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)

Impairments of cortical cholinergic inputs from the nucleus basalis magnocellularis fundamentally alter information processing and attentional function, thereby advancing the severity of psychopathology in major neuropsychiatric disorders. It was previously shown in adult rats that bilateral 192 IgG saporin-induced selective immunolesioning of the cholinergic neurons in the nucleus basalis produces pronounced and long-lasting deficits in sensorimotor gating measured by prepulse inhibition of the startle reflex. This behavioral paradigm is considered a valid model of sensorimotor gating deficits in the psychotic spectrum and efforts to analyze the significance of the cholinergic basal forebrain in this context are of great interest. In the present study the predictive value of the selective cholinergic immunolesioning model was tested by examining the ability of the cholinesterase inhibitor rivastigmine to restore prepulse inhibition in immunolesioned rats. We report here a pronounced restoring effect of acute (0.75 or 1.5 mg/kg s.c.) as well as repeated (0.75 mg/kg s.c. b.i.d., for 10 days) treatment with rivastigmine in this model of disrupted prepulse inhibition. Intra-nucleus basalis magnocellularis infusions of 192 IgG saporin resulted in extensive loss of basal-cortical cholinergic neurons as shown by the marked decrease in basal telencephalic choline acetyltransferase immunopositive neurons and cortical choline acetyltransferase activity. In this condition, rivastigmine was found to significantly increase cortical acetylcholine extracellular levels in lesioned animals measured by in vivo microdialysis. Taken together, our results strengthen the proposal that the nucleus basalis represents a critical station of the startle gating circuitry. In addition, our findings strongly indicate that even after dramatic decrease of cholinergic neurons, inhibition of acetylcholinesterase restores the cholinergic synaptic function to a point approaching normalization of experimentally induced psychopathology.
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PMID:Rivastigmine antagonizes deficits in prepulse inhibition induced by selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis. 1220 57

Because of the demonstration of a selective alpha nicotinic receptor abnormality in patients with schizophrenia, galantamine was added to the stable regimen of atypical and other antipsychotic medications in a 43-year-old man manifesting severe and persistent positive and negative symptoms, as well as mood disturbance and cognitive dysfunction. Galantamine is an inhibitor of acetylcholinesterase and a positive allosteric modulator of nicotinic cholinergic receptors (with a FDA-approved indication for the treatment of patients with mild to moderate Alzheimer disease (AD) under the trade name Reminyl). Galantamine HBr was initiated at a dose of 4 mg po BID, which was maintained for the first week of adjuvant therapy, and eventually was increased to 12 mg po BID during the final weeks of his 2-month trial. Remarkably, within 1 week of its initiation, there was a dramatic and clinically significant decrease of negative symptoms, as reflected in formal ratings on the Scale for the Assessment of Negative Symptoms. Moreover, within a few days of galantamine discontinuation, negative symptoms worsened, returning to the baseline level of severity. In addition to targeting memory dysfunction in AD, acetylcholinesterase inhibitors may have an expanded range of targets and clinical indications, including behavioral and psychotic symptoms. Galantamine is distinguished from other acetylcholinesterase inhibitors by its positive allosteric modulatory properties, improving the efficiency of transduction of the acetylcholine signal at nicotinic receptors. This latter property may have contributed to the observed improvement in negative symptoms observed in this patient. Importantly, positive symptoms were unchanged during this 2-month trial.(7)
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PMID:Adjuvant galantamine administration improves negative symptoms in a patient with treatment-refractory schizophrenia. 1241 61

The overall goal of all therapeutic interventions in Alzheimer s disease (AD) is the optimisation of the adaptive functions and quality of life of these patients. The general strategy for the use of pharmacological interventions in the treatment of neuropsychiatric manifestations of AD includes the following: 1) An exhaustive evaluation of the psychiatric symptomatology; 2) Establish a hierachy of the simptoms to treat based on their severity of symptoms and on their impact on the caregiver; 3) The identification of an adequate agent based on the type of symptoms and subject s characteristics; 4) The initial use of low doses with gradual titration, and 5) Changing one drug at a time. Regarding psychotic symptons, the introduction of new agents (e.g., risperidone) has replaced the use of traditional treatments (e.g., thioridazine) in patients with AD. The presence of psychomotor agitation and aggression can be treated with great variety of drugs, such as antipsychotics, anticonvulsants, antidepressants, and sedatives. Selective serotonine re uptake inhibitors are the treatment of choice for depressive symptomatology. The cholinesterase inhibitors have shown to be useful in the treatment of hallucinations, anxiety and apathy.
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PMID:[Treatment of neuropsychiatric symptoms in Alzheimer's disease]. 1243 83

