title: Genetic polymorphisms of candidate markers and in vitro susceptibility of Plasmodium falciparum isolates from Thai-Myanmar border in relation to clinical response to artesunate-mefloquine combination.
abstract: The genetic polymorphisms of the candidate markers of antimalarial drug resistance pfcrt, pfmdr1, pfatp6, and pfmrp1 were investigated in relationship with in vitro susceptibility of Plasmodium falciparum isolates and clinical response following artesunate (AS)-mefloquine (MQ) combination in 21 and 27 samples obtained from patients with recrudescence and adequate clinical response, respectively. MQ (21.0 vs. 49.9nM) and AS (1.6 vs. 2.8nM) IC50 values (concentrations that inhibit parasite growth by 50%) were significantly higher in isolates collected from patients with recrudescence. Furthermore, a significantly higher MQ IC50 was found in isolates from patients with recrudescence that carried pfmrp1 mutations at amino acid residues 191Y, 437A, and 876V. For AS sensitivity, a significant association was also detected in isolates from patients with recrudescence that carried gene mutations at amino acid residues 437A and 876V. MQ IC50 of the isolates with recrudescence which carried ≥4 pfmdr1 gene copies was significantly higher than that carrying only one gene copy. In addition, a significantly higher proportion of isolates carrying one gene copy was detected in the group with adequate clinical response compared with recrudescence. Results from this limited sample size suggested the potential link between pfmdr1 gene copy number and pfmrp1 gene mutation, in vitro parasite susceptibility, and AS-MQ treatment response.
authors.affiliation: Graduate program in Biomedical Sciences, Faculty of Allied Health Sciences, Thammasat University (Rangsit Campus), Patumthani 12121, Thailand.
authors.forename: Papichaya
authors.initials: P
authors.lastname: Phompradit
authors.affiliation: Thailand center of Excellence on Drug Discovery and Development, Thammasat University (Rangsit campus), Patumthani 12121, Thailand.
authors.forename: Poonuch
authors.initials: P
authors.lastname: Muhamad
authors.affiliation: Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Patumthani 12121, Thailand.
authors.forename: Wanna
authors.initials: W
authors.lastname: Chaijaroenkul
authors.affiliation: Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Patumthani 12121, Thailand. Electronic address: kesaratmu@yahoo.com.
authors.forename: Kesara
authors.initials: K
authors.lastname: Na-Bangchang
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D004351:Drug Resistance / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D018628:Gene Dosage; D006239:Haplotypes; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D008297:Male; D015767:Mefloquine / Q000494:pharmacology*; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009154:Mutation; D002052:Myanmar; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics; D013785:Thailand; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; D015767:Mefloquine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins
keywords: Gene amplification; Multidrug resistance; Plasmodium falciparum; Single nucleotide polymorphism; pfmdr1; pfmrp1