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Cholinesterase inhibitors

Stephanie Behrens, Gail B Rattinger, Sarah Schwartz, Joshua Matyi, Chelsea Sanders, M Scott DeBerard, Constantine G Lyketsos, JoAnn T Tschanz
BACKGROUND: The use of FDA approved medications for Alzheimer's disease [AD; FDAAMAD; (cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists)] has been associated with symptomatic benefit with a reduction in formal (paid services) and total costs of care (formal and informal costs). We examined the use of these medications and their association with informal costs in persons with dementia. METHOD: Two hundred eighty participants (53% female, 72% AD) from the longitudinal, population-based Dementia Progression Study in Cache County, Utah (USA) were followed up to ten years...
March 21, 2018: International Psychogeriatrics
Miran Brvar, Ming Yin Chan, Andrew H Dawson, Richard R Ribchester, Michael Eddleston
INTRODUCTION: Treatment of acute organophosphorus or carbamate insecticide self-poisoning is often ineffective, with tens of thousands of deaths occurring every year. Researchers have recommended the addition of magnesium sulfate or calcium channel blocking drugs to standard care to reduce acetylcholine release at cholinergic synapses. OBJECTIVE: We aimed to review systematically the evidence from preclinical studies in animals exposed to organophosphorus or carbamate insecticides concerning the efficacy of magnesium sulfate and calcium channel blocking drugs as therapy compared with placebo in reducing mortality or clinical features of poisoning...
March 20, 2018: Clinical Toxicology
Adriana Ferreira Lopes Vilela, Cláudia Seidl, Juliana Maria de Lima, Carmen Lúcia Cardoso
Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are key cholinesterase enzymes responsible for the hydrolysis of acetylcholine into choline and acetic acid, an essential process for the restoration of the cholinergic neuron. The loss of cholinergic function in the central nervous system contributes to the cognitive decline associated with advanced age and Alzheimer's disease (AD). Inhibitions assays represent a significant role in the drug discovery process. Herein, we describe an improved label free method to screen and characterize new BChE ligands...
March 14, 2018: Analytical Biochemistry
Jaime McDonald, Emmanuelle Pourcher, Alexandra Nadeau, Philippe Corbeil
OBJECTIVES: The objective of this study was to compare the efficacy and safety of oral and transdermal rivastigmine for postural instability in patients with Parkinson disease dementia (PDD) who were candidates for a cholinesterase inhibitor. The primary outcome was the change in mean velocity of the center of pressure (CoP) after 6 months. Secondary outcomes included structural parameters of dynamic posturography, clinical rating scales, and adverse events requiring dose reduction. METHODS: Patients with PDD were randomized in a 1:1 ratio to oral or transdermal rivastigmine with target doses of 6 mg twice daily and 9...
March 13, 2018: Clinical Neuropharmacology
Etta Y L Liu, Miranda L Xu, Yan Jin, Qiyun Wu, Tina T X Dong, Karl W K Tsim
Genistein, 4',5,7-trihydroxyisoflavone, is a major isoflavone in soybean, which is known as phytestrogen having known benefit to brain functions. Being a common phytestrogen, the possible role of genistein in the brain protection needs to be further explored. In cultured PC12 cells, application of genistein significantly induced the expression of neurofilaments (NFs), markers for neuronal differentiation. In parallel, the expression of tetrameric form of proline-rich membrane anchor (PRiMA)-linked acetyl-cholinesterase (G4 AChE), a key enzyme to hydrolyze acetylcholine in cholinergic synapses, was induced in a dose-dependent manner: this induction included the associated protein PRiMA...
2018: Frontiers in Molecular Neuroscience
V Hepnarova, J Korabecny, L Matouskova, P Jost, L Muckova, M Hrabinova, N Vykoukalova, M Kerhartova, T Kucera, R Dolezal, E Nepovimova, K Spilovska, E Mezeiova, N L Pham, D Jun, F Staud, D Kaping, K Kuca, O Soukup
Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line...