Behavioral and psychological symptoms of dementia (BPSD) are a common manifestation of Alzheimer's disease (AD) and other dementia syndromes. Patients experience prominent and multiple symptoms, which are both distressing and a source of considerable social, health, and economic cost. Development of symptoms is in part related to progressive neurodegeneration and cholinergic deficiency in brain regions important in the regulation of behavioral and emotional responses including the cortex, hippocampus, and limbic system. Cholinesterase (ChE) inhibitors offer a mechanism-based approach to therapy to enhance endogenous cholinergic neurotransmission. Studies using ChE inhibitors have demonstrated their clear potential to improve or stabilize existing BPSD. Differences have been noted between selective acetylcholinesterase (AChE) inhibitors (donepezil and galantamine) and dual ChE inhibitors (rivastigmine) in terms of treatment response. While donepezil has shown efficacy in moderate to severe noninstitutionalized AD patients, conflicting results have been obtained in mild to moderate patients and in nursing home patients. Galantamine has been shown to delay the onset of BPSD during a five-month study but has been otherwise poorly studied to-date. Both donepezil and galantamine have not as yet demonstrated efficacy in reducing psychotic symptoms or in reducing levels of concomitant psychotropic medication use. Studies with the dual ChE inhibitor rivastigmine in mild to moderately severe AD and in Lewy body dementia (LBD) have shown improvements in behavioral symptoms including psychosis. Improvements have been maintained over a period of up to two years. In addition, institutionalized patients with severe AD have shown symptomatic benefits with a reduction in the requirement for additional psychotropic drugs following treatment with rivastigmine. The psychotropic properties associated with rivastigmine may in part be mediated through effects on butyrylcholinesterase. Current treatment options are limited for patients with dementia syndromes other than AD. However, data concerning rivastigmine in patients with LBD and preliminary studies in Parkinson's disease dementia and vascular dementia suggest a role for ChE inhibitors across the spectrum of dementia syndromes. Finally, studies that incorporated a delayed start design demonstrate that ChE inhibitors may delay the progression of BPSD.
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PMID:The ABC of Alzheimer's disease: behavioral symptoms and their treatment. 1263 79

Traditionally, the neuropsychiatric symptoms of Alzheimer's disease (AD) have been managed with neuroleptics or benzodiazepines, which have serious side effects. Preliminary observations suggest the possible value of cholinesterase inhibitors in the amelioration of psychotic symptoms in patients with dementia of the Alzheimer's type, dementia with Lewy bodies, and in patients with Parkinson's disease. Twelve inpatients with AD with psychotic symptoms and lack of improvement of their delusions/hallucinations during perphenazine treatment (8 mg/day) for 3 weeks received random open-label donepezil 5 mg daily in addition to an ongoing treatment of 8 mg/day perphenazine or 16 mg/day perphenazine. Assessments conducted at baseline and after weeks 2 and 4 included the Mini-Mental State Examination, the Global Deterioration Scale, the Positive and Negative Symptoms Scale, and the Clinical Global Impressions scale. Frequency of extrapyramidal symptoms was measured according to the Abnormal Involuntary Movement Scale. The donepezil-perphenazine group exhibited substantially greater and clinical improvements in mental state. At the end of the trial (4 weeks), Positive and Negative Symptoms Scale scores revealed significant differences between both groups (p = 0.006). The Clinical Global Impressions scale and the Mini-Mental State Examination scores also showed significant differences between the donepezil-perphenazine group and the perphenazine group (p = 0.028 and p = 0.027 respectively). No significant differences were found in the Global Deterioration Scale scores. Abnormal Involuntary Movement Scale scores showed a significant deterioration in extrapyramidal symptoms in the perphenazine group compared with the donepezil-perphenazine group (p = 0.016). Donepezil augmentation of neuroleptics may be appropriate for those patients for whom neuroleptic monotherapy either does not lead to symptom remission or is associated with intolerable adverse effects. This was an open-label study and there is need for larger studies with double-blind control and a long-term study design to define the efficacy of donepezil for patients with AD and psychotic symptoms.
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PMID:Donepezil as add-on treatment of psychotic symptoms in patients with dementia of the Alzheimer's type. 1267 28

