In vitro chloroquine susceptibility and PCR analysis of pfcrt and pfmdr1 polymorphisms in Plasmodium falciparum isolates from Senegal.

Thomas, Susan M.; Ndir, O.; Dieng, T; Mboup, Souleymane; Wypij, David; Maguire, James H.; Wirth, Dyann F.

doi:10.4269/ajtmh.2002.66.474

Cited by 68 publications

(63 citation statements)

References 38 publications

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“…Some isolates of P. falciparum harboring the mutant pfcrtT76 and pfmdr1 Y86 alleles were sensitive to CQ in-vitro. These finding are similar to earlier reports from Senegal [41], the Philippines [42] and South East Asia [24,43 ].…”

Section: Discussionsupporting

confidence: 92%

Chloroquine Resistant Plasmodium falciparum in Nigeria: Relationship between pfcrt and pfmdr1 Polymorphisms, In-Vitro Resistance and Treatment Outcome

Folarin

Gbotosho²,

Sowunmi³

et al. 2008

TOTMJ

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This study was designed to evaluate the association between polymorphisms in pfcrt and pfmdr1 genes and in-vitro chloroquine (CQ) sensitivity in fresh isolates of P. falciparum and patients' treatment outcome. The modified schizont inhibition assay was used to determine in-vitro sensitivity of P. falciparum. Polymorphisms in pfcrt and pfmdr1 genes were detected using nested PCR and RFLP techniques in 84 P. falciparum isolates obtained from patients with acute uncomplicated malaria.Eighty five percent (71/84) and 15% (13/84) of the parasites were resistant and sensitive in-vitro to CQ respectively. Molecular analysis showed presence of mutant pfcrtT76, pfmdr1Y86 and pfmdr1F184 alleles in 60%, 33% and 14% of the isolates respectively. There was a significant association between in-vitro and in-vivo CQ resistance (p=0.029) and also between the presence of mutant pfcrtT76+pfmdr1 Y86-Y184 haplotype and in-vitro (p=0.013) or in-vivo CQ resistance (p=0.024).Overall results from this study demonstrates that the presence of pfcrtT76+ pfmdr1 Y86-Y184 haplotype in Nigerian isolates of Plasmodium falciparum is predictive of in-vitro and in-vivo CQ resistance and therefore may be useful for monitoring resistance to this drug.

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Section: Discussionsupporting

confidence: 92%

Chloroquine Resistant Plasmodium falciparum in Nigeria: Relationship between pfcrt and pfmdr1 Polymorphisms, In-Vitro Resistance and Treatment Outcome

Folarin

Gbotosho²,

Sowunmi³

et al. 2008

TOTMJ

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“…2) (65). Furthermore, as observed with the Laotian and Kenyan samples in the present study, the prevalence of sensitive and resistant alleles of both Pfcrt and Pfmdr1 in the parasite population in any given location could be heterogeneous due to several local factors: the history of drug selection pressure (16,30,49), parasite population genetic structure (33), and, possibly, host-intrinsic factors (42,54). Genetic variation at CQR Pfcrt and Pfmdr1 loci in parasites from Asia and Africa.…”

supporting

confidence: 58%

Discordant Patterns of Genetic Variation at Two Chloroquine Resistance Loci in Worldwide Populations of the Malaria Parasite Plasmodium falciparum

