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)

Current treatment of Alzheimer's disease (AD) has focused on the use of cholinesterase inhibitors. This review emphasizes emerging therapies for the treatment and/or prevention of AD with a focus on glutamatergic excitotoxicity in dementia and the therapeutic promise of the uncompetitive, low to moderate affinity N-methyl-D-aspartate (NMDA) receptor antagonist, memantine. Preclinical studies and clinical trials in AD, as well as the extensive clinical use of memantine for neurodegenerative conditions in Europe since 1982 support the safety, tolerability, and efficacy of this agent. Memantine was recently approved in Europe for the treatment of moderately severe to severe AD and is an investigational drug in the United States.
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PMID:Alzheimer's disease and the glutamate NMDA receptor. 1456 13

Memantine, a non-competitive NMDA antagonist, has been clinically used in the treatment of dementia in Germany for over ten years. The rationale for this indication is strongly related to the physiological and to the pathological role of glutamate in neurotransmission. Physiologically, NMDA receptors mediate synaptic plasticity by acting as a coincidence detector. Only those synapses that show temporally and spatially discrete activation of NMDA receptors undergo plastic changes secondary to Ca++ influx after rapid unblocking of Mg++, thus crucially contributing to memory and learning processes. The voltage-dependency of Mg++ is so pronounced that under pathological conditions it leaves the NMDA channel upon moderate depolarisation, thus interrupting memory and learning. Its pharmacological properties allow memantine to rapidly leave the NMDA channel upon transient physiological activation by synaptic glutamate (restoring significant signal transmission), but to block the sustained activation of low glutamate concentration under pathological conditions, i.e. to protect against excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent in various animal models based on both neurodegenerative and vascular processes as it ameliorates cognitive and memory deficits. Memantine has shown to be effective and safe in the treatment of dementia, particularly Alzheimer's disease, in controlled clinical trials. Provided that the dose is slowly increased it is generally well tolerated and safe up to 20 and 30 mg per day, with intake preferably in the morning. The compound is completely absorbed after oral intake with Cmax values after 6 hours, undergoes little metabolism and has a terminal elimination half life between 60 and 100 hours. Due to its low potential of interaction, memantine can be combined with acetylcholinesterase inhibitors, the mainstay of current symptomatic treatment of Alzheimer's disease and it is suited in elderly patients receiving multiple drug therapy.
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PMID:NMDA-antagonism (memantine): an alternative pharmacological therapeutic principle in Alzheimer's and vascular dementia. 1475 85

By some estimates moderate-to-severe Alzheimer's disease accounts for 50% of all patients with Alzheimer's disease. However, there are numerous issues that remain to be resolved in the management of patients with more advanced Alzheimer's disease. The first prospective, randomised, controlled trial of the cholinesterase inhibitor donepezil in more advanced Alzheimer's disease has reported quite encouraging results, with further studies being undertaken. Post-hoc analyses of rivastigmine and galantamine in patients with more advanced Alzheimer's disease have supported the hypothesis that acetylcholinesterase inhibitors are likely be efficacious in this subgroup. Memantine, a glutamate NMDA receptor antagonist, is newly licensed in Europe for the treatment of more advanced Alzheimer's disease and will provide the first non-cholinesterase inhibitor option for the treatment of Alzheimer's disease. The combination of donepezil and memantine has been shown to have superior efficacy than donepezil alone in this severe Alzheimer's disease subgroup, potentially supporting a role for dual treatment in more advanced Alzheimer's disease. Further studies of all aspects of more advanced Alzheimer's disease are clearly needed. The problems of translating clinical trial results to routine clinical practice are even more complex and challenging in this patient group, with the true impact of any one given treatment ranging over a spectrum of clinical domains from improved cognition to reduced caregiver burden. Increased attentiveness by clinicians to treatment response across this multidisciplinary spectrum in more advanced Alzheimer's disease is warranted.
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PMID:What are the treatment options for patients with severe Alzheimer's disease? 1522 74

