Cholinesterase Inhibitor Donepezil Research Articles

Antipsychotic Initiation Among Older Dementia Patients Using Cholinesterase Inhibitors: A National Retrospective Cohort Study.

Evidence regarding the initiation of antipsychotic medications across individual cholinesterase inhibitors (ChEIs) to manage the behavioral symptoms of dementia is lacking. This study compared the risk of initiation of antipsychotic medications among older adults with dementia treated with the ChEIs donepezil, rivastigmine, or galantamine. This retrospective cohort study used multiyear (2013-2015) Medicare claims data involving Parts A, B, and D. The study sample included community-dwelling older adults (aged ≥ 65years) with a diagnosis of dementia. The study identified new users of ChEIs and followed them for up to 180days for antipsychotic initiation. The ChEIs included donepezil, rivastigmine, and galantamine, whereas antipsychotics included typical and atypical agents. Donepezil was used as the reference category as it is the most commonly used ChEI and only acts on acetylcholinesterase, whereas both rivastigmine and galantamine have dual mechanisms of action. Multivariable Cox proportional hazards regression compared the risk of and time to antipsychotic initiation among the three ChEIs, adjusting for other risk factors. The study cohort consisted of178,441 older adults with dementia whowere new users of ChEIs. A total of 23,433 (15.14%) donepezil users, 4114 (19.04%) rivastigmine users, and 324 (15.77%) galantamine users initiated antipsychotics. The mean time to antipsychotic initiation among patients who received antipsychotics was 109.29 ± 69.72days for donepezil users, 96.70 ± 71.60days for rivastigmine users, and 104.15 ± 72.53days for galantamine users. The Cox regression analysis showed that rivastigmine (adjusted hazard ratio [aHR]=1.27; 95% confidence interval [CI], 1.20-1.34) was significantly associated with antipsychotic initiation compared with donepezil, whereas no significant difference was observed between galantamine and donepezil (aHR=0.98; 95% CI, 0.81-1.20). The study found a 27% increased risk of antipsychotic initiation among users of rivastigmine compared with donepezil users. There was no difference between galantamine and donepezil for antipsychotic initiation. Although the limitations of the study should be considered, the results suggest that donepezil or galantamine may be more appropriate treatments for older patients with dementia, to minimize antipsychotic use.

Effect of QT Prolongation in Patients Taking Cholinesterase Inhibitors (Donepezil) for Alzheimer's Disease.

Background: Cholinesterase inhibitors such as donepezil are used in the treatment of Alzheimer’s disease. Patients taking cholinesterase inhibitors can develop cholinergically mediated QT prolongation, which may lead to life-threatening arrhythmias. In this study we investigated the corrected QT interval (QTc) of patients taking donepezil.Methods and Results: This study enrolled 114 outpatients attending Tarumizu Chuo Hospital. Subjects were divided into a donepezil group (n=57) or an age- and sex-matched control group (n=57). Physical findings, laboratory data, and electrocardiographic parameters were compared between the groups. QTc was significantly prolonged (mean [±SD] 0.443±0.032 s vs. 0.426±0.026s; P<0.001) and the percentage of patients with prolonged QTc was significantly higher (30% vs. 9%; P<0.01) in the donepezil than control group. Furthermore, in the donepezil group, QTc was significantly prolonged after patients started taking donepezil compared with baseline (from 0.433±0.034 to 0.442±0.033s; n=46; P<0.05). On univariate analysis, QTc was significantly associated with taking donepezil, as well as with hemoglobin, serum calcium concentration, and estimated glomerular filtration rate (eGFR; all P<0.01). On multivariate analysis, QTc was significantly associated with taking donepezil (P<0.001), serum potassium concentration (P<0.05), and eGFR (P<0.05).Conclusions: The incidence of QTc prolongation was more frequent in patients taking donepezil than in the control group, and was difficult to predict. Periodic electrocardiogram examinations are recommended considering the possibility of adverse events, such as fatal arrhythmias.

Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network meta-analysis.

Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network meta-analysis.

