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)

The latency of P300 "cognitive" event-related potentials changes if cholinergic activities of the central nervous system are pharmacologically manipulated. We tested the hypothesis that the new cholinesterase inhibitors donepezil (DPZ) and rivastigmine (Riv) may have an effect on the frequently abnormal P300 component in patients with Alzheimer disease (AD), thereby allowing a significant evaluation of cholinesterase inhibitors. We evaluated 60 patients with mild to moderately severe probable AD, in comparison with 60 age-matched control subjects, with P300 recordings and neuropsychologic examinations. Forty patients were randomly assigned in a double-blinded trial to 5-10 mg/d DPZ versus 2,000 IU/d vitamin E, and 20 patients were instead treated in an open trial with 1.5 to 12 mg/d Riv. In patients treated with vitamin E, we observed latency increments (7.4 +/- 3.5 msec) correlated with worsening neuropsychologic test scores. In patients treated with DPZ and Riv, we found significant P300 latency reductions (15.3 +/- 3.2 msec and 22.0 +/- 3.3 msec). Shorter P300 latencies were associated with higher Wechsler Adult Intelligence Scale scores and with lower AD Assessment Scale-cognitive subscale (ADAS-cog) scores (R = 0.72). Correlations between ADAS-cog changes and P300 changes significantly separated patients treated with DPZ and Riv from those treated with vitamin E. Administration of DPZ and Riv reduced the latencies of P300 components proportionately to neuropsychologic test improvements. Combined P300 and neuropsychologic test evaluation significantly separated DPZ-treated patients and Riv-treated patients from vitamin E-treated patients.
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PMID:Donepezil, rivastigmine, and vitamin E in Alzheimer disease: a combined P300 event-related potentials/neuropsychologic evaluation over 6 months. 1129 Aug 80

Alzheimer's disease is a chronic and progressive neurodegenerative disorder characterized by cognitive and functional deficit and by behavior disturbance. This disease presents a major clinical and social challenge. Increasing evidence suggests that early intervention can delay the progression of the disease and improve symptoms and cognitive functioning. Recent research focuses on genetic susceptibility. Genetic testing may eventually prove to be useful in identifying persons at risk before the onset of symptoms, but at this stage, this testing plays a limited role in identifying and confirming the diagnosis and in genetic counseling. The diagnostic work in all suspected cases of dementia should be started by family physicians; confirmed cases should be treated as soon as possible by the family physician or referred to a psychiatrist or neurologist for appropriate treatment. Donepezil, new cholinesterase inhibitors, and vitamin E have proved effective in delaying progression of Alzheimer's disease.
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PMID:Alzheimer's disease: recent advances in etiology, diagnosis, and management. 1176 66

The management of dementia patients encompasses pharmacologic, behavioral, and psychosocial intervention strategies. Before pharmacologic intervention is instituted, it is important that sources of excess disability and comorbidity be eliminated or reduced. Identification of comorbid medical and psychiatric conditions, such as depression and delirium, should be identified and appropriately treated. Providing caregivers with education, support, and practical advice is a critical component of the management of the demented patient. The current standard of care for pharmacologic management of the cognitive and functional disabilities of AD consists of the combination of a cholinesterase inhibitor and high-dose vitamin E. This standard is based on the results of large-scale, double-blind, placebo-controlled trials. Cholinesterase inhibitors are the only FDA-approved pharmacologic treatments for AD. Cholinesterase inhibitors have been shown to be effective in the treatment of the cognitive, behavioral, and functional deficits of AD. Large-scale placebo-controlled trials of tacrine, donepezil, rivastigmine, and galantamine have demonstrated moderate benefits in patients with mild to moderate AD. Donepezil, rivastigmine, and galantamine are the first-line choices in the treatment of AD because of their lack of hepatotoxicity, ease of administration, few significant drug-drug interactions, and mild to moderate side effects. There are few contraindications to the use of cholinesterase inhibitors. Known hypersensitivity to a specific drug or its derivatives is the only true contraindication. Cautious administration of cholinesterase inhibitors is advised in patients who have a previous history of allergy or adverse reactions to prior cholinesterase inhibitors, severe liver disease, preexisting bradycardia, peptic ulcer disease, current alcoholism, asthma, or chronic obstructive pulmonary disease. Nausea, vomiting, diarrhea, and anorexia are the most common side effects of cholinesterase inhibitors. These gastrointestinal side effects can be minimized by gradual dose increases, administration with food, adequate hydration, and judicious use of an antiemetic. Vitamin E has been demonstrated to slow the progression of AD in several small and one large placebo-controlled trials. Because of its low cost and safety, it is recommended in addition to a cholinesterase inhibitor for the treatment of AD. There are no FDA-approved treatments for DLB and VaD. One small placebo-controlled trial demonstrated that rivastigmine may be effective in the treatment of DLB. More large-scale placebo-controlled trials are needed to confirm the results of this study. Treatment of VaD focuses on the control, identification, and management of cerebrovascular disease and vascular risk factors. Although there are no peer-reviewed reports on the efficacy of cholinesterase inhibitors for VaD or mixed AD/VaD, early reports suggest that these agents may also be effective for mixed AD/VaD. The indications for the use of cholinesterase inhibitor drugs are eventually likely to broaden to include DLB, mixed AD/VaD, and AD in its more advanced stages.
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PMID:Pharmacologic treatments of dementia. 1217 Oct 61

