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)

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of donepezil are reviewed. Donepezil is a synthetic noncovalent reversible inhibitor of acetylcholinesterase (AChE) for the treatment of mild to moderate dementia associated with Alzheimer's disease. In contrast to tacrine hydrochloride, the only comparable agent currently approved by FDA, donepezil exhibits a relatively high degree of selectivity for neuronal AChE as opposed to butyrylcholinesterase. It has a half-life of 60 hours in young adults and 104 hours in elderly patients. In clinical trials, donepezil has been associated with significant improvements in Alzheimer's Disease Assessment Scale-cognitive subscale and Clinical Interview-Based Impression of Change scores. The most common adverse effects associated with donepezil are nausea, diarrhea, anorexia, and vomiting, which are most likely to occur during dose initiation or adjustment. Hepatotoxicity, a dose-limiting adverse effect that sometimes requires discontinuation of tacrine, has not been reported with donepezil. Donepezil does not appear to interact with theophylline, cimetidine, warfarin, or digoxin. Ketoconazole and quinidine inhibit the metabolism of donepezil in vitro, but there is a lack of clinical data showing that these drugs decrease the clearance of donepezil. The initial recommended dosage is 5 mg daily before bedtime, with a dosage increase to 10 mg after four to six weeks according to the patient's response and tolerance. Donepezil appears to be preferable to tacrine as the initial agent for patients with mild to moderate dementia associated with Alzheimer's disease.
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PMID:Donepezil: an anticholinesterase inhibitor for Alzheimer's disease. 942 50

Memory dysfunction is a recognized and difficult to treat complication of traumatic brain injury (TBI). Since medial-temporal lobe injury is a frequent contributor to memory dysfunction in TBI, it is likely that an acetylcholine deficit contributes to memory dysfunction in this population. Recently, Donepezil, an acetylcholine-esterase inhibitor which has demonstrated a high selectivity for neural Ach-esterase (with minimal side effects), was approved for use in dementia in Alzheimer's patients. Due to its promising results in Alzheimer's patients, and reports in the literature describing the use of physostigmine (an anti-cholinesterase with significant cardiovascular and autonomic side effects) to treat memory deficits in closed head injury, we decided to begin a trial of Donepezil in two patients with TBI who were experiencing long term static memory dysfunction refractory to conventional treatment. Both patients were admitted to our facility for physical and cognitive rehabilitation, and were started on a trial of Donepezil. Modified memory tests and subjective observations by both family and staff pointed to an improvement in memory within three weeks of starting Donepezil. Should these initial results be supported in larger trials, Donepezil may prove to be a valuable tool for the treatment of memory dysfunction in TBI.
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PMID:Donepezil medicated memory improvement in traumatic brain injury during post acute rehabilitation. 948 40

Samples of cerebrospinal fluid (CSF) were examined, looking mainly at total cholinesterase (ChE) and acetyl-cholinesterase (AChE) levels from 139 living subjects. At the completion of the study, 35 of the 139 patients had died and pathological confirmation of the presence of dementia had been obtained. These results, together with results from other laboratories, provide evidence that a low CSF ChE level presenting in demented patients may indicate a depletion of the brain AChE system, and this may confirm a clinical diagnosis of AD as well as other types of dementia which are associated with an alteration of the brain AChE system. The overlap in the levels of CSF biochemical markers between demented and non-demented subjects which has led to many conflicting reports has always disappointed investigators. It is suggested that some 'control' subjects with CSF ChE activity indistinguishable from that in AD patients may have an abnormal ageing process in their brains (brain at risk), although the symptoms of dementia have not yet been detected. Recognition of a pre-clinical or incubation period is very beneficial for explaining discrepancies in biochemistry and pathology in the literature, and must be considered for both the treatment and the prevention of dementia. The long used treatment, which was designed to inhibit AChE, should no longer be used: treatment must be designed to enhance the activity of the neuronal AChE system, or slow its degeneration.
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PMID:CSF cholinesterase activity in demented and non-demented subjects. 951 94

As the population of the United States continues to age, age-related diseases such as Alzheimer's, the most common form of dementia, pose an increasing clinical challenge. The diagnosis of Alzheimer's disease hinges on the evaluation of cognitive function. Management options are expanding and include new cholinesterase inhibitors, cholinergic agonists, antioxidants, monoamine oxidase inhibitors, and estrogen.
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PMID:Progress in the management of Alzheimer's disease. 952 40

The primary pathology in Alzheimer's disease (DAT) occurs in the basal forebrain cholinergic system (BFCS), which provides the major cholinergic innervation to the neocortex, hippocampus and amygdala. Consistent with the 'cholinergic hypothesis' of dementia in DAT, the most effective treatments so far developed for DAT are drugs which act to boost the functions of the BFCS. These include the centrally acting cholinesterase inhibitor tacrine, and the cholinergic agonist nicotine, acute administration of which leads to an improvement in attentional functions, in line with recent animal studies of the role of the BFCS in cognition. We conclude that future research should include the development of more potent, longer-lasting, less toxic cholinergic agents, which appear to be the best candidates for alleviating the cognitive symptomatology of DAT. Such drugs may also be useful in the treatment of a number of other cognitive disorders, including Lewy body dementia, attention deficit/hyperactivity disorder, and schizophrenia.
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PMID:The cognitive psychopharmacology of Alzheimer's disease: focus on cholinergic systems. 956 19

