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)

The 5th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy focused on new therapeutic approaches for the treatment of Alzheimer 's disease (AD) based on the latest basic science data. The two major pharmacological principles of cholinergic therapy are 1) reduction of acetylcholine hydrolysis by means of acetylcholinesterase (AChE) inhibitors; and 2) direct stimulation of nicotinic or muscarinic receptors with selective agonists. Currently used AChE inhibitors are tacrine, donepezil hydrochloride, rivastigmine and metrifonate. In the area of muscarinic and nicotinic receptor modulation, studies were presented on AF-102B and AF-150(S), BIBN-99, CI-1017, RJR-2403, ABT-418, ABT-089, GTS-21 and SIB-1553A. Based on evidence of inflammatory mechanisms in the pathogenesis of AD, selective COX-2 inhibitors for the prevention and treatment of AD are a target of several pharmaceutical companies. Concerning known antiinflammatory drugs, results from controlled trials are expected soon. Estrogen replacement has been reported to produce cognitive and affective improvement in women with AD, and results from a number of studies were presented. Age-associated increases in oxidative stress may play a role in AD and thus antioxidants may also have a place in the therapy of this disease. The antioxidants vitamin E and selegiline are being investigated. Other drugs under investigation are propentofylline, Cerebrolysin, citicoline sodium, CDP-choline, memantine, Egb-761, calagualine and AIT-082. Iododoxorubicin may represent a new class of compounds able to interfere with the beta-amyloid cascade in AD and other brain amyloid diseases. Future preventive strategies in AD include genotype analysis and screening, presymptomatic diagnosis and avoidance of environmental risk factors.
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PMID:Alzheimer's disease therapy - an update. 1561 67

The purpose of this study was to evaluate the efficacy of an integrative treatment approach on cognitive performance. The study sample comprised 35 medically ill patients (20 male, 15 female) with an average age of 71.05, who were diagnosed with mild dementia and depression. These patients were evaluated at baseline and at six, 12, and 24 months of treatment, which included antidepressants (sertraline, citalopram, or venlafaxine XR, alone or in combination with bupropion XR), cholinesterase inhibitors (donepezil, rivastigmine or galantamine), as well as vitamins and supplements (multivitamins, vitamin E, alpha-lipoic acid, omega-3 and coenzyme Q-10). Patients were encouraged to modify their diet and lifestyle and perform mild physical exercises. Results show that the integrative treatment not only protracted cognitive decline for 24 months but even improved cognition, especially memory and frontal lobe functions.
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PMID:Integrated treatment approach improves cognitive function in demented and clinically depressed patients. 1575 50

As our population ages, the incidence and prevalence of Alzheimer disease (AD) will increase dramatically. A number of therapies have been investigated for the treatment and prevention of AD. Clinicians should be prepared to provide evidence-based answers to inquiries regarding AD treatment. There is insufficient evidence to recommend ginkgo biloba, estrogen, statins, or nonsteroidal anti-inflammatory drugs for the prevention or treatment of AD. The use of vitamin E is supported by a single randomized controlled trial, while data on other antioxidants is mixed. There is good evidence that cholinesterase inhibitors and memantine are modestly effective in the treatment of AD. Cholinesterase inhibitors appear to be effective throughout the spectrum of AD, while memantine, alone or in combination with cholinesterase inhibitors, is effective in late stage disease. There is insufficient evidence to suggest superiority of one cholinesterase over another.
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PMID:Treatments for Alzheimer disease. 1600 63

Mild cognitive impairment (MCI) is an operational definition for a cognitive decline in individuals with a greater risk of developing dementia. The amnestic subtype of MCI is of particular interest because these individuals most likely progress to Alzheimer's disease (AD). Currently hypothesised therapeutic approaches in MCI are mainly based on AD treatment strategies. Long term secondary prevention randomised clinical trials have been completed in amnestic MCI populations, encompassing agents with various mechanisms of action: acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine), antioxidants (vitamin E), anti-inflammatories (rofecoxib), and nootropics (piracetam). The design of clinical trials in MCI is influenced by study objectives and definition of primary end points: time to clinical diagnosis of dementia, and AD in particular, or symptom progression. As none of the drugs previously shown to have clinical efficacy in AD trials or benefit in everyday practice have met the primary objectives of the respective trials, design of future clinical trials in MCI should be further developed particularly as regards the selection of more homogeneous samples at entry, optimal treatment duration, and multidimensional and reliable outcomes.
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PMID:Clinical trials in mild cognitive impairment: lessons for the future. 1630 54

