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)

Cholinesterase inhibitors are licensed for the treatment of dementia in Alzheimer's disease. In clinical practice, these drugs have little effect on the cognitive symptoms of dementia. Several studies report a beneficial effect of cholinesterase inhibitors on neuropsychiatric symptoms. We hypothesise that symptoms such as the impairment of attention and concentration, anxiety, restlessness and hallucinations, delineate a specific central cholinergic deficiency syndrome. It is postulated that this syndrome crosses boundaries of nosological entities and occurs in various neurodegenerative diseases. Symptoms resulting from cholinergic deficiency might be a much better target for treatment than cognitive deficits.
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PMID:[Cholinergic deficiency syndrome as an indicator for the cholinesterase inhibitors]. 1464 55

Neurodegenerative diseases are increasingly common in elderly patients, who present a particular anaesthetic challenge. The majority of people over the age of 70 years have some degree of cerebral atrophy. The pathogenesis of neurodegenerative diseases is due to alterations in the transport, degradation and aggregation of proteins. Alterations in physiology that occur with advancing age affect both the pharmacokinetics and pharmacodynamics of drugs used in the elderly. Changes in pharmacokinetics result in either increased or reduced drug concentrations depending on the variable contributions of absorption, metabolism and elimination. The distribution of a drug depends on its protein binding, cardiac output and blood volume, which are all altered in the elderly. Metabolism and excretion of drugs are also affected due to changes in hepatic and renal mass and blood flow in the elderly. A number of drugs are used in neurodegenerative disorders including antidepressants, benzodiazepines, antipsychotics, acetylcholinesterase inhibitors and levodopa. Polypharmacy is a common problem, which can lead to adverse drug interactions and an exacerbation of dementia. Levodopa, bromocriptine and tricyclic antidepressants are known to cause orthostatic hypotension in patients with neurodegenerative disease. Elderly patients are liable to excessive sedation from benzodiazepines in both the pre- and postoperative period; therefore these drugs should be prescribed in low doses. For induction of general anaesthesia propofol is a suitable agent in patients with neurodegenerative disease due to its rapid metabolism, but may not be suitable in patients with Parkinson's disease as it can induce spontaneous involuntary movements. Volatile inhalational agents should be administered carefully in the elderly, as they are more sensitive to the depressant cerebral and cardiovascular effects. Levodopa should be avoided in conjunction with halothane, which sensitises the heart to catecholamines. Co-administration of monoamine oxidase inhibitors and opioids should be avoided as it can cause agitation, muscular rigidity, sweating and hyperpyrexia. If an anticholinergic agent is required, then glycopyrronium bromide is the drug of choice in this group of patients, as it does not cross the blood brain barrier. Patients should continue to take their usual medications in hospital and do not let the change in routine alter the times at which treatments are administered. This is particularly relevant to the timing of levodopa in Parkinson's disease, as missed treatment can be detrimental. Regional anaesthesia may, however, have significant advantages in patients with Parkinson's disease, who can continue to take oral levodopa preoperatively, during surgery, if required, and early in the postoperative period. Anti-emetic drugs such as phenothiazines, butyrophenones and metoclopramide should be used carefully in the postoperative period in these patients as their antidopaminergic effects may induce or exacerbate parkinsonian effects.
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PMID:Anaesthesia in elderly patients with neurodegenerative disorders: special considerations. 1501 69

Patients with dementias, such as Alzheimer's disease (AD), often have nocturnally disrupted sleep. Clinically, this may present as agitation during the nighttime hours, which may affect as many as a quarter of AD patients during some stage of their illness. Sleep disturbance in AD may be multifactorial and involve sleep-disordered breathing and disrupted chronobiology, both often characterized by excessive daytime napping. Polysomnographically, AD patients show decreased rapid eye movement (REM) sleep in proportion to the extent of their dementia; some evidence suggests that cholinesterase inhibitors, commonly used pharmacologic agents for cognitive loss in AD, may increase REM sleep measures. Unfortunately, such agents may also induce insomnia and vivid dreams. There have been no randomized clinical trials of sedative-hypnotic medications specifically targeted at AD patients with sleep problems. Evidence suggests that sedative-hypnotics, such as benzodiazepine site-specific agonists, may have a role in some cases, whereas atypical antipsychotics may be necessary in other cases. There are also reports of successful interventions with nonpharmacologic options (eg, exercise, illumination). The utility of melatonin as a hypnotic in this population appears equivocal.
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PMID:Sleep disorders in Alzheimer's disease and other dementias. 1525 36

