title: Chemosensitizing action of cepharanthine against drug-resistant human malaria, Plasmodium falciparum.
abstract: We have established a system of in vitro and in vivo assays to prioritize plant extracts that can serve as a source of drug candidates for the treatment of malaria, an infectious disease that affects nearly 40% of the world's population. In the present study, we have investigated the biological potential of one such plant-derived drug lead, cepharanthine. In vitro growth inhibition studies indicated this compound possessed good antiplasmodial activity without mediating a cytotoxic response. Based on this selectivity, evaluations were performed with an in vivo mouse model. Moderate activity was observed, inhibiting parasite growth by 46% at a dose of 100 mg/kg body weight (BW). We further assessed the ability of cepharanthine to serve as a drug in combination with a standard antimalarial regimen. Like chloroquine, cepharanthine inhibited the trophozoite stage of parasite growth. Isobolographic analyses revealed synergism with chloroquine, but only with the drug-resistant malaria clone, and single-dose drug-interaction studies demonstrated that cepharanthine lowered the half-maximal inhibitory concentration of chloroquine from 148.5 to 37.8 nM. In summary, since activity in the mouse model was only moderate, cepharanthine may be of greater value as a modulator of resistance, capable of prolonging the clinical utility of chloroquine.
authors.affiliation: Program for Collaborative Research in the Pharmaceutical Sciences (M/C 877), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Tamez
authors.forename: Dan
authors.initials: D
authors.lastname: Lantvit
authors.forename: Eulenia
authors.initials: E
authors.lastname: Lim
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D044182:Benzylisoquinolines; D002738:Chloroquine / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004351:Drug Resistance / Q000235:genetics*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D020128:Inhibitory Concentration 50; D007624:KB Cells; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000235:genetics / Q000469:parasitology; D008297:Male; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D021261:Parasitic Sensitivity Tests / Q000379:methods; D010962:Plasmodium berghei / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D011803:Quinine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology; D052117:Benzodioxoles
chemical_list: D000470:Alkaloids; D044182:Benzylisoquinolines; D002738:Chloroquine; D004338:Drug Combinations; D011803:Quinine; D014700:Verapamil; C006947:cepharanthine; D052117:Benzodioxoles