Drug Safety

, Volume 19, Issue 6, pp 465–480

Cholinesterase Inhibitors in the Treatment of Alzheimer’s Disease

A Comparison of Tolerability and Pharmacology
Review Article Drug Experience

Abstract

Cholinesterase inhibitors are currently the most established treatment strategy in Alzheimer’s disease. The treatment effect appears mainly to be symptomatic. Effects on progression of the disease following long term treatment, and possible neuroprotective effects, have been investigated. Delay until nursing home placement has been reported. Three cholinesterase inhibitors, tacrine, donepezil and rivastigmine, are in clinical use. Other cholinesterase inhibitors, such as galantamine (galanthamine), metrifonate, physostigmine, eptastigmine, are currently under clinical evaluation. So far the efficacy appears to be comparable between the various cholinesterase inhibitors; treatment for up to 6 months has produced an improvement in Alzheimer’s Disease Assessment Scale — Cognitive Subscale score (ADAS-cog) of between 1.8 and 4.9 in patients with Alzheimer’s disease.

Tacrine, donepezil, galantamine and physostigmine are reversible inhibitors of acetylcholinesterase and butyrylcholinesterase, while metrifonate is considered to be an irreversible inhibitor and rivastigmine a pseudoirreversible inhibitor. Tacrine and physostigmine have lower bioavailability, 17 to 37% and 3 to 8%, respectively, than the other cholinesterase inhibitors such as rivastigmine, galantamine and donepezil (40 to 100%). The elimination half-life is considerably longer for donepezil (70 to 80h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12h). Donepezil is therefore administered once daily in comparison to rivastigmine which is administered twice daily and tacrine which is administered 4 times daily.

Simultaneous food intake lowers the plasma concentration of tacrine and reduces the adverse effects of rivastigmine. Drugs like theophylline and cimetidine have been reported to change the pharmacokinetics of tacrine and donepezil. In contrast, concomitant medication with various drugs with rivastigmine does not seem to cause any drug interactions in patients with Alzheimer’s disease. Tacrine, donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Active metabolites are known for tacrine and galantamine. Rivastigmine is not metabolised via CYP enzymes, but via esterases and is excreted in the urine.

Tacrine is associated with hepatotoxicity while other cholinesterase inhibitors seem devoid this adverse effect. Increased liver enzyme values have been observed in 49% of patients with Alzheimer’s disease treated with tacrine. Rechallenge with tacrine reduces the incidence of elevated liver enzyme levels. Peripheral cholinergic adverse effects are common for the cholinesterase inhibitors, with a n incidence ranging between 7 to 30% For some cholinesterase inhibitors, such as rivastigmine, the cholinergic adverse effects such as nausea, vomiting, dizziness, diarrhoea and abdominal pain can be reduced by slowing the rate of dose titration.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Fratiglioni L. Epidemiology of Alzheimer’s disease. Acta Neurol Scand 1993; Suppl. 87: 1–70CrossRefGoogle Scholar
  2. 2.
    Masters CL, Beyreuther K. Alzheimer’s disease. BMJ 1998; 316: 446–8PubMedCrossRefGoogle Scholar
  3. 3.
    Nordberg A. Pharmacological treatment of cognitive dysfunction in dementia disorders. Acta Neurol Scand 1996; Suppl. 168: 87–92CrossRefGoogle Scholar
  4. 4.
    Knopman DS, Morris JC. An update on primary drug therapies for Alzheimer’s disease. Arch Neurol 1997; 54: 1406–9PubMedCrossRefGoogle Scholar
  5. 5.
    Nordberg A. Biological markers and the cholinergic hypothesis in Alzheimer’s disease. Acta Neurol Scand 1992; Suppl. 139: 54–8CrossRefGoogle Scholar
  6. 6.
    Lawrence AD, Sahakian BJ. Alzheimer’s disease, attention and the cholinergic system. Alzheimer Dis Assoc Disord 1995; 9: 43–39PubMedCrossRefGoogle Scholar
  7. 7.
