Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Donepezil HCI is a piperidine-based reversible acetylcholinesterase (AChE) inhibitor, chemically distinct from other cholinesterase (ChE) inhibitors and rationally designed to treat the symptoms of Alzheimer's disease (AD). It is highly selective for AChE in the central nervous system (CNS), with little or no affinity for butyrylcholinesterase (BuChE). In preclinical studies in animals, donepezil produced increased CNS acetylcholine. The resultant enhancement of cholinergic activity gave rise to improved performance by rats on tests of learning and memory, with no evidence of hepatic or renal toxicity. In subsequent phase I clinical evaluations in healthy volunteers, donepezil demonstrated favorable pharmacokinetic, pharmacodynamic and safety profiles. Its long terminal disposition half-life supported once-daily administration, with no requirement for dose modification in the elderly or in patients with renal or hepatic impairment. A 14-week, phase II dose-finding study in patients with mild to moderate AD (Clinical Dementia Rating [CDR], 1-2; Mini-Mental State Examination [MMSE], 10-26) showed that donepezil at a dose of 5 mg/day produced highly significant improvements in cognition (as measured by the Alzheimer's Disease Assessment Scale, cognitive subscale [ADAS-cog]). Subsequently, two pivotal parallel-group, placebo-controlled phase III trials (of 15 and 30 weeks' duration) showed highly statistically significant improvements in ADAS-cog, MMSE, Clinician's Interview-Based Impression of Change with caregiver input (CIBIC plus) and CDR-SB (Sum of the Boxes) scores, compared with placebo, in mild to moderate AD patients treated with either 5 or 10 mg/day donepezil. Adverse events in the phase II and III trials were mild and transient and resolved with continued donepezil administration. The donepezil clinical trials program has shown that this drug is a clinically effective and well-tolerated once-daily treatment for the symptoms of mild to moderate AD.
 ...
PMID:Perspectives in the management of Alzheimer's disease: clinical profile of donepezil. 985

Alzheimer's disease (AD) is associated with a deficiency of acetylcholine (ACh) in the forebrain that correlates with brain pathology and cognitive dysfunction. The most promising approach to enhancing central ACh neurotransmission has been the utilization of agents that inhibit cholinesterases which block its catabolism. Initially, the success of this strategy was limited by subtherapeutic levels of acetylcholinesterase (AChE) inhibition, tolerability problems and toxicity of the first agents. Donepezil HCI represents a new chemical class of AChE inhibitors, the piperidines. In clinical trials, donepezil has been shown to improve significantly cognition and global function in patients with mild to moderately severe AD, and has demonstrated an excellent tolerability and safety profile. These benefits, as well as a simple, once-daily dosing regimen, make donepezil a viable therapeutic option for AD patients.
 ...
PMID:Clinical benefits of a new piperidine-class AChE inhibitor. 1033 37

The dissociation of hexafluorosilicate has been reinvestigated due to recent suggestions that fluorosilicate intermediates may be present in appreciable concentrations in drinking water. 19F NMR spectroscopy has been used to search for intermediates in the hydrolysis of hexafluorosilicate. No intermediates were observable at 10(-5) M concentrations under excess fluoride forcing conditions over the pH range of 3.5-5. A single intermediate species, assigned as SiF5(-) or its hydrate, was detected below pH 3.5. At moderate pH values of 4 and 5 silica oligomerization in the solutions studied made it difficult to directly determine the hexafluorosilicate equilibrium constant. Under more acidic conditions the average pKd, or negative log of the dissociation constant Kd, determined by 19F NMR measurements, was 30.6. We also investigated the behavior of hexafluorosilicate in common biological buffer reagents including phosphate/citrate, veronal/HCI buffers, and Ringer's solution. The buffer capacity of all of these systems was found to be insufficient to prevent acidic shifts in pH when hexafluorosilicate was added. The pH change is sufficient explanation for the observed inhibition of acetylcholinesterase that was previously attributed to hexafluorosilicate hydrolysis intermediates.
 ...
PMID:Reexamination of hexafluorosilicate hydrolysis by 19F NMR and pH measurement. 1668 94