Withdrawal or continuation of cholinesterase inhibitors or memantine or both, in people with dementia.

Withdrawal or continuation of cholinesterase inhibitors or memantine or both, in people with dementia.

New therapeutics beyond amyloid-β and tau for the treatment of Alzheimer's disease.

As the population ages, Alzheimer's disease (AD), the most common neurodegenerative disease in elderly people, will impose social and economic burdens to the world. Currently approved drugs for the treatment of AD including cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and an N-methyl-D-aspartic acid receptor antagonist (memantine) are symptomatic but poorly affect the progression of the disease. In recent decades, the concept of amyloid-β (Aβ) cascade and tau hyperphosphorylation leading to AD has dominated AD drug development. However, pharmacotherapies targeting Aβ and tau have limited success. It is generally believed that AD is caused by multiple pathological processes resulting from Aβ abnormality, tau phosphorylation, neuroinflammation, neurotransmitter dysregulation, and oxidative stress. In this review we updated the recent development of new therapeutics that regulate neurotransmitters, inflammation, lipid metabolism, autophagy, microbiota, circadian rhythm, and disease-modified genes for AD in preclinical research and clinical trials. It is to emphasize the importance of early diagnosis and multiple-target intervention, which may provide a promising outcome for AD treatment.

9R, the cholinesterase and amyloid beta aggregation dual inhibitor, as a multifunctional agent to improve cognitive deficit and neuropathology in the triple-transgenic Alzheimer's disease mouse model

Alzheimer's disease (AD) is the most common kind of dementia in the aging population leading to great social and financial burdens in many countries around the world. For decades, disease-modifying drug developed using the “one target, one drug” strategy failed to conquer this disease. Recently, we have designed and synthesized 9R, which exhibited dual inhibition of cholinesterase and amyloid beta (Aβ) aggregation in vitro. Herein, we evaluated the in vivo efficacy of 9R in a triple transgenic AD (3xTg-AD) mouse model. 3xTg-AD mice (10-month-old) were dosed intraperitoneally with 9R (daily 3, 10 or 30 mg/kg) for a month. Known cholinesterase inhibitor donepezil (0.3 mg/kg) and Aβ aggregation inhibitor tramiprosate (30 mg/kg) were used as positive controls. Cognitive performance of the mice was then evaluated by using Morris Water Maze (MWM), Y-maze tasks and Open Field test. The acetylcholine level, degree of Aβ deposition, amyloid precursor protein (APP) processing, neuroinflammation, tau deposition and tau hyperphosphorylation in the brains of the 3xTg-AD mice were examined. We have observed that one-month treatment with 9R significantly improved cognitive deficits in 3xTg-AD mice. Moreover, 9R treatment enhanced the brain acetylcholine level and mitigated the amyloid burden, tau hyperphosphorylation and neuroinflammation in the mouse brains. The effects of 9R on APP processing, neuroinflammation, tau hyperphosphorylation and Cdk-p25 action demonstrated its multifunctional role in 3xTg-AD mouse model. Our results suggested that the use of multi-target compound could be a potential approach to treat AD.

The cholinesterase inhibitor donepezil has antidepressant-like properties in the mouse forced swim test

Finding new antidepressant agents is of high clinical priority given that many cases of major depressive disorder (MDD) do not respond to conventional monoaminergic antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. Recent findings of effective fast-acting antidepressants indicate that there are biological substrates to be taken advantage of for fast relief of depression and that we may find further treatments in this category. In this vein, the cholinergic system may be a relatively overlooked target for antidepressant medications, given its major role in motivation and attention. Furthermore, the classically engaged monoaminergic neurotransmitter systems in depression treatment—serotonin, norepinephrine, and dopamine—interact directly at times with cholinergic signaling. Here we investigate in greater detail how the cholinergic system may impact depression-related behavior, by administering widely ranging doses of the cholinesterase inhibitor drug, donepezil, to C57BL/6J mice in the forced swim test. First, we confirm prior findings that this drug, which is thought to boost synaptic acetylcholine, promotes depression-like behavior at a high dose (2.0 mg/kg, i.p.). But we also find paradoxically that it has an antidepressant-like effect at lower doses (0.02 and 0.2 mg/kg). Further this antidepressant-like effect is not due to generalized hyperactivity, since we did not observe increased locomotor activity in the open field test. These data support a novel antidepressant-like role for donepezil at lower doses as part of an overall u-shaped dose-response curve. This raises the possibility that donepezil could have antidepressant properties in humans suffering from MDD.

