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)

Decline in cognitive function, especially memory, is the core feature of Alzheimer's disease (AD). However, other characteristic aspects of the disease are also important. These include patients' activities of daily living (ADL), including quality of sleep, behavioural disturbances and the impact of the disease on the caregiver. Therefore, increasing attention is being paid to clinically meaningful outcome measures, such as the Disability Assessment for Dementia (DAD) scale, the Neuropsychiatric Inventory (NPI), caregiver time and the Pittsburgh Sleep Quality Index (PSQI). Galantamine is a new treatment for AD that combines modulation of nicotinic receptors with inhibition of acetylcholinesterase. The present review outlines the positive and sustained effects of this agent on patients' behaviour and daily functioning as well as on caregiver time. In studies of up to 5 months' duration, galantamine-treated patients had a significantly better outcome on ADL than placebo-treated patients, and after 12 months of treatment with galantamine, patients' functional ability was preserved. Galantamine also significantly benefits behavioural disturbances in patients with AD. These functional and behavioural benefits are associated with a decrease in the burden on caregivers, as indicated by a reduction, relative to placebo, in the time spent supervising and assisting patients. These clinical benefits are not offset by disruption of patients' sleep, as has been reported with other cholinergic treatments.
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PMID:Galantamine: therapeutic effects beyond cognition. 1097 Oct 49

A number of studies indicate that free radicals are involved in the neurodegeneration in Alzheimer's disease (AD). The present study was mainly conducted to examine the effect of Huperzine B on H(2)O(2) induced toxicity in rat pheochromocytoma line PC12 by measuring cell lesion, level of lipid peroxidation and antioxidant enzyme activities. Following a 30 min exposure of the cells to H(2)O(2) (150 microM), a marked decrease in cell survival, activities of glutathione peroxidase and catalase as well as increased production of malondialdehyde (MDA) were found. Pretreatment of the cells with huperzine B (10-100 microM) prior to H(2)O(2) exposure significantly elevated the cell survival, antioxidant enzyme activities and decreased the level of MDA. The above-mentioned neuroprotective effects are also observed with tacrine (1 microM), donepezil (10 microM) and galanthamine (10 microM), suggesting that the neuroprotective effects of cholinesterase inhibitor might partly contribute to the clinical efficacy in AD treatment.
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PMID:Huperzine B, a novel acetylcholinesterase inhibitor, attenuates hydrogen peroxide induced injury in PC12 cells. 1099 45

Transient forebrain ischaemia is widely observed in clinical practice. We have examined the effect of a single administration of the cholinesterase inhibitor galanthamine (2mg kg(-1) i.p.) 25 min after reperfusion in male Sprague-Dawley rats (180 +/- 20 g) after a 20-min common carotid artery occlusion. Twenty-four-hours post-ischaemia there was no difference in motor co-ordination or muscle tonus of the rats treated with or without galanthamine as assessed by the rota-rod test. Learning ability was examined using the shuttle-box test, evaluating the latency time and the number of errors for six days in succession. The performance of the ischaemic saline-injected rats was significantly impaired on days 4, 5, 6 (latency time) compared with the non-ischaemic rats and with the ischaemic animals administered galanthamine (P < 0.05). Similar results were obtained when counting the number of errors (failure to cross the cage during conditioned or unconditioned stimulus). The monitoring of body temperature during the first 12-h post-ischaemia did not show any significant difference between the groups. The data showed a beneficial effect of galanthamine on the recovery of learning ability when administered once only post-ischaemia. This suggests a direct effect on the early pathologic mechanisms of CNS damage. Cholinesterase inhibitors may prove useful in the early clinical treatment of ischaemic conditions.
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PMID:A post-ischaemic single administration of galanthamine, a cholinesterase inhibitor, improves learning ability in rats. 1104 97

Galanthamine (or galantamine, Reminyl) is a tertiary alkaloid acetylcholinesterase inhibitor (AChEI) which has been approved in several countries for the symptomatic treatment of senile dementia of the Alzheimer's type. Derived from bulbs of the common snowdrop and several Amaryllidaceae plants, (-)-galanthamine (GAL) has long been used in anaesthetics to reverse neuromuscular paralysis induced by turbocurarine-like muscle relaxants and more recently, has been shown to attenuate drug- and lesion-induced cognitive deficits in animal models of learning and memory. GAL directly inhibits acetylcholinesterase activity, while demonstrating much weaker activity on butyrylcholinesterase (BuChE). GAL also stimulates pre- and postsynaptic nicotinic receptors, although the clinical significance of this finding is yet unclear. Numerous variants and analogues of GAL have also been developed, with varying potency in inhibiting AChE activity. GAL is readily absorbed after oral administration, with a t(max) of 52 min and a plasma elimination t(1/2) of 5.7 h. The efficacy of GAL administered to Alzheimer's disease (AD) patients has been well demonstrated by large-scale clinical trials. Typical of AChEIs, the most common adverse events associated with GAL are nausea and vomiting. In conclusion, evidence to date suggests galanthamine to be similar to other AChEIs in improving cognitive function in AD patients.
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PMID:Review of the acetylcholinesterase inhibitor galanthamine. 1106 Aug 14

Three new cholinesterase inhibitors, donepezil, rivastigmine, and galantamine, all inhibit the enzyme AChE. Rivastigmine also inhibits BuChE, which could lead to additional benefits in late-stage Alzheimer's disease, but also cause more GI side effects at initiation of therapy. Galantamine is also an allosteric modulator of nicotinic receptors, which could lead to additional efficacy for attention and for behaviors mediated by neurotransmitters other than ACh. We are now entering an exciting era where the options for treating the devastating illness Alzheimer's disease are multiplying and creating a foundation upon which new therapies with new mechanisms of action can be built.
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PMID:The new cholinesterase inhibitors for Alzheimer's disease, Part 1: their similarities are different. 1107 30