Alzheimer's disease (AD) is characterized by a gradual decline in 3 domains: cognition, behavior, and function. Ideally, an effective treatment would target all 3 types of impairment. However, available treatments for AD diminish only certain symptoms and cannot halt the dementing process. Most pharmacologic agents currently available or in development target a specific symptom cluster (e.g., cognitive loss), and are based on the known neurobiology of the disease (e.g., neurotransmitter deficit) or hypothesized antidementia approaches (e.g., anti-inflammation, antioxidation). Two currently available cholinesterase inhibitors improve memory and other aspects of cognition during short-term treatment. Additional cholinergic agents will soon become available. Other promising agents under study for cognitive enhancement or protection include vitamin E, selegiline, estrogen, and nonsteroidal anti-inflammatory drugs. As scientists uncover the basic pathogenetic mechanisms of AD, additional treatments will likely emerge. Therapies for behaviors associated with dementia (e.g., depression, agitation, anxiety) are sometimes effective. Choices of specific medications, including antidepressants, antipsychotics, and anxiolytics, depend on specific side-effect profiles. Psychotherapies aimed at enhancing cognition are ineffective for dementia but nonpharmacologic interventions may minimize depression and agitation and may improve quality of life.
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PMID:Treatment of Alzheimer's disease: current approaches and promising developments. 961 51

1. Object working memory, a function which declines in aging and dementia, was tested in young and aged pretrained monkeys using a delayed match-to-sample task. 2. During drug treatment, monkeys were given the m 1 muscarinic agonist AF102B (0.1-2.1 mg/kg i.m.), the cholinesterase inhibitor tacrine (0.5-2.0 mg/kg p.o.), or vehicle controls in a repeated measures design to assess putative cognitive enhancement. 3. Both agents improved task performance in both young and aged monkeys, AF102B yielding equivalent or greater, and less variable, improvement than tacrine. 4. AF102B may represent a low-toxicity alternative to tacrine for the treatment of age-related memory disorders.
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PMID:Effects of AF102B and tacrine on delayed match-to-sample in monkeys. 968 79

Current treatment approaches in Alzheimer's disease are primarily symptomatic, with the major therapeutic strategy based on acetylcholinesterase inhibition. Alzheimer's disease research should advance over ensuing decade(s) to yield better symptomatic therapies, drugs designed to slow the rate of progression, and disease preventing agents. The next generation of cholinergic agents will include long acting cholinesterase inhibitors with a good safety profile and brain specific muscarinic agonists. The most critical advances in Alzheimer's disease treatment, however, will target slowing of disease progression and prevention of dementia. Therapeutic agents are being developed that interfere with the synthesis, deposition and aggregation of beta-amyloid protein. Clinical trials are presently being conducted with small molecules having nerve growth factor like activity (e.g. AIT-082, cerebrolysin). In addition, estrogen, anti-inflammatory agents (e.g. cyclooxygenase inhibitors) and antioxidant approaches (e.g. vitamin E) are currently being proposed or utilized in disease prevention trials.
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PMID:Perspectives in clinical Alzheimer's disease research and the development of antidementia drugs. 970 Jun 63

Therapeutic approaches to the cognitive impairment of dementia are making their way into clinical practice. Clinical pharmacologic approaches toward improvement of cognitive symptoms are discussed, with an emphasis on cholinergic approaches, since they currently appear most promising and since several cholinesterase inhibitors may soon be available for prescribing. As more knowledge is gained about dosing, side effects, and mechanisms of action, these drugs can be prescribed more efficiently. Current research approaches to slowing the rate of cognitive decline are discussed, including the use of antioxidants, monoamine oxidase-B inhibitors, and cholinesterase inhibitors. Drugs that improve cognition may also have effects on behavioral symptoms, severe dementia, and non-Alzheimer's dementia. Evidence suggests that some dementia patients may be particularly responsive to intervention and that other medications may enhance response. Psychosocial interventions may also contribute to prolonging the time to institutionalization.
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PMID:New therapeutic approaches to cognitive impairment. 973 44

The effect of long-term treatment with tacrine (tetrahydroaminoacridine) was studied in three Alzheimer patients (aged 57, 64, and 68 years) with mild dementia. All three patients had a Mini-Mental State Examination score of 24/30 and carried at least one apolipoprotein E (ApoE) epsilon4 allele. Tacrine was given in doses between 80 and to 160 mg daily for 13-31 months. A lower tacrine concentration was observed generally in cerebrospinal fluid (CSF) compared with plasma. The acetylcholinesterase activity in CSF tended to be increased following longer periods of tacrine treatment, whereas the butyrylcholinesterase activity was decreased. The three patients repeatedly underwent positron emission tomography investigation of cerebral blood flow, nicotinic receptors, cerebral glucose metabolism, and electroencephalogram (EEG) and cognitive tests. Positive influences on these parameters were observed following both short-term and long-term treatment with tacrine. Improvement of nicotinic receptors (measured as 11C-nicotine binding), cerebral blood flow, EEG, and some cognitive tests (trail making test, block design test) occurred earlier after initiation of tacrine treatment compared with the glucose metabolism, which was increased after several months of tacrine treatment. An improvement in attention (trail making test) was observed following tacrine as sign for frontal lobe activation (EEG). The functional effects of tacrine in Alzheimer patients appeared to be related to both dose and length of cholinesterase inhibitor treatment.
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PMID:Long-term tacrine treatment in three mild Alzheimer patients: effects on nicotinic receptors, cerebral blood flow, glucose metabolism, EEG, and cognitive abilities. 977 28


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