    Amberla K, Nordberg A, Viitanen M, et al. Long-term treatment with tacrine (THA) in Alzheimer’s disease-evaluation of neuropsychological data. Acta Neurol Scand 1993; Suppl. 149: 55–7Google Scholar
  8. 8.
    Maltby N, Broe GA, Creasey H, et al. Efficacy of tacrine and lecithin in mild to moderate Alzheimer’s disease: double blind trial. BMJ 1994; 308: 879–83PubMedCrossRefGoogle Scholar
  9. 9.
    Nordberg A, Amberla K, Shigeta M, et al. Long-term tacrine treatment in three mild Alzheimer patients: effects on nicotinic receptors, cerebral blood flow, glucose metabolism, EEG and cognitive abilities. Alzheimer Dis Assoc Disord 1998; 12: 228–37PubMedCrossRefGoogle Scholar
  10. 10.
    Knopman DS, Schneider L, Davis K, et al. Long-term tacrine (Cognex) treatment: effect on nursing home placement and mortality. Neurology 1996; 47: 166–77PubMedCrossRefGoogle Scholar
  11. 11.
    Minthon L, Nilsson K, Edvinsson L, et al. Long-term effect of tacrine on regional cerebral blood flow changes in Alzheimer’s disease. Dementia 1995; 6: 245–51PubMedGoogle Scholar
  12. 12.
    Reisberg B, Burns A, Gauthier S, et al., editors. Outcome methodologies for pharmacologic trials in mild, moderate, and severe Alzheimer’s disease. Int Psychogeriatr 1996; 8: 155-344Google Scholar
  13. 13.
    Nordberg A. Functional studies of new drugs for the treatment of Alzheimer’s disease. Acta Neurol Scand 1996; Suppl. 165: 137–44CrossRefGoogle Scholar
  14. 14.
    Arendt T, Brückner MT, Lange M, et al. Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer’s disease resemble embryonic development- a study of molecular forms. Neurochem Int 1992; 3: 381–96CrossRefGoogle Scholar
  15. 15.
    Kása P, Bakonczay Z, Gulya K. The cholinergic system in Alzheimer’s disease. Prog Neurobiol 1997; 52: 511–35PubMedCrossRefGoogle Scholar
  16. 16.
    Ogane N, Giacobini E, Struble R. Differential inhibition of acetylcholinesterase molecular forms in normal and Alzheimer disease brain. Brain Res 1992; 589: 307–12PubMedCrossRefGoogle Scholar
  17. 17.
    Perry EK, Tomlinson BE, Blessed G, et al. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. BMJ 1978; 2: 1457–9PubMedCrossRefGoogle Scholar
  18. 18.
    Atack JR, Perry EK, Bronham JR, et al. Molecular forms of acetylcholinesterase in senile dementia of Alzheimer’s type: selective loss of the intermediate (10S) form. Neurosci Lett 1983; 40: 199–204PubMedCrossRefGoogle Scholar
  19. 19.
    Inestrosa NC, Alvarez A, Perez CA, et al. Acetylcholinesterase accelerates assembly of amyloid-β-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron 1996; 16: 881–91PubMedCrossRefGoogle Scholar
  20. 20.
    Wright CI, Geula C, Mesulam MM. Neuroglial cholinesterases in the normal brain and Alzheimers disease: relationship to plaques, tangles and pattern of selective vulnerability. Ann Neurol 1993; 34: 373–84PubMedCrossRefGoogle Scholar
  21. 21.
    Appleyard ME, Smith AD, Berman P, et al. Cholinesterase activities in cerebrospinal fluid of patients with senile dementia of Alzheimer type. Brain 1987; 110: 1309–22PubMedCrossRefGoogle Scholar
  22. 22.