Mehlotra

Mattera

Bockarie

et al. 2008

Antimicrob Agents Chemother

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Mutations in the chloroquine resistance (CQR) transporter gene of Plasmodium falciparum (Pfcrt; chromosome 7) play a key role in CQR, while mutations in the multidrug resistance gene (Pfmdr1; chromosome 5) play a significant role in the parasite's resistance to a variety of antimalarials and also modulate CQR. To compare patterns of genetic variation at Pfcrt and Pfmdr1 loci, we investigated 460 blood samples from P. falciparuminfected patients from four Asian, three African, and three South American countries, analyzing microsatellite (MS) loci flanking Pfcrt (five loci [ϳ40 kb]) and Pfmdr1 (either two loci [ϳ5 kb] or four loci [ϳ10 kb]). CQR Pfmdr1 allele-associated MS haplotypes showed considerably higher genetic diversity and higher levels of subdivision than CQR Pfcrt allele-associated MS haplotypes in both Asian and African parasite populations. However, both Pfcrt and Pfmdr1 MS haplotypes showed similar levels of low diversity in South American parasite populations. Median-joining network analyses showed that the Pfcrt MS haplotypes correlated well with geography and CQR Pfcrt alleles, whereas there was no distinct Pfmdr1 MS haplotype that correlated with geography and/or CQR Pfmdr1 alleles. Furthermore, multiple independent origins of CQR Pfmdr1 alleles in Asia and Africa were inferred. These results suggest that variation at Pfcrt and Pfmdr1 loci in both Asian and African parasite populations is generated and/or maintained via substantially different mechanisms. Since Pfmdr1 mutations may be associated with resistance to artemisinin combination therapies that are replacing CQ, particularly in Africa, it is important to determine if, and how, the genetic characteristics of this locus change over time.

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“…Recent data from literature have already discussed the potential inaccuracies of in vitro drug susceptibility tests 45,46 and also some conflicting results between the frequency of pfcrt mutations and in vitro/in vivo tests. [47][48][49] However, we can speculate that in vitro tests data obtained in our study could have resulted from the limited number of tests performed since, according to the WHO protocol, a correct MARK III outcome can be obtained by performing at least 100 tests. If we take into account the recognized strong link between presence of pfcrt mutations Table 1 Frequency of specific point mutations in isolates analyzed in this study * Table 1A Prevalence of point mutations and CQ resistance and we look at the frequency of pfcrt 76T mutation from this study, we can assume that CQ is definitely an unsuitable drug for this area.…”

Section: Discussionmentioning

confidence: 82%

Frequency Distribution of Antimalarial Drug Resistance Alleles among Plasmodium falciparum Isolates from Gezira State, Central Sudan, and Gedarif State, Eastern Sudan

Menegon

Talha²,

Severini³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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In 2004, Sudan adopted artesunate + sulfadoxine/pyrimethamine (SP) combination as the first-line drug, in response to the high level of falciparum resistance to antimalarials. In 2007, a molecular study on antimalarial resistance linked genes, pfcrt, pfmdr1, pfdhfr, pfdhps, and pfATPase6, was conducted on 198 isolates from central and eastern Sudan. We observed a high frequency of point mutations at almost all loci analyzed, mainly of pfcrt 76T (72.7%), pfdhfr 51I (75.3%), and pfdhfr 108N (72.7%) alleles. The MARK III in vitro test for chloroquine sensitivity in 45 P. falciparum isolates showed that 37.8% of the isolates were low resistant and 6.7% were fully resistant. This study represents the most recent molecular investigation on antimalarial resistance in this area after the adoption of artemisinin-based combination therapy (ACT), and underlines the importance of the analysis of SP resistance evolution to monitor the efficacy of ACT therapy in endemic areas.

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In vitro chloroquine susceptibility and PCR analysis of pfcrt and pfmdr1 polymorphisms in Plasmodium falciparum isolates from Senegal.

Cited by 68 publications

References 38 publications

Chloroquine Resistant Plasmodium falciparum in Nigeria: Relationship between pfcrt and pfmdr1 Polymorphisms, In-Vitro Resistance and Treatment Outcome

Chloroquine Resistant Plasmodium falciparum in Nigeria: Relationship between pfcrt and pfmdr1 Polymorphisms, In-Vitro Resistance and Treatment Outcome

Discordant Patterns of Genetic Variation at Two Chloroquine Resistance Loci in Worldwide Populations of the Malaria Parasite Plasmodium falciparum

Frequency Distribution of Antimalarial Drug Resistance Alleles among Plasmodium falciparum Isolates from Gezira State, Central Sudan, and Gedarif State, Eastern Sudan

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