The Effect of Galantamine on Lipopolysaccharide-induced Acute Lung Injury During Neutropenia Recovery in Mice.

BACKGROUND/AIM: Acute lung injury (ALI) is associated with a high mortality rate and cancer patients who receive chemotherapy are at high risk of ALI during neutropenia recovery. Galantamine is a cholinesterase inhibitor used for Alzheimer's disease treatment. Previous studies have shown that galantamine reduced inflammatory response in lipopolysaccharide (LPS)-induced ALI in rats. Mer protein was negatively associated with inflammatory response. The aim of the study was to investigate whether galantamine is effective in LPS-induced ALI during neutropenia recovery and its effect on Mer tyrosine kinase (MerTK) expression in mice. MATERIALS AND METHODS: Intraperitoneal cyclophosphamide was given to mice to induce neutropenia. After 7 days, LPS was administered by intratracheal instillation. Intraperitoneal galantamine was given once before LPS administration and in another group, galantamine was given twice before LPS administration. RESULTS: Galantamine attenuated LPS-induced ALI in histopathological analysis. The neutrophil percentage was lower in the group where galantamine was injected once, compared to the LPS group (p=0.007). MerTK expression was also higher in the group where galantamine was injected once but did not reach statistical significance (p=0.101). CONCLUSION: Galantamine attenuated inflammation in LPS-induced ALI during neutropenia recovery.

Acetylcholinesterase inhibitors for autistic spectrum disorders.

BACKGROUND: Autism spectrum disorder (autism) is a neurodevelopmental condition characterised by impairments in social communication and interaction, plus restricted, repetitive patterns of behaviour and interests. Whilst some people embrace autism as part of their identity, others struggle with their difficulties, and some seek treatment. There are no current interventions that result in complete reduction of autism features. Acetylcholine is a neurotransmitter for the cholinergic system and has a role in attention, novelty seeking, and memory. Low levels of acetylcholine have been investigated as a potential contributor to autism symptomatology. Donepezil, galantamine, and rivastigmine (commonly referred to as acetylcholinesterase inhibitors) all inhibit acetylcholinesterase, and have slightly different modes of action and biological availability, so their effectiveness and side-effect profiles may vary. The effect of various acetylcholinesterase inhibitor on core autism features across the lifespan, and possible adverse effects, have not been thoroughly investigated. OBJECTIVES: To evaluate the efficacy and harms of acetylcholinesterase inhibitors for people with the core features (social interaction, communication, and restrictive and repetitive behaviours) of autism. To assess the effects of acetylcholinesterase inhibitors on non-core features of autism. SEARCH METHODS: In November 2022, we searched CENTRAL, MEDLINE, Embase, eight other databases, and two trials registers. We also searched the reference lists of included studies and relevant reviews, and contacted authors of relevant studies. SELECTION CRITERIA: Randomised controlled trials (RCTs), comparing acetylcholinesterase inhibitors (e.g. galantamine, donepezil, or rivastigmine) of varying doses, delivered orally or via transdermal patch, either as monotherapy or adjunct therapy, with placebo. People of any age, with a clinical diagnosis of autism were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were core features of autism and adverse effects. Secondary outcomes were language, irritability, hyperactivity, and general health and function. We used GRADE to assess certainty of evidence. MAIN RESULTS: We included two RCTs (74 participants). One study was conducted in Iran, the second in the USA, although exact location in the USA is unclear. Galantamine plus risperidone versus placebo plus risperidone One study compared the effects of galantamine plus risperidone to placebo plus risperidone (40 participants, aged 4 years to 12 years). Primary and secondary outcomes of interest were measured postintervention, using subscales of the Aberrant Behavior Checklist (score 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed there was little to no difference between the two groups postintervention for social communication (mean difference (MD) -2.75, 95% confidence interval (CI) -5.88 to 0.38), and restricted and repetitive behaviour (MD -0.55, 95% CI -3.47 to 2.37). Overall autism features were not assessed. Adverse events may be higher in the galantamine plus risperidone group (75%) compared with the placebo plus risperidone group (35%): odds ratio 5.57, 95% CI 1.42 to 21.86, low-certainty evidence. No serious adverse events were reported. Low-certainty evidence showed a small difference in irritability (MD -3.50, 95% CI -6.39 to -0.61), with the galantamine plus risperidone group showing a greater decline on the irritability subscale than the placebo group postintervention. There was no evidence of a difference between the groups in hyperactivity postintervention (MD -5.20, 95% CI -10.51 to 0.11). General health and function were not assessed. Donepezil versus placebo One study compared donepezil to placebo (34 participants aged 8 years to 17 years). Primary outcomes of interest were measured postintervention, using subscales of the Modified Version of The Real Life Rating Scale (scored 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed no evidence of group differences immediately postintervention in overall autism features (MD 0.07, 95% CI -0.19 to 0.33), or in the autism symptom domains of social communication (MD -0.02, 95% CI -0.34 to 0.30), and restricted and repetitive behaviours (MD 0.04, 95% CI -0.27 to 0.35). Significant adverse events leading to study withdrawal in at least one participant was implied in the data analysis section, but not explicitly reported. The evidence is very uncertain about the effect of donepezil, compared to placebo, on the secondary outcomes of interest, including irritability (MD 1.08, 95% CI -0.41 to 2.57), hyperactivity (MD 2.60, 95% CI 0.50 to 4.70), and general health and function (MD 0.03, 95% CI -0.48 to 0.54) postintervention. Across all analyses within this comparison, we judged the evidence to be very low-certainty due to high risk of bias, and very serious imprecision (results based on one small study with wide confidence intervals). The study narratively reported adverse events for the study as a whole, rather than by treatment group. AUTHORS' CONCLUSIONS: Evidence about the effectiveness of acetylcholinesterase inhibitors as a medication to improve outcomes for autistic adults is lacking, and for autistic children is very uncertain. There is a need for more evidence of improvement in outcomes of relevance to clinical care, autistic people, and their families. There are a number of ongoing studies involving acetylcholinesterase inhibitors, and future updates of this review may add to the current evidence.

