SHORT REPORT: ASSOCIATION BETWEEN CHLOROQUINE AND AMODIAQUINE RESISTANCE AND ALLELIC VARIATION IN THE PLASMODIUM FALCIPARUM MULTIPLE DRUG RESISTANCE 1 GENE AND THE CHLOROQUINE RESISTANCE TRANSPORTER GENE IN ISOLATES FROM THE UPPER NILE IN SOUTHERN SUDAN

EDWIN O. OCHONG’ Kenya Medical Research Institute, Wellcome Trust Collaborative Program, Médecins sans Frontières-Holland, South Sudan Section, Nairobi, Kenya; Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom

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INGRID V. F. VAN DEN BROEK Kenya Medical Research Institute, Wellcome Trust Collaborative Program, Médecins sans Frontières-Holland, South Sudan Section, Nairobi, Kenya; Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom

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KEES KEUS Kenya Medical Research Institute, Wellcome Trust Collaborative Program, Médecins sans Frontières-Holland, South Sudan Section, Nairobi, Kenya; Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom

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ALEXIS NZILA Kenya Medical Research Institute, Wellcome Trust Collaborative Program, Médecins sans Frontières-Holland, South Sudan Section, Nairobi, Kenya; Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom

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Amodiaquine, a 4-aminoquinoline compound, is being considered as an alternative to chloroquine and pyrimethamine/sulfadoxine where resistance in Plasmodium falciparum to both drugs has been selected. Although amodiaquine is more potent than chloroquine, its effectiveness is reduced in areas where chloroquine resistance is high. We report an association of the P. falciparum chloroquine resistance transporter (pfcrt) gene and the P. falciparum multiple drug resistance 1 (pfmdr1) gene, two chloroquine resistance markers, with chloroquine and amodiaquine efficacy in vivo in southern Sudan. The data show that the allele of the pfcrt gene with a lysine to threonine change at codon 76 is strongly associated with both chloroquine and amodiaquine resistance. No such association was observed with the pfmdr1 gene.

  • 1

    Schellenberg D, Kahigwa E, Drakeley C, Malende A, Wigayi J, Msokame C, Aponte JJ, Tanner M, Mshinda H, Menendez C, Alonso PL, 2002. The safety and efficacy of sulfadoxine-pyrimethamine, amodiaquine, and their combination in the treatment of uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg 67 :17–23.

    • Search Google Scholar
    • Export Citation
  • 2

    Bloland PB, Ruebush TK, 1996. Amodiaquine. Lancet 348 :1659–1660.

  • 3

    Staedke SG, Kamya MR, Dorsey G, Gasasira A, Ndeezi G, Charlebois ED, Rosenthal PJ, 2001. Amodiaquine, sulfadoxine/pyrimethamine, and combination therapy for treatment of uncomplicated falciparum malaria in Kampala, Uganda: a randomised trial. Lancet 358 :368–374.

    • Search Google Scholar
    • Export Citation
  • 4

    Van Dillen J, Custers M, Wensink A, Wouters B, van Voorthuizen T, Voorn W, Khan B, Muller L, Nevill C, 1999. A comparison of amodiaquine and sulfadoxine-pyrimethamine as first-line treatment of falciparum malaria in Kenya. Trans R Soc Trop Med Hyg 93 :185–188.

    • Search Google Scholar
    • Export Citation
  • 5

    Brasseur P, Guiguemde R, Diallo S, Guiyedi V, Kombila M, Ringwald P, Olliaro P, 1999. Amodiaquine remains effective for treating uncomplicated malaria in west and central Africa. Trans R Soc Trop Med Hyg 93 :645–650.

    • Search Google Scholar
    • Export Citation
  • 6

    Gorissen E, Ashruf G, Lamboo M, Bennebroek J, Gikunda S, Mbaruku G, Kager PA, 2000. In vivo efficacy study of amodiaquine and sulfadoxine/pyrimethamine in Kibwezi, Kenya and Kigoma, Tanzania. Trop Med Int Health 5 :459–463.

    • Search Google Scholar
    • Export Citation
  • 7

    White NJ, 1996. Can amodiaquine be resurrected? Lancet 348 :1184–1185.

  • 8

    Basco LK, Le Bras J, 1993. In vitro activity of monodesethyla-modiaquine and amopyroquine against African isolates and clones of Plasmodium falciparum.Am J Trop Med Hyg 48 :120–125.

    • Search Google Scholar
    • Export Citation
  • 9

    Childs GE, Boudreau EF, Milhous WK, Wimonwattratee T, Pooyindee N, Pang L, Davidson DE Jr, 1989. A comparison of the in vitro activities of amodiaquine and desethylamodiaquine against isolates of Plasmodium falciparum.Am J Trop Med Hyg 40 :7–11.

