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)

Carbaryl, a widely used insecticide, is reputed to have a wide safety margin. It can induce acute cholinesterase poisoning, which is rapidly reversible on discontinuation of exposure. Long-term sequelae from long-term exposure have not previously been described in humans. This report describes the experience of a 75-year-old man who had long-term excessive exposure to carbaryl and in whom a debilitating syndrome, including headaches, memory loss, proximal muscle weakness, muscle fasciculation, muscle cramps, and anorexia with marked weight loss, developed. At the time of diagnosis, serum pseudocholinesterase levels were low, and his major symptoms resolved on termination of exposure. Late clinical features were sleep apnea and progressive development of a peripheral neuropathy. The difficulty in diagnosing the cause of a group of relatively nonspecific symptoms raises the question of whether chronic carbaryl neurotoxicity might be occurring more frequently than previously suspected.
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PMID:Subacute neurotoxicity following long-term exposure to carbaryl. 308 76

A case in which SPECT brain imaging was used in the diagnosis and treatment of chronic effects from acute acetylcholinesterase inhibitor poisoning is presented. The patient was exposed to an insecticide mixture containing phosphorothiate, pyrethrin, piperonyl butoxide, and petroleum distillates, which produced symptoms consistent with acute acetylcholinesterase inhibitor poisoning as well as an upper respiratory tract irritant. Delayed sequelae of gross neurologic symptoms followed, that is, coarse tremor, intermittent hemiballistic movements of the right arm and leg, flaccid muscular tone, fasciculations of muscle groups, muscle cramps, and sensory disturbances. A brain single-photon emission computerized tomography (SPECT) scan was performed 34 mo postexposure, revealing significantly decreased blood flow to the left temporal lobe and to the right and left basal ganglia. The patient's paresthesias were treated with phenytoin, which resulted in worsening of her movement disorder. A trial of amantadine and selegiline (Deprenyl) resulted in a dramatic reduction in dysfunctional movements and ataxia. Post amantadine and selegiline therapy, brain SPECT images revealed significantly improved blood flow with minimally decreased blood flow to the right and left basal ganglia. The use of SPECT scan techniques helped to elucidate objective chronic central nervous system effects subsequent to an acute insecticide exposure and also assisted in the evaluation of the effectiveness of therapeutic intervention.
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PMID:Evaluation of chronic neurological sequelae after acute pesticide exposure using SPECT brain scans. 812 50

Cholinesterase inhibitors (ChEIs) are dosed in two phases for the treatment of dementia, an initial dose-escalation phase to achieve a therapeutic dose and a maintenance phase where the therapeutic dose is given for long-term therapy. ChEIs are associated with a range of side effects as a result of cholinergic stimulation in different areas of the brain and the periphery Acute, centrally-mediated gastrointestinal events (mostly nausea and vomiting) are class effects of all ChEIs, and are reported mostly during the dose-escalation phase of therapy. These events have been associated more with the dual acetylcholinesterase/butyrylcholinesterase (AChE/BuChE) inhibitor rivastigmine than with the AChE-selective inhibitors donepezil and galantamine, probably due to rivastigmine's higher potency. However, these events can be minimised using slow dose escalation with small dose graduations and administration with food. Other side effects associated with ChEIs include central nervous system events, extrapyramidal symptoms, sleep disturbances and cardiorespiratory events, associated with cholinergic activity in the cortex, caudate nucleus, brainstem and medulla, respectively, and muscle cramps and weakness, cardiorespiratory events and urinary incontinence, associated with peripheral cholinergic activity. These symptoms are mostly reported during the maintenance phase of therapy. They are more frequently reported with donepezil, but are rarely reported with rivastigmine, and galantamine may not have been marketed long enough to make an adequate assessment. These differences are due to the drugs' respective pharmacology. For example, donepezil and rivastigmine are active centrally, in contrast to galantamine, which is more active peripherally. Furthermore, rivastigmine preferentially inhibits the G1 isoform of cholinesterase, predominantly located in the cortex, hippocampus and in neuritic plaques, while donepezil and galantamine are not selective for any cholinesterase isoforms and have wide cholinergic activity both centrally and peripherally The cholinergic activity of rivastigmine, in contrast to donepezil and galantamine, is apparently more targeted at clinically relevant brain sites. The pharmacological profile of rivastigmine results in it having a low potential to interact with other drugs and it may be used with a high margin of safety in patients having a wide variety of concomitant diseases. Donepezil and galantamine may have significant interactions with other drugs that are metabolised by the hepatic cytochrome system and therefore need to be used with caution in patients with many concomitant illnesses. When dosed with care, ChEIs are well tolerated and patient compliance and patient and caregiver acceptability are good. The favourable tolerability and safety profiles of these agents make them suitable first-line therapy for dementia. In addition, patients who have tolerability and/or safety problems in maintenance treatment that limit the use of donepezil or galantamine may benefit from switching to rivastigmine.
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PMID:The tolerability and safety of cholinesterase inhibitors in the treatment of dementia. 1213 67