    Sáez-Valero J, McLean CA, Masters C, et al. Glycosylation of acetylcholinesterase as diagnostic marker for Alzheimer’s disease. Lancet 1997; 350: 929PubMedCrossRefGoogle Scholar
  23. 23.
    Navaratnam DS, Priddle JD, McDonald, et al. Anomalous molecular form of acetylcholinesterase in cerebrospinal fluid in histopathological diagnosed Alzheimer’s disease. Lancet 1991; 337: 447–50PubMedCrossRefGoogle Scholar
  24. 24.
    Shen ZX. An CSF anomalous molecular form of acetylcholinesterase in demented and non-demented subjects. Neuroreport 1997; 8: 3229–32PubMedCrossRefGoogle Scholar
  25. 25.
    Shen ZX. CSF cholinesterase activity in demented and non-demented subjects. Neuroreport 1998; 9: 483–8PubMedCrossRefGoogle Scholar
  26. 26.
    Pappata S, Tavitian B, Traykov L, et al. In vivo imaging of human acetylcholinesterase. J Neurochem 1996; 67: 876–9PubMedCrossRefGoogle Scholar
  27. 27.
    Iyo M, Namba H, Fukushi K, et al. Measurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer’s disease. Lancet 1997; 349: 1805–9PubMedCrossRefGoogle Scholar
  28. 28.
    Nilsson L, Adem A, Hardy J, et al. Do tetrahydroaminoacridine (THA) and physostigmine restore acetylcholine release in Alzheimer brains via nicotinic receptors? J Neural Transm 1987; 70: 357–68PubMedCrossRefGoogle Scholar
  29. 29.
    Svensson AL, Zhang X, Nordberg A. Biphasic effect of tacrine on acetylcholine release in rat brain via M1 and M2 receptors. Brain Res 1996; 726: 207–12PubMedCrossRefGoogle Scholar
  30. 30.
    Wagstaff A, McTavish D. Tacrine: a review of its pharmacological and pharmacokinetic properties and therapeutic potential in Alzheimer’s disease. Drugs & Aging 1994; 4: 1–31CrossRefGoogle Scholar
  31. 31.
    Pereira EFR, Alkondon M, Reinhardt S, et al. Physostigmine and galanthamine: probes for a novel binding site on the a4β2 subtype of neuronal nicotinic acetylcholine receptors stably expressed in fibroblast cells. J Pharmacol Exp Ther 1994; 270: 768–78PubMedGoogle Scholar
  32. 32.
    Svensson AL, Nordberg A. Tacrine interacts with an allosteric activator site on a4β2 AChRs in M10 cells. Neuroreport 1996; 7: 2201–5PubMedCrossRefGoogle Scholar
  33. 33.
    Svensson AL, Nordberg A. The acetylcholinesterase inhibitors donepezil, galanthamine and NXX-066 interact differently with the neuronal a4β2 nicotinic receptors in M10 cells. Br J Pharmacol. In pressGoogle Scholar
  34. 34.
    Lahiri DK, Lewis S, Farlow MR. Tacrine alters the secretion of the beta-amyloid precursor protein in cell lines. J Neurosci Res 1994; 37: 777–87PubMedCrossRefGoogle Scholar
  35. 35.
    Mori F, Lai CC, Fusi F, et al. Cholinesterase inhibitors increase secretion of APPs in rat brain cortex. Neuroreport 1995; 6: 633–6PubMedCrossRefGoogle Scholar
  36. 36.
    Haroutunian V, Greig N, Pei XF, et al. Pharmacological modulation of Alzheimer’s β-amyloid precursor protein levels in the CSF of rats with forebrain cholinergic system lesions. Soc Neurosci 1996; 22: 1169Google Scholar
  37. 37.
    Chong YH, Suh YH. Amyloidogenic processing of Alzheimer’s amyloid precursor protein in vitro and its modulation by metal ion and tacrine. Life Sci 1996; 59: 545–57PubMedCrossRefGoogle Scholar
  38. 38.
