title: The safety, tolerability, pharmacokinetics and cognitive effects of GSK239512, a selective histamine H₃ receptor antagonist in patients with mild to moderate Alzheimer's disease: a preliminary investigation.
abstract: BACKGROUND
  The histamine H3 receptor plays a critical role in the negative neuromodulation of neurotransmitters involved in cognitive function. H3 receptor antagonists/inverse agonists have been shown to exert pro-cognitive effects in pre-clinical models. GSK239512 is a potent and selective H₃ receptor antagonist developed for the treatment of cognitive dysfunction in neurodegenerative disorders. In this study we examined the safety, tolerability, pharmacokinetics and pro-cognitive effects of GSK239512 (oral) in patients with mild to moderate Alzheimer's disease using ascending dose titration regimens.
  
  
  METHODS
  The study was conducted in two parts. Part A was a single-blind, placebo run-in, flexible dose titration over 9 days in two cohorts, each consisting of two patients. Part B was a double-blind, randomised, placebo controlled, parallel group, which investigated 3 flexible dose titration regimens over 4 weeks in 3 cohorts, each consisting of eight patients.
  
  
  RESULTS
  Overall, the 5/10/20/40 μg and 10/20/40/80 μg regimens were well-tolerated. The regimen of 20/40/80/150 μg showed the poorest tolerability likely due to the higher starting dose. There were no clinically significant abnormalities in haematology, clinical chemistry, urinalysis parameters and cardiovascular parameters. GSK239512 had positive effects on tasks of attention and memory with effect sizes between 0.56 and 1.37.
  
  
  CONCLUSIONS
  GSK239512 displayed asatisfactory level of tolerability in patients with Alzheimer's disease with evidence for positive effects on attention and memory. The findings suggest that a titration regimen with a starting dose of 5-10 μg and a maximum dose of 80 μg is likely to be a well-tolerated and potentially efficacious regimen for future clinical trials in patients with Alzheimer's disease. These findings await replication in a larger study.
authors.affiliation: GSK Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigations, Cambridge Biomedical Campus, Cambridge CB2 2GG, UK. pradeep.j.nathan@gsk.com
authors.forename: Pradeep J
authors.initials: PJ
authors.lastname: Nathan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Boardley
authors.forename: Nicola
authors.initials: N
authors.lastname: Scott
authors.forename: Alienor
authors.initials: A
authors.lastname: Berges
authors.forename: Paul
authors.initials: P
authors.lastname: Maruff
authors.forename: Tharani
authors.initials: T
authors.lastname: Sivananthan
authors.forename: Neil
authors.initials: N
authors.lastname: Upton
authors.forename: Martin T
authors.initials: MT
authors.lastname: Lowy
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nestor
authors.forename: Robert
authors.initials: R
authors.lastname: Lai
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy*; D001288:Attention / Q000187:drug effects*; D001552:Benzazepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D054828:Histamine H3 Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008568:Memory / Q000187:drug effects*; D016037:Single-Blind Method
chemical_list: D001552:Benzazepines; C584220:GSK239512; D054828:Histamine H3 Antagonists