This review examines key pharmacological strategies that have been clinically studied for the primary or secondary prevention of Alzheimer's disease. Much information (neuropsychological, genetic and imaging) is already available to characterise an individual's risk for developing Alzheimer's disease. However, regulatory pathways for obtaining a prevention indication are less well charted, and such trials tend to involve 3- to 7-year studies of 1000 - 5000 individuals, depending on baseline status. Treatments developed for prevention will also need to have superior safety. For these reasons, > 100 proprietary pharmacological products are currently being developed for an Alzheimer's disease treatment, but only a few are being studied for prevention. Randomised trial data are available for antihypertensive agents (calcium channel blockers, angiotensin-converting enzyme inhibitors), pravastatin, simvastatin, conjugated oestrogen, raloxifene, rofecoxib, CX516 (AMPA agonist) and cholinesterase inhibitors regarding efficacy for Alzheimer's disease prevention. At least four large prevention trials of conjugated oestrogen, selenium and vitamin E, Ginkgo biloba and statins are currently underway. Strategies using other agents have not yet been evaluated in Alzheimer's disease prevention clinical trials. These include anti-amyloid antibodies, active immunisation, selective secretase inhibitors and modulators, microtubule stabilisers (e.g., paclitaxel), R-flurbiprofen, xaliproden, ONO-2506, FK962 (somatostatin releaser), SGS 742 (GABA(B) antagonist), TCH 346 (apoptosis inhibitor), Alzhemedtrade mark, phophodiesterase inhibitors, rosiglitazone, leuprolide, interferons, metal-protein attenuating compounds (e.g., PBT2), CX717, rasagaline, huperzine A, antioxidants and memantine. Studies combining lifestyle modification and drug therapy have not been conducted. Full validation of surrogate markers for disease progression (such as amyloid imaging) should further facilitate drug development. Reducing the complexity of prevention trials and gaining regulatory consensus of design is a high priority for the field.
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PMID:Pharmacological strategies for the prevention of Alzheimer's disease. 1637 Sep 17

The pathophysiology of Alzheimer's disease (AD) includes the deposition of amyloid beta protein (Abeta) and the ensuing initiation of a variety of secondary processes, including tau hyperphosphorylation, excitotoxicity, oxidation, and inflammation. Nerve cell loss in structures responsible for manufacturing neurotransmitters results in a variety of neurochemical deficits. Current therapeutic approaches to the treatment of AD include cholinesterase inhibitors for mild to moderate disease, memantine for moderate to severe disease, and vitamin E or selegiline. Reduction of Abeta generation or aggregation, enhancement of Abeta removal, interruption of tau hyperphosphorylation, and the use of more efficacious antioxidant or anti-inflammatory agents represent promising therapeutic strategies currently being investigated. Improved methodologies for clinical trial design and analysis and the development of biological markers may hasten the identification of effective treatments for AD.
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PMID:Treatment of Alzheimer's disease: current and future therapeutic approaches. 1640 Feb 59

Anticholinesterase compounds, organophosphates (OPs) and carbamates (CMs) are commonly used for a variety of purposes in agriculture and in human and veterinary medicine. They exert their toxicity in mammalian system primarily by virtue of acetylcholinesterase (AChE) inhibition at the synapses and neuromuscular junctions, leading into the signs of hypercholinergic preponderance. However, the mechanism(s) involved in brain/muscle damage appear to be linked with alteration in antioxidant and the scavenging system leading to free radical-mediated injury. OPs and CMs cause excessive formation of F2-isoprostanes and F4-neuroprostanes, in vivo biomarkers of lipid peroxidation and generation of reactive oxygen species (ROS), and of citrulline, a marker of NO/NOS and reactive nitrogen species (RNS) generation. In addition, during the course of these excitatory processes and inhibition of AChE, a high rate of ATP consumption, coupled with the inhibition of oxidative phosphorylation, compromise the cell's ability to maintain its energy levels and excessive amounts of ROS and RNS may be generated. Pretreatment with N-methyl D-aspartate (NMDA) receptor antagonist memantine, in combination with atropine sulfate, provides significant protection against inhibition of AChE, increases of ROS/RNS, and depletion of high-energy phosphates induced by DFP/carbofuran. Similar antioxidative effects are observed with a spin trapping agent, phenyl-N-tert-butylnitrone (PBN) or chain breaking antioxidant vitamin E. This review describes the mechanisms involved in anticholinesterase-induced oxidative/nitrosative injury in target organs of OPs/CMs, and protection by various agents.
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PMID:Anticholinesterase toxicity and oxidative stress. 1651 18

