scholarly journals A critical review of cholinesterase inhibitors as a treatment modality in Alzheimer's disease

2000 ◽  
Vol 2 (2) ◽  
pp. 111-128 ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinesterase Inhibitors ◽  
Acetylcholinesterase Inhibitors ◽  
Synaptic Cleft ◽  
Dose Effect ◽  
Number Needed To Treat ◽  
Serious Adverse Events ◽  
Number Of Patients ◽  
Clinical Measures

Early research into Alzheimer's disease launched the cholinergic hypothesis, based on the correlation between central cholinergic deficiency and clinical measures of cognitive decline. This was epitomized in therapeutic strategies employing a variety of procholinergic agents, of which only the inhibitors of cholinesterase (ChE), the enzyme thai hydrolyzes acetylcholine in the synaptic cleft, have been proven clinically viable. Five such agents are reviewed: tacrine and donepezil, which act at the ionic subsite of acetylcholinesterase (AChE), and rivastigmine, galantamine, and metrifonate, which act at its catalytic esteratic subsite. Despite statistical evidence of efficacy from numerous well-controlled multicenter trials, important clinical utility issues remain outstanding: (i) number-needed-to-treat (NNT) analyses, quantifying the number of patients needing to be treated for one patient to show benefit, find values of 3 to 20; (ii) the pivotal trials themselves were conducted in nonrepreseniative populations, largely comprised of physically healthy outpatients with mildto-moderate Alzheimer's disease and a mean age of 72 years (thereby excluding over 30% of typical Alzheimer patients in State of California-funded clinics), treated for up to 6 months; and (Hi) tolerability is underreported and characterized by a positive correlation between dose, effect and cholinergic side effects - potentially serious adverse events include bradycardia, anorexia, weight loss and myasthenia with respiratory depression. Therapies thus require titration and constant monitoring. Nevertheless, acetylcholinesterase inhibitors (AChEls) constitute the first class of effective agents and are likely to remain so in the continuing absence of viable alternatives.

Cholinesterase Inhibitors and Memantine: Best Practices

CNS Spectrums ◽  
2008 ◽  
Vol 13 (S16) ◽  
pp. 34-35 ◽  
Author(s):  
Rachelle S. Doody
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Best Practices ◽  
Cholinesterase Inhibitors ◽  
Treatment Guidelines ◽  
Case Reports ◽  
Case Series ◽  
Added Value ◽  
Case Control Studies ◽  
Number Of Patients

Today’s therapies must be put in the context of both currently available treatments as well as treatment trials with exciting potential for use in the near future. Current clinical trial methodologies do not allow for clear separation of symptomatic treatments from disease-modifying therapies; it may be unproductive to maintain this distinction given the current range of treatments available. A more currently relevant focus is added value. Therapies should aim to provide added value through incremental benefits above and beyond existing treatments, as well as enduring benefits.Alzheimer’s disease (AD) treatment guidelines are not used by physicians only. Healthcare payers often make use of these guidelines to delimit coverage. Cost concerns will also impact AD treatments after generic cholinesterase inhibitors are made available; it is widely believed that a great number of patients will switch to generics. Therefore, treatment guidelines must account for the possible adverse effects of switching therapies as well as the desirability of persistent treatment. There are many AD treatment guidelines, among them the American Academy of Neurology (AAN) Management of Dementia Guidelines, which are currently being revised. The Institute for the Study on Aging (ISOA) Management of Alzheimer’s Disease in Managed Care Guideline also presents a different approach for a different audience.The first step to creating evidence-based best practices guidelines is to determine what is meant by “evidence.” A system of classification exists for examining forms of evidence: Class I evidence is provided by one or more well-designed, randomized, controlled clinical trials, including overviews or meta-analyses of such trials. Class II evidence is provided by well-designed observational studies with concurrent controls; for example, case-control studies that generate hypotheses about epidemiologic associations. Class III evidence is provided by expert opinion, case series, case reports, and studies with historical controls.

