title: Haem polymerase as a novel target of antimalarial action of cyproheptadine.
abstract: An antihistaminic drug, cyproheptadine (20-25mg/kg x 4 days), showed significant schizontocidal activity in the blood against a lethal multidrug-resistant (MDR) strain of Plasmodium yoelii nigeriensis (highly resistant to chloroquine, mefloquine, and quinine); the protection of mice ranged between 75 and 100%. A combination of cyproheptadine (15 mg/kg) and chloroquine improved antimalarial activity compared to treatment with either drug alone, whereas a combination of cyproheptadine with quinine or mefloquine did not improve its antimalarial activity. Chloroquine and cyproheptadine inhibited haem polymerization activity in cell-free extracts and in in vivo experiments with MDR P. yoelii, but the combination did not cause a more significant inhibition than found with either drug alone. Cyproheptadine has been shown to produce dose-dependent inhibition of haem polymerization activity both in vitro and in vivo. The mechanism of the antimalarial action of cyproheptadine and its enhanced antimalarial activity with chloroquine could be due, in part, to their inhibitory effect on haem polymerization.
authors.affiliation: Division of Parasitology, Central Drug Research Institute, 226001, Lucknow, India.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Agrawal
authors.forename: Renu
authors.initials: R
authors.lastname: Tripathi
authors.forename: Babu L
authors.initials: BL
authors.lastname: Tekwani
authors.forename: S K
authors.initials: SK
authors.lastname: Jain
authors.forename: Guru P
authors.initials: GP
authors.lastname: Dutta
authors.forename: Onkar P
authors.initials: OP
authors.lastname: Shukla
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use; D003533:Cyproheptadine / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006420:Hemeproteins / Q000378:metabolism; D015767:Mefloquine / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D010967:Plasmodium yoelii / Q000187:drug effects / Q000201:enzymology*; D011803:Quinine / Q000494:pharmacology / Q000627:therapeutic use; D014166:Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D006420:Hemeproteins; D003533:Cyproheptadine; C020753:hemozoin; D002738:Chloroquine; D011803:Quinine; D014166:Transferases; C072176:heme polymerase; D015767:Mefloquine