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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gait disorders form part of the axial symptoms observed in Parkinson's disease (PD) and also represent a major source of therapeutic failure in the later stages of PD, with the appearance of freezing of gait (FOG) and falls. Double-blind clinical trials and, above all, clinical experience have demonstrated that l-DOPA is effective in reducing FOG. Dopaminergic agonists appear to be less effective than l-DOPA and lack formal proof of their efficacy. The enzyme inhibitors provide modest benefits, which need to be confirmed. Hence, these symptoms appear to be partially doparesistant and justify investigation of other major neurotransmission systems. Of the various drugs with partial noradrenergic activity, methylphenidate may improve FOG and attention disorders. Memantine has shown some value in improving motor symptoms and gait in fluctuating parkinsonian patients - possibly by reducing the effect of glutamatergic hyperactivation of the subthalamic nucleus on the pedunculopontine nucleus (PPN). The PPN's dense cholinergic innervation also suggests that cholinesterase inhibitors may be of use, although any benefits must be set against a potential aggravation of rest tremor. The many interactions between the serotoninergic and dopaminergic systems require the implementation of clinical studies on the complex motor impact of serotoninergic treatments, which may aggravate the parkinsonian syndrome while improving gait (as is the case with paroxetine and ritanserin). This review seeks to develop the various pathophysiological hypotheses prompted by the results of fundamental studies and pilot clinical trials, with a view to justifying the implementation of confirmatory, double-blind, placebo-controlled therapeutic trials.
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PMID:[Pharmacological hypotheses and therapeutic strategies for gait disorders in Parkinson's disease]. 1981 97

Memantine is an uncompetitive N-methyl-D-aspartate receptor antagonist with moderate affinity. Its mechanism of action is neuroprotective and potentially therapeutic in several neuropsychiatric diseases. It has been approved by the FDA for the treatment of moderate to severe Alzheimer's disease (AD) either as a monotherapy or in combination with cholinesterase inhibitors. This review covers key studies of memantine's safety and efficacy in treating moderate to severe AD. It also covers current research into other dementias including but not exclusively mild AD and vascular dementia. Other studies on the efficacy of memantine for other neuropsychiatric diseases are discussed. Memantine is a safe and effective drug that merits further research on several topics. Clinicians should be aware of new studies and potential uses of memantine because of its safety and efficacy.
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PMID:Memantine: a review of studies into its safety and efficacy in treating Alzheimer's disease and other dementias. 1985 12

This study examined in detail patterns of cholinesterase inhibitors (ChEIs) and memantine use and explored the relationship between patient characteristics and such use. Patients with probable Alzheimer disease AD (n=201) were recruited from the Predictors Study in 3 academic AD centers and followed from early disease stages for up to 6 years. Random effects logistic regressions were used to examine effects of patient characteristics on ChEIs/memantine use over time. Independent variables included measures of function, cognition, comorbidities, the presence of extrapyramidal signs, psychotic symptoms, age, sex, and patient's living situation at each interval. Control variables included assessment interval, year of study entry, and site. During a 6-year study period, rate of ChEIs use decreased (80.6% to 73.0%) whereas memantine use increased (2.0% to 45.9%). Random effects logistic regression analyses showed that ChEI use was associated with better function, no psychotic symptoms, and younger age. Memantine use was associated with better function, poorer cognition, living at home, later assessment interval, and later year of study entry. Results suggest that high rate of ChEI use and increasing memantine use over time are consistent with current practice guidelines of initiation of ChEIs in mild-to-moderate AD patients and initiation of memantine in moderate-to-severe patients.
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PMID:Longitudinal medication usage in Alzheimer disease patients. 2062 71

