Article thumbnail
Location of Repository

A critical review of cholinesterase inhibitors as a treatment modality in Alzheimer's disease

By Lon S. Schneider

Abstract

Early research into Alzheimer's disease launched the cholinergic hypothesis, based on the correlation between central cholinergic deficiency and clinical measures of cognitive decline. This was epitomized in therapeutic strategies employing a variety of procholinergic agents, of which only the inhibitors of cholinesterase (ChE), the enzyme thai hydrolyzes acetylcholine in the synaptic cleft, have been proven clinically viable. Five such agents are reviewed: tacrine and donepezil, which act at the ionic subsite of acetylcholinesterase (AChE), and rivastigmine, galantamine, and metrifonate, which act at its catalytic esteratic subsite. Despite statistical evidence of efficacy from numerous well-controlled multicenter trials, important clinical utility issues remain outstanding: (i) number-needed-to-treat (NNT) analyses, quantifying the number of patients needing to be treated for one patient to show benefit, find values of 3 to 20; (ii) the pivotal trials themselves were conducted in nonrepreseniative populations, largely comprised of physically healthy outpatients with mildto-moderate Alzheimer's disease and a mean age of 72 years (thereby excluding over 30% of typical Alzheimer patients in State of California-funded clinics), treated for up to 6 months; and (Hi) tolerability is underreported and characterized by a positive correlation between dose, effect and cholinergic side effects - potentially serious adverse events include bradycardia, anorexia, weight loss and myasthenia with respiratory depression. Therapies thus require titration and constant monitoring. Nevertheless, acetylcholinesterase inhibitors (AChEls) constitute the first class of effective agents and are likely to remain so in the continuing absence of viable alternatives

Topics: Pharmacological Aspects
Publisher: Les Laboratoires Servier
OAI identifier: oai:pubmedcentral.nih.gov:3181592
Provided by: PubMed Central

