Pharmacological Basis of Cholinergic Therapy in Alzheimer Disease

  • Ezio Giacobini


Cholinesterase inhibitors (ChEI) presently in clinical trials or in current use (1998) in Japan, USA and Europe include less than ten drugs. Most of these compounds have advanced to clinical phase III and IV and two (tacrine and donepezil) are registered in USA and in Europe (1). Other two compounds (rivastigmine and metrifonate) are close to registration. This second generation ChEI, in order to replace tacrine, had to fulfill specific requirements such as lower toxicity (1). Based on current selection criteria and occurrence of complications a number of ChEI has been discontinued. Are there major differences among various compounds with regard to efficacy, percentage of treatable patients and incidence of side effects? Table 1 compares the effect of six ChEI on ADAS-cog test using ITT (intention to treat) criteria. The duration of clinical trials varied from 24 to 30 weeks and the number of treated patients was above 4000. All six ChEI produced statistically significant improvements evaluated with scales of standardized and internationally validated measures of both cognitive and non-cognitive function. The magnitude of cognitive effects measured with the ADAS-cog scale is similar for all six drugs either expressed as difference between drug- and placebo-treated patients or by the difference of drug-treated patients from baseline (Table 1) (2–7). This similarity in cognitive improvement suggests a ceiling effect of approximately five ADAS-cog points average for ChEI tested in mild to moderate (CDR 1–1.5) stages of the disease and at present level of dosage. This result does not imply that maximal effect had been reached with a each drug. The high percentage of drop-outs and more severe side-effects seen with some drugs such as tacrine (hepatotoxicity and general cholinergic toxicity), suggests a limit in practically achievable levels of ChE inhibition as well as in drug effect. Similarity of clinical efficacy is emphasized by the practical identical effect on global scales such as the clinicians interview-based impresssion of change-plus (CIBIC-plus) of 0,4 points difference seen for tacrine, rivastigmine and metrifonate. These drugs have very different chemical structures and pharmacological profiles.