    Svensson AL, Nordberg A. Tacrine and donepezil attenuate the neurotoxic effect of Aβ (25–35) in rat PC12 cells. Neuroreport 1998; 9: 1519–22PubMedCrossRefGoogle Scholar
  39. 39.
    Freeman SE, Dawson RM. Tacrine: a pharmacological review. Prog Neurobiol 1991; 36: 257–77PubMedCrossRefGoogle Scholar
  40. 40.
    Johansson M, Hellström-Lindahl E, Nordberg A. Steady-state pharmacokinetics of tacrine in long-term treatment of Alzheimer patients. Dementia 1996; 7: 111–7PubMedGoogle Scholar
  41. 41.
    Hartvig P, Askmark H, Aquilonius SM, et al. Clinical pharmacokinetics of intravenous and oral 9-amino-1,2,3,4-tetrahydroacridine, tacrine. Eur J Clin Pharmacol 1990; 38: 259–63PubMedCrossRefGoogle Scholar
  42. 42.
    Hartvig P, Pettersson E, Wiklund L, et al. Pharmacokinetics and effects of 9-amino-1,2,3,4-tetrahydroacridine in the immediate postoperative period in neurosurgical patients. J Clin Anesth 1991; 3: 137–42PubMedCrossRefGoogle Scholar
  43. 43.
    Forsyth DR, Wilcock GK, Morgan RA, et al. Pharmacokinetics of tacrine hydrochloride in Alzheimer’s disease. Clin Pharmacol Ther 1989; 46: 634–41PubMedCrossRefGoogle Scholar
  44. 44.
    Cutler NR, Sedman AJ, Prior P, et al. Steady-state pharmacokinetics of tacrine in patients with Alzheimer’s disease. Psychopharmacol Bull 1990; 26: 231–4PubMedGoogle Scholar
  45. 45.
    Åhlin A, Adem A, Junthé T, et al. Pharmacokinetics of tetrahydroaminoacridine: relations to clinical and biochemical effects in Alzheimer patients. Int Clin Psychopharmacol 1992; 7: 29–36PubMedCrossRefGoogle Scholar
  46. 46.
    Nybäck H, Nyman H, Öhman G, et al. Preliminary experiences and results with THA for the amelioration of symptoms of Alzheimer’s disease. In: Giacobini E, Becker R, editors. Current Research in Alzheimer Therapy. New York: Taylor, Francis, 1988: 231–6Google Scholar
  47. 47.
    Selen A, Balogh L, Siedlik P, et al. Pharmacokinetics of tacrine in healthy subjects. Pharmacol Res 1988; 5: S–218Google Scholar
  48. 48.
    Askmark H, Aquilonius S-M, Gillberg P-G, et al. Functional and pharmacokinetic studies of tetrahydroaminoacridine in patients with amyotrophic lateral sclerosis. Acta Neurol Scand 1990; 82: 253–8PubMedCrossRefGoogle Scholar
  49. 49.
    Ford JM, Truman CA, Wilcock GK, et al. Serum concentrations of tacrine hydrochloride predict its adverse effects in Alzheimer’s disease. Clin Pharmacol Ther 1993; 53: 691–5PubMedCrossRefGoogle Scholar
  50. 50.
    Samuels SC, Davies K. A risk-benefit assessment of tacrine in the treatment of Alzheimer’s disease. Drug Saf 1997; 16: 66–77PubMedCrossRefGoogle Scholar
  51. 51.
    Murphy MF, Hardiman ST, Nash RJ, et al. Evaluation of HP 029 (velnacrine maleate) in Alzheimer’s disease. Ann N Y Acad Sci 1991; 640: 253–62PubMedGoogle Scholar
  52. 52.
    Knapp MJ, Knopman DS, Solomon PR, et al. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. JAMA 1994; 271: 985–91PubMedCrossRefGoogle Scholar
  53. 53.