Adverse Drug Event Profile Associated with Anti-dementia Drugs: Analysis of a Spontaneous Reporting Database.

Adverse drug events (ADEs) rates associated with anti-dementia acetylcholinesterase inhibitors are estimated to be 5%-20% and show a wide range of symptoms. No report has examined whether there is a difference in the anti-dementia drugs' ADEs profile. This study aimed to establish whether anti-dementia drugs' ADEs profile differed. Data was based on the Japanese Adverse Drug Event Report (JADER) database. The reporting odds ratios (RORs) was used to analyze data for ADEs from April 2004-October 2021. The target drugs were donepezil, rivastigmine, galantamine, and memantine. The top ten most frequently occurring adverse events were selected. The association between the RORs and antidementia drug ADEs was evaluated, and compared the distribution rate of expression age related to ADEs and each ADEs' timing of onset due to anti-dementia drugs. The primary outcome was RORs. Secondary outcome were expression age and time-to-onset of ADE associated with anti-dementia drugs. A total of 705,294 reports were analyzed. The adverse events incidence differed. Bradycardia, loss of consciousness, falls, and syncope incidence were significantly diverse. The Kaplan-Meier curve results for the cumulative ADEs incidence showed that donepezil had the slowest onset, while galantamine, rivastigmine, and memantine had approximately the same timing of onset.

Risk of Serious Adverse Events Associated With Individual Cholinesterase Inhibitors Use in Older Adults With Dementia: A Population-Based Cohort Study.

