title: Old and new acetylcholinesterase inhibitors for Alzheimer's disease.
abstract: BACKGROUND
  To date, pharmacological treatment of Alzheimer's disease (AD) includes Acetylcholinesterase Inhibitors (AChEIs) for mild-to-moderate AD, and memantine for moderate-to-severe AD. AChEIs reversibly inhibit acetylcholinesterase (AChE), thus increasing the availability of acetylcholine in cholinergic synapses, enhancing cholinergic transmission. These drugs provide symptomatic short-term benefits, without clearly counteracting the progression of the disease.
  
  
  METHODS
  On the wake of successful clinical trials which lead to the marketing of AChEIs donepezil, rivastigmine and galantamine, many compounds with AChEI properties have been developed and tested mainly in Phase I-II clinical trials in the last twenty years. Here, we review clinical trials initiated and interrupted, and those ongoing so far.
  
  
  CONCLUSIONS
  Despite many clinical trials with novel AChEIs have been carried out after the registration of those currently used to treat mild to moderate AD, none so far has been successful in a Phase III trial and marketed. Alzheimer's disease is a complex multifactorial disorder, therefore therapy should likely address not only the cholinergic system but also additional neurotransmitters. Moreover, such treatments should be started in very mild phases of the disease, and preventive strategies addressed in elderly people.
authors.affiliation: a Neurology Unit, Department of Pathophysiology and Transplantation , University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico , Milan , Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.affiliation: a Neurology Unit, Department of Pathophysiology and Transplantation , University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico , Milan , Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D018450:Disease Progression; D015195:Drug Design; D006801:Humans; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D002800:Cholinesterase Inhibitors; D000109:Acetylcholine
keywords: Acetylcholinesterase inhibitors (AChEI); Alzheimer’s disease (AD); clinical trial