The course of behavioural and psychotic features of patients with Alzheimer's disease treated with an inhibitor of the acetylcholinesterase (rivastigmine), and their association to cognitive impairment is presented in the study. Standardized examination of global functional deterioration (GDS), cognitive impairment (MMSE) and behavioural or psychotic symptoms (Behave-AD) were performed over two years. We could analyse the complete data from 44 of initially 91 patients with mild to moderate Alzheimer's disease. The cognitive component (measured by MMSE, ADAS-cog) and the functional assessment (GDS) showed a continuous decline after a one year period of stabilization, in contrast with behavioural and psychotic symptoms, especially delusions, which still improved after treatment of two years. While cognitive items in correlation with functional aspects formed a homogeneous factor over the two-year period, psychotic features displayed more variability over time evaluated by factor analysis. Nevertheless mood and anxiety disorder in combination with aggressive behaviour as well as hallucinations formed an independent factor in the course of Alzheimer's disease. In addition to other studies of the course of Alzheimer's disease we could demonstrate that distinct behavioural and psychotic symptoms may also present as independent factors in Alzheimer patients under constant treatment conditions with an inhibitor of the acetylcholinesterase (rivastigmine).
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PMID:[Presentation and stability of cognitive and noncognitive symptom patterns in patients with Alzheimer's disease. Disease course over a two-year period under constant treatment conditions with rivastigmine]. 1267 53

Dementia with Lewy bodies (DLB) accounts for 15-20% of all autopsy confirmed dementias in old age. Characteristic histopathological changes are intracellular Lewy bodies and Lewy neurites, with abundant senile plaques but sparse neurofibrillary tangles. Core clinical features are fluctuating cognitive impairment, persistent visual hallucinations and extrapyramidal motor symptoms (parkinsonism). One of these core features has to be present for a diagnosis of possible DLB, and two for probable DLB. Supportive features are repeated falls, syncope, transient loss of consciousness, neuroleptic sensitivity, delusions and hallucinations in other modalities. DLB is clinically under-diagnosed and frequently misclassified as systemic delirium or dementia due to Alzheimer's disease or cerebrovascular disease. Therapeutic approaches to DLB can pose difficult dilemmas in pharmacological management. Neuroleptic medication is relatively contraindicated because some patients show severe neuroleptic sensitivity, which is associated with increased morbidity and mortality. Antiparkinsonian medication has the potential to exacerbate psychotic symptoms and may be relatively ineffective at relieving extrapyramidal motor symptoms. Recently there is converging evidence that treatment with cholinesterase inhibitors can offer a safe alternative for the symptomatic treatment of cognitive and neuropsychiatric features in DLB. This review will focus on the clinical characteristics of DLB, its differential diagnosis and on possible management strategies.
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PMID:Dementia with lewy bodies--diagnosis and treatment. 1270 40

