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Acetylcholinesterase (AChE) is an enzyme responsible for metabolism of the neurotransmitter acetylcholine, and inhibition of AChE can have therapeutic applications (e.g., drugs for Alzheimer's disease) or neurotoxic consequences (e.g., pesticides). A common absorbance-based AChE activity assay that uses 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) can have limited sensitivity and be prone to interference. Therefore, an alternative assay was developed, in which AChE activity was determined by measuring fluorescence of resorufin produced from coupled enzyme reactions involving acetylcholine and Amplex Red (10-acetyl-3,7-dihydroxyphenoxazine). The Amplex Red assay was used for two separate applications. First, AChE activity was measured in rat whole blood, which is a biomarker for exposure to AChE inhibitor pesticides. Activity was quantified from a 10(5)-fold dilution of whole blood, and there was a linear correlation between Amplex Red and DTNB assays. For the second application, Amplex Red assay was used to measure AChE inhibition potency in a human neuroblastoma cell line (SH-SY5Y), which is important for assessing pharmacological and toxicological potential of AChE inhibitors including drugs, phytochemicals, and pesticides. Five known reversible inhibitors were evaluated (IC50, 7-225 nM), along with irreversible inhibitors chlorpyrifos-oxon (ki=1.01 nM(-1)h(-1)) and paraoxon (ki=0.16 nM(-1)h(-1)). Lastly, in addition to inhibition, AChE reactivation was measured in SH-SY5Y cells incubated with pralidoxime chloride (2-PAM). The Amplex Red assay is a sensitive, specific, and reliable fluorescence method for measuring AChE activity in both rat whole blood and cultured SH-SY5Y cells.
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Huperzine A may be an optimal choice for the combined therapy with memantine in treating AD.
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This is a secondary analysis of the open-label Atlantic Canada Alzheimer's Disease Investigation of Expectations study of donepezil for mild-moderate AD in 100 community-dwelling people. Goal Attainment Scaling, an individualized account of the goals of treatment, was the primary outcome measure.
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Single subject, unblinded, multiple baseline design.
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Out of 264 patients, 140 (53.1%) discontinued taking donepezil during the two-year observation period. The mean age of the continued group and the discontinued group did not differ significantly (79.5 +/- 6.7, 79.8 +/- 6.4, respectively). Kaplan-Meier analysis showed that the patients with more severe cognitive impairment (CDR score = 3) discontinued donepezil earlier and more frequently. The reasons for discontinuation were a change in the doctors treating the patients (n = 71), ineffectiveness (n = 16), gastrointestinal side-effects (n = 11), and others (n = 41). In patients with CDR = 1 or 2, changes of doctors were the most frequent reason for discontinuation. However, in patients with CDR = 3, ineffectiveness of the medication was the major reason for discontinuation.
Cochrane Central Register of Controlled Trials, MEDLINE, PREMEDLINE, EMBASE, Allied and Complementary Medicine Database, CINAHL, AgeLine, and PsycINFO from January 1986 through November 2006.
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DDIs were present in more than one-third of spontaneous reports including ChEIs registered in the French Pharmacovigilance Database. Approximately, one-third of these DDIs were the cause of ADRs. The informativity of European drug dictionaries differs substantially and Vidal was found to be more informative than BNF for all the ChEIs.
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A substantial relation has not been established between sex and the second-generation ChEIs currently used in clinical settings for the treatment of AD. If an interaction between sex and ChEI treatment does exist, as suggested in 10 of the studies we analyzed, it is likely to be small and subtle, with much individual variation, as is the case with most neurologic sex differences. Nevertheless, sexual dimorphism in response to ChEI therapy warrants further investigation, especially in regard to its role in the development of novel AD therapies.
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To assess the efficacy and safety of a pharmacological treatment with donepezil over cognitive and behavioral disturbances on patients with Down syndrome older than 40 years, areas where family and professional educators of reference have observed cognitive and behavioral changes in comparison with their previous level of disability.
In addition to hourly red blood cell cholinesterase sampling, neurobehavioral function was assessed before and after a single oral dose of huperzine A (100 or 200 μg), galantamine (4 or 8 mg), donepezil (2.5 or 5mg), or placebo (n=12 subjects per drug/dose).
Donepezil, a highly selective acetylcholinesterase inhibitor (AChEI), is approved as a symptomatic treatment mild, moderate, and severe Alzheimer's disease (AD). Donepezil exerts its treatment effect through multiple mechanisms of action including nicotinic receptor stimulation, mitigation of excitotoxicity, and influencing APP processing. The use of donepezil at higher doses is justified given the worsening cholinergic deficit as the disease advances. Donepezil has been investigated in several clinical trials of subjects with moderate-to-severe AD. While the side effects are class specific (cholinergically driven), demonstrable benefit has been shown at the 10 mg dose and the 23 mg doses. Here, we review the clinical justification, efficacy, safety, and tolerability of use of donepezil in the treatment of moderate-to-severe AD.
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Therapies for Alzheimer's disease (AD) at present augment the deteriorating cholinergic system, are reasonably well tolerated, and are convenient, given once or twice a day. They may, however, support or oppose endogenous circadian cholinergic rhythms. Drugs with a duration of action longer than a day are at odds with the physiology of the cholinergic system, which is active during the day and quiescent at night. Sleep and the consolidation of daytime experience into memory may be disturbed. Tolerance commonly develops, substantial counterregulatory increases in acetylcholinesterase (AChE) have been measured, and brain AChE inhibition is lower than predicted. Therefore, the duration of action and timing of administration, as they relate to natural cholinergic rhythms, are factors to be considered in optimizing cholinergic AD therapeutics.
