Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent health technology assessments have given us the go-ahead to use cholinesterase inhibitors, which, in combination with community services, are currently the most appropriate treatment for patients with Alzheimer's disease (AD). Initial research focused upon acetylcholinesterase (AChE)-selective agents, but it is now thought that dual inhibitors of AChE and butyrylcholinesterase (BuChE) may provide more sustained efficacy over the course of AD and may help to slow disease progression. Rivastigmine is a potent inhibitor of AChE and BuChE and has demonstrated broad benefits across the severity of AD and across the cognitive, functional and behavioural domains of AD. In addition, rivastigmine has shown cognitive and behavioural benefits in patients with dementia with the Lewy body variant of AD. These benefits may reflect the inhibition of both AChE and BuChE, as demonstrated by significant correlations between cognitive improvements and cholinesterase inhibition in rivastigmine-treated patients with AD. Rivastigmine shows a clear dose-response relationship, and physicians should aim to maintain patients on doses of 6 mg/day or higher, to a maximum of 12 mg/day. As with all cholinesterase inhibitors, rapid forced dose escalation may increase the incidence of typical cholinergic side-effects, resulting in lower maintenance doses. In a chronic disease such as AD, there is time to implement slow dose escalation and higher final maintenance doses. If used appropriately, the benefits of rivastigmine seen in clinical practice may prove to be even greater than those reported in clinical trials.
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PMID:The clinical benefits of rivastigmine may reflect its dual inhibitory mode of action: an hypothesis. 1201 28

Multiple behavioural and psychological symptoms of dementia (BPSD) are commonly associated with all dementia subtypes, and worsen during disease progression. BPSD arise due to impairment of cholinergic function in the cortex, hippocampus and related limbic systems. Recent studies have investigated the effect of cholinesterase inhibitors on BPSD. The dual acetylcholinesterase/butyrylcholinesterase (AChE/BuChE) inhibitor rivastigmine was shown to have several potential advantages over the AChE-selective inhibitors donepezil and galantamine for the treatment of BPSD. Rivastigmine appears to be effective across the range of dementia severity from mild to severe, and across the spectrum of dementia (Alzheimer's disease [AD], the AD variant with Lewy bodies, Parkinson's disease dementia and vascular dementia subtypes). It also appears to have a disease-modifying potential. Rivastigmine improved a wider range of behavioural symptoms (apathy, anxiety/depression, hallucinations and delusions) than donepezil and galantamine (which improved apathy and depression/anxiety only). Unlike donepezil, rivastigmine reduced the need for psychotropic medications to treat BPSD. Dual inhibition of AChE and BuChE and brain-region selectivity through preferential inhibition of the G1 isoform of AChE may provide the underlying reasons for the apparently greater and broader efficacy of rivastigmine over AChE-selective inhibitors for the treatment of BPSD. However, randomised, controlled trials are required to compare dual inhibitors, such as rivastigmine, and AChE-selective agents, to confirm and quantify any differences in their effects on BPSD.
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PMID:The efficacy of cholinesterase inhibitors in treating the behavioural symptoms of dementia. 1213 65

In the absence of a cure for Alzheimer's disease (AD), treatment has focused on therapy to provide symptomatic benefits and to slow progression of the disease, so that patients can maintain their independence for as long as possible. New research suggests that rivastigmine, a potent, pseudo-irreversible inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase that shows preferential selectivity for the G1 form of AChE, may provide symptomatic and disease progression slowing effects. The drug's pharmacological properties may help to slow the conversion of diffuse, benign amyloid plaques to neuritic plaques associated with clinical dementia. In 'delayed-start' paradigms--open-label extensions of placebo-controlled studies involving mild to moderate AD patients--the treatment effects of rivastigmine on cognitive and non-cognitive outcomes at 52 weeks were even greater than those observed at 26 weeks, and patients who received rivastigmine for the entire 52 weeks had better outcomes than those who received rivastigmine only for the latter 26 weeks (having received placebo for the first 26 weeks during the placebo-controlled phase). These treatment effects were even more robust in patients with moderately severe disease, indicating that the sustained long-term benefits of rivastigmine apply across the continuum of disease severity. The results seen in those patients with mild and moderately severe AD suggest that the progression of AD was being slowed in treated patients and that a disease-modifying effect may have been taking place. The effects of rivastigmine on cognition remain clinically relevant for at least 2 years, with benefits over projected placebo increasing over time. The long-term benefits of rivastigmine have also been reported in behavioural domains of patients with mild to moderate AD for 104 weeks and in patients with the Lewy body variant of AD for 96 weeks. Rivastigmine may slow AD progression, allowing patients to maintain autonomy for longer.
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PMID:Do cholinesterase inhibitors slow progression of Alzheimer's disease? 1213 66