BACKGROUND AND OBJECTIVE: Cholinesterase inhibitors (ChEIs) are used as first-line pharmacotherapy to manage dementia. However, there are limited data regarding their relative safety. This study evaluated the risk of serious adverse events (SAEs) associated with individual ChEIs in older adults with dementia and also examined sex-based and dose-based effects on this risk. METHODS: This was a retrospective cohort study using 2013-2015 US Medicare claims data involving Parts A, B, and D. Patients aged ≥ 65 years with a dementia diagnosis and incident use of the ChEIs, namely donepezil, galantamine, or rivastigmine, were included. The primary outcome of interest was SAEs defined as emergency department visits, inpatient hospitalizations, or death within 6 months of ChEI initiation. Multivariable Cox proportional hazards regression with propensity score (PS) as a covariate and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of SAEs across individual ChEIs. RESULTS: The study included 767,684 older adults with dementia who were incident new users of ChEIs (donepezil 79.42%, rivastigmine 17.67%, galantamine 2.91%). SAEs were observed in 15.5% of the cohort within 6 months of ChEI prescription. Cox regression model with PS as covariate found that patients prescribed rivastigmine (adjusted hazard ratio [aHR] 1.12; 95% CI 1.03-1.33) and galantamine (aHR 1.51; 95% CI 1.24-1.84) were at increased risk of SAEs compared with patients on donepezil. Stratified analyses revealed that rivastigmine was associated with an 18% increased risk for SAEs in females (aHR 1.18; 95% CI 1.06-1.31), and galantamine was associated with a 71% increased risk in males (aHR 1.71; 95% CI 1.17-2.51) compared with donepezil. High and recommended index doses of rivastigmine and galantamine were associated with an increased risk of SAEs compared with donepezil. The findings were consistent in sensitivity analyses. CONCLUSION: The study found that the risk of SAEs varied across individual ChEIs, with sex and dose moderating these effects. Therefore, these moderating effects should be carefully considered in personalizing dementia care.

Association between long-term usage of acetylcholinesterase inhibitors and lung cancer in the elderly: a nationwide cohort study.

This retrospective cohort study aimed to evaluate the association between acetylcholinesterase inhibitors (AChEI) usage and the risk of lung cancer. Data from 116,106 new users of AChEI and 348,318, at a ratio of 1:3, matched by age, sex, and index-year, between 2000 and 2015 controls were obtained from the Taiwan Longitudinal Health Insurance Database in this cohort study. The Cox regression model was used to compare the risk of lung cancer. The adjusted hazard ratio (aHR) of lung cancer for AChEI users was 1.198 (95% confidence interval [CI] = 0.765-1.774, p = 0.167). However, the adjusted HR for patients aged ≥ 65 was adjusted to HR: 1.498 (95% CI = 1.124-1.798, p < 0.001), in contrast to the comparison groups. In addition, patients with comorbidities such as pneumonia, bronchiectasis, pneumoconiosis, pulmonary alveolar pneumonopathy, hypertension, stroke, coronary artery disease, diabetes mellitus, chronic kidney disease, depression, anxiety, smoking-related diseases, dementia, and seeking medical help from medical centers and regional hospitals, were associated with a higher risk in lung cancer. Furthermore, longer-term usage of rivastigmine (366-730 days, ≥ 731 days) and galantamine (≥ 731 days) was associated with the risk of lung cancer. AChEI increased the risk of lung cancer in the older aged patients, several comorbidities, and a longer-term usage of rivastigmine and galantamine. Therefore, physicians should estimate the risks and benefits of AChEI usage and avoid prescribing antidepressants concurrently.

Risk of overactive bladder associated with cholinesterase inhibitors in dementia.