Methidathion (MD) [ O, O-dimethyl S-(2,3-dihydro-5-methoxy-2-oxo-1,3,4-thiadiazol-3-ylmethyl) phosphorodithioate] is one of the most widely used organophosphate insecticides (OPIs) in agriculture and public health programmes. We have, therefore, examined the in vivo and in vitro effects of MD on the serum activities of cholinesterase (ChE), enzymes concerning liver damage and lipid peroxidation (LPO; only in vivo), and have evaluated the ameliorating effects of a combination of vitamins E and C against MD toxicity. The in vivo experimental groups were: control group, MD-treated group (MD), and a group treated with MD plus vitamin E plus vitamin C (MD+Vit). The MD and MD+Vit groups were treated orally with a single dose of 8 mg MD/kg body weight at 0 h. Vitamin E and vitamin C were injected at doses of 150 mg/kg body weight i.m. and 200 mg/kg body weight i.p., respectively, 30 min after the treatment with MD in the MD+Vit group. Blood samples were taken 24 h after the MD administration. For in vitro study, venous blood samples were obtained from volunteers, and serum recovered. The activities of serum enzymes were determined in each sample and these served as 0 h values. Each sample was divided into four portions, each of which served as one of the experimental groups, as follows: control group, vitamin E plus vitamin C group (Vit), MD-treated group (MD) and MD plus vitamin E plus vitamin C group (MD+Vit). Vitamin E and vitamin C were added at doses of 7.5 and 10 micro g/ml, respectively, into the Vit and MD+Vit groups. MD was added at doses of 0.4 mg/ml into the MD and MD+Vit groups. The activities of serum enzymes were determined in each sample at 24 h. The results of the in vivo experiment demonstrated that thiobarbituric acid reactive substances were increased in the MD group compared with the control group, and decreased in the MD+Vit group compared with MD group. ChE activity was decreased in both MD and MD+Vit groups compared with controls and increased in the MD+Vit group compared with the MD group. The activities of aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT) and lactate dehydrogenase (LDH) were increased in both the MD and MD+Vit groups compared with the control group. AST activity was decreased in MD+Vit group compared with the MD group. Alanine aminotransferase (ALT) activity was decreased in both the MD and MD+Vit groups compared with control group. The results of in vitro experiment showed that all enzyme activities remained unchanged in both the control and Vit groups compared with values at 0 h. The activities of ChE, ALT and LDH were decreased in both the MD and MD+Vit groups compared with 0 h values. There was no significant difference between the MD and MD+Vit groups. The activities of AST, ALP and GGT remained unchanged in all groups. From these results, it can be concluded that MD caused liver damage, and LPO may be one of the molecular mechanisms involved in MD-induced toxicity. Single-dose treatment with a combination of vitamins E and C after the administration of MD can reduce LPO caused by MD.
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PMID:The effects of methidathion on lipid peroxidation and some liver enzymes: role of vitamins E and C. 1218 16

