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)

Alzheimer's disease (AD) patients exhibit a variety of behavioral alterations including agitation, apathy, depression, anxiety, delusions, irritability and disinhibition. Most patients with AD exhibit neuropsychiatric symptoms, and behavioral changes become more frequent with advancing disease severity. The NPI is a valid and reliable means of assessing neuropsychiatric symptoms in patients with dementia. The NPI correlates with increasing disability in activities of daily living and increasing cognitive impairment. Physical illness contributes little to behavioral symptoms measured by the NPI. Reduced frontal lobe metabolism and perfusion have been identified in patients with apathy, agitation, psychosis and depression. Patients with elevated agitation scores on the NPI have a higher burden of frontal lobe neurofibrillary tangles than patients without agitation. The NPI is sensitive to behavioral improvements following treatment with cholinesterase inhibitors and psychotropic agents. Neuropsychiatric symptom profiles differ among dementia syndromes, and the NPI provides a means of assessing neuropsychiatric symptoms that may aid in differential diagnosis. Evaluation of neuropsychiatric symptoms is a critical aspect of dementia diagnosis and management.
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PMID:Neuropsychiatric assessment of Alzheimer's disease and related dementias. 1144 57

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

Cholinesterase inhibitors are licensed for treatment of dementia in Alzheimer's disease. However, the effects of these drugs on the cognitive symptoms of dementia are very small. We suggest that symptoms like impairment of attention and concentration, anxiety, restlessness and hallucinations, delineate a specific central cholinergic deficiency syndrome (CDS), that may be a much better target for such treatment. Changes in the quantitative electroencephalogram, muscarinic subtype radioimaging and serum anticholinergic activity may potentially help to diagnose the CDS. CDS is suggested to occur in various neurodegenerative diseases like Alzheimer's disease, Lewy body dementia and Parkinson's disease and to respond well to cholinesterase inhibitor therapy.
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PMID:The cholinergic deficiency syndrome and its therapeutic implications. 1245 52

Behavioral and psychologic symptoms of dementia (BPSD) are common manifestations in mid- and late-stage Alzheimer's disease (AD). Traditional treatments for BPSD are neuroleptics and sedatives, which are not devoid of serious adverse effects. A number of studies show beneficial effects in the treatment of BPSD with acetylcholinesterase inhibitors (AChEI). The present study aimed to evaluate the effect of donepezil (using the generic drug Memorit) as monotherapy for AD patients suffering from BPSD. Twenty-eight consecutive patients followed at the Memory Outpatient Clinic and Psychogeriatric Department of the Abarbanel Mental Health Center were treated with donepezil for 6 months. Starting dose was 5 mg daily during the first 4 weeks and continuation with 10 mg daily thereafter. Treatment effects were evaluated using the Mini Mental State Examination (MMSE), the Neuro-Psychiatric Inventory (NPI), and the Clinical Global Impression of Change Scale (CGIC) caregiver version. Twenty-four of 28 patients completed the study. Of these, five patients needed additional rescue neuroleptic treatment due to incomplete response. The mean dose of donepezil was 9.10 mg/day (median 10 mg/day). The overall NPI improved significantly from 33.4 to 21.2 (p = 0.008). The mean CGIC at study's end was 3.0 (mild improvement). The cognitive scores did not change significantly. When compared to the patients who completed the study, patients who discontinued had higher mean scores on the irritability and agitation subscales of the NPI, they were older, and they had longer disease duration and lower MMSE mean scores. Three adverse events were recorded: one syncope causing a toe phalanx fracture and gastrointestinal complaints that resolved over time in two additional patients. Acetylcholinesterase inhibitors should be considered for the treatment of BPSD before neuroleptic treatment is instituted in AD patients with low levels of irritability and agitation.
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PMID:Donepezil for the treatment of behavioral symptoms in patients with Alzheimer's disease. 1246 5

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

The defining characteristic of Alzheimer's disease is cognitive impairment, but commonly this impairment is accompanied by mood and behavioral symptoms such as depression, anxiety, irritability, inappropriate behavior, sleep disturbance, psychosis, and agitation. The symptoms of Alzheimer's disease are not normative to the aging process. Diagnosis of Alzheimer's disease in the majority of cases can be made with confidence through office-based clinical assessment and informant interview. Alzheimer's disease is the most common of the dementing disorders and is exponentially increasing in incidence, projected to affect 8.64 million people in the United States by the year 2047. At present, no treatment can prevent or cure Alzheimer's disease, and the fact that Alzheimer's affects a geriatric population makes treatment all the more challenging. Therapies that could delay onset of symptoms even briefly would have a major impact on public health. As the prevalence of Alzheimer's disease increases, researchers are examining the efficacy of treatment options beyond the realm of the established cholinesterase inhibitors.
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PMID:Diagnosis and treatment of Alzheimer's disease. 1293 67

The effects of four organophosphorous compounds, three oximes and atropine sulphate, injected through an indwelling cannula into the third ventricle of unanaesthetized dogs were examined. The effects of 200 mug of dyflos were involuntary micturition, defaecation, akinesia of hind limbs and pronounced disturbances of awareness; those of 100 mug of ethyl pyrophosphate were tremor, restlessness and signs of fear; 500 mug to 5 mg of dyflos and 250 mug to 500 mug of ethyl pyrophosphate caused vomiting, salivation, twitches of facial muscles and recurrent epileptiform seizures. The injection of 40 to 80 mg of dimefox and of 50 mg of schradan elicited involuntary micturition, vomiting, salivation and defaecation. These effects occur probably after these substances have passed into the blood stream and have been converted in the liver to potent anticholinesterases. This view is supported by the finding of reduced blood cholinesterase activity. At a dose level of 12.5 mg, 1,1'-trimethylenebis(4-hydroxyiminomethylpyridinium bromide) produced strong convulsions. At this dose level pralidoxime iodide and diacetyl monoxime produced no observable effects. Atropine sulphate in a dose of 1 mg caused disturbances in consciousness and behaviour followed by convulsions. Intraventricular atropine and to a minor extent intraventricular oximes were able to antagonize the effects of intraventricular ethyl pyrophosphate. Pralidoxime iodide exerted a strong antagonistic effect also on intravenous injection.
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PMID:Effects of organophosphorous compounds, oximes and atropine injected into the third ventricle of unanaesthetized dogs. 1388 82

