Effects Of Cholinesterase Inhibitors Research Articles

In vitro cholinesterase, lipoxygenase inhibition evaluation of rosemary and coriander essential oil nanoemulsion and characterisation

IntroductionThe low water solubility, high volatility, and instability of essential oils limit the application of various formulations, which can be managed by essential oils nanoemulsions. In this present study, in vitro anti-inflammatory and anticholinesterase activities were evaluated by designing nanoemulsions of rosemary and coriander essential oils with their combinations. MethodsThe chemistry of Rosmarinus officinalis L. (Rosemary, Lamiaceae) and Coriandrum sativum L. (Coriander, Apiaceae) essential oils was confirmed by GC-FID and GC/MS methods. Oil-in-Water (O/W) emulsions of essential oils and their 1:1 (w:w) combination were prepared by water titration. The essential oil/tween 20 ratio of the emulsions were 1:9, 2:8, and 3:7 (w:w) respectively. Characterisation studies were performed by measuring the droplet size, polydispersity index (PDI), zeta potential, and viscosity of the emulsions. Also, resistance to centrifugation, freezing, and heating was determined as part of the stability tests. Anti-inflammatory effects of the essential oils and emulsions were determined by in vitro 5-Lipoxygenase (LOX) inhibition. In addition, in vitro Acetylcholinesterase and Butyrylcholinesterase (AChE and BuChE) effects were evaluated. ResultsThe rosemary (1,8-cineole; 44.1%), coriander (linalool; 74.9%) essential oils, and their nanoemulsion formulations prepared were observed as stable. The anti-inflammatory activity of coriander essential oil was relatively increased by nanoemulsion preparations. However, there was no significant difference in the cholinesterase inhibition effects, when compared. To the best of our knowledge this is the first combination study of bioactivity evaluation of rosemary and coriander nanoemulsion preparations. ConclusionRosemary and coriander essential oil nano emulsifications is a promising application for increasing stability and biological activity as well.

Effects of cholinesterase inhibition on attention and working memory in Lewy body dementias.

Cholinesterase inhibitors are frequently used to treat cognitive symptoms in Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies). However, the selectivity of their effects remains unclear. In a novel rivastigmine withdrawal design, Parkinson's disease dementia and dementia with Lewy bodies patients were tested twice: once when taking rivastigmine as usual and once when they had missed one dose. In each session, they performed a suite of tasks (sustained attention, simple short-term recall, distractor resistance and manipulating the focus of attention) that allowed us to investigate the cognitive mechanisms through which rivastigmine affects attentional control. Consistent with previous literature, rivastigmine withdrawal significantly impaired attentional efficacy (quicker response latencies without a change in accuracy). However, it had no effects on cognitive control as assessed by the ability to withhold a response (inhibitory control). Worse short-term memory performance was also observed when patients were OFF rivastigmine, but these effects were delay and load independent, likely due to impaired visual attention. In contrast to previous studies that have examined the effects of dopamine withdrawal, cognitively complex tasks requiring control over the contents of working memory (ignoring, updating or shifting the focus of attention) were not significantly impaired by rivastigmine withdrawal. Cumulatively, these data support that the conclusion that cholinesterase inhibition has relatively specific and circumscribed-rather than global-effects on attention that may also affect performance on simple short-term memory tasks, but not when cognitive control over working memory is required. The results also indicate that the withdrawal of a single dose of rivastigmine is sufficient to reveal these impairments, demonstrating that cholinergic withdrawal can be an informative clinical as well as an investigative tool.

Concomitant Cholinesterase Inhibitor and Anticholinergic Drug Use Among Older Adults With Dementia

