Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatments for the symptomatic relief of Alzheimer's disease are available but despite advances in our ability to treat persons with various forms of dementia, more effective treatments are needed. The cholinesterase inhibitors donepezil, rivastigmine, and galantamine have demonstrated efficacy in improving cognition and global status and to a lesser extent, behavioral abnormalities relative to placebo in patients with mild-to-moderate Alzheimer's disease. Rivastigmine has been shown to benefit patients with dementia with Lewy Bodies and with dementia associated with Parkinson's disease. Donepezil and galantamine have also been shown to be mildly effective in dementia due to cerebral ischemia. Memantine has a distinct mechanism of action and is effective in moderate-to-severe AD. The benefits from these drugs, however, are limited and their long-term effectiveness has not been well-demonstrated. Their clinical utility is controversial. Many novel approaches that promise to provide more effective treatments are currently being pursued.
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PMID:Current and emerging pharmacological treatment options for dementia. 1672 Sep 56

(1) Cholinesterase inhibitors such as donepezil, galantamine and rivastigmine, are not very effective in slowing the cognitive decline associated with Alzheimer's disease. Memantine, which is no more effective, has dopaminergic and atropinic effects but is not a cholinesterase inhibitor. (2) Cholinesterase inhibitors have mainly cholinergic adverse effects, causing gastrointestinal, neurological, cardiovascular and urinary disorders (incontinence). (3) Increased mortality, mainly due to cardiovascular events, was observed in placebo-controlled trials of galantamine. In one trial there were more deaths in patients on donepezil than on placebo. (4) Atropinic drugs tend to aggravate cognitive disorders that are treated with cholinesterase inhibitors. (5) Cholinesterase inhibitor + neuroleptic combinations are associated with an increased risk of extrapyramidal adverse effects. An increase in mortality was reported during trials of neuroleptics involving patients with dementia, and also during trials of cholinesterase inhibitors. (6) Combining cholinesterase inhibitors with drugs that reduce the heart rate, depress cardiac conduction, or induce torsades de pointes increases the risk of arrhythmias and cardiac conduction disorders. (7) Donepezil and galantamine are metabolised by cytochrome P450 isoenzymes 3A4 and 2D6, creating a strong potential for pharmacokinetic interactions with inhibitors and inducers of these isoenzymes. Rivastigmine is mainly metabolised by cholinesterases, and binds poorly to cytochrome P450 isoenzymes. (8) Cholinesterase inhibitors inhibit the metabolism of suxamethonium and thereby augment and prolong the neuromuscular blockade induced by this curare. (9) In practice, caregivers should be aware of the potential adverse effects of cholinesterase inhibitors, which often resemble symptoms of Alzheimer's disease and may be due to drug-drug interactions or to antagonist effects with other drugs, such as those with atropinic effects. Additionally, the many adverse effects associated with the use of cholinesterase inhibitors highlights the need for regular re-evaluation of the use of these medicines and of the balance of benefit versus risk in individual patients.
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PMID:Alzheimer's disease: beware of interactions with cholinesterase inhibitors. 1676 99

We aimed to determine prospectively whether rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, provided benefits in patients with and without visual hallucinations in a population with dementia associated with Parkinson's disease (PDD). This was a 24-week double-blind placebo-controlled study. Primary efficacy measures were the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary efficacy measures included activities of daily living, behavioral symptoms, and executive and attentional functions. Patients were stratified according to the presence of visual hallucinations at baseline. The study included 188 visual hallucinators (118 on rivastigmine, 70 on placebo) and 348 nonvisual hallucinators (239 on rivastigmine, 109 on placebo). Rivastigmine provided benefits in both visual hallucinators and nonvisual hallucinators. Absolute responses to rivastigmine on the ADAS-cog were comparable over 6 months, although rivastigmine-placebo differences tended to be larger in visual hallucinators (4.27; P = 0.002) than in nonhallucinators (2.09; P = 0.015). On the ADCS-CGIC, differences between rivastigmine and placebo were 0.5 in visual hallucinators (P = 0.030) and 0.3 in nonhallucinators (P = 0.111). Rivastigmine provided benefits on all secondary efficacy measures, and placebo declines and treatment differences were more marked in visual hallucinators. Adverse events were reported more frequently by rivastigmine-treated patients, although this difference was less marked in visual hallucinators. Visual hallucinations appear to predict more rapid decline and possibly greater therapeutic benefit from rivastigmine treatment in PDD.
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PMID:Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson's disease. 1737 57

