all isolates was enhanced by verapamil but we found no clear association between chloroquine sensitivity and gene copy number or intra-allelic variation of pfmdr1. In contrast, clear cross-resistance was seen between mefloquine and halofantrine, with the most sensitive isolates carrying the K1 mutation in pfmdr1.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Phenotypic and genotypic characteristics of recently adapted isolates of Plasmodium falciparum from Thailand.

Mungthin¹,

Bray²,

Ward³

1999

Am J Trop Med Hyg

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“…For purposes of interpretation, when RMI is Ϸ1, there is no change in antimalarial activity, whereas an RMI of Ͻ Ͻ1 represents potentiation of antimalarial activity (i.e., evidence of synergy) and an RMI of Ͼ Ͼ1 represents antagonism (62).…”

Section: Methodsmentioning

confidence: 99%

In VivoandIn VitroAntimalarial Properties of Azithromycin-Chloroquine Combinations That Include the Resistance Reversal Agent Amlodipine

Pereira

Henrich

Sidhu

et al. 2011

Antimicrob Agents Chemother

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Evidence of emerging Plasmodium falciparum resistance to artemisinin-based combination therapies, documented in western Cambodia, underscores the continuing need to identify new antimalarial combinations. Given recent reports of the resurgence of chloroquine-sensitive P. falciparum parasites in Malawi, after the enforced and prolonged withdrawal of this drug, and indications of a possible synergistic interaction with the macrolide azithromycin, we sought to further characterize chloroquine-azithromycin combinations for their in vitro and in vivo antimalarial properties. In vitro 96-h susceptibility testing of chloroquine-azithromycin combinations showed mostly additive interactions against freshly cultured P. falciparum field isolates obtained from Mali. Some evidence of synergy, however, was apparent at the fractional 90% inhibitory concentration level. Additional in vitro testing highlighted the resistance reversal properties of amlodipine for both chloroquine and quinine. In vivo experiments, using the Peters 4-day suppressive test in a P. yoelii mouse model, revealed up to 99.9% suppression of parasitemia following treatment with chloroquine-azithromycin plus the R enantiomer of amlodipine. This enantiomer was chosen because it does not manifest the cardiac toxicities observed with the racemic mixture. Pharmacokinetic/pharmacodynamic analyses in this rodent model and subsequent extrapolation to a 65-kg adult led to the estimation that 1.8 g daily of R-amlodipine would be required to achieve similar efficacy in humans, for whom this is likely an unsafe dose. While these data discount amlodipine as an additional partner for chloroquine-based combination therapy, our studies continue to support azithromycin as a safe and effective addition to antimalarial combination therapies.In the last decade, artemisinin-based combination therapies (ACTs) have become widely adopted as first-line treatment in almost all countries where malaria is endemic (90). These drug combinations display excellent clinical efficacy against Plasmodium falciparum infection, yet recent studies from western Cambodia report decreases in parasite clearance rates following artesunate monotherapy or artesunate-mefloquine combination therapy (18,59,60,76,92). The possible emergence of resistance underscores a clear need to find alternative regimens. While several promising agents are in the pipeline, the development of antimalarial drugs that are effective, well tolerated, and safe remains a very challenging task (6,27,77,89). In addition, the new paradigm of antimalarial therapies based on the combination of drugs that have additive or preferably synergistic properties raises the threshold for drug discovery even further.Chloroquine (CQ) was the most important drug for the treatment of malaria for many decades, until widespread resistance led to its replacement, most recently by ACTs (21,93). Recent data from Malawi and Kenya have shown that in those regions, the removal of CQ from local use has led to the resurgence of CQ-sensitive (CQS) strain...

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“…To know if the synergistic association of ellagic acid with chloroquine and mefloquine was not due to a chloroquine-and mefloquine-resistant reversion effect, a chloroquine-resistant reversion test was carried out as a positive control using verapamil hydrochloride (Sigma, France) on chloroquine-resistant strain W2-Indochina (IC 50 for chloroquine of 300 nM) and on chloroquine-sensitive strain F32- Tanzania (IC 50 for chloroquine of 30 Ϯ 2 nM) according to the experimental procedures described previously by Martin et al (16). For a mefloquine resistance reversion assay, the positive control consisted of using penfluridol (Sigma, France) (17,18), a piperidine analogue, and Plasmodium falciparum strains FcM29-Cameroon, sensitive to mefloquine (IC 50 of 7 Ϯ 4 nM), and Dd2, which showed a reduced susceptibility to mefloquine in vitro (IC 50 of 21 Ϯ 3 nM). Amplification assays of the P. falciparum MDR1 gene on strains Dd2 and FcM29 confirmed that Dd2 showed a reduced susceptibility to mefloquine by expressing an average of three copies, compared with reference strain FcM29, which expressed only one copy (data not shown).…”

Section: Methodsmentioning

confidence: 99%

In Vitro and In Vivo Properties of Ellagic Acid in Malaria Treatment

Soh

Witkowski

Olagnier

et al. 2009

Antimicrob Agents Chemother

128

133

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Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites' resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all Plasmodium falciparum strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against Plamodium vinckei petteri in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of Plasmodium falciparum demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound N-acetyl-L-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on P. falciparum are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route.New drugs against malaria are urgently needed, and traditional methods of malaria treatment could be a promising source of new antimalarial compounds (5). We have recently initiated several collaborative programs with West African countries aimed at selecting, by ethnopharmacological methods, plants largely used by traditional healers and the local populations for malaria treatment. The in vitro antiplasmodial activities of the crude extracts and fractions (from bioguided fractionation of the promising crude extracts of plants) enabled us to identified ellagic acid as one of the active ingredients. The in vitro antimalarial activity of this molecule was previously reported by other researchers (3,10). In this study, we clarify the high level of in vitro and in vivo antiplasmodial properties of ellagic acid, its antioxidant activity, and its potential pro-oxidant effect and gain a deeper understanding of its mechanisms of action. MATERIALS AND METHODSCompounds. Ellagic acid hydrate (Fig. 1) was obtained from Acros Organics (Belgium), with a molecular weight 302.19 g/mol. The following other reagents were also obtained: chloroquine diphosphate salt (Sigma, France), mefloquine hydrochloride (Hoffmann-La Roche, Switzerland), artesunate (Sanofi-Synthelabo, France), artemisinin (Sigma, Germany), and atovaquone (GlaxoSmithKline, United Kingdom).In vitro antiplasmodial activity. Five strains (W2-Indochina, FcM29-Cameroon, FcB1-Colombia, F32-Tanzania, and D...

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Reversal of mefloquine resistance with penfluridol in isolates of Plasmodium falciparum from south-west Nigeria

Cited by 50 publications

References 20 publications

Phenotypic and genotypic characteristics of recently adapted isolates of Plasmodium falciparum from Thailand.

Phenotypic and genotypic characteristics of recently adapted isolates of Plasmodium falciparum from Thailand.

In VivoandIn VitroAntimalarial Properties of Azithromycin-Chloroquine Combinations That Include the Resistance Reversal Agent Amlodipine

In Vitro and In Vivo Properties of Ellagic Acid in Malaria Treatment

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