Cholinesterase inhibitors in Alzheimer’s disease

Lanctot KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM, Einarson TR (2003) Efficacy and safety of cholinesterase inhibitors in Alzheimer s disease A meta-analysis. CMAJ 169 557-564. 

Spilovska K, Korabecny J, Krai J, Horova A, Musilek K, Soukup O et al (2013) 7-Methoxytacrine-adamantylamine heterodimers as cholinesterase inhibitors in Alzheimer s disease treatment-synthesis, biological evaluation and molecular modeling studies. Molecules 18 2397-2418... 

Giacobini, E. (2006) Cholinesterases in human brain the effect of cholinesterase inhibitors on Alzheimer s disease and related disorders. In The brain cholinergic system in health and disease. Giacobini, E., Pepeu, G. (eds.), Informa Healthcare, Oxon, pp. 235-264. 

Musial A, Bajda M, Malawska B (2007) Recent developments in cholinesterases inhibitors for Alzheimer s disease treatment. Curr Med Chem 14 2654—2679... 

First generation of pharmacogenomic studies in Alzheimer s disease with cholinesterase inhibitors, noncholinergic drugs, and multifactorial... 

Ciismon, M.L. (1998) Pharmacokinetics and drug interactions of cholinesterase inhibitors administered in Alzheimer s disease. Pharmacotherapy, 18, 47-54. 

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). 

FIGURE 11—54. Cognitive symptom pharmacy. Atypical antipsychotic dmgs (SDA) may improve cognitive functions in both schizophrenic and Alzheimer patients (first-line treatment). They may boost the actions of cholinesterase inhibitors (ChEIs) in Alzheimer s disease. It may also be useful to discontinue any anticholinergic medication that you can, a welcome bonus when switching from conventional antipsychotics to atypical antipsychotics (decreased A Ch). 

C. Cholinesterase inhibitors as treatments for enhancing memory or slowing the pace of memory loss in Alzheimer s disease... 

Cholinesterase Inhibitors as Treatments for Enhancing Memory or Slowing the Pace of Memory Loss in Alzheimer s Disease... 

FIGURE 12—32. The best responses to cholinesterase inhibitor therapy in Alzheimer s disease can be substantial improvement, large enough to be noticeable to the patient and to his or her caregiver within weeks of initiation of therapy. Some of these patients sustain this robust improvement for many months or have a noticeably slower than expected decline in memory. 

FIGURE 12—34. Palliative responders to cholinesterase inhibitor therapy in Alzheimer s disease. Yet another response to cholinesterase inhibition can be no immediate improvement but a definite slowing in the expected rate of decline. 

Galanthamine is a very interesting cholinesterase inhibitor found in snowdrops and daffodils. It may have a dual mechanism of action, matching cholinesterase inhibition with direct nicotinic agonist actions causing acetylcholine release (Fig. 12—29). Early testing in Alzheimer s disease is underway. 

Cholinesterase inhibitors one class of six drugs or six unique agents Soon three to six cholinesterase inhibitors should be available worldwide for the treatment of cholinergic-related memory disturbances in Alzheimer s disease (Fig. 12—30). Use of these agents will likely be expanded to treat cholinergic-related behavioral disturbances in Alzheimer s disease in addition to memory disturbances, since there is evidence that behavioral problems in this disease may also respond to cholinergic... 

Giacobini E. Do cholinesterase inhibitors have disease-modifying effects in Alzheimer s disease CNS Drugs, 2001, 15(2), 85-91. 

Metrifonate has been used for the treatment of schistosomiasis for almost 40 years. Its identification as a cholinesterase inhibitor, together with recognition of the cholinergic deficit in Alzheimer s disease, has led to its use in Alzheimer s disease. 

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. 

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