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)

PAM, a cholinesterase reactivator, was administered orally and parenterally to 37 patients with multiple sclerosis and a control group of 24 patients with other neurological diseases and pain syndromes. The effects of the administration of this compound in these patients with and without electrical stimulation of the spinal cord were studied. The clinical response to the drug follows a known time course and is dose related. Administration of large doses orally or intravenously aggravates existing neurological dysfunction. With a dose of 1,000 mg intravenously, a characteristic response is the temporary appearance of new ophthalmological abnormalities, followed by significant improvement in motor control and behavior, which gradually subsides. Parenteral administration is superior to oral. Tolerance to the drug is observed. The presence of electrical stimulation of the spinal cord complements the action of the drug. When electrical stimulation is withdrawn, the effect of the drug reproduces the effect of the electrical stimulation. It is suggested there is a defect in cholinesterase in multiple sclerosis patients, and its reactivation may have a significant relationship to signs and symptoms.
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PMID:Improvement of motor function in multiple sclerosis by use of protopam chloride. 135 24

The effect of Semliki Forest Virus, a known central demyelinating agent and a proposed model for multiple sclerosis, on the innervation of the mouse urinary bladder has been examined 3, 6, 9 and 12 weeks after inoculation. Three weeks after Semliki Forest Virus inoculation, vasoactive intestinal polypeptide content of the bladder was reduced and the density of vasoactive intestinal polypeptide-immunoreactive nerves was decreased in the smooth muscle, but not in the mucosa. Choline acetyltransferase activity and neuropeptide Y and substance P content was normal, as was the pattern of innervation by acetylcholinesterase-containing and neuropeptide Y- and substance P-immunoreactive nerve fibres. Six weeks after Semliki Forest Virus inoculation, the choline acetyltransferase activity was significantly reduced. Between 6 and 9 weeks the level of vasoactive intestinal polypeptide in the bladder of Semliki Forest Virus-infected mice significantly increased, so that at 9 weeks it was higher than the control value. However, by 12 weeks both choline acetyltransferase activity and vasoactive intestinal polypeptide content were normal. At this time, the substantial age-related increase in substance P content of the bladder was more pronounced in the Semliki Forest Virus-treated animals. Thus there are transitory changes in the innervation of the mouse bladder by vasoactive intestinal polypeptide-containing and cholinergic nerve fibres after exposure to a central demyelinating agent which may reflect changes in bladder dysfunction seen in multiple sclerosis patients.
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PMID:Neuropeptide immunoreactivity and choline acetyltransferase activity in the mouse urinary bladder following inoculation with Semliki Forest Virus. 170 31

Morphometric analysis of the innervation pattern of the stromal layer of the urinary bladder was done on biopsies from 88 patients with definite multiple sclerosis (MS). The biopsies were stained for acetylcholinesterase and for S100 protein, and a semiquantitative score was assigned. Nearly 30% of the samples showed increased immunoreactivity for S100, indicating Schwann cell hyperplasia. In 16% a decreased S100 immunoreactivity was found, the significance of which is unclear. More than 90% had normal acetylcholinesterase activity. No correlation could be demonstrated for age, sex, severity and duration of the disease, the presence of cystitis and type of detrusor dysfunction. The finding of altered S100 immunoreactivity in MS bladders could indicate that MS also affects the peripheral nervous system and is not limited to the central nervous system as classically described. This finding warrants further investigations.
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PMID:Neuropathological examination of the alterations of the intrinsic innervation in multiple sclerosis cystopathy. 262 82

Urinary bladder biopsies from 31 multiple sclerosis patients, 9 diabetics, 5 patients after transtrigonal phenolization and 20 control patients were stained for acetylcholinesterase, S100 and vasoactive intestinal polypeptide (VIP). The VIP immunoreactivity was not decreased in all neuropathic bladders and its depletion was not related to cholinergic depletion. There was no correlation between bladder over- or underactivity and VIP content. VIP can act as a modulator of detrusor function in normal conditions. The significance of its depletion in neurogenic bladders needs further elaboration.
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PMID:Vasoactive intestinal polypeptidergic innervation of human urinary bladder in normal and pathological conditions. 318 88