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The simulated binding profiles of acetylcholine, ACh, and the inhibitor (+/-)-2,3-dihydro-5,6- dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-on e hydrochloride (E2020), 1, and some of its analogs to acetylcholinesterase, AChE, were determined using full force field energetics and allowing complete conformational flexibility in both the ligand and receptor. A new mode of binding of ACh to AChE was found which involves the carboxyl oxygen of ACh interacting with Gly 118 and 119. Multiple modes of binding of 1 and some of its analogs were found which include alignment models observed in previous more restricted modeling studies. The key ligand-receptor interactions identified, and the corresponding energetics, are consistent on a relative basis, with observed binding constants for both the individual isomers of each of the inhibitors, as well as among the inhibitors themselves. The multiple modes of binding of 1 to AChE arises from small changes in binding at a single subsite and also from multiple subsite changes. Thus, an independent subsite model for ligand-receptor binding holds for some modes of binding, but not for others. A comparison of the simulated AChE-1 (and analog inhibitors) binding models to the receptor-independent 3D-QSARs previously developed for this class of inhibitors reveals extensive mutual consistency. The findings from these two modeling studies provides greater guidelines for inhibitor design than can be realized from either one. The combined docking and 3D-QSAR studies permit a detailed understanding of the SAR of more than 100 compound 1 analog inhibitors. A simple molecular recognition model can also be gleaned from the docking studies. A cylindrical "plug" (the inhibitor) having a large dipole moment must sterically fit into a cylindrical hole (the active site gorge of AChE), the lining of which also has a large dipole moment. Our simulations suggest that the dynamic "back door" to the active site of AChE does not form a large enough opening for sufficiently long time periods so as to be an effective entrance/exit pathway.
Both switch strategies were safe and well tolerated. The majority of patients may be able to switch directly to rivastigmine patches without a withdrawal period. Appropriate clinical judgment should be used for patients with existing bradycardia or receiving beta blockers.
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Hesperidin (HSP), a flavanoglycone found in citrus fruits, has antioxidant, anti-inflammatory and neuroprotective properties.
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Between Dec 8, 2009, and Dec 23, 2011, we randomly allocated 278 patients to treatment: 133 to placebo and 145 to idalopirdine. 132 patients in the placebo group and 140 in the experimental group were included in the final analysis. At week 24, the change from baseline in ADAS-cog total score was +1·38 (SD 0·53) in the placebo group and -0·77 (0·55) in the idalopirdine group (treatment difference of -2·16 points, 95% CI -3·62 to -0·69; p=0·0040). 25 patients (seven taking placebo and 18 taking idalopirdine) discontinued treatment because of adverse events, the difference between groups being mainly due to asymptomatic transient increases in transaminase concentrations in some idalopirdine-treated patients. The most common adverse events (occurring in >3% of patients) were increased γ-glutamyltransferase (14 [10%] patients in the idalopirdine group vs two [2%] in the placebo group), diarrhoea (six [4%] vs nine [7%]), urinary tract infection (three [2%] vs nine [7%]), fall (three [2%] vs eight [6%]), increased alanine aminotransferase (nine [6%] vs none), and benign prostatic hyperplasia (two [5%] vs none). Serious adverse events were reported by 14 (10%) patients in the idalopirdine group and 13 (10%) patients in the placebo group. One death occurred in each treatment group, neither were regarded as being related to treatment.
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Improved ease of administration was the main reason for switching to transdermal rivastigmine. Other reasons involved in the decision to switch to rivastigmine patches included sociodemographic and clinical characteristics, including the educational level of patients and caregivers, number of concomitant diseases, and previous treatment for Alzheimer's disease.
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General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods.
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Cognitive disturbances in Parkinson's disease (PD) are dominated by troubles in executive functions which affects to a vast majority of parkinsonian patients since the onset of the disease. A common clinical observation is that parkinsonian patients, who eventually develop dementia, exhibit subtle cognitive disturbances quite earlier. The main biochemical substrate of cognitive dysfunction in PD, even of the early dysexecutive syndrome, might be a cholinergic deficiency. The aim of this pilot study was to determine the efficacy and safety of donepezil in the treatment of 10 patients with PD and dysexecutive alterations without dementia. All the items of the Clinical Global Impression were significantly improved. An improvement on both the modified Wisconsin Card Sorting Test and DIGIT Span was found. Parkinsonism remained unchanged during the study. Only 1 out of 10 patients experienced transient and mild gastrointestinal side effects. This study suggests that donepezil may be useful in the treatment of the dysexecutive syndrome associated with PD.
With the ever-growing geriatric population, research on brain diseases such as dementia is more imperative now than ever. The most prevalent of all dementias is Alzheimer's disease, a progressive neurodegenerative disease that presents with deficits in memory, cognition, motor skills, and a general decline in the quality of life. The social and economic burden associated with Alzheimer's disease is tremendous and is projected to grow even greater over the coming years. There is a specific need to elucidate and improve the treatments available, not only to alleviate the symptoms related to dementias such as Alzheimer's but also to prevent the formation of the disease. This is an effort that can be expedited and made more efficient by utilizing an animal model such as the zebrafish. This paper reviews the utility of zebrafish in Alzheimer's research by examining research on a sampling of the treatments available for the disease, specifically donepezil, memantine, and methylene blue. The human model and the shortcomings of the rodent model are also discussed.