This article reviews the piperidine derivative, donepezil hydrochloride (E2020, Aricept), a reversible central acetylcholinesterase inhibitor currently approved for treatment of mild-to-moderate Alzheimer's disease. Donepezil is well absorbed orally, unaffected by food or by time of administration; it reaches therapeutic levels in doses of 5-10 mg/day and peak plasma concentrations are obtained 3-4 h after oral administration. A single bedtime dose is recommended due to the long elimination half-life of the drug (70 h). Donepezil does not cause liver toxicity or significant drug interactions and is relatively well-tolerated. Initial side effects include nausea, vomiting, diarrhoea, insomnia, muscle cramps, fatigue, anorexia and syncope. Caution is advised in patients with bradycardia. Long-term use of donepezil in AD has been found to delay nursing-home placement and to result in caregiver respite. Donepezil also slows deterioration of cognition and global function in patients with moderate-to-severe AD, with improvement of abnormal behaviours. In addition to AD, donepezil demonstrates significant improvement in cognition, global function and activities of daily living in comparison with placebo-treated patients with vascular dementia and has potential therapeutic benefit for other neurological conditions.
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PMID:Donepezil: a clinical review of current and emerging indications. 1468 Apr 45

Caregivers play a determining role in choosing treatments for persons with Alzheimer's disease. The objective of this study was to examine caregivers' willingness to have persons with Alzheimer's disease continue taking cholinesterase inhibitors in the event that any 1 of 11 adverse effects was to occur. Data were gathered via postal questionnaire from 375 caregivers in Montreal. Sixty-four per cent of caregivers responded ( n = 201), and most (> or =59%) were willing to continue treatment if persons with Alzheimer's disease suffered from weight loss or loss of appetite. However, most (> or =53%) were not willing to continue treatment in the event of headache, dizziness, nausea, diarrhea, vomiting, drop in blood pressure, insomnia, muscle cramps, or stomach bleeding. The use of cholinesterase inhibitors by persons with Alzheimer's disease was positively associated with caregivers' willingness to accept greater numbers of adverse effects (adjusted relative risk = 1.97; 95% CI = 1.11 to 3.61). Caregivers appear to make a risk-benefit assessment when they decide whether or not care-recipients should continue pharmacotherapy in the event of adverse effects.
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PMID:Caregiver acceptance of adverse effects and use of cholinesterase inhibitors in Alzheimer's disease. 1823 27

Rivastigmine is a potent acetyl- and butyrylcholinesterase inhibitor widely used for cognitive improvement in Alzheimer's disease (AD) therapy. However, dose-limiting adverse effects restrict its tolerability and clinical outcomes. This study explored new combined therapy, in which peripheral cholinergic adverse effects and central cognitive amelioration of rivastigmine were differentiated by a peripheral cholinoceptor antagonist anisodamine. The results demonstrated that rivastigmine (0.75 and 2.0 mg/kg) could significantly reverse the scopolamine-induced cognitive deficit in mice through passive avoidance test. Nevertheless, a high dose of rivastigmine (3.25 mg/kg) would compromise cognitive amelioration and produce obvious adverse effects, including hypersalivation, intestinal hyperperistalsis and muscle cramp. Interestingly, concomitant administration of anisodamine (10 mg/kg) effectively counteracted both the muscarinergic and nicotinergic adverse effects, while facilitating cognitive amelioration of rivastigmine (3.25 mg/kg). These findings provide an insight into the feasibility of combined therapy with cholinesterase inhibitors and peripheral cholinoceptor antagonists for the treatment of AD.
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PMID:Peripheral cholinoceptor antagonist anisodamine counteracts cholinergic adverse effects and facilitates cognitive amelioration of rivastigmine. 1975 70

A 65-year-old male developed fatigable weakness of ocular and bulbar muscle and positive anti-acetyl cholinesterase antibodies suggesting the diagnosis of myasthenia gravis. His condition responded to anticholinesterase and immunotherapy. However, 18 months later, he developed painful paresthesiae, muscle cramps with hyperhiderosis, and was diagnosed as having Isaac's syndrome (neuromyotonia, continuous muscle fibre activity). Computed tomography of the chest revealed a thymic mass, which was confirmed after surgery and histopathology as thymic cell carcinoma. The co-occurrence of myasthenia gravis and continuous muscle fiber activity should prompt the consideration of the occurrence of these disorders as one of the paraneoplastic manifestations, most often due to a thymic neoplasm. Both these conditions respond to treatment of underlying thymoma. This case is a very rare presentation worth reporting.
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PMID:Isaac's syndrome associated with myasthenia gravis and thymoma. 2291 73

Donepezil (DPZ) is an acetylcholinesterase inhibitor used for the clinical treatment of mild cognitive impairment. However, DPZ has been reported to have adverse effects, including causing abnormal cardiac rhythm, insomnia, vomiting, and muscle cramps. However, the existence of these effects in subjects without Dementia is unknown. In this study, we use zebrafish to conduct a deeper analysis of the potential adverse effects of DPZ on the short-term memory and behaviors of normal zebrafish by performing multiple behavioral and biochemical assays. Adult zebrafish were exposed to 1 ppm and 2.5 ppm of DPZ. From the results, DPZ caused a slight improvement in the short-term memory of zebrafish and induced significant elevation in aggressiveness, while the novel tank and shoaling tests revealed anxiolytic-like behavior to be caused by DPZ. Furthermore, zebrafish circadian locomotor activity displayed a higher reduction of locomotion and abnormal movement orientation in both low- and high-dose groups, compared to the control group. Biomarker assays revealed that these alterations were associated with an elevation of oxytocin and a reduction of cortisol levels in the brain. Moreover, the significant increases in reactive oxygen species (ROS) and malondialdehyde (MDA) levels in muscle tissue suggest DPZ exposure induced muscle tissue oxidative stress and muscle weakness, which may underlie the locomotor activity impairment. In conclusion, we show, for the first time, that chronic waterborne exposure to DPZ can severely induce adverse effects on normal zebrafish in a dose-dependent manner. These unexpected adverse effects on behavioral alteration should be carefully addressed in future studies considering DPZ conducted on zebrafish or other animals.
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PMID:Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments. 3296 60