There is a growing body of evidence that the central nervous system (CNS), even in the adult animal, is capable of adaptation and reorganization not only as a result of partial damage to the CNS but also in response to stimulation. Environmental stimulation produces changes including expansion of visual cortex, increases in dendritic branching, glia and cholinesterase. Environmental stimulation also produces behavioural changes. Experimental electrical stimulation produces changes in synapse size, synaptic vesicle change, dendritic branching and changes in synaptic transmission. In man, repetitive electrical stimulation via epidural electrodes increases plasma levels of norepinephrine, epinephrine, and dopamine, and CSF levels of norepinephrine. Repetitive electrical stimulation in man dates back to 1967 and has been used for the control of pain, to improve spasticity, bladder control, motor deficit and the autonomic hyperreflexia of spinal cord injury. In addition, improvement has been reported in epilepsy, cerebral palsy, torticollis and peripheral vascular diseases. The best controlled studies are in multiple sclerosis and peripheral vascular disease, and these results will be presented in more detail.
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PMID:Rehabilitation following brain damage: some neurophysiological mechanisms. The effects of repetitive stimulation in recovery from damage to the central nervous system. 718 88

A 42-year-old housewife with myasthenia gravis (MG) for 22 years, who was initially treated by radiation to the hyperplastic thymus and anti-cholinesterase therapy, developed bilateral ptosis, paresthesia of her right face and decreased taste sensation after house work at the age of 42 years. Neurological examinations revealed lateral and vertical gaze palsy, upward nystagmus, decreased taste sensation, peripheral facial palsy on the left side. She also had hypalgesia on the right face, arm and chest up to Th7 level, and urinary retention. She had hyperreflexia on the right side but no extensor toe signs. CSF study revealed 5 cells/microliters and protein of 23 mg/dl. Serum IgG anticardiolipin antibody was positive. Magnetic resonance imaging studies revealed high intensity areas in the brainstem tegmentum and periventricular white matter. Diagnosis of multiple sclerosis (MS) was made. This is the first case in which MG, MS and serum anticardiolipin antibody were present simultaneously, which may be all due to some immunological abnormality. Steroid therapy made anti-cardiolipin antibody negative, but new MS plaque developed in 7 months, which favors diagnosis of MS rather than infarction, since the activities of ACLA were not correlating to clinical symptoms. MRI was helpful in detecting MS plaques in MG patients.
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PMID:[A case of myasthenia gravis associated with multiple sclerosis and positive anticardiolipin antibodies]. 836 70

Donepezil was developed in order to overcome the disadvantages of physostigmine and tacrine. Its use is based on the cholinergic hypothesis. Donepezil is a piperidine-based, reversible acetylcholinesterase inhibitor, that is chemically unrelated to other cholinesterase inhibitors. It was developed for the symptomatic treatment of Alzheimer's disease (AD). Donepezil is highly selective for acetylcholinesterase with a significantly lower affinity for butyrylcholinesterase, which is present predominantly in the periphery. Phase I and II clinical trials demonstrated donepezil's favorable pharmacokinetic, pharmacodynamic and safety profile. There is no need to modify the dose of donepezil in the elderly or in patients with renal and hepatic failure. Pivotal phase-III trials in the US, European countries, and Japan showed that donepezil significantly improved cognition and global function in patients with mild to moderate AD. In long-term trials, donepezil maintained cognitive and global function for up to 1 year prior to the resumption of gradual deterioration. Donepezil is generally well tolerated; most of its adverse events are mild, transient and cholinergic in nature. Donepezil produces no clinically significant changes in laboratory parameters, including liver function. The drug is approved for the treatment of mild to moderate Alzheimer's disease, but donepezil therapy does not have to be discontinued if a patient continues to deteriorate. Possible new indications for donepezil in psychiatric and neurologic diseases, other than AD, include dementia with Lewy bodies, brain injury, attention deficit hyperactivity, multiple sclerosis, Down's syndrome, delirium, mood disorders, Huntington's disease and sleep disorders.
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PMID:Donepezil for Alzheimer's disease: pharmacodynamic, pharmacokinetic, and clinical profiles. 1183 Jul 54