Cholinesterase inhibitors are the only pharmacological class indicated for the treatment of mild to moderate Alzheimer's disease. These drugs are also being used off label to treat severe cases of Alzheimer's disease or vascular dementia and other disorders. The widespread use of cholinesterase inhibitors raises the possibility of their use in combination regimens, with the subsequent risk of deleterious drug-drug interactions in high-risk populations. The purpose of this review is to present the possible sources of pharmacokinetic or pharmacodynamic drug-drug interactions involving cholinesterase inhibitors. The four cholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine) that are currently available have different pharmacological properties that expose patients to the risk of several types of drug interactions of nonequivalent clinical relevance. The principal proven clinically relevant drug interactions involve tacrine and drugs metabolised by the cytochrome P450 (CYP) 1A2 enzyme, as well as tacrine or donepezil and antipsychotics (which results in the appearance of parkinsonian symptoms). The bioavailability of galantamine is increased by coadministration with paroxetine, ketoconazole and erythromycin. It is of interest to note that because rivastigmine is metabolised by esterases rather than CYP enzymes, unlike the other cholinesterase inhibitors, it is unlikely to be involved in pharmacokinetic drug-drug interactions. Care must be taken to reduce the risk of inducing central (excitation, agitation) or peripheral (e.g. bradycardia, loss of consciousness, digestive disorders) hypercholinergic effects via drug interactions with cholinesterase inhibitors. A review of the literature does not reveal any alarming data but does highlight the need for prudent prescription, particularly when cholinesterase inhibitors are given in combination with psychotropics or antiarrhythmics. Possible interactions involving other often coprescribed antidementia agents (e.g. memantine, antioxidants, cognitive enhancers) remain an open area requiring particularly prudent use.
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PMID:Clinically significant drug interactions with cholinesterase inhibitors: a guide for neurologists. 1453 45

Psychosis is common in patients with Alzheimer's disease (AD) and contributes substantially to patient morbidity and caregiver distress. Antipsychotic medications are used to treat psychosis and other psychiatric or behavioral symptoms in AD, although optimal treatment guidelines have been elusive. Choosing the most advantageous medication for an individual patient is challenging. This article provides an overview of clinical management principles and medication treatment strategies for patients with AD and psychosis. Effects of individual medications are also described. Medications in the conventional neuroleptic, atypical antipsychotic, cholinesterase inhibitor, and serotonergic classes have been shown to ameliorate psychosis and behavioral symptoms in patients with AD, although the evidence is not conclusive for many medications. Side effects vary substantially across medication classes and modestly among individual patients. Improvement in agitation, aggression, or other behaviors with antipsychotic medication treatment may not depend on distinct antipsychotic effects. In contrast, there is preliminary evidence that delusions and hallucinations may respond to treatment with medications outside the antipsychotic class. Many important clinical questions warrant further research study. In particular, studies to compare how individual symptoms respond to different medications, and to examine how to best manage overlapping symptoms or incomplete treatment response are needed.
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PMID:Psychosis and antipsychotic medications in Alzheimer's disease: clinical management and research perspectives. 1456

The purpose of the study was to investigate the effect of hydroxypropyl beta cyclodextrin (HPbetaCD) on aqueous solubility, stability, and in vitro corneal permeation of acyl ester prodrugs of ganciclovir (GCV). Aqueous solubility and stability of acyl ester prodrugs of Ganciclovir (GCV) were evaluated in pH 7.4 isotonic phosphate buffer solution (IPBS) in the presence and absence of HPbetaCD. Butyryl cholinesterase-mediated enzymatic hydrolysis of the GCV prodrugs was studied using various percentage w/v HPbetaCD. In vitro corneal permeation of GCV and its prodrugs (with and without 5% HPbetaCD) across isolated rabbit cornea was studied using side-by-side diffusion cells. HPbetaCD-prodrug complexation was of the A(L) type with values for complexation constants ranging between 12 and 108 M(-1). Considerable improvement in chemical and enzymatic stability of the GCV prodrugs was observed in the presence of HPbetaCD. The stabilizing effect of HPbetaCD was found to depend on the degree of complexation and the degradation rate of prodrug within the complex. Five percent w/v HPbetaCD was found to enhance the corneal permeation of only the most lipophilic prodrug GCV dibutyrate (2.5-fold compared with 0% HPbetaCD). All other prodrugs showed little or no difference in transport in the presence of 5% w/v HPbetaCD. Agitation in the donor chamber largely influenced the transport kinetics of GCV dibutyrate across cornea. Results indicate the presence of an unstirred aqueous diffusion layer at the corneal surface that restricts the transport of the highly lipophilic GCV dibutyrate prodrug. HPbetaCD improves corneal permeation by solubilizing the hydrophobic prodrug and delivering it across the mucin layer at the corneal surface.
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PMID:Effect of hydroxypropyl beta cyclodextrin complexation on aqueous solubility, stability, and corneal permeation of acyl ester prodrugs of ganciclovir. 1462 77


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