Despite recognition that cholinesterase inhibitors can provide clinical benefits for patients with Alzheimer's disease (AD), the average durations of treatment and beneficial effects are not optimal in all cases. This may be due to disappointing efficacy or poor tolerability of the initial treatment, as well as secondary efficacy failure or adverse effects emerging during the maintenance phase. In such cases, pharmacological differences between available cholinesterase inhibitors provide a good rationale to switch to another drug in the same class. The pharmacological properties of rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase, and donepezil and galantamine, two AChE-selective inhibitors, are reviewed. Rivastigmine is reported to show brain- and brain region-selectivity. Donepezil appeared to be more selective for central than peripheral enzymes in rats. Galantamine and donepezil have also been shown to exert nicotinic receptor allosteric modulation in vitro, while rivastigmine has been shown to increase binding of acetylcholine to nicotinic receptors in the AD brain. Donepezil and galantamine are metabolised by the hepatic CYP450 system, whereas rivastigmine is metabolised by its target enzymes. Several switching studies indicated that a substantial proportion of patients who fail to benefit from treatment with donepezil could draw benefits after being switched to rivastigmine. An immediate switch from donepezil to rivastigmine was reported to be well tolerated and was not associated with cholinergic side effects. A post hoc analysis of a 5-month trial with galantamine showed that patients had similar efficacy outcomes, whether or not they had received prior anticholinesterase therapy, suggesting that a previous failure to respond to another cholinesterase inhibitor did not predict response to galantamine. On the basis of available data it is suggested that patients not tolerating or not responding to one particular cholinesterase inhibitor may still draw benefits upon switching to another.
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PMID:Switching cholinesterase inhibitors in patients with Alzheimer's disease. 1213 69

Cholinesterase inhibitors are the 'first-line' agents in the treatment of Alzheimer's disease. This article presents the latest information on their pharmacokinetic properties and pharmacodynamic activity. Tacrine was the first cholinesterase inhibitor approved by regulatory agencies, followed by donepezil, rivastigmine and recently galantamine. With the exception of low doses of tacrine, the cholinesterase inhibitors exhibit a linear relationship between dose and area under the plasma concentration-time curve. Cholinesterase inhibitors are rapidly absorbed through the gastrointestinal tract, with time to peak concentration usually less than 2 hours; donepezil has the longest absorption time of 3 to 5 hours. Donepezil and tacrine are highly protein bound, whereas protein binding of rivastigmine and galantamine is less than 40%. Tacrine is metabolised by hepatic cytochrome P450 (CYP) 1A2, and donepezil and galantamine are metabolised by CYP3A4 and CYP2D6. Rivastigmine is metabolised by sulfate conjugation. Two cholinesterase enzymes are present in the body, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Tacrine and rivastigmine inhibit both enzymes, whereas donepezil and galantamine specifically inhibit AChE. Galantamine also modulates nicotine receptors, thereby enhancing acetylcholinergic activity at the synapse. These different pharmacological profiles provide distinctions between these agents. Cholinesterase inhibitors show a nonlinear relationship between dose and cholinesterase inhibition, where a plateau effect occurs. Cholinesterase inhibitors display a different profile as each agent achieves its plateau at different doses. In clinical trials, cholinesterase inhibitors demonstrate a dose-dependent effect on cognition and functional activities. Improvement in behavioural symptoms also occurs, but without a dose-response relationship. Gastrointestinal adverse events are dose-related. Clinical improvement occurs with between 40 and 70% inhibition of cholinesterase. A conceptual model for cholinesterase inhibitors has been proposed, linking enzyme inhibition, clinical efficacy and adverse effects. Currently, measurement of enzyme inhibition is used as the biomarker for cholinesterase inhibitors. New approaches to determining the efficacy of cholinesterase inhibitors in the brain could involve the use of various imaging techniques. The knowledge base for the pharmacokinetics and pharmacodynamics of cholinesterase inhibitors continues to expand. The increased information available to clinicians can optimise the use of these agents in the management of patients with Alzheimer's disease.
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PMID:Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. 1216 59

