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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Management of the most common type of dementia--Alzheimer's disease--is becoming increasingly sophisticated. Differentiation of Alzheimer's disease from vascular dementia has become therapeutically important, since the choice of treatments depends on the diagnosis. Two cholinesterase inhibitors, donepezil and tacrine, are labeled for use in patients with Alzheimer's disease. Other therapies, such as estrogen, nonsteroidal anti-inflammatory drugs and vitamin E, are sometimes used and show promise in delaying the progression of this dementia. Behavior problems, which often accompany the disease, can be managed using environmental modification, alterations in caregiving and medication. In the terminal phase of the illness, quality care involves implementing advance directives, communicating with the family, individualizing care and attending to patient comfort.
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PMID:Advances in the treatment of Alzheimer's disease. 982 56

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.
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PMID:Perspectives in the management of Alzheimer's disease: clinical profile of donepezil. 985

Several cholinesterase inhibitors have recently become available for Alzheimer's disease. To reach consensus about their relevance and use in daily practice, a meeting with clinical experts was organised by the section of Geriatric Psychiatry of the Dutch Society for Psychiatry. So far, available drugs have only very modest effects on cognitive functioning and clinical impression, compared with placebo. The question whether these effects are clinically relevant cannot be answered yet. Awaiting the results of further studies, it was decided not to use cholinesterase inhibitors on a routine basis but to limit prescription of these drugs to research setting or under well-controlled conditions with regard to diagnosis and evaluation. Furthermore, prescription must be limited to mild or moderately severe dementia caused by 'probable Alzheimer's disease'. Proper evaluation in the individual patient is still an unresolved problem. Therefore, n = I protocols are to be designed. These should include the use of appropriate and standardised instruments measuring cognitive functions, behavioural functions and activities of daily life. The skills and experience required will be available in specialised and multidisciplinary units for dementia. Pharmaceutical treatment for Alzheimer's disease must be integrated with all other available forms of patient care.
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PMID:[Cholinesterase inhibitors for Alzheimer disease: preliminary recommendations for treatment. Dutch Society for Psychiatry, Section of Geriatric Psychiatry]. 1002 68

Neuropsychiatric abnormalities, as well as the commonly associated neuropsychological symptoms, are clinical characteristics of Alzheimer's disease (AD), the most common form of dementia. Thus, in addition to a general cognitive and functional decline, neuropsychiatric manifestations, such as agitation, apathy, anxiety, psychoses and disinhibition, are frequently evident in AD patients. Such neuropsychiatric symptoms of AD are the source of considerable patient and caregiver distress, resulting in the prescription of neuroleptics, benzodiazepines or other psychotropic agents, and are a major factor in the decision to transfer the care of patients into nursing homes. Recent evidence suggests that some neuropsychiatric changes associated with AD are related to the cholinergic deficits in the brains of AD patients and that such abnormalities may be responsive to cholinergic therapy. Cholinergic drug therapies indicated for the symptomatic treatment of AD, for example tacrine and the newer cholinesterase (ChE) inhibitors such as donepezil, have been demonstrated to improve memory, language and praxis. Furthermore, although less is known about the effect of ChE inhibitors on the neuropsychiatric symptoms of AD, preliminary evidence suggests that they reduce apathy, anxiety, hallucinations, disinhibition and aberrant motor behaviour. Thus, the newer-generation ChE inhibitors that are well tolerated, easy to administer and show promise in reducing the cognitive, as well as neuropsychiatric disturbances of AD, may emerge as important treatments for some neuropsychiatric symptoms in patients with central cholinergic deficits, including AD.
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PMID:Neuropsychiatric symptoms and cholinergic therapy for Alzheimer's disease. 987 14

Delirium is a common complication of dementia and may produce considerable morbidity. In addition to psychotic symptoms such as hallucinations and delusions, delirium may produce considerable agitation, which may be refractory to conventional medications such as antipsychotics and benzodiazepines. The main approach to delirium is to treat any underlying medical problem that could cause the delirium. However, delirium is not always reversible, and there is no specific treatment for persistent delirium. The authors present a case of delirium complicating a preexisting dementia that resolved rapidly following initiation of the cholinesterase inhibitor donepezil, suggesting that cholinergic dysfunction may have played a role in the etiology of this patient's delirium. Future research needs to be directed at the issue of cholinergic activity in delirium through monitoring of serum anticholinergic activity and its response to procholinergic therapy.
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PMID:Donepezil improves symptoms of delirium in dementia: implications for future research. 989 35

