title: Pfmdr1 alleles and response to ultralow-dose mefloquine treatment in Gabonese patients.
abstract: 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)-F(184) or Y(86)-Y(1246)) and 11 had triple mutations (Y(86)-D(1042)-Y(1246), Y(86)-F(184)-Y(1246), or Y(86)-F(184)-D(1042)). These findings are not consistent with those of previous in vitro studies and suggest that further evaluation of pfmdr1 gene polymorphism and in vivo mefloquine sensitivity are needed.
authors.affiliation: Unité de Recherche Médicale, Hôpital Albert Schweitzer, Lambaréné, Gabon.
authors.forename: Denise P
authors.initials: DP
authors.lastname: Mawili-Mboumba
authors.forename: Jürgen F J
authors.initials: JF
authors.lastname: Kun
authors.forename: Bertrand
authors.initials: B
authors.lastname: Lell
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.forename: Francine
authors.initials: F
authors.lastname: Ntoumi
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000293:Adolescent; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance / Q000235:genetics*; D005681:Gabon / Q000453:epidemiology; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D015767:Mefloquine / Q000008:administration & dosage* / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D017354:Point Mutation; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D015767:Mefloquine