Cholinergic muscarinic M1/M4 receptor networks in dementia with Lewy bodies.

Cholinergic dysfunction is central in dementia with Lewy bodies, possibly contributing to the cognitive and psychiatric phenotypes of this condition. We investigated baseline muscarinic M1/M4 receptor spatial covariance patterns in dementia with Lewy bodies and their association with changes in cognition and neuropsychiatric symptoms after 12 weeks of treatment with the cholinesterase inhibitor donepezil. Thirty-eight participants (14 cholinesterase inhibitor naive patients, 24 healthy older individuals) underwent 123I-iodo-quinuclidinyl-benzilate (M1/M4 receptor assessment) and 99mTc-exametazime (perfusion) single-photon emission computed tomography scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of inter-correlated voxels across individuals. Linear regression analyses derived specific M1/M4 and perfusion spatial covariance patterns associated with patients. A discreet M1/M4 pattern that distinguished patients from controls (W1,19.7 = 16.7, P = 0.001), showed relative decreased binding in right lateral temporal and insula, as well as relative preserved/increased binding in frontal, precuneus, lingual and cuneal regions, implicating nodes within attention and dorsal visual networks. We then derived from patients an M1/M4 pattern that correlated with a positive change in mini-mental state examination (r = 0.52, P = 0.05), showing relative preserved/increased uptake in prefrontal, temporal pole and anterior cingulate, elements of attention-related networks. We also generated from patients an M1/M4 pattern that correlated with a positive change in neuropsychiatric inventory score (r = 0.77, P = 0.002), revealing relative preserved/increased uptake within a bilateral temporal-precuneal-striatal system. Although in a small sample and therefore tentative, we posit that optimal response of donepezil on cognitive and neuropsychiatric signs in patients with dementia with Lewy bodies were associated with a maintenance of muscarinic M1/M4 receptor expression within attentional/executive and ventral visual network hubs, respectively.

Anti-dementia drugs for Alzheimer disease

Alzheimer’s disease (AD) is the most common cause of dementia that leads over time to profound disability. Current pharmacological interventions for AD are limited to three cholinesterase inhibitors (donepezil, rivastigmine and galantamine) and the N-Methyl-D-Aspartate (NMDA)-receptor antagonist memantine, both of which provide modest impact on cognitive and functional outcomes. In this study we aimed to evaluate the effect of current treatment for Alzheimer’s disease in different stages of dementia. Cholinesterase inhibitors alone, or in combination with memantine may be beneficial in Alzheimer’s disease depending on stage of AD. There is evidence for stabilization of cognitive function in AD for 2–5 months after the initiation of anti-dementia drugs and the efficacy over time is not fully understand.

Volume Analysis of Brain Cognitive Areas in Alzheimer's Disease: Interim 3-Year Results from the ASCOMALVA Trial.