Parkinson's disease patients may suffer from cognitive impairment and behavioural problems such as apathy, personality changes, speech disturbances and visual hallucinations (Parkinson's disease dementia). However, there is currently no recommended treatment for Parkinson's disease dementia and antipsychotic agents can worsen extrapyramidal symptoms, making them unsuitable for patients with this condition. The observation that patients with Parkinson's disease dementia have extensive cholinergic deficits led to the hypothesis that cholinesterase inhibitors may provide benefits for patients with this condition. Here, we present a case series of patients with Parkinson's disease and dementia who we treated with rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) that shows brain region-selectivity. The introduction of rivastigmine led to improvements in cognitive and functional abilities, as well as the resolution of behavioural problems and visual hallucinations. Rivastigmine was well tolerated by our patients when the dose was escalated slowly, including one patient who had previously experienced severe side-effects with the AChE-selective inhibitor donepezil. Despite the large number and range of concomitant medications being received by the patients, no side-effects thought to be related to drug-drug interactions were reported. A large, placebo-controlled study is warranted to ascertain the full clinical profile of rivastigmine in Parkinson's disease dementia.
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PMID:Rivastigmine for the treatment of dementia and visual hallucinations associated with Parkinson's disease: a case series. 1224 Jul 87

Alzheimer's disease (AD) is characterized by deterioration in the ability to perform activities of daily living (ADL) in addition to loss of cognitive function and behavioral changes. This decline in day-to-day functioning is increasingly recognized as a source of considerable social, health, and economic costs. Inability to perform ADL results in growing caregiver burden and may lead to the eventual need for alternative care or nursing home placement. The measurement of ADL, which enables monitoring of the effectiveness of therapeutic interventions, can be performed using a number of inventories including the Progressive Deterioration Scale (PDS), the Disability Assessment for Dementia (DAD), and the Alzheimer Disease Cooperative Study ADL (ADCS/ADL) assessment scale. Clinical studies using these and other scales have indicated that cholinesterase (ChE) inhibitors offer an effective approach to treating the functional decline of AD. Donepezil, rivastigmine, and galantamine have been shown in some studies to prevent or slow decline in ADL over treatment periods of one to two years. For instance, in a 24-week study in subjects with moderate to severe AD, donepezil-treated patients remained stable compared with the placebo-treated patients. Rivastigmine has shown improvement or stabilization of PDS scores in patients with mild to moderate disease following 26 weeks of treatment and slowed deterioration in patients with more severe disease. Evidence to date suggests that these agents may not be equally effective at slowing or stabilizing loss in ADL over time and that these differences may reflect differences in pharmacology. In addition to inhibition of acetylcholinesterase (AChE), these compounds have other putative differences in mechanisms of action. Galantamine allosterically modulates the nicotinic receptor and may prevent the loss of ADL. Rivastigmine robustly inhibits butyrylcholinesterase in addition to AChE and therefore acts as a dual ChE inhibitor. Comparative studies evaluating the differential effects of these ChE inhibitors on ADL are awaited.
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PMID:The ABC of Alzheimer's disease: ADL and improving day-to-day functioning of patients. 1263 78