March 2, 2018: European Journal of Medicinal Chemistry
Eva Mezeiova, Katarina Spilovska, Eugenie Nepovimova, Lukas Gorecki, Ondrej Soukup, Rafael Dolezal, David Malinak, Jana Janockova, Daniel Jun, Kamil Kuca, Jan Korabecny
Alzheimer's disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Sirin Uysal, Sulunay Parlar, Ayse H Tarikogullari, Fadime Aydin Kose, Vildan Alptuzun, Zeynep Soyer
A series of N-substituted-5-chloro-2(3H)-benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)) assay...
March 12, 2018: Archiv der Pharmazie
Franko Burčul, Ivana Generalić Mekinić, Mila Radan, Patrick Rollin, Ivica Blažević
Finding a new type of cholinesterase inhibitor that would overcome the brain availability and pharmacokinetic parameters or hepatotoxic liability has been a focus of investigations dealing with the treatment of Alzheimer's disease. Isothiocyanates have not been previously investigated as potential cholinesterase inhibitors. These compounds can be naturally produced from their glucosinolate precursors, secondary metabolites widely distributed in our daily Brassica vegetables. Among 11 tested compounds, phenyl isothiocyanate and its derivatives showed the most promising inhibitory activity...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Kurt A Jellinger, Amos D Korczyn
BACKGROUND: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which share many clinical, neurochemical, and morphological features, have been incorporated into DSM-5 as two separate entities of major neurocognitive disorders with Lewy bodies. Despite clinical overlap, their diagnosis is based on an arbitrary distinction concerning the time of onset of motor and cognitive symptoms, namely as early cognitive impairment in DLB and later onset following that of motor symptoms in PDD...
March 6, 2018: BMC Medicine
Joseph H Friedman
Psychosis is a common problem for people treated for Parkinson's disease. The syndrome is quite stereotypic, with hallucinations being the most common, followed by delusions. While the hallucinations are usually not very bothersome, the delusions are typically paranoid in nature. Treatment is often, but not always, required. Areas covered: This article reviews the therapeutic approaches of this syndrome focusing on drug treatments used once contributory factors have been removed. This includes a review of the evidence supporting the use of clozapine and, most recently, pimavanserin, the first drug with antipsychotic efficacy that has no effect on dopamine...
March 1, 2018: Expert Opinion on Pharmacotherapy
Po-Heng Tsai
PURPOSE OF REVIEW: The purpose of this review was to discuss therapeutic options available for the treatment of memory difficulties in dementia. RECENT FINDINGS: Because of the lack of progress in the availability of new medications, there has been an increased interest in focusing on non-pharmacological means to management cognitive symptoms related to dementia. The clinical management of memory loss should focus both on pharmacological and non-pharmacological approaches...
February 28, 2018: Current Treatment Options in Neurology
Rita Khoury, Jayashree Rajamanickam, George T Grossberg
Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders worldwide. Despite all research efforts, therapeutic options for AD are still limited to two drug classes: cholinesterase inhibitors (ChEIs) and the NMDA-receptor antagonist memantine. Donepezil, rivastigmine and galantamine are the three ChEIs FDA-approved as first-line treatment for AD. Although they share the same mode of action, they differ in terms of their pharmacologic characteristics and route of administration, which can impact their safety and tolerability profile...
March 2018: Therapeutic Advances in Drug Safety
Nicole Eady, Rory Sheehan, Khadija Rantell, Amanda Sinai, Jane Bernal, Ingrid Bohnen, Simon Bonell, Ken Courtenay, Karen Dodd, Dina Gazizova, Angela Hassiotis, Richard Hillier, Judith McBrien, Kamalika Mukherji, Asim Naeem, Natalia Perez-Achiaga, Vijaya Sharma, David Thomas, Zuzana Walker, Jane McCarthy, André Strydom
BACKGROUND: There is little evidence to guide pharmacological treatment in adults with Down syndrome and Alzheimer's disease. Aims To investigate the effect of cholinesterase inhibitors or memantine on survival and function in adults with Down syndrome and Alzheimer's disease. METHOD: This was a naturalistic longitudinal follow-up of a clinical cohort of 310 people with Down syndrome diagnosed with Alzheimer's disease collected from specialist community services in England...