The pathophysiology of Alzheimer's disease is complex and involves several different biochemical pathways. These include defective beta-amyloid (Abeta) protein metabolism, abnormalities of glutamatergic, adrenergic, serotonergic and dopaminergic neurotransmission, and the potential involvement of inflammatory, oxidative and hormonal pathways. Consequently, these pathways are all potential targets for Alzheimer's disease treatment and prevention strategies. Currently, the mainstay treatments for Alzheimer's disease are the cholinesterase inhibitors, which increase the availability of acetylcholine at cholinergic synapses. Since the cholinesterase inhibitors confer only modest benefits, additional non-cholinergic Alzheimer's disease therapies are urgently needed. Several non-cholinergic agents are currently under development for the treatment and/or prevention of Alzheimer's disease. These include anti-amyloid strategies (e.g. immunisation, aggregation inhibitors, secretase inhibitors), transition metal chelators (e.g. clioquinol), growth factors, hormones (e.g. estradiol), herbs (e.g. Ginkgo biloba), nonsteroidal anti-inflammatory drugs (NSAIDs, e.g. indomethacin), antioxidants, lipid-lowering agents, antihypertensives, selective phosphodiesterase inhibitors, vitamins (E, B12, B6, folic acid) and agents that target neurotransmitter or neuropeptide alterations. Neurotransmitter receptor-based approaches include agents that modulate certain receptors (e.g. nicotinic, muscarinic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid [AMPA], gamma-aminobutyric acid [GABA], N-methyl-D-aspartate [NMDA]) and agents that increase the availability of neurotransmitters (e.g. noradrenergic reuptake inhibitors). Of these strategies, the NMDA receptor antagonist memantine is in the most advanced stage of development in the US and is already approved in Europe as the first treatment for moderately severe to severe Alzheimer's disease. Memantine is proposed to counteract cellular damage due to pathological activation of NMDA receptors by glutamate. Results with Ginkgo biloba have been mixed. Data for neurotrophic therapies and vitamin E (tocopherol) appear promising but require confirmation. NSAIDs and conjugated estrogens have not proven to be of value to date for the treatment of Alzheimer's disease. Statins may have a potential role in reducing the risk or delaying the onset of Alzheimer's disease, although this has yet to be confirmed in randomised trials. There are currently no data to support the use of statins as a treatment for dementia. This article provides an update on the current status of selected agents, focusing primarily on those agents with the most extensive clinical evidence at present.
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PMID:Non-cholinergic strategies for treating and preventing Alzheimer's disease. 1242 Nov 15

Development of dementia depends on genetic susceptibility and on risk factors accessible to primary prevention. Among the latter, vascular risk factors are well defined: prevention of hyperhomocysteinemia, diabetes mellitus, hypercholesterolemia, and, to some extent, of arterial hypertension could avoid the cognitive decline of dementia. Estrogen replacement therapy, antiinflammatory drugs, alcohol, vitamin E and intellectual activities seem efficacious in term of primary prevention. When dementia is present, only vitamin E, selegiline and some antiinflammatory drugs have proved efficacy compared to placebo to slow the cognitive decline. Long-term effects of cholinesterase inhibitors need to be investigated in future trials.
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PMID:[Prevention of dementia: is it possible?]. 1286 24

A cascade of pathophysiological events is triggered in Alzheimer disease (AD) that ultimately involves common cellular signaling pathways and leads to cellular and network dysfunction, failure of neurotransmission, cell death, and a common clinical outcome. The process is asynchronous, meaning that viable neurons remain as targets for therapy even in the diseased state, and each stage of the cascade affords the possibility for therapeutic intervention. Cholinesterase inhibitors are the only available treatment in the United States for patients with mild to moderate AD, helping maintain cognitive and functional abilities in most patients and conferring beneficial behavioral effects in some. Memantine is an NMDA receptor antagonist that has recently been approved in Europe for treatment of moderately severe to severe AD and is under investigation in the United States. Its mechanism of action may include enhanced neurotransmission in several systems as well as antiexcitotoxic effects. There are data regarding the effectiveness of the combination of memantine with cholinesterase inhibitors that will be useful for the practicing clinician. Other agents have shown some benefit in clinical trials, including the antioxidants vitamin E, selegiline, and Ginkgo biloba extracts, although the weight of evidence regarding their effects is not sufficient to define clinical practice. Potential future therapies currently are in development that target multiple aspects of the illness cascade, including aberrant inflammation, neurotrophic function, and processing of beta amyloid and tau proteins. These newer approaches hold promise for disease modification but are as yet unproven. Whether or not disease-modifying or preventive therapies become a reality, clinicians will be faced with AD patients who require treatment at all stages of illness for the indefinite future. Cholinergic and emerging noncholinergic medications will likely prevail as the standards of treatment for years to come.
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PMID:Current treatment for Alzheimer disease and future prospects. 1451 16