    Watkins PB, Zimmerman HJ, Knapp MJ, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA 1994; 271: 992–8PubMedCrossRefGoogle Scholar
  54. 54.
    Gracon SI, Knapp MJ, Berghoff WG, et al. Safety of tacrine: clinical trials, treatment IND, and postmarketing experience. Alzheimer Dis Assoc Disord 1998; 12: 93–101PubMedCrossRefGoogle Scholar
  55. 55.
    Nochi S, Asakawa N, Saro T. Kinetic study on the inhibition of acetylcholinesterase by 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl] methylpiperidine hydrochloride (E2020). Biol Pharm Bull 1995; 18: 1145–7PubMedCrossRefGoogle Scholar
  56. 56.
    Galli A, Mori F, Benini L, et al. Acetylcholinesterase protection and the anti-diisopropylfluorophosphate efficacy of E2020. Eur J Pharmacol Environ Toxicol Pharmacol 1994; 270: 183–93CrossRefGoogle Scholar
  57. 57.
    Rogers SL, Walters EJ, Friedhoff LT. The pharmacokinetics (PK) and pharmacodynamics (PD) of E2020 (R, S)-1-benzyl-4-(5,6-dimethoxy-1-indanon)-2-yl)-methylpiperidine hydrochloride) a novel inhibitor of acetylcholinesterase (AChE): implications for use in the treatment of Alzheimer’s disease. Neurobiol Aging 1992; 13: 496Google Scholar
  58. 58.
    Barner EL, Gray SL. Donepezil use in Alzheimer disease. Ann Pharmacother 1998; 12: 70–7Google Scholar
  59. 59.
    Bryson HM, Benfield P. Donepezil. Drugs Aging 1997; 10: 234–9PubMedCrossRefGoogle Scholar
  60. 60.
    Rogers SL, Farlow MR, Doody RS, et al. A 24 week, doubleblind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Neurology 1998; 50: 136–45PubMedCrossRefGoogle Scholar
  61. 61.
    Rogers SL, Friedhoff LT. Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: an interim analysis of the results of a US multicentre open label extension study. Eur Neuropharmacol 1998; 8: 67–75CrossRefGoogle Scholar
  62. 62.
    Rogers SL, Friedhoff LT, Donepezil Study Group. The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. Dementia 1996; 7: 293–303PubMedGoogle Scholar
  63. 63.
    Rainer M. Galanthamine in Alzheimer’s disease: a new alternative to tacrine? CNS Drugs 1997; 7: 89–97CrossRefGoogle Scholar
  64. 64.
    Kewitz H. Pharmacokinetics and metabolism of galanthamine. Drugs Today 1997; 33: 265–72CrossRefGoogle Scholar
  65. 65.
    Rainer M. Clinical studies of galanthamine. Drugs Today 1997; 4: 273–9CrossRefGoogle Scholar
  66. 66.
    Holmstedt B, Nordgren I, Sandoz M, et al. Metrifonate: summary of toxicological and pharmacological information available. Acta Toxicol 1978; 41: 3–29CrossRefGoogle Scholar
  67. 67.
    Hintz VC, Grewig S, Schmidt BH. Metrifonate induces cholinesterase inhibition exclusively via slow release of dichlorvos. Neurochem Res 1996; 21: 331–7CrossRefGoogle Scholar
  68. 68.
    Lamb HM, Faulds D. Metrifonate. Drugs Aging 1997; 11: 490–6PubMedCrossRefGoogle Scholar
  69. 69.
    Becker RE, Colliver JA, Markwell SJ, et al. Effects of metrifonate on cognitive decline in Alzheimer disease: a double-blind, placebo-controlled, 6-months study. Alzheimer Dis Assoc Disord 1998; 12: 54–7PubMedCrossRefGoogle Scholar
  70. 70.
    Abdi YA, Villén T. Pharmacokinetics of metrifonate and its rearrangement product dichlorvos in whole blood. Pharmacol Toxicol 1991; 68: 137–9PubMedCrossRefGoogle Scholar
  71. 71.