BACKGROUND: Although cholinesterase inhibitors (ChEIs) are the primary treatment for dementia, they are associated with overactive bladder (OAB), necessitating antimuscarinic use. Limited data exist regarding the risk of OAB across individual ChEIs in dementia. This study evaluated the risk of OAB associated with individual ChEIs in older adults with dementia. METHODS: This was a new user retrospective cohort study using Medicare claims data involving Parts A, B, and D claims dataset from 2013 to 2015. The study included older adults (aged 65 and older) with a diagnosis of dementia using donepezil, galantamine, or rivastigmine. New ChEI claims were identified with a 6-month baseline washout period. Patients with OAB diagnosis or any antimuscarinic or mirabegron use in the baseline period were excluded. The primary outcome of interest was OAB diagnosis or prescription of antimuscarinics or mirabegron within 6 months of ChEI initiation. Multivariable cox proportional hazards regression with propensity scores (PS) as covariates and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of OAB among donepezil, galantamine, and rivastigmine users. RESULTS: The study included 524,975 older adults with dementia who were incident users of ChEIs (donepezil 80.72%, rivastigmine 16.41%, galantamine 2.87%). Overall, OAB diagnosis/antimuscarinic/mirabegron prescription was observed in 5.07% of the cohort within 6 months of ChEIs prescription. The Cox regression model with PS as covariate approach found that donepezil use increased the risk of OAB compared to rivastigmine (aHR, 1.13; 95% CI, 1.08-1.28; p < 0.0001). However, there was no differential risk of OAB between galantamine and rivastigmine. The findings were consistent with the generalized boosted models. CONCLUSIONS: The study found that the risk of OAB varies across individual ChEIs with an increased risk of OAB with donepezil compared to rivastigmine. The study findings suggest the need to understand and manage medication-related morbidity in older adults with dementia.

Therapeutic effects of carvacrol on beta-amyloid-induced impairments in in vitro and in vivo models of Alzheimer's disease.

Due to the complex nature of Alzheimer's disease (AD), it is important to investigate agents with multiple effects in the treatment of AD. Carvacrol possesses anti-acetylcholinesterase, anti-oxidant, and neuroprotective properties. We therefore investigated therapeutic effects of carvacrol on cell viability, oxidative stress, and cognitive impairment in Aß1-42-induced in vitro and in vivo models of AD. SH-SY5Y cells differentiated into neurons by retinoic acid were pretreated with carvacrol or galantamine before Aß1-42 administration. For in vivo experiments, a rat model of AD was established by bilateral intrahippocampal injection of Aß1-42. The groups received 1% DMSO, carvacrol, or galantamine intraperitoneally twice a day (morning and afternoon) for 6 days. Cell viability was determined using MTT and LDH tests. Learning and memory functions were assessed using a passive-avoidance test. Oxidant-antioxidant parameters (MDA, H2 O2 , SOD, and CAT) and Tau, Aß1-40, and Aß1-42 peptide levels in in vitro supernatant or in vivo serum and hippocampal samples were measured using ELISA. Carvacrol increased cell viability and exhibited a protective effect against oxidative stress by preventing Aß1-42-induced cytotoxicity, LDH release, and increments in MDA and H2 O2 levels in vitro. Additionally, it improved memory impairment by reversing Aß1-42-induced changes on passive-avoidance test. Carvacrol ameliorated Aß1-42-induced increments in MDA and H2 O2 levels in in vitro supernatant and in vivo hippocampal samples. However, none of the treatments changed in vitro SOD and Tau-peptide levels, or in vivo serum levels of MDA, H2 O2 , SOD, CAT, Tau peptide, Aß1-40, or Aß1-42. Our results suggest that multi-target pharmacological agent carvacrol may be promising in treatment of AD by preventing beta-amyloid-induced neurotoxicity, oxidative stress, and memory deficits.

Acute response to cholinergic challenge predicts long-term response to galantamine treatment in patients with Alzheimer's disease.