Fluctuating cognition is evidenced in different forms of dementia and is accompanied by electroencephalographic (EEG) abnormalities. The authors hypothesize that cholinesterase inhibitors are effective mostly in patients with fluctuating cognition. Twenty-three patients affected by mild dementia with similar scores on Mini-Mental State Examination (MMSE), Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog), and Unified Parkinson's Disease Rating Scale evaluation were classified in a group with fluctuating cognition (n = 11) and a group of nonfluctuators (n = 12). All patients were assigned randomly to the branches of a double-blind crossover study of donepezil (DPZ), a 5 to 10-mg dose, versus vitamin E, a 2000 IU dose, for 30 days. MMSE, ADAS-cog, University of California at Los Angeles Neuropsychiatric Inventory (NPI), quantitative EEG, P3 event-related potentials, choice reaction time variability (CRTV) were assessed at baseline and at the end of treatments. At the end of the crossover study all patients received DPZ for 6 months. The dominant EEG frequency variability, low EEG frequencies amplitude, the P3 latency and jitter, CRTV, and NPI was significantly different in the fluctuating cognition group than the nonfluctuating group at baseline (P < 0.001). Short-term DPZ administration induced a significant increase in MMSE scores, reduction of ADAS-cog and of NPI scores (P < 0.003-0.001), increase of EEG alpha activity and reductions of P3 latency and jitter, dominant frequency variability and CRTV (P < 0.009-0.001) in the fluctuating cognition group, and significant increases of MMSE scores (P = 0.03) and a decrease of P3 jitter and dominant frequency variability (P < 0.034-0.041) in the nonfluctuating group. Short-term DPZ effects differed significantly between fluctuating cognition and nonfluctuating patients (0.001). Significant effects of the 6-month observation were observed only in fluctuating cognition patients. Logistic analysis showed that P3 latency predicts the effect of DPZ (P = 0.04, P < 0.01) in the crossover study, and CRTV predicts the effect at the 6-month follow-up.
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PMID:The effects of a cholinesterase inhibitor are prominent in patients with fluctuating cognition: a part 3 study of the main mechanism of cholinesterase inhibitors in dementia. 1452 Jan 64

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

We have examined the effect of subchronic methidathion (MD) administration on heart damage, and have evaluated possible ameliorating effects of a combination of vitamins E and C against MD toxicity. The experimental groups were: control group, rats treated with 5 mg/kg MD and rats treated with 5 mg/kg body weight MD plus vitamin E and vitamin C (MD+Vit). The groups were given MD by gavage 5 days a week for four weeks at a dose level of 5 mg/kg/day (MD and MD+Vit) by using corn oil as the vehicle. Vitamin E and vitamin C were injected at doses of 50 mg/kg i.m. and 20 mg/kg i.p., respectively, after the treatment with MD in the MD+ Vit group. The levels of malondialdehyde (MDA) were determined in the heart tissue, and the levels of cardiac troponin I (TnI) in serum. An autoanalyser was used to determine the serum activities of cholinesterase (ChE). Histopathological examination was carried out in the heart tissue. MDA significantly increased in the MD group as compared to controls (P <0.01). When MD was given concurrently with vitamins E and C, the increase in MDA was significantly less (P <0.01). ChE activity significantly decreased in the MD group as compared to controls (P <0.01). When MD was given concurrently with vitamins E and C, the decrease in ChE activity was significantly higher (P <0.05). The serum TnI levels significantly increased in the MD group as compared to controls (P <0.01). When MD was given concurrently with vitamins E and C, the increase in the serum TnI was significantly less (P <0.01). MD caused the diffuse loss of striation and myocytolysis of the cardiomyocytes, whereas the combination of vitamins E and C caused a significant decrease in these effects of MD. In conclusion, subchronic MD administration caused heart damage and, in addition, treatment with a combination of vitamins E and C after the administration of MD reduced heart damage caused by MD.
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PMID:Cardiotoxicity in rats induced by methidathion and ameliorating effect of vitamins E and C. 1531 49


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