Dementia is an acquired global impairment of cognitive capacities. Approximately 5% of people aged over 65 yr are affected by dementia, and some 70% of cases are thought to be due primarily to Alzheimer's disease. Descriptions of the clinical manifestations of Alzheimer's disease have been increasingly refined in the last decade but there is no diagnostic test for what remains fundamentally a pathologically defined condition. At the present time interventions for Alzheimer's disease are limited to those that modify the manifestations of the disease, and foremost amongst the candidates available are the cholinesterase inhibitors. The rationale for the use of cholinergic drugs for Alzheimer's disease lies in enhancing the secretion of, or prolonging the half-life of, acetylcholine in the brain. Several potential compounds have been tested, but short half-lives and a high incidence of cholinergic and other adverse effects have eliminated most. Only three are widely licensed for use, donepezil, galantamine and rivastigmine. Their efficacy is relatively modest. These drugs have been tested in 32 randomized, placebo-controlled trials. The trials assess cognitive function primarily, and in addition they may assess global function, activities of daily living, quality of life and behavioural disturbance typically over 3 or 6 months. The performance of each drug is summarized in a Cochrane review, a systematic review carried out according to strict guidelines. There was a significant benefit in favour of treatment compared with placebo for cognition and activities of daily living, but withdrawals due to adverse events were significantly higher for treatment than placebo for all three drugs. There is little evidence from direct comparisons between the three drugs. There are several economic analyses of the cost-effectiveness of these drugs, but the findings cannot be considered robust owing to inadequate data. A range of other pharmacological treatments have been tested, including selegiline, piracetam, vitamin E, Ginkgo biloba, anti-inflammatory drugs and hormone replacement therapy, but, so far, Cochrane reviews have not established the efficacy of these interventions for Alzheimer's disease. A Cochrane review of memantine shows benefits on cognitive and global function of the same order of magnitude as seen for the cholinesterase inhibitors. Memantine has been licensed in Europe for treatment of patients with moderately severe to severe Alzheimer's disease.
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PMID:Evidence-based pharmacotherapy of Alzheimer's disease. 1522 42

Recent clinical trials have shown that galantamine is efficacious in the treatment of mild to moderate Alzheimer's and vascular dementia, and memantine in severe stages of these diseases. Hence, the hypothesis that these two drugs might exert different degrees of neuroprotection has been tested. Rat hippocampal slices were subjected to oxygen and glucose deprivation (OGD) and to a re-oxygenation period. Neuronal damage was monitored using the lactate dehydrogenase (LDH) released into the Krebs-bicarbonate medium as an indicator. Galantamine, a mild acetylcholinesterase (AChE) blocker and nicotinic receptor modulator, given 30 min before and during OGD plus re-oxygenation (1, 2 and 3 h) significantly reduced LDH release by around 50%. Galantamine 5 microM reduced LDH release significantly during the re-oxygenation period while at 15 microM it afforded significant reduction of LDH release both during OGD and re-oxygenation. Memantine, a reversible blocker of NMDA receptors, at 10 microM only significantly reduced (40%) LDH release after 3 h re-oxygenation. The classical NMDA blocker MK-801 reduced LDH released around 40% at 1 microM at all re-oxygenation times studied. These data indicate that galantamine has a neuroprotective window against anoxia wider than memantine. Whether these differences can be clinically relevant remain to be studied in appropriate clinical trials.
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PMID:Galantamine and memantine produce different degrees of neuroprotection in rat hippocampal slices subjected to oxygen-glucose deprivation. 1524 94

