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)

The purpose of our studies was to determine the effects of muscarinic receptor agonists on conditioned avoidance responding in the rat. Rats were trained to avoid or escape an electric shock delivered to the feet in a discrete trial procedure. The muscarinic receptor agonists pilocarpine and [2-ethyl-8-methyl-2,8-diazaspiro(4. 5)decane-1,3-dione] hydrochloride (RS86) and the cholinesterase inhibitor physostigmine all decreased the percentage of avoidance responses at doses that produced less than approximately 30% response failures. Similar results were obtained with the antipsychotic drugs haloperidol, trifluoperazine, chlorpromazine, and clozapine. However, the benzodiazepine anxiolytic diazepam did not decrease avoidance responding up to doses that produced ataxia. On the other hand, oxotremorine and arecoline decreased avoidance responding only by producing response failures, whereas aceclidine produced intermediate changes. The muscarinic receptor antagonists scopolamine, trihexyphenidyl, and benztropine were without effect when administered alone but antagonized the decreases in avoidance responding produced by pilocarpine and RS86. Scopolamine had little effect on the decreases in avoidance responding produced by haloperidol. The newer muscarinic receptor partial agonists or agonist/antagonists [R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2. 2]octane-3-acetonitrile] hydrochloride, talsaclidine, milameline, and xanomeline also produced dose-related decreases in avoidance responding. Our results demonstrate that muscarinic receptor agonists can decrease avoidance responding in a manner similar to dopamine-receptor antipsychotic drugs, suggesting that muscarinic receptor agonists may provide an alternative approach to the treatment of psychosis.
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PMID:Muscarinic receptor agonists, like dopamine receptor antagonist antipsychotics, inhibit conditioned avoidance response in rats. 1041 7

Dementia with Lewy bodies (DLB) has been associated with important behavioural disturbances, such as psychotic symptoms. Unfortunately, neuroleptic sensitivity in these patients limits effective pharmacological management of these symptoms. Seven patients, five male and two female (mean age 75.3+/-4.7 years, range 68-81), diagnosed with DLB were treated with the acetylcholinesterase inhibitor donepezil (5-10 mg once daily) to determine its effect on treating behavioural disorders. Although the intended length of treatment was a minimum of 8 weeks, only three patients completed 8 weeks of therapy, one patient completed 6 weeks, two patients completed 4 weeks and one patient was discontinued after 5 days. The primary outcome (behavioural disturbances) was measured prospectively by the Neuropsychiatric Inventory (NPI), while other outcomes included cognition (Mini-Mental State Examination (MMSE)) and Clinical Global Impression. Three of the seven subjects showed marked improvement in behaviour, with NPI scores dropping significantly over time. Donepezil therapy was discontinued prematurely in three of the cases due to insufficient response and/or adverse events. Overall, five of the seven patients were rated at least minimally improved in behavioural symptoms. Our experience with donepezil in this group of patients shows promise. Given the limited experience with this agent in treating behavioural disorders associated with DLB, further studies are warranted.
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PMID:Donepezil for behavioural disorders associated with Lewy bodies: a case series. 1076 34

In addition to cognitive deficits, dementia is characterized by noncognitive behavioral disorders that are highly prevalent as the disease progresses into its later stages. These "behavioral and psychological signs and symptoms of dementia" are probably more important on a day to day basis than the cognitive deficits: in some patients, they are not a source of major disability but rather just a nuisance and may not require active pharmacological treatment; in others, they can be source of substantial anxiety and distress. Among the many behavioral symptoms of dementia, the group of behaviors included under the label of depression, anxiety, agitation, aggressiveness or uncooperativeness are the most burdensome and frequently lead to the prescription of an antipsychotic drug. They often precipitate institutional placement. The rationale for the use of psychotropic drugs is partially based upon phenomenological similarities of some behaviors observed in elderly demented patients to signs and symptoms of psychiatric disorders such as depressive illnesses, anxiety or psychotic disorders in non-elderly patients. In fact, the "psychiatric symptoms" in Alzheimer's disease or other dementia are often qualitatively different from those that characterize depressive, anxious or psychotic disorders. Many monoaminergic acquired deficits in dementia may also explain why treatment outcome studies suggest that the psychotropic drugs are less effective in patients with Alzheimer's disease or frontal lobe dementia than in patients with psychiatric disorders. The role of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms in Alzheimer's disease may represent a novel and promising therapeutical approach.
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PMID:[Biological therapies of behavioral and psychological symptoms of dementia: update and prospects]. 1095 9