Anticholinergic medications (ACh) are frequently prescribed to older adults despite being associated with impaired physical functioning. Moreover, the concomitant use of ACh and cholinesterase inhibitors (ChEI) reduces the body’s response to both drugs, thereby diminishing the modest effectiveness of ChEI at slowing the progression of dementia symptoms. The objective of this study was to assess the risk of concomitant ACH/ChEI use on functional outcomes, including fall, fracture, and traumatic brain injury (TBI). We conducted a retrospective review of data from the OptumLabs® Data Warehouse, a de-identified administrative claims database for commercially insured and Medicare Advantage (MA) enrollees, representing a diverse mixture of ages, ethnicities, and geographical regions across the U.S. Our cohort included adults 65 and older enrolled in MA between 1998 and 2017. Subjects were required to have dementia (by a diagnosis and/or prescription for a dementia drug (memantine or ChEI)) and at least one claim for ChEI during 12 months of follow-up. Subjects had to be enrolled in MA 6 months prior to the dementia index date. We defined concomitant ACh/ChEI use as an overlap of 30 days or more. Nearly one-third (29%) were concomitantly prescribed ACh and ChEI. Half (51%) of concomitant users were prescribed ChEI first, 46% were prescribed ACh first, and 3% received prescriptions on the same day. Results from multiple logistic regression analyses show that older adults with dementia who had concomitant ACh/ChEI use were 18%, 16%, and 25% more likely to experience a fall, fracture, or TBI, respectively, than those taking ChEI alone.

Systematic Review of Cholinesterase Inhibitors on Cognition and Behavioral Symptoms in Patients of Chinese Descent with Alzheimer's Disease, Vascular Dementia, or Mixed Dementia.

Cholinesterase inhibitors (ChEIs) are the primary pharmacologic treatment for dementia. Their efficacy in patients of Chinese descent is not well described. We reviewed how ChEIs could affect cognition and behavioral and psychological symptoms (BPSD) in Chinese patients with Alzheimer’s disease (AD), vascular dementia (VaD), or mixed (AD with vascular component) dementia. MEDLINE, PsycINFO, EMBASE and CINAHL were systematically searched for controlled trials of ChEIs, including donepezil, galantamine, and rivastigmine, for Chinese patients with AD, VaD, or mixed dementia. Outcomes for cognition and BPSD were extracted for discussion. Fifty-four studies were identified. While one larger study found that dementia patients of Chinese descent treated with ChEIs had significantly higher mean Mini-Mental State Examination (MMSE) score, other studies showed no significant difference. Evidence on BPSD after use of ChEIs was also conflicting. ChEIs may be effective in improving cognition among patients of Chinese descent with dementia. Further studies are needed to examine the possible effects of ChEIs on BPSD in Chinese patients with dementia in view of the small number of studies and limitations in their methodologies.

The Long-Lasting Enhancing Effect of Distigmine on Acetylcholine-Induced Contraction of Guinea Pig Detrusor Smooth Muscle Correlates with Its Anticholinesterase Activity.

Distigmine bromide (distigmine), a reversible, long-lasting cholinesterase (ChE) inhibitor, is used for the treatment of underactive bladder in Japan and has been shown to potentiate urinary bladder (UB) contractility. We studied the duration of distigmine's potentiating effects on acetylcholine (ACh)-induced UB contraction and its inhibitory effects on ChE activity, and compared that with those of other ChE inhibitors (neostigmine, pyridostigmine, and ambenonium). The duration of potentiating/inhibitory effects of ChE inhibitors, including distigmine, on ACh-induced guinea pig UB contraction/ChE activity was evaluated for 12 h following washout. Dissociation rate constants (k) of the inhibitors were also tentatively calculated based on the time courses of their ChE inhibitory effects. The potentiating effect of distigmine (10-6 M) on ACh-induced UB contraction and its inhibitory effect on ChE activity were significantly sustained 12 h after washout. The potentiating effect of other ChE inhibitors on ACh-induced UB contraction, however, was sustained only until 3 h after washout. The ChE inhibitory effects of these inhibitors dissipated in a time-dependent manner after washout, with more than 75% of ChE activity restored by 4 h after washout. The k values of ChE inhibitors approached 0.50 h-1, except for distigmine, where k could not be determined. Compared with that of other ChE inhibitors, the potentiating effect of distigmine on UB contractile function was significantly more sustainable following washout, which was likely associated with its corresponding long-lasting ChE inhibitory effect. Distigmine may associate more strongly with UB ChE than other ChE inhibitors, which would partly explain its sustained effects.

Alzheimer's Disease: A Review from the Pathophysiology to Diagnosis, New Perspectives for Pharmacological Treatment.