AIMS: Cholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer's disease (AD) patients, but are associated with multiple side effects and only 20-40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of administration of a single dose of galantamine on central nervous system (CNS) functioning in mild to moderate AD patients and its potential to predict long-term treatment response. METHODS: This study consisted of a challenge and treatment phase. In the challenge phase, a single dose of 16 mg galantamine was administered to 50 mild to moderate AD patients in a double-blind, placebo-controlled cross-over fashion. Acute PD effects were monitored up to 5 hours after administration with use of the NeuroCart CNS test battery and safety and pharmacokinetics were assessed. In the treatment phase, patients were treated with open-label galantamine according to regular clinical care. After 6 months of galantamine treatment, patients were categorized as either responder or as non-responder based on their minimental state examination (MMSE), neuropsychiatric inventory (NPI) and disability assessment in dementia (DAD) scores. An analysis of covariance was performed to study the difference in acute PD effects during the challenge phase between responders and non-responders. RESULTS: A single dose of galantamine significantly reduced saccadic reaction time (-0.0099; 95% CI = -0.0195, -0.0003; P = .0430), absolute frontal EEG parameters in alpha (-14.9; 95% CI = -21.0, -8.3; P = .0002), beta (-12.6; 95% CI = -19.4, -5.3; P = .0019) and theta (-17.9; 95% CI = -25.0, -10.0; P = .0001) frequencies. Relative frontal (-1.669; 95% CI = -2.999, -0.339; P = .0156) and occipital (-1.856; 95% CI = -3.339, -0.372; P = .0166) EEG power in theta frequency and relative occipital EEG power in the gamma frequency (1.316; 95% CI = 0.158, 2.475; P = .0273) also increased significantly compared to placebo. Acute decreases of absolute frontal alpha (-20.4; 95% CI = -31.6, -7.47; P = .0046), beta (-15.7; 95% CI = -28.3, -0.93; P = .0390) and theta (-25.9; 95% CI = -38.4, -10.9; P = .0024) EEG parameters and of relative frontal theta power (-3.27%; 95% CI = -5.96, -0.58; P = .0187) on EEG significantly distinguished responders (n = 11) from non-responders (n = 32) after 6 months. CONCLUSIONS: This study demonstrates that acute PD effects after single dose of galantamine are correlated with long-term treatment effects and that patients who demonstrate a reduction in EEG power in the alpha and theta frequency after a single administration of galantamine 16 mg will most likely respond to treatment.

