Tacrine in Alzheimer’s disease

Dysken MW, Mendels J, LeWitt P Milacemide a placebo-controlled study in senile dementia of the Alzheimer type. J Am Geriatr Soc 40 503-506, 1992 Dysken MW, Johnson SB, Holden L, et al Haloperidol concentrations in patients with Alzheimer s Disease. Am J Geriatr Psychiatry 2 124-133, 1994 Eagger SA, Levy R, Sahakian BJ Tacrine in Alzheimer s disease. Lancet 337 989-929, 1991... 

Falloon IR, Lloyd GG, Harpin RE The treatment of social phobia real-hfe rehearsal with nonprofessional therapists. J Nerv Ment Dis 169 180-184, 1981 Farlow M, Gracon SI, Hershey LA, et al A controlled trial of tacrine in Alzheimer s disease. JAMA 268 2523-2529, 1992... 

Eagger SA, Levy R, Sahakian BJ Tacrine in Alzheimer s disease. Lancet... 

Tacrine (tetrahydroaminoacridine) was one of the first drugs to be widely marketed for the loss of memory and intellectual decline in Alzheimer s disease. However, its efficacy is controversial. A Cochrane review of the use of tacrine in Alzheimer s disease produced results that were compatible with improvement, no change, or even harm (1). For measures of overall clinical improvement, the intention-to-treat analyses did not detect any difference between tacrine and placebo (OR = 0.87 95%CI = 0.61, 1.23). There was no effect on behavioral disturbance (SMD = 0.04 95% Cl = -0.52,0.43) or cognitive function (SMD = 0.14 95% Cl = -0.02, 0.30). The odds ratio for withdrawal due to an adverse event was significantly different from 1, the control group experiencing fewer events (OR = 0.7 95%CI = 4.1, 7.9). Raised serum liver cnzym cs caused the most withdrawals. 

Authors evaluating the adverse effects of tacrine in Alzheimer s disease recommend regular monitoring for hepatotoxicity (SEDA-15,136). 

Trials also sometimes actively recruit patients who are likely to respond well to treatment (often termed enrichment ). For example, some trials of antipsychotic drugs have selectively recruited patients who had a good response to antipsychotic drugs previously (Rothwell 2005a). Other trials have excluded non-responders in a run-in phase. One trial of a cholinesterase inhibitor, tacrine, in Alzheimer s disease recruited 632 patients to a six-week enrichment phase in which they were randomized to different doses of tacrine or placebo (Davis et al. 1992). After a washout-period, only the 215 (34%) patients who had a measured improvement on tacrine in the enrichment phase were randomized to tacrine (at their best dose) versus placebo in the main phase of the trial. External vaUdity is clearly undermined here. 

FIGURE 20.5 The upper curve shows the time course of predicted responses in a patient receiving placebo treatments as part of the three-part trial design used to evaluate tacrine in Alzheimer s disease. The lower curve shows the simulated response in a patient receiving a particular sequence of placebo (P) followed by tacrine (40 or 80 mg/day). (Reproduced with permission from Holford NH, Peace KE. Proc Natl Acad Sci USA 1992 89 11466-70.)... 

Rigaud AS, Traykov L, Caputo L, Guel-fi MC, Latour F, Couderc R et al. The apolipoprotein E epsilon4 allele and the response to tacrine therapy in Alzheimer s disease. Eur J Neurol 2000 7 255— 258. 

Langstrom B. (1997). Imaging of nicotinic and muscarinic receptors in Alzheimer s disease effect of tacrine treatment. Dement Geriatr Cogn Disord. 8(2) 78-84. 

Nonannulated aminopyrans 22 and tetrahydrochromenes 104 were used in the synthesis of heteroanalogs 294 and 295 of tacrine 302, a cholinesterase inhibitor applied in Alzheimer s disease treatment (01BML727, 02BML2077, 04BMC2199, 05BMC1167, 06BMC8176). 

Davies P, Maloney AJF Selective loss of central cholinergic neurons in Alzheimer s disease. Lancet 2 1403, 1976 Davis KL, Powchik P Tacrine. Lancet 345 625-630, 1995... 

Wilson MA, Dwyer KD, Roy EJ Direct effects of ovarian hormones on antidepressant binding sites. Brain Res Bull 22 181-185, 1989 Winblad B, Adolfsson R, Carlsson A, et al Biogenic amines in brains with Alzheimer s disease, in Alzheimer s Disease A Report of Progress (Ageing, Vol 19). Edited by Corkin S, Davis KL, Growdon JH, et al. New York, Raven, 1982, pp 25-33 Winker MA Tacrine for Alzheimer s disease. Which patient, what dose JAMA 271 1023-1024, 1994... 

Rivastigmine, Donepezil, Tacrine etc. (used in Alzheimer s disease). ... 

Tacrine has numerous mechanisms of action. The putative principle mechanism of action of tacrine for Alzheimer s disease is reversible inhibition of acetylcholinesterase (AChE), which thereby slows the breakdown of the chemical messenger acetylcholine (ACh) in the brain. In addition, tacrine blocks the sodium and potassium channels. 

The Cochrane Library is a relatively new and growing electronic library that provides more than 850 summaries of published literature about pharmaceutical and other interventions to improve health. The Library adds new titles four times a year to its cumulative online and CD versions (the latter, available by subscription, offers more databases). The Library s 2000 Issue 3 contains evidence on dozens of clinical dilemmas, such as antibiotic treatment for traveler s diarrhea, antileukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma, opioid antagonists for alcohol dependence, and bromocriptine versus levodopa in early Parkinson s disease. The Cochrane Library also updates earlier reviews when important new evidence becomes available. Among the newest updates are tacrine for Alzheimer s disease, tricyclic and related drugs for nocturnal enuresis in children, and nicotine replacement therapy for smoking cessation. 

APOE E4 allele in Alzheimer s disease Presence of E4 allele associated with poor response to tacrine 117... 

Nordberg, A., 1993. Effect of long-term treatment with tacrine (THA) in Alzheimer s disease as visualized with PET. Acta Neurol. Scand., Suppl. 149, 62-65. 

Cholinomimetics that can increase central cholinergic activity have produced some improvements in Alzheimer s disease AChE inhibitors, particularly physostigmine, have been most studied. A study with an experimental potent, centrally acting anticholinesterase compound l,2,3,4-tetrahydro-9-aminoacridine (THA, Tacrine) involving Alzheimer s patients over a year-long period showed encouraging improvement without some side effects. 

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