Dementia is characterized by the impairment of cognition and behavior of people over 65 years. Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the world, as approximately 47 million people are affected by this disease and the tendency is that this number will increase to 62% by 2030. Two microscopic features assist in the characterization of the disease, the amyloid plaques and neurofibrillary agglomerates. All these factors are responsible for the slow and gradual deterioration of memory that affect language, personality or cognitive control. For the AD diagnosis, neuropsychological tests are performed in different spheres of cognitive functions but since not all cognitive functions may be affected, cerebrospinal fluid biomarkers are used along with these tests. To date, cholinesterase inhibitors are used as treatment, they are the only drugs that have shown significant improvements in the cognitive functions of AD patients. Despite the proven effectiveness of cholinesterase inhibitors, an AD carrier, even while being treated, is continually subjected to progressive degeneration of the neuronal tissue. For this reason, other biochemical pathways associated with the pathophysiology of AD have been explored as alternatives to the treatment of this condition such as inhibition of β-secretase and glycogen synthase kinase-3β. The present study aims to conduct a review of the epidemiology, pathophysiology, symptoms, diagnosis and treatment of Alzheimer's disease, emphasizing the research and development of new therapeutic approaches.

Cholinergic Toxicity

Cholinergic drugs exert their functions by inhibiting acetylcholinesterase, the enzyme responsible for hydrolyzing acetylcholine and ending neuronal or neuromuscular neurotransmission. These compounds are used in clinical medicine to treat various disorders, as pesticides, and as weapons of mass destruction. This review describes the drugs that affect the cholinergic system and discusses stabilization, diagnosis and definitive therapy, principles and controversies of definitive care, and disposition and outcomes for these agents. Figures show acetylcholinesterase hydrolysis of acetylcholine, neurotransmission in the nervous system, the mechanism of inhibition of acetylcholinesterase by an organophosphorus (OP) compound, and the general chemical structure of thion OP and oxon OP agents and carbamates. Tables list OP pesticides associated with OP-induced delayed neuropathy, the effects of cholinesterase inhibition, the symptoms of cholinergic poisoning according to severity, and a treatment algorithm for acetylcholinesterase poisoning. This review contains 4 highly rendered figures, 4 tables, and 85 references.

Cholinergic Toxicity

Cholinergic drugs exert their functions by inhibiting acetylcholinesterase, the enzyme responsible for hydrolyzing acetylcholine and ending neuronal or neuromuscular neurotransmission. These compounds are used in clinical medicine to treat various disorders, as pesticides, and as weapons of mass destruction. This review describes the drugs that affect the cholinergic system and discusses stabilization, diagnosis and definitive therapy, principles and controversies of definitive care, and disposition and outcomes for these agents. Figures show acetylcholinesterase hydrolysis of acetylcholine, neurotransmission in the nervous system, the mechanism of inhibition of acetylcholinesterase by an organophosphorus (OP) compound, and the general chemical structure of thion OP and oxon OP agents and carbamates. Tables list OP pesticides associated with OP-induced delayed neuropathy, the effects of cholinesterase inhibition, the symptoms of cholinergic poisoning according to severity, and a treatment algorithm for acetylcholinesterase poisoning. This review contains 4 highly rendered figures, 4 tables, and 85 references.

The effect of cholinesterase inhibition on liver dysfunction in experimental acute liver failure: Retraction

The effect of cholinesterase inhibition on liver dysfunction in experimental acute liver failure: Retraction

The effect of cholinesterase inhibition on liver dysfunction in experimental acute liver failure: a randomized controlled study

Introduction Acute liver failure (ALF), similar to sepsis, is associated with an overwhelming activation of the immune response in which hepatic and circulating inflammatory cytokines play a pivotal role. The cholinesterase inhibitor neostigmine has been shown to have anti-inflammatory properties in experimental sepsis. We investigated the role of neostigmine in attenuating d-galactosamine (d-GalN)-induced ALF. Materials and methods Thirty-six female Wistar rats were randomly allocated to three groups: the control group, the d-GalN group receiving a single intraperitoneal injection of d-GalN (400 mg/kg body weight), and the neostigmine-treated d-GalN group receiving a single intraperitoneal injection of d-GalN followed 24 h later by intraperitoneal injection of neostigmine methylsulfate 0.25% (80 μg/kg body weight) three times daily for 3 successive days. Rats were killed 24 h after the last injection. Plasma levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total proteins, albumin, prothrombin, total bilirubin, and hepatic levels of superoxide dismutase and malondialdehyde were measured. Liver expression of cytokines (HMGB-1, TNF-α, and IL-10) and histopathology were evaluated. Results Neostigmine attenuated liver dysfunction and improved liver synthetic and excretory functions. It reduced proinflammatory cytokine HMGB-1 [95% confidence interval (CI) 0.33-1.09] and TNF-α (95% CI 1.26-2.06) expression compared with the d-GalN group (95% CI 2.67-4.73 and 7.33-14.53, respectively, P P Conclusion Neostigmine improved liver function in a rat ALF model through an anti-inflammatory activity.