Anti-Acetylcholinesterase Derivatives: A Privileged Structural Framework in Drug Discovery to Treat Alzheimer’s Disease

2019 ◽  
Vol 15 (1) ◽  
pp. 8-21
Author(s):  
Monika Bhardwaj ◽  
Vaishali M. Patil ◽  
Rakhi Dhiman ◽  
Satya P. Gupta ◽  
Neeraj Masand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Acetylcholinesterase Inhibitors ◽  
Synaptic Cleft ◽  
Ache Inhibitors ◽  
Structural Framework ◽  
Natural Alkaloid ◽  
Synthetic Derivatives

Alzheimer’s disease (AD) is a complex neurological disorder characterised by decrease level of ACh and increased AChE expression. Inhibition of AChE is one of the common strategies to treat AD as it leads to increase Ach level quantitatively at the synaptic cleft. Acetylcholinesterase inhibitors (AChEIs) are used to treat various neurodegenerative disorders, and many are FDA approved for the management and cure of AD. AChEIs produce long term symptomatic effect, that contribute in other pathological mechanisms of the disease (e.g. formation of amyloid–β plaques) and have provided a rationale to the discovery of this class of inhibitors. Currently prescribed AChE inhibitors are Galantamine (natural alkaloid) and Rivastigmine (synthetic alkaloid compound) and have been considered beneficial for the treatment of mild to moderate AD. However, there is a need for the discovery of more effective compounds derived from natural sources as well as form synthetic sources as potential AChEIs. Findings and advances about natural and synthetic derivatives as potential sources of AChEIs will be collectively summarised in this review paper.

Biochemical investigations in patients with dementia

2002 ◽  
Vol 39 (3) ◽  
pp. 211-220 ◽  
Author(s):  
Alison Green
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Acetylcholinesterase Inhibitors ◽  
Amyloid Peptide ◽  
Number Of Patients ◽  
Diagnosis Of Dementia ◽  
Jakob Disease ◽  
Β Amyloid ◽  
Detection And Diagnosis ◽  
Β Amyloid Peptide

The recent development of acetylcholinesterase inhibitors to treat patients with Alzheimer's disease has increased interest in the use of biochemical markers for the early detection and diagnosis of dementia, but only the measurement of the protein 14-3-3 in cerebrospinal fluid (CSF) to help diagnose sporadic Creutzfeldt-Jakob disease has become accepted clinical practice. CSF concentrations of t protein and β-amyloid peptide 42 have been widely investigated as potential diagnostic tests for Alzheimer's disease, but neither has shown sufficient sensitivity and specificity for clinical use. Preliminary investigations suggest that β-amyloid peptide 42 may be useful in monitoring disease progression, but this needs to be verified. In addition, biochemical investigations may help to identify the small number of patients with treatable causes of dementia such as hypothyroidism and vitamin B12 deficiency, as well as any other compounding condition such as anaemia or diabetes mellitus that increase morbidity.

scholarly journals Reassessment of the dementia diagnosis of Alzheimer's disease in patients enrolled on the cholinesterase inhibitors dispensation program

2012 ◽  
Vol 6 (4) ◽  
pp. 270-275
Author(s):  
Magda Cristina Flaitt Sanches Piovesana ◽  
Fúlvio Rogério Garcia ◽  
Kátia G. Carrasco ◽  
Waldir Antonio Tognola
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinesterase Inhibitors ◽  
Treatment Time ◽  
Significance Level ◽  
Number Of Patients ◽  
Study Results ◽  
A Prospective Study ◽  
Diagnosis Criteria ◽  
Related Association

ABSTRACT Objective: Reassess the diagnosis of Alzheimer's Disease (AD) in patients treated with anti-cholinesterases dispensed by High Cost Drug stores (Exceptional Drugs Program). Methods: A prospective study to reassess the diagnosis of probable Alzheimer's Disease was conducted (AD). The patients were submitted to the protocol of dementia investigation at the Neurogeriatric Outpatient Clinic of the Teaching Hospital de Base de São José do Rio Preto. Groups were classified using the criteria of the National Institute of Neurologic and Communicative Diseases and Vascular Cerebral Accident and Alzheimer Disease Related Association (NINCDS-ADRDA). The study was completed by applying the Disability Assessment for Dementia (DAD). The significance level was set at 5%. Results: 106 patients participated, selected randomly from a group of 390 patients contacted when receiving their medication at the High Cost Drug store. Two groups were formed: the first, containing 52 patients who fulfilled criteria for AD (FC Group); and a second, with 54 patients not fulfilling criteria (NFC). The FC Group had older age, worse performance on the Mini-Mental State Exam (MMSE) and poorer performance on the DAD. Also, treatment time was longer and drugs doses higher in the FC Group. Conclusion: Study results showed a high number of patients using anti-cholinesterases that did not fulfill the diagnosis criteria for probable AD. Comparison of the two groups revealed different behavior between them, corroborating the hypothesis of inadequate inclusion of the NFC Group patients in the Exceptional Drugs Program.