The cholinergic hypothesis suggests that Alzheimer's disease (AD) results from a selective loss in cholinergic neurons with decreased acetylcholine levels. Treatments that increase the level of acetylcholine would be expected to provide clinical benefit. Clinical trials of dietary precursors of acetylcholine and muscarinic receptor agonists have been unsuccessful. Further research is needed to confirm whether nicotine or nicotinic agonists are of value. The most successful approach has been to increase acetylcholine levels by inhibiting cholinesterase function. A number of cholinesterase inhibitors (ChEI) show clinical efficacy including phyostigmine but it is poorly tolerated. Tacrine, the first ChEI to be licensed for AD, needs frequent administration and causes a specific reversible hepatotoxicity. Three ChEI, donepezil, rivastigmine and galantamine are widely available. They are effective in mild to moderate (and possibly severe) AD. Tolerability is improved by slow dose titration and there are a significant number of non-responders. Donepezil appears to be effective, the simplest to use and the best tolerated. Rivastigmine is effective but less well tolerated: galantamine is also very effective with intermediate tolerability. Although there are pharmacological differences between the three compounds, it remains uncertain whether these are clinically relevant. There are still unanswered questions. It is difficult to predict who will respond to the drugs and it is unclear how long treatment benefits last. At present there are little data to support the suggestion of activity beyond symptomatic benefit. Trials are also being conducted in Mild Cognitive Impairment, other dementias and other conditions where cognitive impairment is a problem.
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PMID:Have cholinergic therapies reached their clinical boundary in Alzheimer's disease? 1297 45

Rivastigmine is an acetylcholinesterase inhibitor used in Alzheimer's disease therapy. In the present study, we investigated the effects of rivastigmine on the transient outward K+ current (IK(A)) and the delayed rectifier K+ current (IK(DR)) in acutely dissociated rat hippocampal pyramidal neurons using the whole-cell patch-clamp technique. Rivastigmine inhibited the amplitudes of IK(A) and IK(DR) in a reversible and concentration-dependent manner. At a concentration of 100 mum, rivastigmine inhibited IK(A) and IK(DR), recorded when the cells were depolarized from -50 to +40 mV, by 65.9 (P<0.01) and 67.3% (P<0.01), respectively. The IC50 values for IK(A) and IK(DR) were 3.8 and 1.7 microM, respectively. The decay time constant of IK(A), recorded following a test pulse to +40 mV, was prolonged reversibly by rivastigmine at concentrations of 10 and 100 microM (both P<0.05). Rivastigmine affected the voltage dependence of IK(A) and IK(DR). At a concentration of 10 mum, it shifted the steady-state inactivation curve of IK(A) towards more negative potentials by -11 mV (P<0.05), but had no effect on the steady-state activation curve or the recovery from inactivation. Regarding the kinetic properties of IK(DR), 10 microM rivastigmine shifted the steady-state activation and inactivation curves towards more negative potentials by -10 (P<0.05) and -27 mV (P<0.01), respectively. Our findings that rivastigmine inhibits IK(A) and IK(DR) in rat hippocampal pyramidal neurons suggest that this agent has other pharmacological actions besides its antiacetylcholinesterase activity.
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PMID:Rivastigmine blocks voltage-activated K+ currents in dissociated rat hippocampal neurons. 1450 31

We aimed to determine whether the cholinesterase inhibitor rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), would improve quality of life and cognitive function in 16 clinically stable subjects affected by schizophrenia in the residual phase. Study subjects began rivastigmine treatment at a dose of 1.5 mg bid. This dose was escalated at monthly intervals in increments of 1.5 mg bid to a maximum of 6 mg bid. All subjects were followed for 12 months. Quality of life was assessed using the Satisfaction with Life Domains Scale (SLDS, a self-report scale containing 10 "satisfaction" items); cognitive function, attentional function, and aspects of learning and memory were evaluated using common neuropsychological tests. Psychopathology was evaluated by means of the Brief Psychiatric Rating Scale (BPRS). Rivastigmine treatment resulted in significant improvements in quality of life, which were paralleled by significant improvements in cognitive function, learning and memory, and trends for improvement in attention. The BPRS factor "anergia" showed significant improvement, while low baseline scores in other psychotic factors did not permit further improvements. There were no reports of nausea or vomiting. In conclusion, rivastigmine significantly improved quality of life in subjects with schizophrenia. These benefits may relate to the drug's effects on cognitive deficits and negative symptoms associated with the condition.
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PMID:Effects of rivastigmine on cognitive function and quality of life in patients with schizophrenia. 1464 12


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