The effect of cholinesterase inhibition on liver dysfunction in experimental acute liver failure

IntroductionAcute liver failure (ALF), like sepsis, is associated with an overwhelming activation of the immune response in which hepatic and circulating inflammatory cytokines play a pivotal role. Cholinesterase inhibition has been shown to have anti-inflammatory properties in experimental sepsis. We investigated the role of neostigmine in attenuating d-galactosamine (d-GalN)-induced ALF. MethodsThirty-six female wistar rats were randomly allocated to three groups: a control group, a d-GalN group receiving a single i.p. injection of d-galactosamine (400 mg kg−1 BW) and a neostigmine-treated d-GalN group receiving a single i.p. injection of d-galactosamine followed 24 h later by i.p. injection of neostigmine methylsulfate 0.25% (80 μg kg−1 BW) three times daily for 3 successive days. Rats were sacrificed 24 h after the last injection. Plasma levels of liver transaminases, total proteins, albumin, prothrombin, total bilirubin and hepatic levels of superoxide dismutase and malondialdehyde were measured. Liver expression of cytokines (HMGB-1, TNF-α and IL-10) and histopathology were evaluated. ResultsNeostigmine attenuated liver dysfunction and improved liver synthetic and excretory functions, reduced proinflammatory cytokine HMGB1 (95% CI 0.33–1.09) and TNF-α (95% CI 1.26–2.06) expression compared to d-GalN group (95% CI 2.67–4.73 and 7.33–14.53, respectively, P < 0.001) and increased expression of the anti-inflammatory cytokine IL-10 in liver tissue (95% CI 2.49–4.17 vs 0.04–0.21 in d-GalN group, P < 0.001). Neostigmine also significantly increased antioxidant level, and decreased oxidative burden caused by d-GaIN. ConclusionNeostigmine improved liver function in a rat ALF model through an anti-inflammatory activity.

Should We Listen to People Affected by Dementia?

Should We Listen to People Affected by Dementia?

Effects of cholinesterase inhibition in supraspinal and spinal neural pathways on the micturition reflex in rats

To investigate whether activation of brain and spinal cholinergic pathways affects the micturition reflex in rats. The effects of intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of neostigmine as a cholinesterase inhibitor and oxotremorine-M (OXO-M) as a muscarinic acetylcholine receptor (mAChRs) agonist, on the micturition reflex were evaluated by infusion cystometrography (CMG) in urethane-anaesthetized untreated rats or rats pretreated with capsaicin. Neostigmine injected i.c.v. increased bladder capacity (BC) and pressure threshold (PT) dose-dependently, with an increase in maximum voiding pressure (MVP) and a decrease in voiding efficiency (VE) at higher doses. Also, neostigmine injected i.t. increased the BC and PT dose-dependently without changing MVP or VE, and these effects were not apparent in capsaicin-pretreated rats. In both routes, atropine as an antagonist of mAChRs, but not mecamylamine as a nicotinic-AChR antagonist, almost completely antagonized the effects of neostigmine. The rank order of potencies of the antagonists for increasing effects of BC induced by 1 nmol of neostigmine was: pirenzepine (an M(1) mAChR antagonist) = atropine > 4-DAMP (an M(3) mAChR antagonist) " methoctramine (an M(2) mAChR antagonist) and tropicamide (an M(4) mAChR antagonist) via the i.c.v. route; and atropine > methoctramine > pirenzepine > tropicamide and 4-DAMP via the i.t. route, respectively. OXO-M injected via i.c.v. and i.t. had the same effects on BC, PT, MVP and VE as neostigmine by i.c.v. and i.t., respectively. These results indicate that activation of muscarinic cholinergic mechanisms by the cholinesterase inhibitor in the brain and spinal cord can inhibit the micturition reflex, mainly by affecting afferent pathways. These mAChR-induced inhibitory effects seem to be mediated through M(1)/M(3) receptor subtypes in the brain, while in the spinal cord, the M(1)/M(2) receptor subtypes might be involved in inhibitory effects, which are mediated via inhibition of mechanoceptive C-fibre afferent pathways.

