Tacrine inhibitors

Although controversy exists over the cholinergic involvement in AD dementia, as of 1993 the only AD therapy approved by the U.S. FDA was the cholinesterase inhibitor, tacrine [321-64-2] C 2H 4N2, sold as Cognex (Warner-Lambert). 

The anainoacridines, tacrine (19) and its 1-hydroxy metaboUte, velnacrine (20), are reversible inhibitors of AChE. Tacrine was synthesi2ed in the 1940s and has been used clinically for the treatment of myasthenia gravis and tardive dyskinesia (115). Placebo-controUed studies have indicated modest efficacy of tacrine to treat AD dementia (122,123) and in 1993 the dmg was recommended for approval by the PDA under the trade name Cognex. Tacrine (19) has been shown to interact with sites other than AChE, such as potassium channels (124) and muscarinic receptors. However, these interactions are comparatively weak and are not thought to contribute to the biological activity of the dmg at therapeutic levels (115). 

The acetylcholinesterase inhibitor tacrine (64) was approved for the treatment of mild-to-moderate SDAT in the United States in 1993 followed by several other countries. The acetylcholinesterase inhibitor galanthamine (65), which has long been in clinical use in Austria for the treatment of indications such as facial neuralgia and residual poliomyelitis paralysis, has also been approved for use in... 

Tacrine is particularly damaging to the liver and can result in hepatotoxicity. Because tacrine is more likely to cause adverse reactions and drug interactions, it must be administered more frequently (4 times a day) and is rarely used in current therapy. Donepezil has fewer and milder side effects than tacrine It is considered the agent of first choice However, some patients may achieve a better response with one drug than another. Additional adverse reactions are listed in the Summary Drug Table Cholinesterase Inhibitors. 

When Hie cholinesterase inhibitors are administered with the anticholinergic drugp, there is a potential decrease in activity of the anticholinergic drug. There is an increased risk of toxicity of theophylline when the cholinesterase inhibitors are administered with tacrine There is a synergistic effect when tacrine is administered with succinyl-choline, cholinesterase inhibitors, or cholinergic agonists (eg, bethanechol). 

Giacobini, E. (1998) Invited review cholinesterase inhibitors for Alzheimer s disease therapy from tacrine to future applications. Neuro chemistry International 32,413-419. 

Apolipoprotein E (APOE) Cholinesterase inhibitor (Tacrine) Susceptibility to Alzheimer s disease, increased by the epsilon-4 allele, and decreased by epsilon-2 allele (91)... 

Tacrine was the first cholinesterase inhibitor approved for the treatment of AD, but it has been replaced by safer drugs which are better tolerated. 

Enzymes Acetylcholine reuptake inhibitor Tacrine First Horizon/OTL Pharma... 

Tacrine Cholinesterase inhibitor APOE Retrospective Genotype dependent Cognition Controversial results depending on authors and study model... 

Almkvist, O., Jelic, V., Amberla, K., Hellstrom-Lindahl, E., MeurUng, L., Nordberg, A. (2001) Responder characteristics to a single oral dose of cholinesterase inhibitor a doubleblind placebo-controlled study with tacrine in Alzheimer patients. Dement. Geriatr. Cogn. Disord., 12, 22-32. 

Naproxen Olanzapine Tacrine Tertiary TCAs Theophylline Warfarin Type 1C antiarrhythmics Codeine Erythromycin Estrogen Quinidine Phosphodiesterase-5 inhibitors Protease inhibitors TCAs Terfenadine Zolpidem... 

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. 

M., Cavrini, V. SAR of 9-amino-l,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMEA of tacrine analogues./. Med. Chem. 2000, 43, 2007-2018. 

Another drug with a high incidence of hepatotoxicity is the acetylcholinesterase inhibitor tacrine. Binding of reactive metabolites to liver tissue correlated with the formation of a 7-hydroxy metabolite [13], highly suggestive of a quinone imine metabolite as the reactive species. Such a metabolite would be formed by further oxidation of 7-hydroxy tacrine (Figure 8.11). 

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). 

Pharmacology Tacrine is a centrally acting reversible cholinesterase inhibitor, commonly referred to as THA. 

Gl disease/dysfunction Tacrine is an inhibitor of cholinesterase and may be expected to increase gastric acid secretion caused by increased cholinergic activity. Therefore, closely monitor patients at increased risk for developing ulcers for symptoms of active or occult Gl bleeding. 

Drugs that may be affected by tacrine include anticholinergics, cholinomimetics, cholinesterase inhibitors, and theophylline. 

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