Plasmodium falciparum: in vitro chloroquine susceptibility and allele-specific PCR detection of Pfmdr1 Asn86Tyr polymorphism in Lambarene, Gabon

Mp, Grobusch; Is, Adagu; Pg, Kremsner; Dc, Warhurst

doi:10.1017/s0031182097002266

Cited by 48 publications

(30 citation statements)

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“…From 1994 to 1996 the 50% effective concentration of mefloquine ranged between 510 and 360 nmol/liter below the threshold for resistance, which was 3,200 nmol/liter. The presence of mutations on the pfmdr1 gene was investigated in isolates from patients treated with chloroquine in the same area in Gabon (10), and the results showed a high prevalence (80%) of Y 86 , whereas no mutation at position 1246 (Y 1246 ) was observed. This high prevalence of mutations at codon 86 was also observed in Cameroonian isolates resistant to chloroquine (2).…”

Section: Discussionmentioning

confidence: 99%

Pfmdr1 Alleles and Response to Ultralow-Dose Mefloquine Treatment in Gabonese Patients

Mawili-Mboumba

Kun

Lell

et al. 2002

Antimicrob Agents Chemother

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The identification of parasite molecular markers involved in resistance to antimalarial compounds is of great interest for monitoring the development and spread of resistance in the field. Polymorphisms in Plasmodium falciparum multidrug resistance gene 1 (pfmdr1) have been associated with chloroquine resistance and mefloquine susceptibility. In the present study, carried out in Lambaréné, Gabon, we investigated the relationship between the presence of mutations at codons 86, 184, 1034, 1042, and 1246 in the pfmdr1 gene and the success of ultralow-dose mefloquine treatment (1.1 mg/kg of body weight). Sixty-nine patients were included in the study, and depending on the level of in vivo resistance to mefloquine, they were classified as sensitive responders (S), patients with low-grade resistance (RI), and nonresponders (NR). We found that the prevalences of the Tyr-86 mutation among isolates from patients in groups S, RI, and NR were 100, 96, and 90%, respectively, and that the prevalence of the Phe-184 mutation among the isolates was 80% in each group. A prevalence of about 10% point mutations at codons 1042 and 1246 was detected only in isolates from patients in groups RI and NR. There was no statistically significant association between the presence of the Tyr-86 mutation and the in vivo response (P ‫؍‬ 0.79). Among the parasite isolates from patients with drug-resistant infections, 83% had the wild-type pfmdr1 genotype (S 1034 -N 1042 -D 1246 ). No link between the presence of this genotype and parasite resistance was detected (P ‫؍‬ 0.42). Among the isolates analyzed, 85 had double mutations (Y 86

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Section: Discussionmentioning

confidence: 99%

Pfmdr1 Alleles and Response to Ultralow-Dose Mefloquine Treatment in Gabonese Patients

Mawili-Mboumba

Kun

Lell

et al. 2002

Antimicrob Agents Chemother

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“…Point mutations, most notably 86Y, have been associated with a decrease in CQ susceptibility (5). However, in some epidemiological studies, the number of CQsusceptible samples is too limited to provide a statistically meaningful analysis (4,6). Using precautions, no relationship or only weak relationships have been established between CQ resistance and mutations in Pfmdr1 in P. falciparum (3).…”

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confidence: 99%

Role of Pfmdr1 in In Vitro Plasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