Effects of cholinesterase inhibition on brain white matter volume in mild Alzheimer's disease

Effects of cholinesterase inhibition on brain white matter volume in mild Alzheimer's disease

Effects of cholinesterase inhibition on brain white matter volume in Alzheimer's disease

Brain white matter volume changes were quantified by using voxel-based morphometry in 26 minimal-to-mild Alzheimer's disease patients receiving cholinesterase inhibitors over 20 weeks. Patients treated with rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, did not show those reductions in white matter volume that were observed in patients treated with acetylcholinesterase-selective agents, donepezil and galantamine. This is the first time that dual cholinesterase inhibition has been shown to influence white matter volume specifically. The findings are consistent with a thesis that dual cholinesterase inhibition may have neuroprotective potential. Attenuated loss of brain volumes and delayed/slower long-term clinical decline in patients treated with agents such as rivastigmine may be due to less extensive white matter damage and loss of corticosubcortical connectivity.

What Constitutes Clinical Evidence for Neuroprotection in Alzheimer Disease

The progression of Alzheimer disease (AD) corresponds to a prolonged course of neuronal loss in the cerebral cortex. Strategies aimed at reducing the rates of neuronal loss are therefore particularly important. The clinical measures to evaluate the disease-modifying effect of an intervention are readily confounded by any symptomatic benefit of the intervention. Thus, when testing putative neuroprotective agents that are known to have symptomatic effects, it can be difficult to separate the 2 effects. The hypothesis that cholinesterase inhibitors (ChEIs) only treat symptoms caused by cholinergic imbalances in AD is overly simplistic. Evidence has now accumulated that ChEIs have a neuroprotective, disease-modifying property. In this paper, to answer the question of what constitutes clinical evidence for neuroprotection in AD, we have reviewed clinical studies with specific designs, including "delaying end point," "withdrawal," and "randomized start" designs. We have also reviewed data on surrogate biomarkers of disease progression that may indicate a disease-modifying action. In addition, we have reviewed evidence indicating that ChEIs may protect cells in the brain of patients with AD. Among the clinical data suggesting a possible neuroprotective effect of ChEIs, the most rigorous published evidence comes from magnetic resonance imaging (MRI) hippocampal volumetric studies with donepezil.

Treatment of dementia

Dementia describes a chronic and progressive clinical syndrome characterised by cognitive impairment (particularly memory loss), inability to perform activities of daily living, and neuropsychiatric features (psychiatric symptoms and behavioural disturbances,...

Cardiac Effect of Cholinesterase Inhibitors Used in Alzheimers Disease - from Basic Research to Bedside

In this review, the basic mechanism of the parasympathetic nervous effect on the heart is discussed. This is expanded to clinical situations to clarify what can happen to patients after cholinesterase (ChE) inhibitor is administered and to avoid unnecessary adverse effects. The parasympathetic nervous system can affect heart as well as brain function, and its effect on the heart is more complicated than is generally thought. The best-known effect is the cardioinhibitory effect, i.e. slowing of the heart rate. Its effect is also very sensitive to the time at which the stimulus falls within the cardiac cycle (phase-dependent effect). On some occasions, a cardiostimulatory effect can be observed. The parasympathetic nervous system also interacts with the sympathetic nervous system (sympathetic-parasympathetic interaction). ChE inhibitors or acetylcholinesterase inhibitors are often being administered to improve cognitive function of patients with Alzheimer's disease. The heart is naturally rich with ChE, and its inhibition may affect cardiac function, especially in elderly patients, many of whom have concomitant cardiovascular disease. Inhibition of ChE retards ACh degradation and potentiates the cardioinhibitory effect. However, the effect of ChE inhibitor is only slight in patients that receive a typical dose. After administration of ChE inhibitor in humans, the phase-dependent effect is reduced because the parasympathetic nervous effect is potentiated and saturated (saturation mechanism). Beat-by-beat fluctuation is reduced. ChE inhibitor increases arterial blood pressure through central M1 and M2 subtypes of muscarinic receptors (Br J Pharmacol 127:1657-1665, 1999). However, diastolic blood pressure increases slightly.