    Unni LK, Womack C, Hannant ME, et al. Pharmacokinetics and pharmacodynamics of metrifonate in humans. Methods Find Exp Clin Pharmacol 1994; 16: 285–9PubMedGoogle Scholar
  72. 72.
    Becker RE, Moriearty P, Unni L, et al. Cholinesterase inhibitors as therapy in Alzheimer’s disease: benefit to risk consideration in clinical application. In: Becker R, Giacobini E, editors. Alzheimer Disease: from molecular biology to therapy. Boston: Birkhäuser 1996; 257–66Google Scholar
  73. 73.
    Morris JC, Cyrus PA, Orazem J, et al. Metrifonate benefits cognitive, behavioural, and global functions in patients with Alzheimer’s disease. Neurology 1998; 50: 1222–30PubMedCrossRefGoogle Scholar
  74. 74.
    Holmstedt B, Nordgren I, Sandoz M, et al. Metrifonate: summary of toxicological and pharmacological information available. Arch Toxicol 1978; 41: 3–29PubMedCrossRefGoogle Scholar
  75. 75.
    Reutter SA, Filbert MG, Moore DH. et al. A role for butyrylcholinesterases in respiratory pathophysiology following nerve-agent intoxication. Proceedings of the Sixth Medical Chemical Defense Bioscience Review 1987; 13: 393–6Google Scholar
  76. 76.
    Anon. Bayer suspends metrifonate trials. SCRIP 1998 Sep 30; 2374: 19Google Scholar
  77. 77.
    Somani SM. Pharmacokinetics and pharmacodynamics of physostigmine in the rat after oral administration. Biopharm Drug Dispos 1989; 10: 187–203PubMedCrossRefGoogle Scholar
  78. 78.
    Thal LJ, Schwartz G, Sano M, et al. A multicenter double-blind study of controlled-release physostigmine for the treatment of symptoms secondary to Alzheimer’s disease. Neurology 1996; 47: 1389–95PubMedCrossRefGoogle Scholar
  79. 79.
    Walter K, Müller M, Barkworth F, et al. Pharmacokinetics of physostigmine in man following a single application of a transdermal system. Br J Clin Pharmacol 1995; 39: 59–63PubMedCrossRefGoogle Scholar
  80. 80.
    Becker RE, Moriearty P, Unni L. The second generation of cholinesterase inhibitors: clinical and pharmacological effects. In: Becker R, Giacobini E, editors. Cholinergic basis for Alzheimer therapy. Boston: Birkhüser 1991: 263–96Google Scholar
  81. 81.
    Williams FM. Serum enzymes of drug metabolism. Pharmacol Ther 1987; 34: 99–109PubMedCrossRefGoogle Scholar
  82. 82.
    Whelpton R, Hurst P. Bioavailability of oral physostigmine. New Engl J Med 1985; 313: 1293–4PubMedCrossRefGoogle Scholar
  83. 83.
    McClellan KJ, Benfield P. Eptastigmine. CNS Drugs 1997; 9: 69–75CrossRefGoogle Scholar
  84. 84.
    Auteri A, Mosca A, Lattuada N, et al. Pharmacodynamics and pharmacokinetics of eptastigmine in elderly subjects. Eur J Clin Pharmacol 1993; 45: 373–6PubMedCrossRefGoogle Scholar
  85. 85.
    Imbimbo B P, Licini M, Schettino M, et al. Relationship between pharmacokinetics and pharmacodynamics of eptastigmine in young healthy volunteers. J Clin Pharmacol 1995; 35: 285–90PubMedGoogle Scholar
  86. 86.
    Stramek JJ, Block GA, Reines SA, et al. A multiple-dose safety trial of eptastigmine in Alzheimer’s disease, with pharmacodynamic observations of red blood cell cholinesterase. Life Sci 1995; 56: 319–26CrossRefGoogle Scholar
  87. 87.
