Alzheimer Treatments tacrine

Tacrine An anticholinesterase used in the treatment of Alzheimer s disease. 

Farlow MR, Lahiri DK, Poirier J, Da-vignon J, Schneider L, Hui SL. Treatment outcome of tacrine therapy depends on apolipoprotein genotype and gender of the subjects with Alzheimer s disease. Neurology 1998 50 669-677. 

Farlow, M.R., "Treatment Outcome of Tacrine Therapy Depends on Apolipoprotein Genotype and Gender of the Subjects with Alzheimer s Disease," Neurology, 50, 669-677 (1998). 

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. 

Nordberg A, Amberla K, Shigeta M, Lundqvist H, Viitanen M, Hellstrom-Lindahl E, Johansson M, Andersson J, Hartvig P, Lilja A, et al. (1998). 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. 12(3) 228-37. 

Donepezil (Aricept). Donepezil is the second cholinesterase inhibitor approved for the treatment of dementia. Most physicians find it much easier to use than its predecessor. It can be given once a day and carries none of the risk of liver toxicity seen with tacrine. It has been shown in multiple clinical trials to delay the decline in cognitive function in patients with Alzheimer s disease. 

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). 

The results with the recently introduced centrally acting inhibitors of acetylcholinesterase like tacrine and rivastigmine for the treatment of Alzheimer s disease are modest at best. 

Division of Neuropharmacological Drug Products, U.S. Food and Drug Administration Tacrine as a treatment for Alzheimer s disease an interim report from the FDA. N Engl J Med 324 349-352, 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... 

Arrieta, J.L., Artalejo, F.R. (1998). Methodology, results and quality of clinical trials of tacrine in the treatment of Alzheimer s disease a systematic review of the literature. Age Ageing, 27, 161-79. 

FIGURE 12-30. Alzheimer s disease pharmacy. Currently, donepezil is first-line for memory loss, and atypical antipsychotics (SDA) are first-line for positive psychotic symptoms together they may work synergistically. Soon the cholinesterase inhibitors metrifonate and/or rivastigmine may become available. Second-line treatments are tacrine for memory and conventional antipsychotics (D2) for positive psychotic symptoms. Several other agents are in clinical and preclinical development. 

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. 

Badia, A. Banos, J. E. Camps, R Contreras, J. Gorbig, D. M. Munoztorrero, D. Simon, M. Vivas, N. M. Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer s disease. Bioorg. Med. Chem., 1998, 6(4) 427-440. 

Reduced in Alzheimer s brains and CSF. Elevated levels following tacrine and rivastigmine treatments are correlated to improved cognition Attenuates disease progression following MPTP exposure (neuroprotective) Overexpressed and involved... 

Acetylcholinesterase. A pronounced decrease in the level of the neurotransmitter acetylcholine is one of the most pronounced changes in brain chemistry observed in the sufferers of Alzheimer s disease (139). Several drugs that are approved for the treatment of the dementia thought to result from this neurotransmitter deficit act by inhibiting acetylcholinesterase. These include (63) (tacrine, or... 

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.)... 

Other broad-based examples besides that of asthma could surely be found. However, there are other established though more restricted examples. Well known is the failure of treatment of Alzheimer s disease by tacrin if the patient has a variant of ApoE4, an apoli-poprotein. Tacrin is a cholinesterase inhibitor, one of the first anti-Alzheimer drugs,chosen to elevate... 

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