EFFECTIVENESS AND SAFETY OF CHOLINESTERASE INHIBITORS IN ELDERLY SUBJECTS WITH ALZHEIMER’S DISEASE: A “REAL WORLD” STUDY

Clinical trials have demonstrated the efficacy of cholinesterase inhibitors (ChEI) in improving cognitive status and disability in subjects with mild to moderate Alzheimer's disease (AD). However, little is known about the effectiveness of ChEI in clinical practice, and no large clinical trials comparing different ChEI are available at present. Aim of this study was to evaluate safety and effectiveness of ChEI in a sample of elderly outpatients diagnosed with mild to moderate AD. We selected 407 subjects for ChEI treatment (donepezil,rivastigmine or galantamine). Their cognitive function was evaluated by means of the mini mental state examination (MMSE), and the global functional status was estimated by using the activities of daily living (ADL) and the instrumental activities of daily living (IADL) scales at baseline (To), then after 1 (T1), 3 (T2) and 9 months (T3), respectively. T3 follow-up was completed by 212 subjects. The patients were considered as responders (R), if the MMSEscore at T2 was unchanged or improved, if compared to that of T0. In 35 patients (8.6 %)treatment was withdrawn because of mostly gastrointestinal adverse events. Compared to the other drugs, donepezil was associated with a lower incidence of withdrawals due to adverse events. Subjects who completed T3 follow-up (age 78 +/- 6 years, MMSE scores 18.8 +/- 3.9) showed an increase at T2 of 0.7 +/- 2.7 (p = 0.001) and a decrease at T3 of -0.6 +/- 3.4 (p = 0.008) in the MMSE scores, as compared to To . The ADL and IADL scores did not show significant changes at T2; however, both decreased significantly at T3. The patients Rat-T2 showed a better cognitive and functional outcome at T3 , compared to the nonresponders(NR-at-T2), displaying values of MMSE R-at-T2 0.4 +/- 3.1 vs. NR-at-T2 -3.0 +/- 2.5, p = 0.001, and ADL values of -0.3 +/- 1.2 vs. -0.7 +/- 1.3, p = 0.03, respectively. No significant difference was found in the changes of MMSE scores between donepezil and rivastigmine (galantamine was not included in the comparison due to the small number of treated subjects). In conclusion, in this sample of elderly subjects with mild to moderate AD,treated with ChEI, a small but significant decline in cognitive and functional status was observed after 9 months. Subjects who showed a good response to treatment after 3 months, had a better cognitive and functional outcome at 9 months. No significant difference in cognitive outcome was found between drugs, while donepezil was better tolerated.

The effect of cholinesterase inhibitors on the regional blood flow in patients with Alzheimer's disease and vascular dementia

The effects of therapy with cholinesterase inhibitors (ChE-I) on regional cerebral blood flow (rCBF) disturbances were investigated by means of single photon emission computed tomography (SPECT). The changes in rCBF were compared with the results of the medical examination and neuropsychological tests. The sample consisted of 41 patients with the Alzheimer's dementia (AD) and vascular dementia (VaD). The effect of ChE-I (rivastigmine) treatment was studied on 33 patients, while the nontreated control group consisted of 8 patients. In the treated patients, an increase in the rCBF was observed, while the scores of the neuropsychological tests decreased slightly. In the VaD group, the increase in rCBF was more significant in the frontal regions, whereas in the group with AD in the temporal regions, respectively. In the nontreated patients, a decrease of both rCBF and scores of neuropsychological tests were observed. The scores of the neuropsychological tests correlated with the results of rCBF. Increased levels of acetylcholine in the brain after ChE-I treatment may support the cholinergic regulation of rCBF, and in result increase it. Such effects seem to be more pronounced in the more affected brain regions.