Background:Cerebral atrophy is a common feature of several neurodegenerative disorders, including Alzheimer’s disease (AD). In AD, brain atrophy is associated with loss of gyri and sulci in the temporal and parietal lobes, and in parts of the frontal cortex and cingulate gyrus.Objective:The ASCOMALVA trial has assessed, in addition to neuropsychological analysis, whether the addition of the cholinergic precursor choline alphoscerate to treatment with donepezil has an effect on brain volume loss in patients affected by AD associated with cerebrovascular injury.Methods:56 participants to the randomized, placebo-controlled, double-blind ASCOMALVA trial were assigned to donepezil + placebo (D + P) or donepezil + choline alphoscerate (D + CA) treatments and underwent brain magnetic resonance imaging and neuropsychological tests every year for 4 years. An interim analysis of 3-year MRI data was performed by voxel morphometry techniques.Results:The D + P group (n = 27) developed atrophy of the gray and white matter with concomitant increase in ventricular space volume. In the D + CA group (n = 29) the gray matter atrophy was less pronounced compared to the D + P group in frontal and temporal lobes, hippocampus, and amygdala. These morphological data are consistent with the results of the neuropsychological tests.Conclusion:Our findings indicate that the addition of choline alphoscerate to standard treatment with the cholinesterase inhibitor donepezil counters to some extent the loss in volume occurring in some brain areas of AD patients. The observation of parallel less pronounced decrease in cognitive and functional tests in patients with the same treatment suggests that the morphological changes observed may have functional relevance.

Transient cholinergic enhancement does not significantly affect either the magnitude or selectivity of perceptual learning of visual texture discrimination.

Perceptual learning (PL), often characterized by improvements in perceptual performance with training that are specific to the stimulus conditions used during training, exemplifies experience-dependent cortical plasticity. An improved understanding of how neuromodulatory systems shape PL promises to provide new insights into the mechanisms of plasticity, and by extension how PL can be generated and applied most efficiently. Previous studies have reported enhanced PL in human subjects following administration of drugs that increase signaling through acetylcholine (ACh) receptors, and physiological evidence indicates that ACh sharpens neuronal selectivity, suggesting that this neuromodulator supports PL and its stimulus specificity. Here we explored the effects of enhancing endogenous cholinergic signaling during PL of a visual texture discrimination task. We found that training on this task in the lower visual field yielded significant behavioral improvement at the trained location. However, a single dose of the cholinesterase inhibitor donepezil, administered before training, did not significantly impact either the magnitude or the location specificity of texture discrimination learning compared with placebo. We discuss potential explanations for discrepant findings in the literature regarding the role of ACh in visual PL, including possible differences in plasticity mechanisms in the dorsal and ventral cortical processing streams.

4-Oxobenzo[d]1,2,3-triazin-pyridinium-phenylacetamide derivatives as new anti-Alzheimer agents: design, synthesis, in vitro evaluation, molecular modeling, and molecular dynamic study

A new series of 4-oxobenzo[d]1,2,3-triazin-pyridinium-phenylacetamide hybrids 8a–p was designed, synthesized, and screened as the potential cholinesterase inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Obtained anti-cholinesterase activities demonstrated that all the title compounds exhibited excellent inhibition against BuChE and moderate inhibitory activity toward AChE in comparison to standard cholinesterase inhibitor donepezil. For example, compound 8e exhibited about 49-fold higher inhibitory activity than donepezil (IC50 = 3.2 ± 0.3 μM) against BuChE. This compound inhibited BuChE via a mixed-type inhibition mode. This finding demonstrated that compound 8e in addition to catalytic anionic site (CAS) can also interact with the peripheral anionic site (PAS) of BuChE. Molecular modeling and molecular dynamic studies were also performed on synthesized compounds.

Is Combining an Anticholinergic with a Cholinesterase Inhibitor a Good Strategy for High-Level CNS Cholinesterase Inhibition?

The currently approved cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) produce gastrointestinal toxicity which limits dosing to that which produces only about 25% to 35% CNS cholinesterase inhibition in Alzheimer's disease patients undergoing treatment, below the minimum therapeutic target of about 40% to 50% CNS inhibition considered necessary to treat cognitive impairment. A recent strategy for producing high-level CNS acetylcholinesterase (AChE) inhibition (50% or higher) is to co-administer a muscarinic anticholinergic with the AChE inhibitor to block the dose-limiting cholinergic overstimulation of the gastrointestinal system, allow more robust AChE inhibition in the CNS, and improve efficacy in the treatment of Alzheimer's disease. Unfortunately, most common muscarinic anticholinergics, including solifenacin, readily penetrate the CNS and are directly associated with long-term exacerbation of the underlying neuropathology of Alzheimer's disease and increased brain atrophy. The co-administration of an anticholinergic with an AChE inhibitor is a rational strategy for improving efficacy in the symptomatic treatment of dementia, but there are significant long-term risks that have not yet been considered. For long-term safety against accelerating the underlying disease processes in Alzheimer's disease, anticholinergics used to increase the tolerability of AChE inhibitors should not penetrate, or have very limited penetration, of the blood-brain barrier. Neurotrophic-mediated mechanisms by which cholinergic drugs may affect neurodegeneration in Alzheimer's disease are explored and improved treatment options are suggested.