Alzheimer Disease Cholinesterase Inhibitor Brain AChE Alzheimer Therapy Generation ChEI 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Giacobini E. Cholinesterase inhibitors do more than inhibit cholinesterase. In Alzheimer Disease: From molecular biology to therapy 1996, pp 187-204 Ed. by Becker, R. and Giacobini, E. Boston: Birkhäuser.Google Scholar
  2. 2.
    Mori F, Lai CC, Fusi F, Giacobini E. Cholinesterase inhibitors increase secretion of APPs in rat brain cortex. Neum Rep.:1995; 6: (4) pp 633-636.Google Scholar
  3. 3.
    Anand R, Hartman RD, Hayes P.E. An overview of the development of SDZ ENA 713, a brain selective cholinesterase inhibitor. In Alzheimer Disease: From molecular biology to therapy 1996, pp 239-243. Ed. by Becker, R. and Giacobini, E. Boston: Birkhäuser.Google Scholar
  4. 4.
    Farlow M, Gracon SI, Hershey LA. Lewis KW, Sadowski, C.H., Dolan-Ureno, J:A. Controlled trial of tacrine in Alzheimer’s disease J.Am.Med Ass 1992; 268.:2523–2529CrossRefGoogle Scholar
  5. 5.
    Knapp M.J, Knopman DS, Solomon PR.A 30 week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. J. Am. Med. Ass.: 1994; 271:985–991.CrossRefGoogle Scholar
  6. 6.
    Roger S.L, Farlow M R, Doody R S et al. A 24 week, double blind, placebo controlled trial of donepezil in patients with AD. Neurology.1998; 50: 136–145CrossRefGoogle Scholar
  7. 7.
    Becker R, Colliver J.A, Markwell SJ, Moriearty P, Unni LK, Vicari S. Double-blind, placebo-controlled study of metrifonate, an AChE inhibitor for Alzheimer disease. Alz. Dis. and Assoc. Dis 1996; 10.124–131.CrossRefGoogle Scholar
  8. 8.
    Amberia K, Nordberg A, Viitanen M, Winblad B. Long-term treatment with tacrine (THA) in Alzheimer disease evaluation of neuropsychological data.Acta.Neurol Scand 1993; Suppl: 149:55–57.Google Scholar
  9. 9.
    Giacobini E, Becker R, McIlhany M, Kumar V. Intracerebroventricular administration of cholinergic drugs:preclinical trials and clinical experience in Alzheimer patients. In Current Research in Alzheimer Therapy 1988, pp 113-122 Ed. by Giacobini, E. and Becker, R. New York: Taylor and Francis.Google Scholar
  10. 10.
    Giacobini E. Cholinesterase inhibitors: From preclinical studies to clinical efficacy in Alzheimer disease. In Enzymes of the cholinesterase family 1995, pp 463–469. Ed. by Quinn, D., Balasubramaniam, A.S., Doctor, B.P. and Taylor, P., New York: Plenum Press.CrossRefGoogle Scholar
  11. 11.
    Mattio T, Mcllhany M, Giacobini E, Hallak M. The effects of physostigmine on acethylcholinesterase activity of CSF, plasma and brain.Neuropharmacology 1986; 25:1167–1177PubMedCrossRefGoogle Scholar
  12. 12.
    Giacobini E, DeSarno P, Clark B, Mcllhany M. The cholinergic receptor system of the human brain-Neurochemical and pharmacological aspects in aging and Alzheimer. In Progress in Brain Research, 1989, pp 335-343 Ed. by Nordberg, A., Fuxe, K. and Holmstedt, B. Amsterdam: ElsevierGoogle Scholar
  13. 13.
    Giacobini E, Cuadra G, Second and third generation cholinesterase inhibitors: From preclinical studies to clinical efficacy. In: Alzheimer Disease: Therapeutic Strategies 1994, pp. 155-171. Edit. by Giacobini, E. and Becker, R., Boston: Birkhäuser.Google Scholar
  14. 14.
    Giacobini E. Cholinomimetic therapy of Alzheimer disease: does it slow down deterioration? In Recent Advances in the Treatment of Neurodegenerative Disorders and Cognitive Dysfunction 7 (23) 1994, pp 51-57. Ed. by Racagni, G., Brunello, N. and Langer, S.Z. Internatonal Academy of Biomedicai Drug Research. New York: Karger.Google Scholar
  15. 15.
    Rupniak N.M.J, Field M.J, Samson NA, Steventon M.J, Iversen SD, Direct comparison of cognitive facilitation by physostigmine and tetrahydroaminoacridine in two primate models. Neurob. of Aging: 1990; 11: 609–613.CrossRefGoogle Scholar
  16. 16.
    Becker E, Giacobini E. Mechanisms of cholinesterase inhibition in senile dementia of the Alzheimer type. Drug Devel Res 1988; 12: 163–195CrossRefGoogle Scholar
  17. 17.
    Becker R, Giacobini E. Pharmacokinetics and pharmacodynamics of acetylcholinesterase inhibition. Drug Devel Res 1988; 14: 235–246CrossRefGoogle Scholar
  18. 18.
    Cummings J.L, Cyrus PA, Bieber F, et al Metrifonate treatment of the cognitive deficits of Alzheimre’s Disease.Neurology 1998 In PressGoogle Scholar
  19. 19.
    Canal I. Imbimbo B.P. Clinical trials and therapeutics: Relationship between pharmacodynamic activity and cognitive effects of eptastigmine in patiens with Alzheimer’s disease. Clin. Pharm. & Therap 1996; 15: 49–59Google Scholar
  20. 20.
    Imbimbo BP, Eptastigmine: A cholinergic approach to the treatment of Alzheimer’s disease. In Alzheimer Disease: From molecular biology to therapy 1996 pp 223-230. Edited by Becker, R. and Giacobini, E. Boston: BirkhäuserGoogle Scholar
  21. 21.
    Becker R, Moriearty P, Unni, L. and Vicari, S. Cholinesterase inhibitors as therapy in Alzheimer’s disease: benefit to risk considerations in clinical application. In Alzheimer Disease: From molecular biology to therapy, 1996:pp 257-266. Ed. by Becker, R. and Giacobini, E. Boston: Birkhäuser.Google Scholar
  22. 22.
    Morris J, Cyrus P, Orazem J., Mas J, Bieber F, Gulanski B. Metrifonate: potential therapy for Alzheimer’s Disease. Amer. Soc. Neurol. Meeting (Boston,) 1997 Abstr.155Google Scholar
  23. 23.
    Thal L, Fuld PA, Masur, D.M, Sharpless NS. Oral physostigmine and lecithin improve memory in Alzheimer disease. Ann. Neurol.1983; 13.491–496PubMedCrossRefGoogle Scholar
  24. 24.
    Imbimbo BP, Lucchelli PE. A pharmacodynamic strategy to optimize the clinical response to eptastigmine. In Alzheimer Disease: Therapeutic Strategies, 1994, pp.223-230. Ed. by Becker, R. and Giacobini, E. Boston.Birkhäuser.Google Scholar
  25. 25.
    Becker R, Colliver J, Elbe R. Effects of Metrifonate, a long-acting cholinesterase inhibitor. Drug Devel.Res 1990; 19:425–434CrossRefGoogle Scholar
  26. 26.
    Wilkinson D. Fulton B and Benfield P. Galanthamine, Drugs and Aging 1996; 1: 60–66Google Scholar
  27. 27.
    Pettigrew L C, Bieber F, Lettieri J et al A study of pharmacokinetics and safety of metrifonate in Alzheimres’ disease patients J.Clin.Pharm. 1998 In PressGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Ezio Giacobini
    • 1
  1. 1.HUG, Belle-Idée Department of GeriatricsUniversity Hospitals of GenevaThonex, GenevaSwitzerland

Personalised recommendations