    Canal N, Imbimbo B P, Eptastigmine Study Group. Relationship between pharmacodynamic activity and cognitive effects of eptastigmine in patients with Alzheimer’s disease. Clin Parmacol Ther 1996; 60: 218–28CrossRefGoogle Scholar
  88. 88.
    Unni LK. Beyond tacrine: recently developed cholinesterase inhibitors for the treatment of Alzheimer’s disease. CNS Drugs. In pressGoogle Scholar
  89. 89.
    Enz A, Floersheim P. Cholinesterase inhibitors: an overview of their mechanisms of action. In: Becker R, Giacobini E, editors. Alzheimer disease: from molecular biology to therapy. Boston: Birkhüser 1996: 211–5Google Scholar
  90. 90.
    Cutler NR, Polinsky RJ, Sramek JS, et al. Dose-dependent CSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer’s disease. Acta Neurol Scand 1998; 97: 244–50PubMedCrossRefGoogle Scholar
  91. 91.
    Anand R, Hartman D, Hayes P, et al. An overview of the development of SDZ ENA 713, a brain selective cholinesterase inhibitor. In: Becker R, Giacobini E, editors. Boston: Birkhüser 1996: 239–43Google Scholar
  92. 92.
    Anand R, Gharabawi G, Enz A. Efficacy and safety results of the early phase studies with exelon™ (ENA-713) in Alzheimer’s disease: an overview. J Drug Dev Clin Pract 1996; 8: 1–14Google Scholar
  93. 93.
    Enz A, Armstutz R, Boddeke H, et al. Brain selective inhibition of acetylcholinesterase: a novel approach to therapy for Alzheimer’s disease. Prog Brain Res 1993; 98: 431–8PubMedCrossRefGoogle Scholar
  94. 94.
    Anand R, Gharabawi G. Clinical development of ExelonTM (ENA-713): the adena program. J Drug Dev Clin Pract 1996; 8: 9–14Google Scholar
  95. 95.
    Spencer CS, Noble S. Rivastigmine: review of its use in Alzheimer’s disease. Drug & Aging 1998; 13: 391–411CrossRefGoogle Scholar
  96. 96.
    Corey-Bloom J, Anand R, Veach J. 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. Int J Geriatr Psychopharmacol 1998; 1: 55–65Google Scholar
  97. 97.
    Cummings JL. Changes in Neuropsychiatric symptoms as outcome measures in clinical trials with cholinergic therapies for Alzheimer disease. Alzheimer Dis Assoc Disord 1997; Suppl. 4: S1–9Google Scholar
  98. 98.
    Giacobini E. From molecular structure to Alzheimer therapy. Jpn J Pharmacol 1997; 74: 225–41PubMedCrossRefGoogle Scholar
  99. 99.
    Troetel WM, Imbimbo BP. Overview of the development of eptastigmine, a longacting cholinestesterase inhibitor. In: Iqbal K, Winblad B, Nishimura T, et al., editors. Alzheimer’s disease: biology, diagnosis and therapeutics. Chichester: John Whiley & Sons, 1997: 671–6Google Scholar
  100. 100.
    Kaufer D, Friedman A, Scidman, et al. Acute stress facilitates long-lasting changes in cholinergic gene expression. Nature 1998; 393: 373–6PubMedCrossRefGoogle Scholar
  101. 101.
    von der Krammer, Mayhaus M, Albrecht C, et al. Muscarinic acetylcholine receptors activate expression of the Erg gene family. J Biol Chem 1998; 273: 14538-44CrossRefGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  1. 1.Department of Clinical Neuroscience and Family Medicine, Division of Molecular Neuropharmacology, Karolinska InstitutetHuddinge University HospitalHuddingeSweden
  2. 2.Geriatric ClinicHuddinge University HospitalHuddingeSweden

Personalised recommendations