scholarly journals New Acetylcholinesterase Inhibitors for Alzheimer's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Mona Mehta ◽  
Abdu Adem ◽  
Marwan Sabbagh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Target ◽  
Cholinesterase Inhibitors ◽  
Treatment Approach ◽  
Acetylcholinesterase Inhibitors ◽  
Symptomatic Treatment ◽  
Symptomatic Improvement ◽  
Ache Inhibition ◽  
Different Types

Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.

Drug Design of Inhibitors of Alzheimer’s Disease (AD): POM and DFT Analyses of Cholinesterase Inhibitory Activity of β-amino di-Carbonyl Derivatives

2019 ◽  
Vol 19 (8) ◽  
pp. 688-705
Author(s):  
Taibi Ben Hadda ◽  
Abdur Rauf ◽  
Hsaine Zgou ◽  
Fatma Sezer Senol ◽  
Ilkay Erdogan Orhan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinesterase Inhibitors ◽  
Metal Accumulation ◽  
Microtiter Plate ◽  
Metal Chelation ◽  
Carbonyl Derivatives ◽  
Cholinesterase Inhibitory Activity ◽  
Inhibitory Potential

Background:Since deficit of acetylcholine has been evidenced in the Alzheimer’s disease (AD) patients, cholinesterase inhibitors are currently the most specified drug category for the remediation of AD.Method:In the present study, 16 compounds (1-16) with dicarbonyl skeletons have been synthesized and tested for their inhibitory potential in vitro against AChE and BChE using ELISA microtiter plate assays at 100 μg/mL. Since metal accumulation is related to AD, the compounds were also tested for their metal-chelation capacity.Results and Conclusion:All the investigated dicarbonyl compounds exerted none or lower than 30% inhibition against both cholinesterases, whereas compounds 2, 8 and 11 showed 37, 42, 41% of inhibition towards BChE, being the most active. The highest metal-chelation capacity was observed with compound 8 (53.58 ± 2.06%). POM and DFT analyses are in good harmonization with experimental data.

Identify Compounds' Target Against Alzheimer's Disease Based on In-Silico Approach

2019 ◽  
Vol 16 (3) ◽  
pp. 193-208 ◽  
Author(s):  
Yan Hu ◽  
Guangya Zhou ◽  
Chi Zhang ◽  
Mengying Zhang ◽  
Qin Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecule ◽  
Characteristic Curve ◽  
Machine Learning Algorithms ◽  
Learner Model ◽  
Mao B ◽  
Number Of Patients ◽  
Sar Model ◽  
Set Up

Background: Alzheimer's disease swept every corner of the globe and the number of patients worldwide has been rising. At present, there are as many as 30 million people with Alzheimer's disease in the world, and it is expected to exceed 80 million people by 2050. Consequently, the study of Alzheimer’s drugs has become one of the most popular medical topics. Methods: In this study, in order to build a predicting model for Alzheimer’s drugs and targets, the attribute discriminators CfsSubsetEval, ConsistencySubsetEval and FilteredSubsetEval are combined with search methods such as BestFirst, GeneticSearch and Greedystepwise to filter the molecular descriptors. Then the machine learning algorithms such as BayesNet, SVM, KNN and C4.5 are used to construct the 2D-Structure Activity Relationship(2D-SAR) model. Its modeling results are utilized for Receiver Operating Characteristic curve(ROC) analysis. Results: The prediction rates of correctness using Randomforest for AChE, BChE, MAO-B, BACE1, Tau protein and Non-inhibitor are 77.0%, 79.1%, 100.0%, 94.2%, 93.2% and 94.9%, respectively, which are overwhelming as compared to those of BayesNet, BP, SVM, KNN, AdaBoost and C4.5. Conclusion: In this paper, we conclude that Random Forest is the best learner model for the prediction of Alzheimer’s drugs and targets. Besides, we set up an online server to predict whether a small molecule is the inhibitor of Alzheimer's target at http://47.106.158.30:8080/AD/. Furthermore, it can distinguish the target protein of a small molecule.

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