Novel N-benzylpiperidine carboxamide derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer's disease

A series of fifteen acetylcholinesterase inhibitors were designed and synthesised based upon the previously identified lead compound 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (5) which showed good inhibitory activity (IC50 0.03 ± 0.07 μM) against acetylcholinesterase. A series of compounds were prepared wherein the ester linker in the original lead compound was exchanged for a more metabolically stable amide linker and the indanone moiety was exchanged for a range of aryl and aromatic heterocycles. The two most active analogues 1-benzyl-N-(5,6-dimethoxy-8H-indeno[1,2-d]thiazol-2-yl)piperidine-4-carboxamide (28) and 1-benzyl-N-(1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) piperidine-4-carboxamide (20) afforded in vitro IC50 values of 0.41 ± 1.25 and 5.94 ± 1.08 μM, respectively. In silico screening predicts that 20 will be a blood brain-barrier permeant, and molecular dynamic simulations are indicative of a close correlation between the binding of 20 and the Food and Drug Administration-approved cholinesterase inhibitor donepezil (1).

Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network meta-analysis

Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network meta-analysis

Tunable ternary nanocomposite prepared by electrodeposition for biosensing of centrally acting reversible acetyl cholinesterase inhibitor donepezil hydrochloride in real samples

This paper describes the decoration of pencil graphite electrode (PGE) with a thin film of solochrome black T (SBT) and N-doped carbon nanodots (N-CNDs)/ cobalt nanoparticles (CoNPs) to amplify signal of the measurement. This nanocomposite was chosen to enhance surface activity and electron transfer toward donepezil HCl (DZ HCl) oxidation. The physical properties of nanocomposite were characterized by scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR), electron impedance spectroscopy (ESI) and energy dispersive X-ray (EDX) spectroscopy. Cyclic voltammetry was utilized to quantify DZ HCl at the modified PGE in Britton-Robinson buffer (pH = 6.5). Under optimized experimental conditions, peak current increased with the increase in the concentration of DZ HCl and was linear between the range of 1.5 nM–400 μM with a relatively low detection limit of 0.0005 μM. Due to high sensitivity, simplicity and cost-effectiveness of the designated sensor; it was used as a simple method for detecting DZ HCl in rabbit plasma and during its pharmacokinetic study.

Epidemiology of Dementia in Elderly Chronic Obstructive Pulmonary Disease Patients Living in China's Northwestern High-Elevation Area.

BackgroundThe aim of this study was to investigate the effects of oxygen and cholinesterase inhibitor (donepezil) therapy on dementia in patients with age-exacerbated chronic obstructive pulmonary disease (COPD) in China’s northwestern high-altitude area.Material/MethodsA total of 145 patients with acute exacerbation of COPD admitted to the Gerontology Department of the First People’s Hospital of Xining City were initially retrospectively screened. From among these 145 patients, we selected 33 cases with dementia and 33 patients without dementia through use of the Mini-Mental State Examination (MMSE), the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Activities of Daily Living (ADL) Scale evaluated before, 7 days after, and at the end of the treatment after 3 months. Both patient groups received oxygen therapy for 7 days, but patients with dementia in the intervention group were medicated additionally with donepezil (5 mg/day for 1 week, followed by 10 mg/day for another 12 weeks).ResultsMild dementia was found in 35 of the 145 COPD patients. ADL, MMSE, and ADAS-Cog scores were all significantly lower in the intervention group before treatment, improved after the first 7 days, and continued to improve significantly until week 12 in the intervention group, but were still significantly lower than in the control group.ConclusionsDementia in elderly COPD patients was mainly manifested as decreased executive function, attention, language, and delayed recall, while oxygen and donepezil therapy had beneficial effects on the symptoms.