Delayed disease progression and symptomatic improvement occur with cholinesterase inhibitors (ChEIs) in dementia with Lewy bodies (DLB). In this study, complications (insomnia, dyskinesias, agitation, and delirium) occurred in three patients switched from donepezil to galantamine. The authors describe evidence-based recommendations for ChEI switchover in DLB.
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PMID:Emergent complications following donepezil switchover to galantamine in three cases of dementia with Lewy bodies. 1638 98

Memantine, a moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist, is currently the only agent approved for moderately severe to severe Alzheimer disease (AD) in Europe and for moderate-to-severe Alzheimer disease in the United States. In clinical trials, memantine has consistently demonstrated a reduced rate of deterioration on global, cognitive, functional, and behavioral measures, across a range of outcome measures compared with usual care. Notably, improvements versus placebo were seen in individual activities of daily living and behavior, particularly agitation. Efficacy was demonstrated in patients with newly diagnosed Alzheimer disease, patients previously or currently receiving acetylcholinesterase inhibitors, and both institutionalized and community-dwelling Alzheimer disease patients. Memantine has a tolerability profile similar to placebo. This review presents the results of key clinical trials, and includes clinically relevant analyses, such as numbers-needed-to-treat and effect sizes. Increased dependency and institutionalization are significant cost drivers in Alzheimer disease. Memantine is able to reduce dependency, caregiver time required, and mean monthly caregiver and societal costs. Recent studies of the relationship between Alzheimer disease progression, caregiver burden, and healthcare costs emphasize the need for treatments such as memantine that can slow the rate of decline in Alzheimer disease.
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PMID:Efficacy and safety of memantine in moderate-to-severe Alzheimer disease: the evidence to date. 1649 32

Parkinson's disease is a neurodegenerative disorder causing not only motor dysfunction but also cognitive, psychiatric, autonomic and sensory disturbances. Symptoms of dementia and psychosis are common: longitudinal studies suggest that up to 75% of patients with Parkinson's disease may eventually develop dementia, and the prevalence of hallucinations ranges from 16-17% in population-based surveys to 30-40% in hospital-based series. These cognitive and behavioural features are important in terms of prognosis, nursing home placement and mortality. The pattern of cognitive deficits in Parkinson's disease is variable, but often includes executive impairment similar to that seen in patients with frontal lesions, as well as episodic memory impairment, visuospatial dysfunction and impaired verbal fluency. The most common manifestation of psychosis in Parkinson's disease is visual hallucinations, but delusions, paranoid beliefs, agitation and florid psychosis can also occur. An understanding of the pathophysiology underlying these symptoms is essential to the development of targeted therapeutic strategies. Post-mortem studies suggest an association between Lewy body deposition and dementia in Parkinson's disease, and indeed Parkinson's disease and dementia with Lewy bodies may form part of the same disease spectrum. Whether Lewy bodies actually play a causative role in cognitive dysfunction, however, is unknown. Deficits in neurotransmitter systems provide more obvious therapeutic targets and dysfunction of dopaminergic, cholinergic, noradrenergic and serotonergic systems have all been implicated; these may each underlie different features of Parkinson's disease dementia, perhaps explaining some of the heterogeneity of the syndrome. Psychosis has traditionally been considered as a dopaminergic drug-induced phenomenon, but factors intrinsic to the disease process itself also cause hallucinations and delusions. These factors may include Lewy body deposition in the limbic system, cholinergic deficits and impairments of primary visual processing. Therapeutic intervention for cognitive and behavioural symptoms in Parkinson's disease currently focuses on two main groups of drugs: cholinesterase inhibitors and atypical antipsychotics. A recent large, randomised, controlled trial suggests that cholinesterase inhibitors can produce a modest improvement in cognitive function, as well as psychotic symptoms, generally without an adverse effect on motor function. Certain atypical antipsychotics allow hallucinations, delusions and behavioural problems to be brought under control with minimal deleterious effects on motor function and cognition, but their safety in elderly patients has recently been called into question. Deep brain stimulation does not appear to be a useful treatment for cognitive and psychiatric dysfunction in patients with Parkinson's disease. Modafinil improves alertness in Parkinson's disease and warrants further investigation to establish its effects on cognitive performance.
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PMID:Cognitive deficits and psychosis in Parkinson's disease: a review of pathophysiology and therapeutic options. 1673 99