Suggested articles

Citations

  1. [Interaction of reversible inhibitors with the catalytic centers and allosteric sites of cholinesterases].
  2. (1998). A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group [see comments].
  3. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group [see comments].
  4. A 5-month, randomized, placebo-controlled trial of galantamine in AD.
  5. A controlled trial of tacrine in Alzheimer's disease. The Tacrine Study Group [see comments].
  6. (1995). A double-blind placebo-controlled trial of tacrine in Alzheimer's disease.
  7. A multicentre, randomized, double-blind, placebo-controlled study to evaluate the efficacy, tolerability and safety of two doses of metrifonate in patients with mild-to-moderate Alzheimer's disease: the MALT study.
  8. (1999). A phase II study in patients with Alzheimer’s disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine (Exelon).
  9. (1998). A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease.
  10. (1996). Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme.
  11. (1986). Acute and chronic effects of oral physostigmine and lecithin in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry.
  12. (1999). Age is not a barrier to donepezil treatment of Alzheimer's disease in the long-term care setting, Paper presented at:
  13. (1997). Albuquerque EX. Allosteric modulation of Torpedo nicotinic acetylcholine receptor ion channel activity by noncompetitive agonists. J Recept Sig Transd Res.
  14. Amyloid beta-peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons.
  15. (1996). An enriched-population, double-blind, placebo-controlled, crossover study of tacrine and lecithin in Alzheimer's disease.
  16. Cholinergic agonists and interleukin-1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor.
  17. Cholinergic deficiency in Alzheimer's disease. Pathogenic model.
  18. Cholinesterase inhibition for Alzheimer disease: a meta-analysis of the tacrine trials. Dementia Trialists' Collaboration [see comments].
  19. (1995). Cholinesterase inhibitors proposed for treating dementia in Alzheimer's disease: selectivity toward human brain acetylcholinesterase compared with butyrylcholinesterase. J Pharmacol Exp Ther.
  20. (1997). Cholinesterase inhibitors: an overview of their mechanisms of action.
  21. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia.
  22. (1998). Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group [see comments]. Arch Intern Med.
  23. (1996). Effect of tacrine on behavioral symptoms in Alzheimer's disease: an open-label study.
  24. (1997). Effect of tacrine on language, praxis, and noncognitive behavioral problems in Alzheimer disease. Arch Neurol.
  25. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial [see comments].
  26. (1997). Eligibility of Alzheimer’s disease clinic patients for clinical trials.
  27. (1996). Fisher Symposium: strategies for the prevention of Alzheimer disease—overview of research planning meeting III. Alzheimer Dis Assoc Disord.
  28. (1989). Galantamine hydrobromide in the treatment of senile dementia of the Alzheimer's type. In: Kewitz
  29. Galantamine in Alzheimer’s disease—a 6-month, randomized, placebo-controlled trial with a 6-month extension.
  30. Galantamine treatment in Alzheimer's disease: a preliminary evaluation of 40 patients [abstract].
  31. Galanthamine and the treatment of Alzheimer's disease.
  32. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease [see comments].
  33. How useful are cholinesterase inhibitors in the treatment of Alzheimer's disease? A number needed to treat analysis.
  34. Long-term administration of oral physostigmine in Alzheimer's disease.
  35. (1998). Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: an interim analysis of the results of a US multicenter open-label extension study. Euro Neuropsychopharmacol.
  36. Long-term outpatient treatment of senile dementia with oral physostigmine.
  37. (1996). Long-term tacrine (Cognex) treatment: effects on nursing home placement and mortality, Tacrine Study Group [see comments].
  38. (1998). Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease [see comments].
  39. Metrifonate: overview of safety and efficacy.
  40. (1990). Multiple effects of tetrahydroaminoacridine on the cholinergic system: biochemical and behavioural aspects. J Neural Transm Park Dis Dement Sect.
  41. Neuropathological implications for therapy. In:
  42. (1998). Parke-Davis Cognex Prescribing Information.
  43. (1998). Pharmacokinetics, pharmacodynamics, and safety of metrifonate in patients with Alzheimer's disease.
  44. (1997). Pharmacological modulation of Alzheimer's beta-amyloid precursor protein levels in the CSF of rats with forebrain cholinergic system lesions. Brain Res Mol Brain Res.
  45. (1997). Prevention protocols for Alzheimer disease. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. Alzheimer Dis Assoc Disord.
  46. (1996). Progress in understanding the pathogenesis of Alzheimer's disease [news; comment]. Mol Psychiatry.
  47. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset.
  48. (1997). Rational design of new acetylcholinesterase inhibitors.
  49. (1992). Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors.
  50. (2000). Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev.
  51. (1998). Rivastigmine: a review of its use in Alzheimer's disease. Drugs Aging.
  52. (1998). Safety of tacrine: clinical trials, treatment IND, and postmarketing experience. Alzheimer Dis Assoc Disord.
  53. (1990). Selective inhibition of human acetylcholinesterase by galanthamine in vitro and in vivo. Life Sci.
  54. (1990). Stereoselectivity of cholinesterase inhibition by galanthamine and tolerance in humans.
  55. (1998). Systematic review of the efficacy of rivastigmine for the patients with Alzheimer's disease. Int J Geriatr Psychopharmacol.
  56. (1991). Tacrine: a pharmacological review. Prog Neurobiol.
  57. (1992). The cholinergic agonist carbachol reduces intracellular beta-amyloid precursor protein
  58. The effect of long-term physostigmine administration in Alzheimer's disease.
  59. (1999). The effects of donepezil in Alzheimer's disease—results from a multinational trial. Dement Geriatr Cogn Disord.
  60. The effects of metrifonate on the cognitive, behavioral, and functional performance of Alzheimer's disease patients. Metrifonate Study Group [see comments].
  61. (1996). The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicenter, randomized, doubleblind, placebo-controlled trial. The Donepezil Study Group.
  62. The incidence of dementia: a meta-analysis.
  63. (1995). The pharmacology of galanthamine and its analogues. Pharmacol Ther.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.