The efficacy and safety of memantine for the treatment of Alzheimer’s disease

ABSTRACTIntroduction: Currently, five pharmacotherapeutic options are available to treat Alzheimer’s disease: memantine; the three cholinesterase inhibitors donepezil, galantamine, and rivastigmine; and combination treatments with memantine and one cholinesterase inhibitor. Selection of the best course of treatment is based upon the evidence gathered by systematic reviews and meta-analyses of randomized controlled trials.Areas covered: This article provides a risk–benefit analysis of these treatments using evidence from meta-analyses on their safety and their efficacy.Expert opinion: Memantine improves cognitive functions and behavioral disturbances more efficiently than the placebo, both as monotherapy and in combination with donepezil. Although memantine monotherapy and combination therapy are associated with a few individual adverse events such as somnolence, it is well-tolerated and its safety (all-cause discontinuation) is comparable or superior to that of the placebo (agitation). Pooled cholinesterase inhibitors are superior to the placebo in the improvement of cognitive functions, but not behavioral disturbances and they are not well-tolerated, as evaluated by the high discontinuation rate. Donepezil (10 mg/day) and oral rivastigmine and galantamine monotherapies carry the risk for some adverse events including gastrointestinal symptoms. Therefore, we consider that combined treatment with memantine and donepezil is the most useful treatment for Alzheimer’s disease.

Effects of Cholinergic Lesions and Cholinesterase Inhibitors on Aromatase and Estrogen Receptor Expression in Different Regions of the Rat Brain

Cholinergic projections have been shown to interact with estrogens in ways that influence synaptic plasticity and cognitive performance. The mechanisms are not well understood. The goal of this study was to investigate whether cholinergic projections influence brain estrogen production by affecting aromatase (ARO), or influence estrogen signaling by affecting estrogen receptor expression. In the first experiment, ovariectomized rats received intraseptal injection of the selective immunotoxin 192IgG-saporin to destroy cholinergic inputs to the hippocampus. In the second experiment ovariectomized rats received daily intraperitoneal injections of the cholinesterase inhibitors donepezil or galantamine for 1 week. ARO activity and relative levels of ARO, ERα, ERß, and GPR30 mRNAs were quantified in the hippocampus, frontal cortex, amygdala and preoptic area. Results show that the cholinergic lesions effectively removed cholinergic inputs to the hippocampus, but had no significant effect on ARO or on relative levels of ER mRNAs. Likewise, injections of the cholinesterase inhibitors had no effect on ARO or ER expression in most regions of the brain. This suggests that effects of cholinergic inputs on synaptic plasticity and neuronal function are not mediated by effects on local estrogen production or ER expression. One exception was the amygdala where treating with galantamine was associated with a significant increase in ARO activity. The amygdala is a key structure involved in registering fear and anxiety. Hence this finding may be clinically relevant to elderly patients who are treated for memory impairment and who also struggle with fear and anxiety disorders.

Intermittent stimulation in the nucleus basalis of meynert improves sustained attention in rhesus monkeys

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. Administration of the cholinesterase inhibitor donepezil or the muscarinic antagonist scopolamine alone impaired performance, whereas the nicotinic antagonist mecamylamine alone improved performance. Applying NB stimulation while mecamylamine or donepezil were administered impaired CPT performance. Methylphenidate, a monoaminergic psychostimulant, was applied in conjunction with intermittent stimulation as a negative control, as it does not directly modulate cholinergic output. Methylphenidate also improved performance, and it produced further improvement when combined with NB stimulation. The additive effect of the combination suggested NB stimulation altered behavior independently from methylphenidate effects. We conclude that basal forebrain projections contribute to sustained attention, and that intermittent NB stimulation is an effective way of improving performance.