Extensive research suggests that a number of plant-derived chemicals and traditional Oriental herbal remedies possess cognition-enhancing properties. Widely used current treatments for dementia include extracts of Ginkgo biloba and several alkaloidal, and therefore toxic, plant-derived cholinergic agents. Several non-toxic, European herbal species have pan-cultural traditions as treatments for cognitive deficits, including those associated with ageing. To date they have not received research interest commensurate with their potential utility. Particularly promising candidate species include sage (Salvia lavandulaefolia/officinalis), Lemon balm (Melissa officinalis) and rosemary (Rosmarinus officinalis). In the case of sage, extracts possess anti-oxidant, estrogenic, and anti-inflammatory properties, and specifically inhibit butyryl- and acetyl-cholinesterase. Acute administration has also been found to reliably improve mnemonic performance in healthy young and elderly cohorts, whilst a chronic regime has been shown to attenuate cognitive declines in sufferers from Alzheimer's disease. In the case of Melissa officinalis, extracts have, most notably, been shown to bind directly to both nicotinic and muscarinic receptors in human brain tissue. This property has been shown to vary with extraction method and strain. Robust anxiolytic effects have also been demonstrated following acute administration to healthy humans, with mnemonic enhancement restricted to an extract with high cholinergic binding properties. Chronic regimes of aromatherapy and essential oil respectively have also been shown to reduce agitation and attenuate cognitive declines in sufferers from dementia. Given the side effect profile of prescribed cholinesterase inhibitors, and a current lack of a well tolerated nicotinic receptor agonist, these herbal treatments may well provide effective and well-tolerated treatments for dementia, either alone, in combination, or as an adjunct to conventional treatments.
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PMID:The psychopharmacology of European herbs with cognition-enhancing properties. 1716 69

The treatments of choice in Alzheimer's disease (AD) are cholinesterase inhibitors and NMDA-receptor antagonists, although doubts remain about the therapeutic effectiveness of these drugs. Herbal medicine products have been used in the treatment of Behavioral and Psychological Symptoms of Dementia (BPSD) but with various responses. The objective of this article was to review evidences from controlled studies in order to determine whether herbs can be useful in the treatment of cognitive disorders in the elderly. Randomized controlled studies assessing AD in individuals older than 65 years were identified through searches of MEDLINE, LILACS, Cochrane Library, dissertation Abstract (USA), ADEAR (Alzheimer's Disease Clinical Trials Database), National Research Register, Current Controlled trials, Centerwatch Trials Database and PsychINFO Journal Articles. The search combined the terms Alzheimer disease, dementia, cognition disorders, Herbal, Phytotherapy. The crossover results were evaluated by the Jadad's measurement scale. The systematic review identified two herbs and herbal formulations with therapeutic effects for the treatment of AD: Melissa officinalis, Salvia officinalis and Yi-Gan San and BDW (Ba Wei Di Huang Wan). Ginkgo biloba was identified in a meta-analysis study. All five herbs are useful for cognitive impairment of AD. M. officinalis and Yi-Gan San are also useful in agitation, for they have sedative effects. These herbs and formulations have demonstrated good therapeutic effectiveness but these results need to be compared with those of traditional drugs. Further large multicenter studies should be conducted in order to test the cost-effectiveness of these herbs for AD and the impact in the control of cognitive deterioration.
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PMID:The use of herbal medicine in Alzheimer's disease-a systematic review. 1717 7