Transdermal patches are used for the treatment of various diseases including neurologic and psychiatric disorders such as Parkinson disease (PD), major depression, and attention deficit hyperactivity disorder. They are believed to offer many advantages over conventional oral therapies. By providing smoother, continuous drug delivery and steadier plasma levels, patches may reduce the incidence of side effects, thus making optimal therapeutic doses easier to attain and potentially improving treatment efficacy and compliance. Drug delivery systems such as patches that are more patient- and caregiver-friendly may enable patients to continue treatment for longer periods and to attain greater, more sustained treatment benefits. To date, approved therapies for Alzheimer disease (AD), including cholinesterase inhibitors and memantine, are orally administered. Potential advantages associated with patches provide a therapeutic rationale to offer additional benefits in AD patients. Rivastigmine is well suited to patch administration because it is a small, potent molecule that is both lipophilic and hydrophilic. A rivastigmine patch has been developed and may provide a promising new approach to dementia therapy.
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PMID:Rationale for transdermal drug administration in Alzheimer disease. 1764 21

Cholinesterase inhibitors improve or stabilize cognitive impairment in patients with Alzheimer's disease (AD). The purpose of this study was to detect brain perfusion changes and the effects of rivastigmine, an acetylcholinesterase inhibitor on single photon emission computed tomography (SPECT) before and after treatment. Fifteen patients who fulfilled the clinical criteria for probable AD of mild to moderate severity, as put forth by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association, and as specified by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were included in the study. A control group of 15 healthy individuals from the same age and education range was included in the study. Before treatment was begun, Mini Mental State Examination (MMSE) tests were performed on all patients to evaluate cognitive function. All patients underwent baseline SPECT for evaluation of 25 different brain regions. Rivastigmine 3 mg/d was given for the first 4 wk of treatment; the dosage was then increased to 6 mg/d. The MMSE and SPECT were repeated 6 mo after the start of treatment. SPECT findings revealed that rivastigmine did not significantly affect brain perfusion in AD cases except in the inferior frontal lobe, despite stabilization and improvement noted in MMSE scores during treatment. Rivastigmine treatment of patients with AD did not significantly change brain perfusion as seen on SPECT, except in the inferior frontal lobe, but cognitive performance was stabilized or improved during the treatment course. These findings suggest the need for additional, larger studies to investigate the effects of acetylcholinesterase inhibitors on regional cerebral blood flow.
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PMID:Effect of rivastigmine on regional cerebral blood flow in Alzheimer's disease. 1766 Jan 72

The efficacy of acetylcholinesterase (AChE) inhibitors for the treatment of dementia diseases has been established for both key cognitive symptoms and dementia-associated symptoms such as aggressiveness and the ability to perform activities of daily life. Presently three AChE inhibitors are approved for the treatment of mild to moderately severe Alzheimer dementia: donepezil, rivastigmine and galantamine. Rivastigmine is also approved for the treatment of Parkinson's dementia. The three substances differ in their efficacy and their pharmacological properties. AChE inhibitors should be used for long-term treatment. The clinical course should be monitored every six months.
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PMID:[Acetylcholinesterase inhibitors for dementia--an update]. 1772 73

Our goal was to design, synthesize, and evaluate new cholinesterase inhibitors. Fourteen dehydroamino acids esterified to choline and to its ternary analog were synthesized by a new method that gave a yield of 84-93%. The potency of the amino acid ester derivatives was tested by measuring K(i) values for inhibition of human red cell acetylcholinesterase and human plasma butyrylcholinesterase. The most potent compound was a choline ester of dehydrophenylalanine where the amine group of the amino acid was derivatized with a benzoyl group containing a methoxy in the 2-position, CH(3)O(C(6)H(4))CONHC(CHC(6)H(5))COOCH(2)CH(2)N(+)(CH(3))(3). This compound was a strong inhibitor of both human acetylcholinesterase and human butyrylcholinesterase, with K(i) values of 10 microM and 0.08 microM, respectively. These K(i) values are comparable to that of Rivastigmine. Docking of the most potent compound into the active site of human butyrylcholinesterase showed that the lowest energy model had two benzene rings oriented towards Trp 82 and Tyr 332 whereas the positively charged nitrogen group was stabilized by Trp 231. This orientation placed the ester group 3.89 A from the active site Ser 198, a distance too far for covalent bonding, explaining why the esters are inhibitors rather than substrates. This class of anticholinesterase agents has the potential for therapeutic utility in the treatment of disorders of the cholinergic system.
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PMID:alpha,beta-Dehydrophenylalanine choline esters, a new class of reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase. 1798 Mar 56

