title: Nonylphenolethoxylates as malarial chloroquine resistance reversal agents.
abstract: Malaria-associated morbidity and mortality are increasing because of widespread resistance to one of the safest and least expensive antimalarials, chloroquine. The availability of an inexpensive agent that is capable of reversing chloroquine resistance would have a major impact on malaria treatment worldwide. The interaction of nonylphenolethoxylates (NPEs, commercially available synthetic surfactants) with drug-resistant Plasmodium falciparum was examined to determine if NPEs inhibited the growth of the parasites and if NPEs could sensitize resistant parasites to chloroquine. NPEs inhibited the development of the parasite when present in the low- to mid-micromolar range (5 to 90 microM), indicating that they possess antimalarial activity. Further, the presence of <10 microM concentrations of NPEs caused the 50% inhibitory concentrations for chloroquine-resistant lines to drop to levels (< or =12 nM) observed for sensitive lines and generally considered to be achievable with treatment courses of chloroquine. Long-chain (>30 ethoxylate units) NPEs were found to be most active in P. falciparum, which contrasts with previously observed maximal activity of short-chain ( approximately 9 ethoxylate units) NPEs in multidrug-resistant mammalian cell lines. NPEs may be attractive chloroquine resistance reversal agents since they are inexpensive and may be selectively directed against P. falciparum without inhibiting mammalian tissue P glycoproteins. Antimalarial preparations that include these agents may prolong the effective life span of chloroquine and other antimalarials.
authors.affiliation: Tropical Disease Unit, The Toronto Hospital, University of Toronto, Ontario, Canada. ian.cradall@utoronto.ca
authors.forename: I
authors.initials: I
authors.lastname: Crandall
authors.forename: J
authors.initials: J
authors.lastname: Charuk
authors.forename: K C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D016466:CHO Cells; D002738:Chloroquine / Q000494:pharmacology*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004351:Drug Resistance; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013501:Surface-Active Agents / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D009943:Organophosphorus Compounds; D013501:Surface-Active Agents; C009790:phosphated nonylphenolethoxylate; D002738:Chloroquine