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Cholinesterase inhibitors

Syed Haris Omar, Christopher J Scott, Adam S Hamlin, Hassan K Obied
The focus of this study was on inhibition of enzymes involved in the pathogenesis Alzheimer's disease (AD) including prime amyloid beta (Aβ) producing enzyme (β-secretase: BACE-1) and disease progression enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), histone deacetylase (HDAC), and tyrosinase along with the catecholamine L-DOPA, by using olive biophenols. Here we report the strongest inhibition of BACE-1 from rutin (IC50 : 3.8 nM) followed by verbascoside (IC50 : 6.3 nM) and olive fruit extract (IC50 : 18 ng), respectively...
May 14, 2018: Fitoterapia
George T Grossberg, Gustavo Alva, Suzanne Hendrix, Noel Ellison, Mary C Kane, John Edwards
Memantine extended release (ER) significantly outperformed placebo on co-primary endpoints of Clinician's Interview-based Impression of Change Plus Caregiver Input (CIBIC-Plus) and baseline to endpoint changes on the Severe Impairment Battery (SIB) in a 24-week, randomized trial (NCT00322153) in patients with moderate to severe Alzheimer's disease taking a cholinesterase inhibitor (ChEI). A post hoc analysis compared patients receiving memantine ER/ChEI to placebo/ChEI for time to onset of response and if the response was maintained (achieving improvement at weeks 8, 12, or 18 and maintaining through endpoint/week 24) on the SIB, the Neuropsychiatric Inventory (NPI), CIBIC-Plus, and Activities of Daily Living (ADL) using Fisher exact test...
May 16, 2018: Alzheimer Disease and Associated Disorders
Nasimudeen R Jabir, Fayaz Rahman Khan, Shams Tabrez
Alzheimer's disease (AD) is a progressive irreversible neurodegenerative disorder characterized by excessive deposition of β-amyloid (Aβ) oligomers, and neurofibrillary tangles (NFTs), comprising of hyperphosphorylated tau proteins. The cholinergic system has been suggested as the earliest and most affected molecular mechanism that describes AD pathophysiology. Moreover, cholinesterase inhibitors (ChEIs) are the potential class of drugs that can amplify cholinergic activity to improve cognition and global performance and reduce psychiatric and behavioral disturbances...
May 16, 2018: CNS Neuroscience & Therapeutics
Jan Korabecny, Katarina Spilovska, Eva Mezeiova, Ondrej Benek, Radomir Juza, Daniel Kaping, Ondrej Soukup
Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by memory loss, disorientation, and gradual deterioration of intellectual capacity. Its etiology has not been elucidated yet. To date, only one therapeutic approach has been approved for the treatment of AD. The pharmacotherapy of AD has relied on non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist - memantine, and acetylcholinesterase (AChE) inhibitors (AChEIs) - tacrine, donepezil, rivastigmine and galantamine...
May 16, 2018: Current Medicinal Chemistry
Leili Jalili-Baleh, Hamid Forootanfar, Tuba Tüylü Küçükkılınç, Hamid Nadri, Zahra Abdolahi, Alieh Ameri, Mandana Jafari, Beyza Ayazgok, Maryam Baeeri, Mahban Rahimifard, Syed Nasir Abbas Bukhari, Mohammad Abdollahi, Mohammad Reza Ganjali, Saeed Emami, Mehdi Khoobi, Alireza Foroumadi
A novel series of coumarin-lipoic acid conjugates were synthesized via cycloaddition click reaction to find out new multi-target-directed ligands (MTDLs) for treatment of Alzheimer's disease (AD). All of synthesized compounds were screened for neuroprotective and anti-cholinesterase activities. Based on primary screening, two compounds (5 and 11) were subjected to further biological evaluations. In particular, compound 11 which was the most potent AChE inhibitor showed good inhibitory effect on Aβ-aggregation and intracellular ROS (reactive oxygen species) formation, as well as the ability of selective bio-metal chelation and neuroprotection against H2 O2 - and Aβ1-42 -induced cytotoxicity...
May 2, 2018: European Journal of Medicinal Chemistry
Seyed Mohammad Nabavi, Eugenio Uriarte, Luca Rastrelli, Eduardo Sobarzo-Sanchez
Alzheimer's disease (AD) is a neurodegenerative disease that is reducing progressively the part cognitive inside the Central Nervous System (CNS) and that affects the memories and emotions of the patients who endure this disease. Many drugs have been assessed in patients with different evolutionary grades of the disease, having diverse results, depending on the used compound. Some of them afford dependence and many others with side effects that affect the emotional part and the economic cost of the treatment...
