title: Pharmacologists and Alzheimer disease therapy: to boldly go where no scientist has gone before.
abstract: BACKGROUND
  Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment, inability to perform activities of daily living and mood changes. Acetylcholinesterase inhibitors or NMDA glutamate receptor antagonists are currently used for the treatment of AD, but only the former have weak beneficial effects on cognitive function.
  
  
  METHODS
  The aim of this review is to provide an overview of the main pharmacological features of both current drugs and new compounds which are still under clinical development for the treatment of AD.
  
  
  CONCLUSIONS
  The discovery of new drugs acting at the early stage of AD could be considered as a 'medical need' and inhibitors of γ-secretase or monoclonal antibodies against Aβ seemed good options. However, inhibitors of γ-secretase, that is, tarenflurbil or semagacestat, were discontinued due to their lack of cognitive improvement or unacceptable side effects. A careful evaluation of the risk:benefit ratio should be considered for monoclonal antibodies since, by increasing the disaggregation of fibrillar amyloid-β-peptide (Aβ), they could increase the neurotoxicity of soluble Aβ oligomers. In conclusion, the discovery of new drugs efficacious in AD subjects is an ambitious goal, however, and one that will require close, active collaboration by pharmacologists, chemists and clinicians.
authors.affiliation: Catholic University School of Medicine, Institute of Pharmacology, Largo Francesco Vito, 1, 00168 Rome, Italy. cmancuso@rm.unicatt.it
authors.forename: Cesare
authors.initials: C
authors.lastname: Mancuso
authors.forename: Raffaella
authors.initials: R
authors.lastname: Siciliano
authors.forename: Eugenio
authors.initials: E
authors.lastname: Barone
authors.forename: David Allan
authors.initials: DA
authors.lastname: Butterfield
authors.forename: Paolo
authors.initials: P
authors.lastname: Preziosi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects; D000077265:Donepezil; D005702:Galantamine / Q000627:therapeutic use; D006801:Humans; D007189:Indans / Q000627:therapeutic use; D008559:Memantine / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D048448:Phenylcarbamates / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D011985:Receptors, Serotonin / Q000187:drug effects; D000068836:Rivastigmine
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D007189:Indans; D048448:Phenylcarbamates; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D005702:Galantamine; D000077265:Donepezil; D000068836:Rivastigmine; D008559:Memantine