It has been shown that, during several years preceding the diagnosis of Alzheimer's disease there is a gradual cognitive decline with a continuum between the pre-dementia stage (still known as the prodromal stage but now included within the general concept of mild cognitive impairment [MCI]) and the other stages of the disease. In MCI, the use of cholinesterase inhibitors (ChEIs) is not associated with any delay in the onset of Alzheimer's disease or dementia. During the dementia stages, the three ChEIs (donepezil, galantamine and rivastigmine) are efficacious for mild to moderate Alzheimer's disease; therefore, monotherapy with a ChEI can be envisaged as initial treatment. Confirmation of the efficacy of ChEIs in the mild dementia stage is essentially based on the results from a single, randomized study carried out specifically among patients at this stage of severity. Memantine can represent an alternative to ChEIs in the moderate stage of Alzheimer's disease. At the severe stage of the disease, memantine and donepezil are currently indicated. Indeed, memantine has been approved by numerous drug regulatory agencies for use in severe stages of the disease, whereas donepezil has only been approved by the US FDA. There is currently insufficient evidence for recommending combination therapy in Alzheimer's disease.
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PMID:Managing cognitive dysfunction through the continuum of Alzheimer's disease: role of pharmacotherapy. 2132 93

The primary objective of this study was to evaluate the rate of total brain atrophy (TBA) with serial magnetic resonance imaging (MRI), using the Brain Boundary Shift Integral (BBSI), in patients with probable Alzheimer's disease (AD) over the course of 52 weeks of treatment with memantine or placebo. This was a multi-national, randomized, double-blind, placebo-controlled, fixed-dose 1-year study. Patients were randomized (1 : 1) to treatment with placebo or memantine. Patients randomized to memantine were up-titrated to the target dose of 20 mg/day over 4 weeks. MRI scans were collected at screening and at Weeks 4, 42, and 52. Secondary efficacy assessments included several cognitive and behavioral scales. 518 patients were screened, 278 patients were randomized, and 217 patients completed the study. In the primary efficacy analysis, the differences in TBA rates between memantine (15.2 mL/year) and placebo (15.3 mL/year) were not statistically significant (-0.04 mL/year [(95% CI: -2.60, 2.52), p = 0.98]). There was a statistically significant correlation between change in TBA and change in most cognitive and behavioral scale scores. Patients who were not treated with acetyl cholinesterase inhibitors (AChEIs) showed a significantly lower TBA rate than patients treated with AChEIs. Memantine had a placebo-level incidence of adverse events. There were no statistically significant differences between memantine and placebo in total brain or hippocampal atrophy rates in patients with probable AD treated for 1 year. The biological relevance of cerebral atrophy was supported by a significant correlation between rate of atrophy and decline in cognitive and behavioral outcomes.
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PMID:Memantine and brain atrophy in Alzheimer's disease: a 1-year randomized controlled trial. 2226 60

Until 2010, Donepezil, one of choline esterase inhibitors, was solely available for the treatment of AD. At spring 2011, new 3 anti-dementia drugs were launched. These 3 drugs are Galantamine (choline esterase inhibitor), Rivastigmine (choline esterase inhibitor), and Memantine (NMDA antagonist). Galantamine has the indication for mild to moderate AD, and Rivastigmine, which is available only in the patch formulation, also has the indication for mild to moderate AD. However, co-medication of choline esterase inhibitors is not allowed. Memantine has the indication for moderate to severe AD, and can be prescribed with one choline esterase inhibitor. From now on, we have a variety of therapeutic choices including the co-medication, resulting in the therapy best fit to individual AD patients.
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PMID:[New anti-AD drugs--their possibilities and issues]. 2256 59

With ageing of populations, the worldwide population of persons with dementia will reach over 81 million by 2040, of which the most common cause is Alzheimer's disease. In recent years, there have been major advances in the understanding of its pathogenesis, methods to diagnose it, and treatment. Magnetic resonance brain imaging, cerebrospinal fluid biomarkers, and Pittsburgh compound B and fluorodeoxyglucose positron emission tomography of the brain can facilitate an accurate diagnosis of Alzheimer's disease in its early stage, and diagnose the mild cognitive impairment stage of Alzheimer's disease. At present, only symptomatic but not disease-modifying drug treatments are available. Donepezil, rivastigmine and galantamine are the currently approved cholinesterase inhibitors for the treatment of mild, moderate, and severe Alzheimer's disease. Overall, cholinesterase inhibitors show beneficial effects on cognition, activity of daily living, behaviour, and overall clinical rating. Memantine is another symptomatic treatment for moderate-to-severe Alzheimer's disease patients. It has a small beneficial effect on cognition, activity of daily living, behaviour, and overall clinical rating. Vitamin E has antioxidant properties, and may be used in some Alzheimer's disease patients without vascular risk factors. Concurrent non-pharmacological and psychosocial management of patients and their caregivers have a very important role. Disease-modifying therapies are still under development, whilst immunotherapy may be a viable option in the near future.
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PMID:Alzheimer's disease: early diagnosis and treatment. 2286 86