The relation between disturbances of cholinergic neurotransmission and delusions (DELs) has not been investigated in degenerative dementias such as dementia with Lewy bodies (DLB). A cohort of dementia patients were assessed with standardized clinical evaluations (including the Columbia University Scale for Psychopathology in Alzheimer's Disease), which were repeated annually until death. DLB was confirmed neuropathologically in 21 patients. Neurochemical evaluation included M1 receptor autoradiography (pirenzepine binding), biochemical measurement of choline acetyltransferase (ChAT), and acetylcholinesterase (AChE) histochemistry in brain regions hypothesized to be involved in the genesis of psychosis. Compared with 11 age-matched controls, CHAT and pirenzepine levels were most extensively reduced in the temporal and parietal neocortex of DLB patients. In Brodmann area 36, DELs were significantly associated with elevated pirenzepine binding (131.0 vs 93.5, t = 2.7), whereas visual hallucinations were associated with significant reductions in ChAT (1.7 vs 2.5, t = 2.5). There were no significant associations with other areas or with cholinesterase. Although DELs and visual hallucinations were both linked with disturbances in cholinergic neurotransmission, the nature of the associations was different. Upregulation of the postsynaptic muscarinic receptor may be central in the genesis of DELs, with important treatment implications.
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PMID:Delusions associated with elevated muscarinic binding in dementia with Lewy bodies. 1111 43

Acetylcholine is a modulatory central nervous system (CNS) neurotransmitter involved in diverse brain processes. Historically, drugs that increase CNS cholinergic transmission have been investigated primarily for relieving cognitive symptoms in Alzheimer"s disease (AD). Emerging from these efforts are recent findings that several cholinesterase-inhibitor agents also have a beneficial effect on selected noncognitive symptoms in AD, such as apathy, psychosis, and purposeless motor behaviors. The broad psychotropic effects of cholinergic agents observed in AD and other degenerative conditions highlight potential symptom-based therapeutic indications for these drugs across a variety of neurologic disorders.
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PMID:Cholinergic therapy for neuropsychiatric symptoms in neurologic disorders. 1112 8

The cholinesterase inhibitors provide the first clearly effective treatments for the cognitive deficits of AD and appear to have a beneficial effect on activities of daily living function and noncognitive behavior. There is increasing support for starting donepezil, rivastigmine, or galantamine early in the disease course and maintaining treatment at least during the early and middle stages of AD. Depressive signs and symptoms complicating AD are treated best with SSRIs. Placebo-controlled trials support the use of citalopram and sertraline in AD complicated by depression. The atypical antipsychotics are the first choice for managing psychosis and disruptive agitation in AD and particularly in the Lewy body variant of AD. Studies suggest that low-dose treatment with risperidone, 1 mg/d, or olanzapine, 5 mg/d, offers the optimal ratio of therapeutic to adverse effects.
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PMID:Alzheimer's disease and related disorders. 1134 85