Alzheimer's disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer's disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer's disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no "cure" for Alzheimer's disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer's disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.
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PMID:The cholinergic hypothesis of Alzheimer's disease: a review of progress. 1061 Mar 96

We investigated the effects of a single administration of a cholinesterase inhibitor, tetrahydroaminoacridine (THA, 25 and 50 mg, orally), and an alpha 2-agonist, clonidine (0.5 and 2 micrograms/kg, orally), on neuropsychologic performance in two groups of patients with Alzheimer's disease (AD). Clonidine enhanced a spatial working memory and verbal fluency, but had no effect on spatial span or word priming. THA enhanced word priming, but had no effect on other performance measures. Our data suggests that degeneration of the LC noradrenergic system and the cholinergic cells of the basal forebrain have different functional consequences during the progression of AD. Finally, a combined treatment with noradrenergic and cholinergic drugs might produce a qualitatively broader effect on cognitive functions than either of the treatments alone, and more effectively attenuate clinical dementia.
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PMID:THA improves word priming and clonidine enhances fluency and working memory in Alzheimer's disease. 1008 36

We have established a chronic cerebral hypoperfusion model that is produced by permanent occlusion of bilateral common carotid arteries (2VO) in rats. 2VO rats exhibited rarefaction in the white matter, shrinkage of neurons in the cerebral cortex and hippocampus 1-3 days after 2VO and infarctions in the striatum 7 days after 2VO. These histological changes in the cortex and hippocampus were accompanied by a decrease in immunoreactivity for microtubule-associated protein 2 (MAP2). Immunoreactivity for glial fibrillary acid protein (GFAP) was observed at 3-7 days after 2VO. Marked increase in GFAP staining in astrocytes in the cerebral cortex and hippocampus was found 30 days after ligation. In the 8-arm radial maze performance, the 2VO rats showed a higher rate of errors than the sham-operated control during repeated training periods. THA (9-amino-1,2,3,4-tetrahydroacridine), a cholinesterase inhibitor and GTS-21 (3-(2,4-dimethoxybenzylidene)-anabaseine dihydrochloride), a central nicotinic acetylcholine-receptor agonist improved the learning impairment in the radical maze task of 2VO rats. GTS-21 administration exerted a protective effect against the neuropathological changes that followed 2VO. Taken together, the 2VO rat appears to be a useful model for investigating the pathophysiology of human dementia and to elucidate the therapeutic potential of drugs for this disease.
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PMID:[Availability of 2VO rats as a model for chronic cerebrovascular disease]. 1020 83

The effects of cholinergic drugs proposed for treatment of cognitive impairment in normal aging and dementia on divided attention have been little studied in non-human primates. We tested the hypothesis that cholinergic drugs improve spatial divided attention in primates via a computer task requiring simultaneous tracking of two visual targets in three young and two aged healthy bonnet macaques. Task accuracy (number of correct responses) and reaction time (RT) were measured 2 h after administration of either the m1 agonist +/- -cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine (AF102B; 0.1-2.1 mg/kg IM) or the cholinesterase inhibitor 9-amino-1,2,3,4-tetrahydroamino-acridine (THA; 0.5-2.0 mg/kg orally). Accuracy increased for four of five monkeys at appropriate doses of one or both cholinomimetics, accompanied in two monkeys by a drop in RT. Responses were less uniform to THA than to AF102B. For the five-monkey group at Best dose, accuracy increased 34% (THA) or 43% (AF102B) above baseline (P<0.05 for both drugs), respectively, with no significant change in RT and with minimal untoward effects. Cholinotherapy may improve divided attention in young and aged healthy primates.
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PMID:Divided attention-enhancing effects of AF102B and THA in aging monkeys. 1032 74

Alzheimer's disease accounts for 50-60% of dementia cases in older people. Dementia with Lewy bodies is now recognized as the second most common type of dementia. It is different from Alzheimer's disease and has important pharmacotherapeutic implications. Key features include early-onset, persistent, well-formed, visual hallucinations and motor features of parkinsonism. Pharmacologic management of neurobehavioral symptoms is complicated by an exaggerated response to neuroleptics, which causes excessive morbidity and mortality. Patients with dementia with Lewy bodies may be particularly responsive to cholinesterase inhibitors. When neurobehavioral symptoms are severe enough to require pharmacologic intervention, it is recommended that agents such as trazodone or cholinesterase inhibitors be considered first-line therapy. If these fail, neuroleptics may be prescribed with caution.
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PMID:Dementia with Lewy bodies: review and pharmacotherapeutic implications. 1041 27


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