In the last 20 years a cholinergic dysfunction has been the major working hypothesis for the pharmacology of memory disorders. Cholinergic antagonists and lesions impair and different classes of cholinomimetics (i.e. acetylcholine precursors, cholinergic agonists and acetylcholinesterase inhibitors) enhance attention and memory in experiment animals, healthy human subjects and Alzheimer disease patients. In addition, acetylcholinesterase inhibitors improve different cognitive (i.e. visuospatial and verbal) functions in a variety of unrelated disorders such as dementia with Lewy bodies, Parkinson disease, multiple sclerosis, schizoaffective disorders, iatrogenic memory loss, traumatic brain injury, hyperactivity attention disorder and, as we recently reported, vascular dementia and mild cognitive impairment. In animals, different cholinomimetics dose-dependently increased regional cerebral metabolic rates for glucose (rCMRglc) and regional blood flow (rCBF), two indices of neuronal function, more markedly in subcortical regions (i.e. thalamus, hippocampus and visual system nuclei). In both healthy human subjects and Alzheimer disease patients acetylcholinesterase inhibitors increased rCMRglc and rCBF in subcortical and cortical brain regions at rest but attenuated rCBF increases during cognitive performances. Hence, acetylcholinesterase inhibitors may enhance cognition and rCMRglc by acting primarily on subcortical regions that are involved in attentional (i.e. thalamus) and memory (i.e. hippocampus) processes; such an effect probably is not specific for Alzheimer disease and can be beneficial in patients suffering from a wide array of neuropsychiatric disorders.
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PMID:A short review of cognitive and functional neuroimaging studies of cholinergic drugs: implications for therapeutic potentials. 1211 73

One explanation for the weak relationship between neuropsychological deficits and conventional measures of disease burden in multiple sclerosis is that brain 'plasticity' allows adaptive reorganization of cognitive functions to limit impairment, despite injury. We have tested this hypothesis. Ten patients with multiple sclerosis and 11 healthy controls were studied using a functional MRI (fMRI) counting Stroop task. The two subject groups had comparable performances, but a predominantly left medial prefrontal region [Brodmann area (BA) 8/9/10] was more active during the task in patients than in controls (corrected P < 0.001), while a right frontal region (including BA 45 and the basal ganglia) was more active in controls than in patients (corrected P = 0.004). The magnitude of the differences correlated with the normalized brain parenchymal volume, a measure of disease burden (r = -0.72, P = 0.02). We then tested the effects of acute administration of rivastigmine, a central cholinesterase inhibitor, on patterns of brain activation. In five out of five multiple sclerosis patients there was a relative normalization of the abnormal Stroop-associated brain activation, although no change in the patterns of brain activation was found in any of four healthy controls given the drug and tested in the same way. We suggest that recruitment of medial prefrontal cortex is a form of adaptive brain plasticity that compensates, in part, for relative deficits in processing related to the reduced right prefrontal cortex activity with multiple sclerosis. This functional plasticity is modulated by cholinergic agonism and must arise from potentially highly dynamic mechanisms such as the 'unmasking' of latent pathways.
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PMID:Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine. 1295 82

The UK National Institute for Clinical Excellence (NICE) was set up in 1999 to advise the National Health Service (NHS) on the use of new technologies largely, but not exclusively, on the basis of their clinical and cost effectiveness. There have been problems with this, as with any developing system, most of which have arisen from issues not directly under the control of NICE. Despite this, NICE has already achieved a pivotal role in determining the uptake of new therapies into the NHS. In the area of neuropsychiatric therapies, NICE has examined a number of topics and has generally facilitated the increased use of the agents examined, approving the use, within limitations, of such drugs as riluzole, atypical antipsychotics and cholinesterase inhibitors. Although the use of some of these therapies had been growing, it had previously been restricted by funding in the NHS. As a result of NICE guidance, these funding restrictions have generally been lifted. NICE has rejected one area of neurological therapy so far--that of interferon-beta products and glatiramer acetate for multiple sclerosis--on the grounds of clinical uncertainty about long-term benefits and poor cost effectiveness. However, the UK Government has created a novel risk-sharing scheme in collaboration with the sponsoring companies to make these drugs available at a level of cost effectiveness acceptable to the NHS. The feasibility of this scheme is as yet unclear. This might be seen as either a triumph for NICE or as an undermining of it for political ends. One interesting aspect that is more prominent in neuropsychiatric disorders than in other areas of NICE activity has been the power of patient advocacy in encouraging acceptance of therapies where the evidence base was weak or the incremental cost-effectiveness ratio was unfavourable. The principles behind the activities of NICE attract wide support within the NHS, but the details of its decisions have often not been popular within NHS management who have to deliver them. Some of this relates more to the context and political environment within which NICE operates than to a failing within NICE itself. NICE will continue to become increasingly important in determining the use of new drugs within the UK NHS.
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PMID:Neuropsychotherapeutics in the UK: what has been the impact of NICE on prescribing? 1473 Oct 55


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