Dementia with Lewy bodies (DLB) accounts for 15 to 20% of late-onset dementias. The overlap of cognitive symptoms, neuropsychiatric features, parkinsonism and severe sensitivity to antipsychotic drugs raise a number of key management issues. The neurochemical profile of DLB provides a good theoretical rationale for the potential value of cholinesterase inhibitor therapy, which is supported by clinical evidence from a number of case series and one placebo-controlled double-blind trial. It appears that cholinesterase inhibitor treatment is well tolerated and improves fluctuating confusion, cognition and psychotic symptoms; however, the evidence can still only be considered preliminary and a further double-blind study is imperative. Given the high prevalence of severe sensitivity to antipsychotic drugs in patients with DLB, their role in the treatment of psychiatric symptoms and behavioural problems is uncertain, although a small case report literature indicates that some patients may benefit. On the current balance of evidence, prescription of antipsychotic agents to patients with DLB is not recommended, although further studies focussing on patients with severe and intractable neuropsychiatric symptoms are required. Provisional case series indicate a high degree of motor response to levodopa therapy, although controlled trials are a priority to carefully evaluate the benefits in the context of possible adverse effects, such as the exacerbation of psychosis.
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PMID:Dementia with Lewy bodies: clinical features and treatment. 1141 14

Alzheimer's disease (AD) patients exhibit a variety of behavioral alterations including agitation, apathy, depression, anxiety, delusions, irritability and disinhibition. Most patients with AD exhibit neuropsychiatric symptoms, and behavioral changes become more frequent with advancing disease severity. The NPI is a valid and reliable means of assessing neuropsychiatric symptoms in patients with dementia. The NPI correlates with increasing disability in activities of daily living and increasing cognitive impairment. Physical illness contributes little to behavioral symptoms measured by the NPI. Reduced frontal lobe metabolism and perfusion have been identified in patients with apathy, agitation, psychosis and depression. Patients with elevated agitation scores on the NPI have a higher burden of frontal lobe neurofibrillary tangles than patients without agitation. The NPI is sensitive to behavioral improvements following treatment with cholinesterase inhibitors and psychotropic agents. Neuropsychiatric symptom profiles differ among dementia syndromes, and the NPI provides a means of assessing neuropsychiatric symptoms that may aid in differential diagnosis. Evaluation of neuropsychiatric symptoms is a critical aspect of dementia diagnosis and management.
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PMID:Neuropsychiatric assessment of Alzheimer's disease and related dementias. 1144 57

Depression, hallucinations, psychosis and cognitive deficits may often complicate advanced Parkinson's disease. Their detection and treatment have extraordinary importance, as they may cause significant invalidity and even an increase in mortality. Optimization of antiparkinsonian therapy may exert a positive influence on depressive symptoms, and should therefore be performed before antidepressant drugs are started. On the other hand, hallucinations and dementia do usually benefit from a discontinuation or dosage reduction of anticholinergic drugs, selegiline, DA-agonists and amantadine. When a levodopa monotherapy is indicated, slow-release formulations should be avoided. When a neuroleptic treatment is needed, clozapine and maybe quetiapine should be preferred. Preliminary evidence suggests that cholinesterase inhibitors might partially improve cognitive deficits in Parkinson's disease.
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PMID:[Psychological and cognitive problems in Parkinson disease--therapeutic possibilities]. 1193 48

Several studies have reported the efficacy of donepezil (a cholinesterase inhibitor) in patients with Alzheimer's Disease, not only for memory disturbances but also for psychotic and behavioral disturbances. We have experienced one such case that was a 74-year-old female patient with Alzheimer's Disease. Donepezil remarkably improved, for the most part, these symptoms in this case. The scale of Mini-Mental State Examination (MMSE) was improved from 21/30 to 26/30, and the Alzheimer's Disease Assessment Scale (ADAS) was improved from 21.7/70 to 16.3/70. It took about 8 weeks of treatment with donepezil to achieve these results, although some adverse effects associated with the use of donepezil were found in this case. It became difficult for the nursing staff to give care because of hyperactivity and self-assertion.However, the relationship between donepezil and these behavioral disturbances was not clear.This case indicates that donepezil may exacerbate symptoms in Alzheimer's Disease patients who have psychotic and behavioral problems. From a clinical point of view, we concluded that donepezil is therapeutically efficacious for Alzheimer's Disease sufferers, but that some problems still exist.
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PMID:[The efficacy of donepezil in Alzheimer's disease]. 1218 72


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