Methidathion (MD) phosphorodithioic acid S-[(5-methoxy-2-oxo-1,3,4-thiadiazol-3(2H)-yl)methyl] O,O-dimethyl ester is the organophosphate insecticide (OPI) most commonly used worldwide in the pest control of crops. Subchronic MD exposure was evaluated for its effects on lipid peroxidation, the serum activities of cholinesterase (ChE), and enzymes concerning liver damage, and the protective effects of combination of vitamins E and C in albino rats. Additionally, the histopathological changes in liver tissue were examined. Experimental groups were as follows: control group; a group treated with 5 mg/kg body weight MD (MD group); and a group treated with 5 mg/kg body wight MD plus vitamin E plus vitamin C (MD+AO group). The MD and MD+AO groups were treated orally with MD on five days a week for 4 weeks. The serum activities of cholinesterase (ChE), alanine transferase (ALT), aspartate amiotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), and the concentration of malondialdehyde (MDA) and liver histopathology were studied. In serum samples, MD significantly increased MDA concentration and ALP, AST, GGT, LDH activities but decreased the ALT and ChE activities. In the MD+AO group, MDA level and ALP, AST, LDH activities were significantly decreased and ChE activity was increased compared to the MD group. Histopathological changes found in liver tissue of rats treated with MD included were infiltration with mononuclear cells in all portal areas, sinusoidal dilatation, and focal microvesicular steatosis and hydropic degenerations in parenchymal tissue. The severity of these lesions was reduced by administration of vitamins. From these results, it can be concluded that subchronic MD causes liver damage, and lipid peroxidation may be a molecular mechanism involved in MD-induced toxicity. Furthermore, the combination of vitamins E and C can reduce the toxic effects of MD on liver tissue of rats.
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PMID:The effects of subchronic methidathion toxicity on rat liver: role of antioxidant vitamins C and E. 1658 3

The following parameters were determined in blood serum of apparently healthy Bennett's wallabies (Macropus rufogriseus) using the Hitachi 917 (Roche Diagnostics, Mannheim, Germany) and/or the Vettest 8008 (IDEXX-GmbH, Woerrstadt, Germany): alkaline phosphatase, alanine aminotransferase, ammonia, alpha-amylase, aspartate aminotransferase, Ca, Cl, cholesterol, cholinesterase, creatine kinase, creatinine, gammaglutamyltransferase, glucose, iron, lactate dehydrogenase, magnesium, phosphate, potassium, protein, sodium, total bilirubin, triglyceride, and urea. The results for cholesterol, glucose, total protein, triglyceride and for the enzymes alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyltransferase and lactate dehydrogenase differed significantly between both methods (P < 0.05). There is a negative correlation between the age of the Bennett's wallabies and the activity of the alkaline phosphatase. Five protein fractions could be separated on cellulose acetate electrophoresis. The mean concentrations of fructosamine and beta-hydroxybutyrate were 447.3 micromol/L and 0.27 mmol/L, respectively. The estimated vitamin A intake had no influence on the vitamin A concentration in serum. The serum vitamin E concentration was in general low and vitamin E was below the detection limit of 0.82 micromol/L in 29 out of 42 serum samples. The use of these analytes is discussed concerning the knowledge about the physiology, nutrition and diseases of macropods.
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PMID:On the clinical chemistry of the Bennett's wallaby (Macropus rufogriseus rufogriseus). 1685 6

Previous studies have suggested that statin therapy may be of benefit in treating Alzheimer's disease (AD). We initiated a double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to once-daily atorvastatin calcium (80 mg; two 40 mg tablets) or placebo among individuals with mild-to-moderate AD [Mini-Mental State Examination (MMSE) score of 12-28]. Stable dose use of cholinesterase inhibitors, estrogen and vitamin E was allowed, as was the use of most other medications in the treatment of co-morbidities. We demonstrated that atorvastatin treatment produced significantly (P = 0.003) improved performance on cognition and memory after 6 months of treatment (ADAS-cog) among patients with mild-to-moderate AD. This superior effect persisted at 1 year (P = 0.055). This positive effect on the ADAS-cog performance after 6 months of treatment was more prominent among individuals entering the trial with higher MMSE scores (P = 0.054). Benefit on other clinical measures was identified in the atorvastatin-treated population compared with placebo. Accordingly, atorvastatin therapy may be of benefit in the treatment of mild-to-moderately affected AD patients, but the level of benefit produced may be predicated on earlier treatment. Evidence also suggests that atorvastatin may slow the progression of mild-to-moderate AD, thereby prolonging the quality of an afflicted individual's life.
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PMID:Statin therapy in Alzheimer's disease. 1686 15


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