March 2018: British Journal of Psychiatry: the Journal of Mental Science
Jamshed Iqbal, Muhammad Shakeel Ahmad Abbasi, Sumera Zaib, Saifullah Afridi, Norbert Furtmann, Jurgen Bajorath, Peter Langer
BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia among aging population. This devastating disorder is generally associated with the gradual memory loss, specified by decrease of acetylcholine level in the cortex hippocampus of the brain due to hyper-activation of cholinesterases (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)). OBJECTIVE: Therefore, inactivation of AChE and BChE by inhibitors can increase the acetylcholine level and hence may be an encouraging strategy for the treatment of AD and related neurological problems...
February 21, 2018: Medicinal Chemistry
Paula Rayane de Souza, Kelma Sirleide de Souza, Caio Rodrigo Dias de Assis, Marlyete Chagas de Araújo, Kaline Catiely Campos Silva, Juliett de Fátima Xavier da Silva, Andreia Cybelle Marques Ferreira, Valdir Luna da Silva, Mônica Lúcia Adam, Luiz Bezerra de Carvalho, Ranilson de Souza Bezerra
Enzyme biomarkers from several aquatic organisms have been used for assessing the exposure to contaminants at sublethal levels. Amongst them, the cholinesterases are commonly extracted from several organisms to evaluate/measure organophosphate and carbamate neurotoxic effects. Acetylcholinesterase (AChE; EC is an enzyme of the group of serine esterases that acts on the hydrolysis of the neurotransmitter acetylcholine allowing the intermittence of the nerve impulses responsible for the neuronal communication...
February 12, 2018: Aquatic Toxicology
Javier E Ortiz, Adriana Garro, Natalia B Pigni, María Belén Agüero, German Roitman, Alberto Slanis, Ricardo D Enriz, Gabriela E Feresin, Jaume Bastida, Alejandro Tapia
BACKGROUND: In Argentina, the Amaryllidaceae family (59 species) comprises a wide variety of genera, only a few species have been investigated as a potential source of cholinesterases inhibitors to treat Alzheimer disease (AD). PURPOSE: To study the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of the basic dichloromethane extracts (E) from Hieronymiella aurea, H. caletensis, H. clidanthoides, H. marginata, and H. speciosa species, as well as the isolated compounds from these plant extracts...
January 15, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Archana S Gurjar, Mrunali N Darekar, Keng Yoon Yeong, Luyi Ooi
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters...
February 2, 2018: Bioorganic & Medicinal Chemistry
Valeria Cavallaro, Yanina F Moglie, Ana P Murray, Gabriel E Radivoy
A series of thirty-three alkynyl and β-ketophosphonates were evaluated for their in vitro acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitory activities using Ellman's spectrophotometric method. None of the examined compounds inhibited AChE activity at tested concentrations while twenty-nine of them showed significant and selective inhibition of BChE with IC50 values between 38.60 µM and 0.04 µM. In addition, structure-activity relationships were discussed. The most effective inhibitors were the dibutyl o-methoxyphenyl alkynylphosphonate 3dc and dibutyl o-methoxyphenyl β-ketophosphonate 4dc...
February 7, 2018: Bioorganic Chemistry
Fahimeh Vafadarnejad, Mohammad Mahdavi, Elahe Karimpour-Razkenari, Najmeh Edraki, Bilqees Sameem, Mahnaz Khanavi, Mina Saeedi, Tahmineh Akbarzadeh
A novel series of coumarin-pyridinium hybrids were synthesized and evaluated as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using Ellman's method. Among synthesized compounds, 1-(3-fluorobenzyl)-4-((2-oxo-2H-chromene-3-carboxamido)methyl)pyridinium bromide (7l) was found to be the most active compound toward AChE (IC50 = 10.14 µM), 1-(3-chlorobenzyl)-3-((2-oxo-2H-chromene-3-carboxamido)methyl)pyridinium bromide (7g) and 1-(2,3-dichlorobenzyl)-3-((2-oxo-2H-chromene-3-carboxamido)methyl)pyridinium chloride (7h) depicted the best BChE inhibitory activity (IC50s = 0...
January 27, 2018: Bioorganic Chemistry
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