Rivastigmine, a cholinesterase inhibitor, is successfully used for the symptomatic therapy of Alzheimer's disease (AD) in the clinic. The drug has a very low potential for drug-drug interactions, as has been demonstrated within large clinical trials. Memantine, recently approved by the FDA for the treatment of moderate to severe AD, acts as a low affinity, non-competitive NMDA-antagonist, on a completely different neurotransmitter system, the glutamatergic system. Given the different sites of action, the possibility to combine a cholinergic with a glutamatergic intervention as potentially superior AD therapy has recently been proposed. In vitro studies have demonstrated that memantine, when added to reversible AChE inhibitors, such as tacrine, donepezil or galantamine, did not interfere with the inhibitory action of any of these drugs. The results from the present study provide evidence that rivastigmine as a pseudo-irreversible (or slow-reversible) AChE inhibitor shares this property described for reversible inhibitors, since memantine (1-100 microM), irrespective of whether given prior to or after rivastigmine did not influence rivastigmine's AChE inhibition in vitro. A similar observation was also made under in vivo conditions (ex vivo measurements): following a 21 day chronic, oral administration of 6 micromol/kg rivastigmine alone or of a combination of rivastigmine plus memantine (6 micromol/kg p.o. of either of the two compounds), an identical degree of AChE inhibition was observed. The concentrations of rivastigmine, its metabolite NAP 226-90 and memantine were measured in the brain of the same animals. Following an equimolar oral dose (6 micromol/kg) of both compounds, the brain level of memantine exceeded that of rivastigmine + metabolite, by a factor of around 30, when measured 2 h after the final dosing, irrespective of the duration of treatment (acute, for 3 or 21 days). This indicates that neither of the two drugs showed accumulation but also, and more importantly, that memantine does not modulate the prime therapeutic action of rivastigmine (AChE inhibition) in vitro or in vivo. Clinical trials using a combination of both drugs will provide a final proof of whether a combination therapy would lead to an increased efficacy in AD patients.
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PMID:Co-administration of memantine has no effect on the in vitro or ex vivo determined acetylcholinesterase inhibition of rivastigmine in the rat brain. 1527 30

Memantine is an NMDA receptor antagonist with moderate affinity, which results in neuroprotective potential due to reducing overstimulation caused by glutamate (excitotoxicity) and simultaneous lack of adverse events (especially psychosis) typical for an antagonist with higher affinity like phencyclidine. In randomized, controlled studies it has been shown that memantine is beneficial in the treatment of moderate to severe dementia of Alzheimer's type and it became the very first compound to be registered for this purpose both in Europe (including Poland) and in the United States. Further investigation require usefulness of memantine in less advanced stages of Alzheimer's disease as well as other types of dementia especially vascular; promising results are shown in dual therapy: memantine + cholinesterase inhibitor.
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PMID:[The clinical relevance of memantine use]. 1530 96

Alzheimer's disease is the fourth largest cause of death for people over 65 years of age. Dementia of Alzheimer's type is the commonest form of dementia, the other two forms being vascular dementia and mixed dementia. At present, the therapy of Alzheimer's disease is aimed at improving both, cognitive and behavioural symptoms and thereby, quality of life for the patients. Since the discovery of Alzheimer's disease by Alois Alzheimer, many pathological mechanisms have been proposed which led to the testing of various new treatments. Until recently the available drugs for the treatment of Alzheimer's disease are cholinesterase inhibitors, which have limited success because these drugs improve cognitive functions only in mild dementia and cannot stop the process of neurodegeneration. Moreover, drugs of this category show gastrointestinal side effects. As the cells of central and peripheral nervous system cannot regenerate, newer strategies are aimed at preserving the surviving neurons by preventing their degeneration. NMDA-receptor-mediated glutamate excitotoxicity plays a major role in Abeta-induced neuronal death. Hence, it was thought that NMDA receptors could be a promising target for preventing the progression of Alzheimer's disease. All the compounds synthesized initially in this category showed toxicity mainly because of their high affinity for NMDA receptors. Memantine (1-amino adamantane derivative), NMDA-receptor antagonist was reported to be effective therapeutically in Alzheimer's disease. It was available in Germany as well as European Union and has been approved for moderate to severe dementia in United States of America recently. It is an uncompetitive, moderate affinity antagonist of NMDA receptors that inhibits the pathological functions of NMDA receptors while physiological processes in learning and memory are unaffected. Memantine is also reported to have beneficial effects in other CNS disorders viz., Parkinson's disease (PD), stroke, epilepsy, CNS trauma, amyotrophic lateral sclerosis (ALS), drug dependence and chronic pain. Mechanisms of neuroprotection, preclinical and clinical evidence for effectiveness of memantine have been provided. Pharmacology and pharmacokinetics of memantine and other NMDA-receptor antagonists in comparison with currently approved drugs for dementia treatment have been discussed. The focus is on 'glutamate excitotoxicity' and glutamate receptors as drug target. Various other novel strategies for the treatment of dementia of neurodegenerative disorders have also been discussed.
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PMID:Dementia of Alzheimer's disease and other neurodegenerative disorders--memantine, a new hope. 1551 30