Atypical antipsychotics will continue to be prescribed for the behavioral symptoms of dementia in the absence of more effective, better tolerated, and safer alternatives. The evidence base, although incomplete, suggests that modest treatment effect sizes are offset by risk of considerable adverse effects. How might this information be best applied to clinical practice? Non-pharmacologic strategies should be implemented in routine clinical practice. Placebo-controlled clinical trials of individual antipsychotic agents have historically reported high placebo response rates; CATIE-AD reported that the sum total of the risk/benefit equation of atypical antipsychotic therapy was no greater than that achieved by placebo. CATIE-AD was designed to study the effectiveness of atypical antipsychotic treatment in community dwelling patients with AD. It is uncertain whether the results can be generalized to the populations of dementia patients residing in nursing homes with more severe cognitive and behavioral impairment. There is some suggestion that nursing home patients with dementia complicated by severe behavioral symptoms, particularly agitation and aggression without accompanying psychosis, might achieve greater benefit from atypical antipsychotic treatment than patients with milder behavioral symptoms. The finding that dementia patients without psychosis may respond more robustly to antipsychotic treatment seems counterintuitive, but may support the hypothesis that the neurobiology of the "psychosis of AD" differs from the psychosis of schizophrenia or bipolar disease. Adverse effects associated with antipsychotic therapy should be aggressively monitored throughout therapy. Treatment-emergent sedation was associated with all of the atypical antipsychotics in CATIE-AD and is probably an important mediator of mortality risk in patients with dementia. Sedation exacerbates pre-existing cognitive impairment and increases the risk of complications such as aspiration pneumonia, so concomitant use of benzodiazepines should be discouraged or limited to short periods with careful observation.' Once initiated, the effectiveness and tolerability of antipsychotic therapy should be evaluated routinely. In Alzheimer's disease, the severity and frequency of behavioral symptoms often decreases as illness progresses. In a stable patient, it is prudent to attempt to taper and discontinue the antipsychotic after 2-8 months of therapy. Better understanding of the potential adverse effects of antipsychotic therapy has increased interest in the effects of the dementia-specific medications on behavioral symptoms. Reductions in neuropsychiatric symptoms have been reported from trials of individual cholinesterase inhibitors, memantine monotherapy, and memantine combined with donepezil in AD patients. Studies of small numbers of patients in open trials of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and one double-blind placebo controlled trial (rivastigmine) have reported varying degrees of improvement of behavioral symptoms and psychosis of dementia with Lewy bodies (DLB). Delusions, hallucinations, apathy, and agitation/aggression are cited as the symptom categories most likely to show significant improvement. Since few of these studies were prospectively designed to study behavioral symptoms, results must be interpreted cautiously. Treatment of behavioral symptoms in AD and other dementias is challenging. The limitations of current approaches drive the search for effective, well tolerated therapies.
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PMID:Atypical antipsychotics for the treatment of dementia-related behaviors: an update. 1763 94

Alzheimer's disease (AD) is the most common cause of dementia affecting nearly 18 million people around the world and 4.5 million in the US. It is a progressive neurodegenerative condition that is estimated to dramatically increase in prevalence as the elderly population continues to grow. As the cognitive and neuropsychiatric signs and symptoms of AD progresses in severity over time, affected individuals become increasingly dependent on others for assistance in performing all activities of daily living. The burden of caring for someone affected by the disorder is great and has substantial impact on a family's emotional, social and financial well-being. In the US, the currently approved medications for the treatment of mild to moderate stages of AD are the cholinesterase inhibitors (ChEIs). Cholinesterase inhibitors have shown modest efficacy in terms of symptomatic improvement and stabilization for periods generally ranging from 6 to 12 months. There are additional data that have emerged, which suggest longer-term benefits. For the moderate to severe stages of AD, memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist is in widespread use and has shown modest benefit as monotherapy and in combination with ChEIs. The cost effectiveness of the currently available therapeutic agents for AD has undergone great scrutiny and remains controversial, especially outside the US. Neuropsychiatric symptoms such as agitation and psychosis are common in AD. Unfortunately, in the US there are no Food and Drug Administration (FDA)-approved agents for the treatment of these symptoms, although atypical antipsychotics have shown some efficacy and have been widely used. However, the use of these agents has recently warranted special caution due to reports of associated adverse effects such as weight gain, hyperlipidemia, glucose intolerance, cerebrovascular events, and an increased risk for death. Alternative agents used to treat neuropsychiatric symptoms include serotonergic antidepressants, benzodiazepines, and anticonvulsant medications.
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PMID:Treatment of Alzheimer's disease across the spectrum of severity. 1804 10


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