Alzheimer's disease is the most common form of dementia in industrialized countries. In the European Union, about 54% of dementia cases are believed to be due to Alzheimer's disease. The condition is an age-related neurodegenerative disorder characterized by multiple cognitive deficiencies, including loss of memory, judgment, and comprehension. These manifestations are accompanied by behavioral and mood disturbances. Although no cure has yet been discovered for Alzheimer's disease, symptomatic therapies are now widely available and offer significant relief to patients and benefits to caregivers in terms of reduced care burden. At the start of the 21st century, health technology assessments recommended three agents for the symptomatic treatment of mild to moderate Alzheimer disease: rivastigmine, donepezil, and galantamine. Rivastigmine (Exelon, Novartis Basel-Switzerland) is a slowly reversible inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), while donepezil (Aricept, Pfizer, New York, USA) and galantamine (Reminyl, Janssen, New Jersey, USA) show no functional inhibition of BuChE, and are considered AChE-selective, rapidly-reversible inhibitors. The efficacy of all three agents has been evaluated in large, double-blind, placebo-controlled clinical trials of up to 6 months' duration. Rivastigmine treatment in mild to moderate Alzheimer's disease improves cognition, activities of daily living, and global function.
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PMID:Rivastigmine in the treatment of Alzheimer's disease: an update. 1804 73

Rivastigmine is a newer-generation inhibitor with a dual inhibitory action on both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes, and is used for the treatment of AChE- and BChE-related diseases such as brain Alzheimer's disease and cardiovascular disease. New carbon-11 labeled conformationally restricted rivastigmine analogues radiolabeled quaternary ammonium triflate salts, (3aR,9bS)-1-[(11)C]methyl-1-methyl-6-(methylcarbamoyloxy)-2,3,3a,4,5,9b-hexahydro-1H-benzo[g]indolium triflate ([(11)C]8) and (3aR,9bS)-1-[(11)C]methyl-1-methyl-6-(heptylcarbamoyloxy)-2,3,3a,4,5,9b-hexahydro-1H-benzo[g]indolium triflate ([(11)C]9), were designed and synthesized as potential positron emission tomography (PET) agents for imaging AChE and BChE enzymes. The appropriate precursors were labeled with [(11)C]CH(3)OTf through N-[(11)C]methylation, and the target tracers were isolated by solid-phase extraction (SPE) using a cation-exchange CM Sep-Pak cartridge in 40-50% radiochemical yields decay corrected to end of bombardment (EOB), 15-20 min overall synthesis time, and 148-222 GBq/micromol specific activity at EOB.
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PMID:Facile synthesis of new carbon-11 labeled conformationally restricted rivastigmine analogues as potential PET agents for imaging AChE and BChE enzymes. 1815 15

Cholinergic neuromodulation is pivotal for arousal, attention, and cognitive processes. Loss or dysregulation of cholinergic inputs leads to cognitive impairments like those manifested in Alzheimer's disease. Such dysfunction can be at least partially restored by an increase of acetylcholine (ACh). In animal studies, ACh selectively facilitates long-term excitability changes induced by feed-forward afferent input. Consequently, it has been hypothesized that ACh enhances the signal-to-noise ratio of input processing. However, the neurophysiological foundation for its ability to enhance cognition in humans is not well documented. In this study we explore the effects of rivastigmine, a cholinesterase inhibitor, on global and synapse-specific forms of cortical plasticity induced by transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS) on 10-12 healthy subjects, respectively. Rivastigmine essentially blocked the induction of the global excitability enhancement elicited by anodal tDCS and revealed a tendency to first reduce and then stabilize cathodal tDCS-induced inhibitory aftereffects. However, ACh enhanced the synapse-specific excitability enhancement produced by facilitatory PAS and consolidated the inhibitory PAS-induced excitability diminution. These findings are in line with a cholinergic focusing effect that optimizes the detection of relevant signals during information processing in humans.
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PMID:Focusing effect of acetylcholine on neuroplasticity in the human motor cortex. 1816 Jun 52


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