Disability, characterised by the loss of ability to perform activities of daily living (ADL), is a defining feature of dementia that results in growing caregiver burden and the eventual need for alternative care or nursing home placement. Functional decline in patients with dementia can also result from causes other than dementia, such as comorbid medical and psychiatric illnesses and sensory impairment. ADL consists of instrumental ADL (IADL) [complex higher order skills, such as managing finances] and basic ADL (BADL) [self-maintenance skills, such as bathing]. Assessment of IADL and BADL is recommended to establish a diagnosis of dementia. Functional assessment also helps the healthcare provider to offer appropriate counselling regarding safety concerns and need for custodial care. Functional capacity measures have been used increasingly in pharmacological trials of patients with Alzheimer's disease (AD) and related dementias, although at the present time these measures are generally not primary outcome measures. Functional impairment is not a uniform construct; rather, it is multifaceted and can be measured with various clinical instruments. Many scales have been validated for use in patients with AD for characterising functional impairment and evaluating the efficacy of treatment. Research to date indicates that cholinesterase inhibitors have the potential for modest but meaningful beneficial effects on ADL in patients with mild-to-moderate AD. Memantine also has promising beneficial effects on functional abilities in persons with moderate-to-severe AD. Assessment of ADL as a primary efficacy measure using a validated scale that is non-gender biased and cross-nationally relevant is recommended in new treatment trials of patients with AD and related dementias.
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PMID:Activities of daily living in patients with dementia: clinical relevance, methods of assessment and effects of treatment. 1552 90

The N-methyl-d-aspartate (NMDA) receptor antagonist memantine is an approved drug for treatment of Alzheimer's disease (AD). Other such treatments are cholinesterase inhibitors and nicotinic acetylcholine receptor (nAChR)-sensitizing agents such as galantamine. The present study was designed to test whether memantine exerts any effect on the cholinergic system, in particular the Ca(2+)-conducting alpha7(*) nAChR, in cultured hippocampal neurons. Memantine caused a concentration-dependent reduction of the amplitudes of whole-cell currents evoked by the alpha7(*) nAChR-selective agonist choline (10 mM) or by N-methyl-d-aspartate (NMDA) (50 muM) plus glycine (10 muM). It also inhibited tonically activated NMDA receptors. Memantine was more potent in inhibiting alpha7(*) nAChRs than NMDA receptors; at -60 mV, the IC(50) values for memantine were 0.34 and 5.1 muM, respectively. Consistent with an open-channel blocking mechanism, memantine-induced NMDA receptor inhibition was voltage and use-dependent; the Hill coefficient (n(H)) was approximately 1. Memantine-induced alpha7(*) nAChR inhibition had an n(H) < 1 and showed a variable voltage dependence; the effect was voltage-independent at 0.1 muM, becoming voltage-dependent at >/=1 muM. Thus, memantine interacts with more than one class of sites on the alpha7(*) nAChRs. One is voltage-sensitive and therefore likely to be within the receptor channel. The other is voltage-insensitive and therefore likely to be in the extracellular domain of the receptor. It is suggested that blockade of alpha7(*) nAChRs by memantine could decrease its effectiveness for treatment of AD, particularly at early stages when the degrees of nAChR dysfunction and of cognitive decline correlate well.
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PMID:Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons. 1583 45


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