    • Search Google Scholar
    • Export Citation
  • 10

    Wellems TE, Plowe CV, 2001. Chloroquine-resistant malaria. J Infect Dis 184 :770–776.

  • 11

    Fidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM, Ferdig MT, Ursos LM, Sidhu AB, Naude B, Deitsch KW, Su XZ, Wootton JC, Roepe PD, Wellems TE, 2000. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 6 :861–871.

    • Search Google Scholar
    • Export Citation
  • 12

    Djimde A, Doumbo OK, Cortese JF, Kayentao K, Doumbo S, Diourte Y, Dicko A, Su XZ, Nomura T, Fidock DA, Wellems TE, Plowe CV, Coulibaly D, 2001. A molecular marker for chloroquine-resistant falciparum malaria. N Engl J Med 344 :257–263.

    • Search Google Scholar
    • Export Citation
  • 13

    Sidhu ABR, Pinard DV, Fidock DA, 2002. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298 :210–213.

    • Search Google Scholar
    • Export Citation
  • 14

    Zhang H, Howard EM, Roepe PD, 2002. Analysis of the antimalarial drug resistance protein Pfcrt expressed in yeast. J Biol Chem 277 :49767–49775.

    • Search Google Scholar
    • Export Citation
  • 15

    Thomas SM, Ndir O, Dieng T, Mboup S, Wypij D, Maguire JH, Wirth DF, 2002. In vitro chloroquine susceptibility and PCR analysis of pfcrt and pfmdr1 polymorphisms in Plasmodium falciparum isolates from Senegal. Am J Trop Med Hyg 66 :474–480.

    • Search Google Scholar
    • Export Citation
  • 16

    Mayor AG, Gomez-Olive X, Aponte JJ, Casimiro S, Mabunda S, Dgedge M, Barreto A, Alonso PL, 2001. Prevalence of the K76T mutation in the putative Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene and its relation to chloroquine resistance in Mozambique. J Infect Dis 183 :1413–1416.

    • Search Google Scholar
    • Export Citation
  • 17

    Foote SJ, Kyle DE, Martin RK, Oduola AM, Forsyth K, Kemp DJ, Cowman AF, 1990. Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum.Nature 345 :255–258.

    • Search Google Scholar
    • Export Citation
  • 18

    Basco LK, Le Bras J, Rhoades Z, Wilson CM, 1995. Analysis of pfmdr1 and drug susceptibility in fresh isolates of Plasmodium falciparum from subsaharan Africa. Mol Biochem Parasitol 74 :157–166.

    • Search Google Scholar
    • Export Citation
  • 19

    Haruki K, Bray PG, Ward SA, Hommel M, Ritchie GY, 1994. Chloroquine resistance of Plasmodium falciparum: further evidence for a lack of association with mutations of the pfmdr1 gene. Trans R Soc Trop Med Hyg 88 :694.

    • Search Google Scholar
    • Export Citation
  • 20

    Pillai DR, Labbe AC, Vanisaveth V, Hongvangthong B, Pomphida S, Inkathone S, Zhong K, Kain KC, 2001. Plasmodium falciparum malaria in Laos: chloroquine treatment outcome and predictive value of molecular markers. J Infect Dis 183 :789–795.

    • Search Google Scholar
    • Export Citation
  • 21

    Bray PG, Mungthin M, Ridley RG, Ward SA, 1998. Access to hematin: the basis of chloroquine resistance. Mol Pharmacol 54 :170–179.

  • 22

    Ginsburg H, Famin O, Zhang J, Krugliak M, 1998. Inhibition of glutathione-dependent degradation of heme by chloroquine and amodiaquine as a possible basis for their antimalarial mode of action. Biochem Pharmacol 56 :1305–1313.

    • Search Google Scholar
    • Export Citation
  • 23

    Nzila A, Mberu E, Sulo J, Dayo H, Winstanley P, Sibley C, Watkins WM, 2000. Towards an understanding of the mechanism of pyrimethamine-sulfadoxine resistance in P. falciparum: genotyping of dihydrofolate reductase and dihydropteroate synthase of Kenyan parasites. Antimicrob Agents Chemother 44 :991–996.

    • Search Google Scholar
    • Export Citation
  • 24

    Van den Broek IVF, Gatkoi T, Lowoko B, Nzila A, Ochong’ E, Keus K, 2003. Comparison of chloroquine, sulfadoxine-pyrimethamine and amodiaquine efficacy to treat uncomplicated falciparum malaria in Upper Nile, South Sudan. Trans R Soc Trop Med Hyg 97 : (in press).

    • Search Google Scholar
    • Export Citation
  • 25

    Famin O, Ginsburg H, 2002. Differential effects of 4-aminoquino-line-containing antimalarial drugs on hemoglobin digestion in Plasmodium falciparum-infected erythrocytes. Biochem Pharmacol 63 :393–398.

    • Search Google Scholar
    • Export Citation
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