title: Repositioning: the fast track to new anti-malarial medicines?
abstract: BACKGROUND
  Repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages.
  
  
  METHODS
  Molecules were tested initially against erythrocytic co-cultures of P. falciparum to measure proliferation inhibition using one of the following methods: SYBR®I dye DNA staining assay (3D7, K1 or NF54 strains); [(3)H] hypoxanthine radioisotope incorporation assay (3D7 and 3D7A strain); or 4',6-diamidino-2-phenylindole (DAPI) DNA imaging assay (3D7 and Dd2 strains). After review of the available clinical pharmacokinetic and safety data, selected compounds with low μM activity and a suitable clinical profile were tested in vivo either in a Plasmodium berghei four-day test or in the P. falciparum Pf3D7(0087/N9) huSCID 'humanized' mouse model.
  
  
  RESULTS
  Of the compounds included in the GSK and Pfizer sets, 3.8% (9/238) had relevant in vitro anti-malarial activity while 6/100 compounds from the AZ candidate drug library were active. In comparison, around 0.6% (24/3,800) of the FDA-approved drugs and other bio-actives were active. After evaluation of available clinical data, four investigational drugs, active in vitro were tested in the P. falciparum humanized mouse model: UK-112,214 (PAF-H1 inhibitor), CEP-701 (protein kinase inhibitor), CEP-1347 (protein kinase inhibitor), and PSC-833 (p-glycoprotein inhibitor). Only UK-112,214 showed significant efficacy against P. falciparum in vivo, although at high doses (ED90 131.3 mg/kg [95% CI 112.3, 156.7]), and parasitaemia was still present 96 hours after treatment commencement. Of the six actives from the AZ library, two compounds (AZ-1 and AZ-3) were marginally efficacious in vivo in a P. berghei model.
  
  
  CONCLUSIONS
  Repositioning of existing therapeutics in malaria is an attractive proposal. Compounds active in vitro at μM concentrations were identified. However, therapeutic concentrations may not be effectively achieved in mice or humans because of poor bio-availability and/or safety concerns. Stringent safety requirements for anti-malarial drugs, given their widespread use in children, make this a challenging area in which to reposition therapy.
authors.forename: Julie
authors.initials: J
authors.lastname: Lotharius
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Gamo-Benito
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.forename: Julie
authors.initials: J
authors.lastname: Clark
authors.forename: Michele
authors.initials: M
authors.lastname: Connelly
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer-Bazaga
authors.forename: Tanya
authors.initials: T
authors.lastname: Parkinson
authors.forename: Pavithra
authors.initials: P
authors.lastname: Viswanath
authors.forename: Balachandra
authors.initials: B
authors.lastname: Bandodkar
authors.forename: Nikhil
authors.initials: N
authors.lastname: Rautela
authors.forename: Sowmya
authors.initials: S
authors.lastname: Bharath
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: Medicines for Malaria Venture (MMV), PO Box 1826, 20 rte de Pré-Bois, 1215, Geneva 15, Switzerland. moehrlej@mmv.org.
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Möhrle
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.forename: Timothy
authors.initials: T
authors.lastname: Wells
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D058492:Drug Repositioning; D008288:Malaria / Q000188:drug therapy*; D016778:Malaria, Falciparum / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials
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