title: In vitro sensitivity of Plasmodium falciparum to conventional and novel antimalarial drugs in Papua New Guinea.
abstract: OBJECTIVE
  Recent clinical studies have shown high rates of malaria treatment failure in endemic areas of Papua New Guinea (PNG), necessitating a change of treatment from chloroquine (CQ) or amodiaquine (AQ) plus sulphadoxine-pyrimethamine to the artemisinin combination therapy (ACT) artemether plus lumefantrine (LM). To facilitate the monitoring of antimalarial drug resistance in this setting, we assessed the in vitro sensitivity of Plasmodium falciparum isolates from Madang Province.
  
  
  METHODS
  A validated colorimetric lactate dehydrogenase assay was used to assess growth inhibition of 64 P. falciparum isolates in the presence of nine conventional or novel antimalarial drugs [CQ, AQ, monodesethyl-amodiaquine (DAQ), piperaquine (PQ), naphthoquine (NQ), mefloquine (MQ), LM, dihydroartemisinin and azithromycin (AZ)].
  
  
  RESULTS
  The geometric mean (95% confidence interval) concentration required to inhibit parasite growth by 50% (IC(50)) was 167 (141-197) nM for CQ, and 82% of strains were resistant (threshold 100 nM), consistent with near-fixation of the CQ resistance-associated pfcrt allele in PNG. Except for AZ [8.351 (5.418-12.871) nM], the geometric mean IC(50) for the other drugs was <20 nM. There were strong associations between the IC(50)s of 4-aminoquinoline (CQ, AQ, DAQ and NQ), bisquinoline (PQ) and aryl aminoalcohol (MQ) compounds suggesting cross-resistance, but LM IC(50) only correlated with that of MQ. Conclusions Most PNG isolates are resistant to CQ in vitro but not to other ACT partner drugs. The non-isotopic semi-automated high-throughput nature of the Plasmodium lactate dehydrogenase assay facilitates the convenient serial assessment of local parasite sensitivity, so that emerging resistance can be identified with relative confidence at an early stage.
authors.affiliation: Fremantle Unit, School of Medicine and Pharmacology, University of Western Australia, Nedlands, WA, Australia.
authors.forename: Rina P M
authors.initials: RP
authors.lastname: Wong
authors.forename: Dulcie
authors.initials: D
authors.lastname: Lautu
authors.forename: Livingstone
authors.initials: L
authors.lastname: Tavul
authors.forename: Sara L
authors.initials: SL
authors.lastname: Hackett
authors.forename: Peter
authors.initials: P
authors.lastname: Siba
authors.forename: Harin A
authors.initials: HA
authors.lastname: Karunajeewa
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Ilett
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.forename: Timothy M E
authors.initials: TM
authors.lastname: Davis
mesh_terms: D000655:Amodiaquine / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D017963:Azithromycin / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D018432:Drug Resistance, Multiple / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D020128:Inhibitory Concentration 50; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008297:Male; D015767:Mefloquine / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000235:genetics; D009285:Naphthoquinones / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D015800:Protozoan Proteins / Q000235:genetics; D011804:Quinolines / Q000494:pharmacology; D020711:Threshold Limit Values; D010879:Piperazines
chemical_list: D000655:Amodiaquine; D000962:Antimalarials; D037621:Artemisinins; D017963:Azithromycin; D007770:L-Lactate Dehydrogenase; D015767:Mefloquine; D026901:Membrane Transport Proteins; D009285:Naphthoquinones; D015800:Protozoan Proteins; D011804:Quinolines; C416369:PfCRT protein, Plasmodium falciparum; C034759:piperaquine; D010879:Piperazines