May 13, 2018: Current Medicinal Chemistry
Vladimir Z Ajdžanovic, Svetlana Trifunovic, Dragana Miljic, Branka Šošic-Jurjevic, Branko Filipovic, Marko Miler, Nataša Ristic, Milica Manojlovic-Stojanoski, Verica Miloševic
The pathological phenomenon of somatopause, noticeable in hypogonadal ageing subjects, is based on the growth hormone (GH) production and secretion decrease along with the fall in GH binding protein and insulin-like growth factor 1 (IGF-1) levels, causing different musculoskeletal, metabolic and mental issues. From the perspective of safety and efficacy, GH treatment is considered to be highly controversial, while some other therapeutic approaches (application of IGF-1, GH secretagogues, gonadal steroids, cholinesterase-inhibitors or various combinations) exhibit more or less pronounced weaknesses in this respect...
2018: EXCLI journal
Jakub Kazmierski, Chaido Messini-Zachou, Mara Gkioka, Magda Tsolaki
Cholinesterase inhibitors (ChEIs) are the mainstays of symptomatic treatment of Alzheimer's disease (AD); however, their efficacy is limited, and their use was associated with deaths in some groups of patients. The aim of the current study was to assess the impact of the long-term use of ChEIs on mortality in patients with AD. This observational, longitudinal study included 1171 adult patients with a diagnosis of AD treated with donepezil or rivastigmine. Each patient was observed for 24 months or until death...
January 1, 2018: American Journal of Alzheimer's Disease and Other Dementias
Catarina Oliveira, Fernando Cagide, José Teixeira, Ricardo Amorim, Lisa Sequeira, Francesco Mesiti, Tiago Silva, Jorge Garrido, Fernando Remião, Santiago Vilar, Eugenio Uriarte, Paulo J Oliveira, Fernanda Borges
Alzheimer's disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN 1 (catechol derivative), and AntiOxBEN 2 (pyrogallol derivative) and compounds 15-18 , which have longer spacers...
2018: Frontiers in Chemistry
Kamil Kuca, Daniel Jun, Lucie Junova, Kamil Musilek, Martina Hrabinova, Jorge Alberto Valle da Silva, Teodorico Castro Ramalho, Marian Valko, Qinghua Wu, Eugenie Nepovimova, Tanos Celmar Costa França
Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC and butyrylcholinesterase (BChE; EC, and are therefore highly toxic compounds. For the recovery of inhibited AChE, antidotes from the group of pyridinium or bispyridinium aldoxime reactivators (pralidoxime, obidoxime, HI-6) are used in combination with anticholinergics and anticonvulsives. Therapeutic efficacy of reactivators (called “oximes”) depends on their chemical structure and also the type of organophosphorus inhibitor...
May 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Carina Wattmo, Elisabet Londos, Lennart Minthon
BACKGROUND: A varying response to cholinesterase inhibitor (ChEI) treatment has been reported among patients with Alzheimer's disease (AD). Whether the individual-specific response directly affects time to nursing home placement (NHP) was not investigated. OBJECTIVE: We examined the relationship between the 6-month response to ChEI and institutionalization. METHODS: In a prospective, observational, multicenter study, 881 outpatients with a clinical AD diagnosis and a Mini-Mental State Examination score of 10-26 at the start of ChEI therapy (baseline) were included...
May 6, 2018: Current Alzheimer Research
Muhammad Shahid Ramzan, Muhammad Athar Abbasi, Azizur Rehman, Sabahat Zahra Siddiqui, Syed Adnan Ali Shah, Muhammad Ashraf, Bushra Mirza, Hammad Ismail
An electrophile, N-(1,3-thiazol-2-yl)-2-bromoacetamide (3), was synthesized by the reaction of 1,3-thiazole-2-amine (1) and 2-bromoethanoyl bromide (2) in an aqueous medium. A series of carboxylic acids, 7a-j, were converted into 1,3,4-oxadiazole heterocyclic core, through a series of three steps. The final compounds, 8a-j, were synthesized by stirring 7a-j and 3 in an aprotic polar solvent. The structural elucidation of the synthesized compounds was supported by IR, EI-MS, 1H-NMR, and 13 C-NMR spectral data...
May 2018: Pakistan Journal of Pharmaceutical Sciences
Fayaz Ali Larik, Muhammad Shakil Shah, Aamer Saeed, Hamid Saeed Shah, Pervaiz Ali Channar, Michael Bolte, Jamshed Iqbal
Highly progressive neurodegenerative disorder generally known as Alzheimer's disease (AD), is a type of dementia, which is very common in elderly. The most common symptoms may include loss of memory along with disturbed behavioral and cognitive functions. Until now, only 4 cholinesterase (ChE) inhibitors are approved by FDA for symptomatic treatment of AD. Aroyl thiourea derivatives are well known bioactive organic molecules containing carbonyl and thiocarbonyl functional groups. Here, total 14 different thiourea derivatives (3a-3n) were synthesized and characterized by NMR, FTIR and X-ray crystallographic techniques...