Psychosis only rarely occurs in patients with untreated Parkinson's disease. Much more commonly, psychosis is induced by drug therapy for Parkinson's disease and is the strongest known risk factor for nursing home placement. Delusions are less frequent than hallucinations, but are more concerning as they are often paranoid in nature. Treatment begins with a search for correctable infectious, toxic, and metabolic aetiologies. If symptoms persist, anti-Parkinson's disease medications are slowly reduced. However, withdrawal of these drugs usually worsens parkinsonism and is often not tolerated. Certain atypical antipsychotics can be used to treat psychosis without compromising motor function. The choice of atypical antipsychotic is largely based on ease of use and adverse effect profile as most have comparable efficacy in improving psychosis. Currently, there are five marketed atypical drugs - clozapine, risperidone, olanzapine, quetiapine and ziprasidone. Ziprasidone is the only agent whose adverse effect profile has not been reported in Parkinson's disease. The most common adverse effects of clozapine in Parkinson's disease are sedation, orthostatic hypotension and sialorrhoea. Sedation is generally helpful since these patients are frequently awake at night and tend to have worse behavioural problems then. Clozapine does not induce deterioration of motor function, but it has the potential to cause agranulocytosis, which is idiosyncratic and not dose-related. In risperidone-treated Parkinson's disease patients, reported adverse effects include somnolence, sialorrhoea, dizziness, palpitations, constipation, delirium, fatigue, leg cramps, depression, urinary incontinence and hypotension. Although in some Parkinson's disease studies, risperidone has been well tolerated, others have shown that many patients are unable to tolerate the drug due to deterioration of motor function. While an initial study of olanzapine in Parkinson's disease psychosis showed the drug to be effective without deterioration of motor function, succeeding reports demonstrated a deleterious effect of the drug on motor functioning. The most common adverse effects of quetiapine in Parkinson's disease patients are sedation and orthostatic hypotension. There is a lack of double-blind trials; however, cumulative reports involving >200 Parkinson's disease patients strongly suggest that quetiapine is well tolerated and effective. Unlike clozapine, it does not improve tremor and may induce mild deterioration of motor function. Recently, cholinesterase inhibitors have been reported to alleviate psychosis in Parkinson's disease. Although ondansetron, an antiemetic with antiserotonergic properties, has been reported to relieve psychosis in Parkinson's disease, its prohibitive cost has prevented further study in this population. Electroconvulsive treatment is generally reserved for the patient with psychotic depression who is unable to tolerate any pharmacological therapy.
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PMID:Treatment of psychosis in Parkinson's disease: safety considerations. 1281 32

Numerous advances have taken place in the pharmacological management of Parkinson disease (PD) in recent years. Some of the more clinically relevant will be discussed in the text that follows. New drugs have been developed to treat or prevent the motor fluctuations and dyskinesias that occur frequently with the continuous use of levodopa. Such drugs include the catechol-O-methyl-transferase (COMT) inhibitors, such as tolcapone and entecapone, and new dopamine (DA) agonists with long half lives such as cabergoline, pramipexole or ropirinole. Also new, atyical, antipsychotics have appeared which have revolutionized the treatment of PD since they allow us to control hallucinations and other psychotic behaviour without worsening of motor function. Finally preliminary reports suggest that cholinesterase inhibitors, such as rivastigmine, can be usefull in the management of cognitive impairment in PD, one of the most difficult clinical problems encountered in the management of this neurodegenerative disorder.
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PMID:Advances in the pharmacological management of Parkinson disease. 1283 Sep 29

THE MAJOR THERAPEUTIC TRENDS: The treatment of psychosis in late life depends on the etiology of the delusion but also on its behavioral consequences (agitation, aggressiveness). We distinguish between the treatment of long term old psychosis and delusions occurring late in life (after the age of 60). FOR THE OLD PSYCHOSES: The reduction in the symptomatology often permits a reduction in the doses and the relay to atypical neuroleptics with improved tolerance. FOR DELUSIONS OCCURRING LATE IN LIFE: The treatment will be adjusted to the etiology of the delusion: delirious states associated with dementia, thymus delusion, schizophrenic or non-schizophrenic psychosis, delusion related to cerebral-vascular disorders or to sensorial dysafferentation. One should note that emotional and delusional disorders are often concomitant in the elderly. THE TWO TREATMENT AXES: The first therapeutic element is non-pharmacological: reassurance or even brief psychotherapy, family counseling and prevention of enhancing, notably environmental, factors. The pharmacological element preferably includes atypical anti-psychotics, antidepressants in some cases together with anti-epileptics in cases of concomitant rebellious aggressiveness. In cases of dementia with cholinergic deficiency (Alzheimer, Lewy body dementia, mixed dementia) cholinesterase inhibitors have demonstrated their efficacy on the hallucinations. Advice for a pertinent strategy of action should be provided.
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PMID:[Delirious states in elderly persons. Therapeutic modalities]. 1285 35


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