With the aging population and its rapidly increasing prevalence, dementia has become an important public health concern in developed and developing countries. To date, the pharmacological treatment is symptomatic and based on the observed neurotransmitter disturbances. The four most commonly used drugs are donepezil, galantamine, rivastigmine and memantine. Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors with different pharmacodynamic and pharmacokinetic profiles. Donepezil inhibits selectively the acetylcholinesterase and has a long elimination half-life (t(1/2)) of 70 h. Galantamine is also a selective acetylcholinesterase inhibitor, but also modulates presynaptic nicotinic receptors. It has a t(1/2) of 6-8 h. Donepezil and galantamine are mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4 in the liver. Rivastigmine is a so-called 'pseudo-irreversible' inhibitor of acetylcholinesterase and butyrylcholinesterase. The t(1/2) of the drug is very short (1-2 h), but the duration of action is longer as the enzymes are blocked for around 8.5 and 3.5 h, respectively. Rivastigmine is metabolised by esterases in liver and intestine. Memantine is a non-competitive low-affinity antagonist of the NMDA receptor with a t(1/2) of 70 h. Its major route of elimination is unchanged via the kidneys. Addressing the issue of inter-patient variability in treatment response might be of special importance for the vulnerable population taking anti-dementia drugs. Pharmacogenetic considerations might help to avoid multiple medication changes due to non-response and/or adverse events. Some pharmacogenetic studies conducted on donepezil and galantamine reported an influence of the CYP2D6 genotype on the pharmacokinetics of the drugs and/or on the response to treatment. Moreover, polymorphisms in genes of the cholinergic markers acetylcholinesterase, butyrylcholinesterase, choline acetyltransferase and paraoxonase were found to be associated with better clinical response to acetylcholinesterase inhibitors. However, confirmation studies in larger populations are necessary to establish evidence of which subgroups of patients will most likely benefit from anti-dementia drugs. The aim of this review is to summarize the pharmacodynamics and pharmacokinetics of the four commonly used anti-dementia drugs and to give an overview on the current knowledge of pharmacogenetics in this field.
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PMID:Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease. 2340 70

The effect of memantine administration has been studied on the model of mice poisoning with an anticholinesterase compound. It is established that the memantine action is due to its influence on the cholinesterase activity in the brain, blood plasma, and erythrocytes in addition to its NMDA-blocking action. Memantine promotes oxime-induced erythrocyte enzyme reactivation on the model of mice poisoning with anticholinesterase compound (0.8 LD50).
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PMID:[Specific features of the anticonvulsant effect of memantine in mice intoxicated with a model organic phosphate]. 2363 Dec 74

Galantamine, rivastigmine, and memantine, for the treatment of Alzheimer-type dementia, became covered by national health insurance last year in Japan. Galantamine and rivastigmine are choline esterase inhibitors, and memantine is a glutamate NMDA receptor antagonist. Galantamine also acts on the nicotinic acetylcholine receptor, in addition to ChEI, and it has an APL action and modulates the receptor function by inducing a structural change of the receptor, as its characteristics. Rivastigmine is used only in patch form, and exhibits an inhibitory effect on butyryl choline esterase. Memantine protects nerve cells by inhibiting excess actions of glutamate. These drugs are also effective for BPSD accompanying dementia. Particularly, memantine exhibits an inhibitory effect on aggressiveness and excitement, as its characteristic. The administration of these 3 drugs for diseases other than Alzheimer-type dementia is not covered by national health insurance. These are expected to be effective for dementia with Lewy bodies, but there has been no evidence reported of an effect on frontotemporal dementia. Dementia manifests diverse symptoms in the course, and consideration of the physical symptoms is indispensable. The thoughtless continuation of anti-dementia and psychiatric agents without consideration of temporary changes and diversity and changes in needs for medical care impair a patient's vital functions and QOL. Those who are involved in the treatment of dementia should always consider the clinical course and changes in needs for psychiatric and physical medical care, and novel anti-dementia drugs should be used based on these.
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PMID:[Effectiveness and limitation of newly approved drugs for Alzheimer's disease]. 2369 91


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