May 2, 2018: International Journal of Biological Macromolecules
Marek Toczek, Barbara Malinowska
The endocannabinoid system is up-regulated in numerous pathophysiological states such as inflammatory, neurodegenerative, gastrointestinal, metabolic and cardiovascular diseases, pain, and cancer. It has been suggested that this phenomenon primarily serves an autoprotective role in inhibiting disease progression and/or diminishing signs and symptoms. Accordingly, enhancement of endogenous endocannabinoid tone by inhibition of endocannabinoid degradation represents a promising therapeutic approach for the treatment of many diseases...
May 2, 2018: Life Sciences
I Weichert, R Romero-Ortuno, J Tolonen, T Soe, C Lebus, S Choudhury, C V Nadarajah, P Nanayakkara, M Orrù, S Di Somma
WHAT IS KNOWN AND OBJECTIVE: Drugs with anticholinergic properties increase the risk of falls, delirium, chronic cognitive impairment, and mortality and counteract procholinergic medications used in the treatment of dementia. Medication review and optimisation to reduce anticholinergic burden in patients at risk is recommended by specialist bodies. Little is known how effective this review is in patients who present acutely and how often drugs with anticholinergic properties are used temporarily during an admission...
May 4, 2018: Journal of Clinical Pharmacy and Therapeutics
Benjamin Roeben, Tania Zieschang, Walter Maetzler
Due to the aging population, dementias represent a growing challenge for the health systems and for the society. This overview summarizes the current state of already practice-relevant therapies and management of dementias. Non-pharmacological approaches have a greater impact than pharmacological treatment. Increasing evidence underlines that consistent management of cardiovascular risk factors has beneficial effects on the progression of at least some, possibly almost all types of dementias. The main pharmacological agents for symptomatic treatment of cognitive deficits in Alzheimer's and Parkinson's disease-associated dementias are cholinesterase inhibitors and memantine...
May 2018: Deutsche Medizinische Wochenschrift
Myuri T Ruthirakuhan, Nathan Herrmann, Eleenor H Abraham, Sarah Chan, Krista L Lanctôt
BACKGROUND: Despite the high prevalence of apathy in Alzheimer's disease (AD), and its harmful effects, there are currently no therapies proven to treat this symptom. Recently, a number of pharmacological therapies have been investigated as potential treatments for apathy in AD. OBJECTIVES: Objective 1: To assess the safety and efficacy of pharmacotherapies for the treatment of apathy in Alzheimer's disease (AD).Objective 2: To assess the effect on apathy of pharmacotherapies investigated for other primary outcomes in the treatment of AD...
May 4, 2018: Cochrane Database of Systematic Reviews
Muriel Ramírez-Santana, Cristián Farías-Gómez, Liliana Zúñiga-Venegas, Rodrigo Sandoval, Nel Roeleveld, Koos Van der Velden, Paul T J Scheepers, Floria Pancetti
In Chile, agriculture is a relevant economic activity and is concomitant with the use of pesticides to improve the yields. Acute intoxications of agricultural workers occur with some frequency and they must be reported to the surveillance system of the Ministry of Health. However the impacts of chronic and environmental pesticide exposure have been less studied. Among pesticides frequently used in Chile for insects control are organophosphates (OP) and carbamates (CB). They are inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)...
2018: PloS One
Yoshiko Furiya, Takami Tomiyama, Tesseki Izumi, Naoki Ohba, Satoshi Ueno
Background: Weight loss accelerates cognitive decline and increases mortality in patients with dementia. While acetylcholinesterase (AChE) inhibitors are known to cause appetite loss, we sometimes encounter patients in whom switching from donepezil (AChE inhibitor) to rivastigmine (AChE and butyrylcholinesterase [BuChE] inhibitor) improves appetite. Since BuChE inactivates ghrelin, a potent orexigenic hormone, we speculated that rivastigmine improves appetite by inhibiting BuChE-mediated ghrelin inactivation...
January 2018: Dementia and Geriatric Cognitive Disorders Extra
Ruifeng Liu, Jonathan Crawford, Patrick M Callahan, Alvin V Terry, Christos Constantinidis, David T Blake
Sustained attention is essential in important behaviors in daily life. Many neuropsychiatric disorders are characterized by a compromised ability to sustain attention, making this cognitive domain an important therapeutic target. In this study, we tested a novel method of improving sustained attention. Monkeys were engaged in a continuous performance task (CPT) while the nucleus basalis of Meynert (NB), the main source of cholinergic innervation of the neocortex, was stimulated. Intermittent NB stimulation improved the animals' performance by increasing the hit rate and decreasing the false alarm rate...
April 26, 2018: Neuropharmacology
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