The 3D structure of a complex of the anti-Alzheimer drug galanthamine with Torpedo californica acetylcholinesterase is reported. Galanthamine, a tertiary alkaloid extracted from several species of Amarylidacae, is so far the only drug that shows a dual activity, being both an acetylcholinesterase inhibitor and an allosteric potentiator of the nicotinic response induced by acetylcholine and competitive agonists. The X-ray structure, at 2.5A resolution, shows an unexpected orientation of the ligand within the active site, as well as unusual protein-ligand interactions. The inhibitor binds at the base of the active site gorge, interacting with both the acyl-binding pocket and the principal quaternary ammonium-binding site. However, the tertiary amine group of galanthamine does not directly interact with Trp84. A docking study using the program AUTODOCK correctly predicts the orientation of galanthamine in the active site. The docked lowest-energy structure has a root mean square deviation of 0.5A with respect to the corresponding crystal structure of the complex. The observed binding mode explains the affinities of a series of structural analogs of galanthamine and provides a rational basis for structure-based drug design of synthetic derivatives with improved pharmacological properties. Proteins 2001;42:182-191.
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PMID:Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs. 1111 42

Despite the proven efficacy of acetylcholinesterase inhibitors in Alzheimer's disease, there is a need for new and more effective treatments. Galantamine is a novel treatment for Alzheimer's disease that inhibits acetylcholinesterase and modulates nicotinic receptors. In randomized, double-blind, placebo-controlled studies of up to 6 months duration, galantamine significantly improved cognitive function. Galantamine also had beneficial effects on instrumental and basic activities of daily living, and postponed the progression of behavioral symptoms. Patients who completed one of the 6-month, placebo-controlled studies were eligible to enter a 6-month, open-extension study of the 24-mg/day dose of galantamine. At the end of 12 months, cognitive function and activities of daily living were preserved in those patients who had been treated throughout the study with galantamine 24 mg/day. At 12 months, this group of patients had significantly better cognitive functions than patients who had been treated with a placebo for 6 months before receiving galantamine. These studies indicate that galantamine postpones the progression of symptoms in Alzheimer's disease. Since galantamine shows the greatest benefits when treatment is started early, its long-term benefits may result from an effect on the underlying disease process; such an effect might be mediated by galantamine's concomitant action on nicotinic receptors.
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PMID:Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects on the course of Alzheimer's disease. 1123 Aug 80

Galantamine (Reminyl) is a novel drug treatment for mild to moderate Alzheimer's disease (AD). Originally established as a reversible inhibitor of the acetylcholine-degrading enzyme acetylcholinesterase (AChE), galantamine also acts as an allosterically potentiating ligand (APL) on nicotinic acetylcholine receptors (nAChR). Having previously established this second mode of action on nAChRs from murine brain, we demonstrate here the same action of galantamine on the most abundant nAChR in the human brain, the alpha4/beta2 subtype. This nAChR-sensitizing action is not a common property of all, or most, AChE inhibitors, as is shown by the absence of this effect for other therapeutically applied AChE inhibitors including tacrine, metrifonate, rivastigmine and donepezil. The possible benefits for therapy of AD of an APL action on nicotinic receptors is discussed.
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PMID:Galantamine is an allosterically potentiating ligand of the human alpha4/beta2 nAChR. 1126 8

Thin-layer chromatography (TLC) was used to screen for acetylcholinesterase inhibitors from Amaryllidaceae extracts. The TLC plate was developed and then stained using Ellman's reagent, 5,5'-dithiobis-(2-nitrobenzoic acid), to detect acetylcholinesterase activity. The advantages of this TLC assay method were that we could dereplicate the known inhibitor galanthamine, widely occurring in Amaryllidaceae, at an early stage of the isolation procedure. Moreover, there is no disturbance from sample dissolving solvents as in the microplate assay, and it is a very simple method. The detection limits were 10-200 ng for several known acetylcholinesterase inhibitors tested, and it is thus more sensitive than UV or Dragendorff's reagent detection. Also the minimal detectable amount for an acetylcholinesterase inhibitor tested was much less than that needed for the microplate assay. We screened 15 Amaryllidaceae extracts using this TLC method, and chose candidates for acetylcholinesterase inhibitor isolation.
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PMID:Screening for acetylcholinesterase inhibitors from Amaryllidaceae using silica gel thin-layer chromatography in combination with bioactivity staining. 1135 51

Galantamine, the most recently approved acetylcholinesterase inhibitor (AChEI) for use in the United States, has allosteric modulating activity at nicotinic receptors and inhibits acetylcholinesterase. This dual mechanism of action may make galantamine an attractive option for patients with Alzheimer's disease who have not benefited from their current therapy; thus, methods for switching patients from donepezil or rivastigmine to galantamine are needed. Protocols for switching patients from one AChEI to another must consider both the time required for washout of the first drug and the rate of dose escalation of the second drug. Both issues depend on the pharmacodynamics, pharmacokinetics, and pharmacology of the drugs under consideration. Because the common property of the drugs considered here is their acetylcholinesterase inhibitory activity, it seems reasonable to keep this activity at or below the activity achieved by the first drug at all times. In addition, the patient's condition should be monitored to avoid deterioration resulting from subtherapeutic drug concentrations during the switch. The switching protocol proposed here has been based on an analysis of mean plasma concentrations of donepezil following administration of a single dose and on the established pharmacokinetics of galantamine.
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PMID:Pharmacokinetic rationale for switching from donepezil to galantamine. 1139 71


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