Wurtz

Fall

Pascual

et al. 2014

Antimicrob Agents Chemother

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The involvement of Pfmdr1 (Plasmodium falciparum multidrug resistance 1) polymorphisms in antimalarial drug resistance is still debated. Here, we evaluate the association between polymorphisms in Pfmdr1 (N86Y, Y184F, S1034C, N1042D, and D1246Y) and Pfcrt (K76T) and in vitro responses to chloroquine (CQ), mefloquine (MQ), lumefantrine (LMF), quinine (QN), monodesethylamodiaquine (MDAQ), and dihydroartemisinin (DHA) in 174 Plasmodium falciparum isolates from Dakar, Senegal. The Pfmdr1 86Y mutation was identified in 14.9% of the samples, and the 184F mutation was identified in 71.8% of the isolates. No 1034C, 1042N, or 1246Y mutations were detected. The Pfmdr1 86Y mutation was significantly associated with increased susceptibility to MDAQ (P ‫؍‬ 0.0023), LMF (P ‫؍‬ 0.0001), DHA (P ‫؍‬ 0.0387), and MQ (P ‫؍‬ 0.00002). The N86Y mutation was not associated with CQ (P ‫؍‬ 0.214) or QN (P ‫؍‬ 0.287) responses. The Pfmdr1 184F mutation was not associated with various susceptibility responses to the 6 antimalarial drugs (P ‫؍‬ 0.168 for CQ, 0.778 for MDAQ, 0.324 for LMF, 0.961 for DHA, 0.084 for QN, and 0.298 for MQ). The Pfmdr1 86Y-Y184 haplotype was significantly associated with increased susceptibility to MDAQ (P ‫؍‬ 0.0136), LMF (P ‫؍‬ 0.0019), and MQ (P ‫؍‬ 0.0001). The additional Pfmdr1 86Y mutation increased significantly the in vitro susceptibility to MDAQ (P < 0.0001), LMF (P < 0.0001), MQ (P < 0.0001), and QN (P ‫؍‬ 0.0026) in wild-type Pfcrt K76 parasites. The additional Pfmdr1 86Y mutation significantly increased the in vitro susceptibility to CQ (P ‫؍‬ 0.0179) in Pfcrt 76T CQ-resistant parasites.

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“…Mutations at the 86, 184, 1034, 1042, and 1246 positions have been strongly linked to CQ-resistance in vitro (19)(20)(21)(22)(23) and in vivo (24,25). These mutations of the pfmdr1 gene were thought to play a role in the enhancement of resistance levels in CQ-resistant parasites (26).…”

Section: Discussionmentioning

confidence: 99%

Alta frecuencia de mutaciones puntuales en pfcrt de Plasmodium falciparum y emergencia de nuevos haplotipos mutantes en Colombia

2008

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Introduction. Studies on the molecular epidemiology of antimalarial resistance constitute a useful tool to understand the events underlying treatment failure and resistance in falciparum malaria in Colombia. Several authors have reported on the efficacy of some molecular markers to predict drug resistance in Plasmodium falciparum. The P. falciparum pfcrt gene has been widely characterized in this context. Objective. The frequency of pfcrt gene mutations in P. falciparum were associated with treatment failure to the antimalarials chloroquine, mefloquine, amodiaquine and sulfadoxine/ pyrimethamine. Materials and methods. A representative sample of 172 patients with non-complicated falciparum malaria was selected from two highly malaria-endemic areas of northeastern Colombia, the Turbo and Bajo Cauca regions. These patients were assessed for treatment response together with the status of codons 72, 74, 75 and 76 in the pfcrt gene using a PCR-RFLP approach. Results. A high frequency of treatment failure to chloroquine (82%) and to amodiaquine (29%) was confirmed, whereas mefloquine and combined therapy remained effective. The presence of the T76 mutation in pfcrt was confirmed in all samples. The most common haplotype was CMNT (67%). Conclusions. No significant association was confirmed between specific haplotypes and the treatment response in any of the treatment groups. Two haplotypes, SMET and SMNT, were reported for the first time in Colombia. Twelve percent of the samples carried both mixed mutant and wild-type alleles.

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Plasmodium falciparum: in vitro chloroquine susceptibility and allele-specific PCR detection of Pfmdr1 Asn86Tyr polymorphism in Lambarene, Gabon

Cited by 48 publications

References 0 publications

Pfmdr1 Alleles and Response to Ultralow-Dose Mefloquine Treatment in Gabonese Patients

Pfmdr1 Alleles and Response to Ultralow-Dose Mefloquine Treatment in Gabonese Patients

Role of Pfmdr1 in In Vitro Plasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

Alta frecuencia de mutaciones puntuales en pfcrt de Plasmodium falciparum y emergencia de nuevos haplotipos mutantes en Colombia

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