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

BACKGROUND: Vascular cognitive impairment (VCI) describes a broad spectrum of cognitive impairments caused by cerebrovascular disease, ranging from mild cognitive impairment to dementia. There are currently no pharmacological treatments recommended for improving either cognition or function in people with VCI. Three cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) are licenced for the treatment of dementia due to Alzheimer's disease. They are thought to work by compensating for reduced cholinergic neurotransmission, which is also a feature of VCI. Through pairwise comparisons with placebo and a network meta-analysis, we sought to determine whether these medications are effective in VCI and whether there are differences between them with regard to efficacy or adverse events. OBJECTIVES: (1) To assess the efficacy and safety of cholinesterase inhibitors in the treatment of adults with vascular dementia and other VCI. (2) To compare the effects of different cholinesterase inhibitors on cognition and adverse events, using network meta-analysis. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform on 19 August 2020. SELECTION CRITERIA: We included randomised controlled trials in which donepezil, galantamine, or rivastigmine was compared with placebo or in which the drugs were compared with each other in adults with vascular dementia or other VCI (excluding cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)). We included all drug doses and routes of administration. DATA COLLECTION AND ANALYSIS: Two review authors independently identified eligible trials, extracted data, assessed risk of bias, and applied the GRADE approach to assess the certainty of the evidence. The primary outcomes were cognition, clinical global impression, function (performance of activities of daily living), and adverse events. Secondary outcomes were serious adverse events, incidence of development of new dementia, behavioural disturbance, carer burden, institutionalisation, quality of life and death. For the pairwise analyses, we pooled outcome data at similar time points using random-effects methods. We also performed a network meta-analysis using Bayesian methods. MAIN RESULTS: We included eight trials (4373 participants) in the review. Three trials studied donepezil 5 mg or 10 mg daily (n= 2193); three trials studied rivastigmine at a maximum daily dose of 3 to 12 mg (n= 800); and two trials studied galantamine at a maximum daily dose of 16 to 24 mg (n= 1380). The trials included participants with possible or probable vascular dementia or cognitive impairment following stroke. Mean ages were between 72.2 and 73.9 years. All of the trials were at low or unclear risk of bias in all domains, and the evidence ranged from very low to high level of certainty. For cognition, the results showed that donepezil 5 mg improves cognition slightly, although the size of the effect is unlikely to be clinically important (mean difference (MD) -0.92 Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) points (range 0 to 70), 95% confidence interval (CI) -1.44 to -0.40; high-certainty evidence). Donepezil 10 mg (MD -2.21 ADAS-Cog points, 95% CI -3.07 to -1.35; moderate-certainty evidence) and galantamine 16 to 24 mg (MD -2.01 ADAS-Cog point, 95%CI -3.18 to -0.85; moderate-certainty evidence) probably also improve cognition, although the larger effect estimates still may not be clinically important. With low certainty, there may be little to no effect of rivastigmine 3 to 12 mg daily on cognition (MD 0.03 ADAS-Cog points, 95% CI -3.04 to 3.10; low-certainty evidence). Adverse events reported in the studies included nausea and/or vomiting, diarrhoea, dizziness, headache, and hypertension. The results showed that there was probably little to no difference between donepezil 5 mg and placebo in the number of adverse events (odds ratio (OR) 1.22, 95% CI 0.94 to 1.58; moderate-certainty evidence), but there were slightly more adverse events with donepezil 10 mg than with placebo (OR 1.95, 95% CI 1.20 to 3.15; high-certainty evidence). The effect of rivastigmine 3 to 12 mg on adverse events was very uncertain (OR 3.21, 95% CI 0.36 to 28.88; very low-certainty evidence). Galantamine 16 to 24 mg is probably associated with a slight excess of adverse events over placebo (OR 1.57, 95% CI 1.02 to 2.43; moderate-certainty evidence). In the network meta-analysis (NMA), we included cognition to represent benefit, and adverse events to represent harm. All drugs ranked above placebo for cognition and below placebo for adverse events. We found donepezil 10 mg to rank first in terms of benefit, but third in terms of harms, when considering the network estimates and quality of evidence. Galantamine was ranked second in terms of both benefit and harm. Rivastigmine had the lowest ranking of the cholinesterase inhibitors in both benefit and harm NMA estimates, but this may reflect possibly inadequate doses received by some trial participants and small trial sample sizes. AUTHORS' CONCLUSIONS: We found moderate- to high-certainty evidence that donepezil 5 mg, donepezil 10 mg, and galantamine have a slight beneficial effect on cognition in people with VCI, although the size of the change is unlikely to be clinically important. Donepezil 10 mg and galantamine 16 to 24 mg are probably associated with more adverse events than placebo. The evidence for rivastigmine was less certain. The data suggest that donepezil 10 mg has the greatest effect on cognition, but at the cost of adverse effects. The effect is modest, but in the absence of any other treatments, people living with VCI may still wish to consider the use of these agents. Further research into rivastigmine is needed, including the use of transdermal patches.

Comparative risk of cardiac arrhythmias associated with acetylcholinesterase inhibitors used in treatment of dementias - A narrative review.

Donepezil, galantamine, and rivastigmine are the three acetylcholinesterase inhibitors (AChEIs), out of a total of only four medications prescribed in the treatment of Alzheimer's Disease (AD) and related dementias. These medications are known to be associated with bradycardia given their mechanism of action of increasing acetylcholine (ACh). However, in March 2015, donepezil was added to the CredibleMeds "known-risk" category, a list where medications have a documented risk for acquired long-QT syndrome (ALQTS) and torsades de pointes (TdP) - a malignant ventricular arrhythmia that is a different adverse event than bradycardia (and is not necessarily associated with ACh action). The purpose of this article is to review the three AChEIs, especially with regards to mechanistic differences that may explain why only donepezil poses this risk; several pharmacological mechanisms may explain why. However, from an empirical point-of-view, aside from some case-reports, only a limited number of studies have generated relevant information regarding AChEIs' and electrocardiogram findings; none have specifically compared donepezil against galantamine or rivastigmine for malignant arrhythmias such as TdP. Currently, the choice of one of the three AChEIs for treatment of AD symptoms is primarily dependent upon clinician and patient preference. However, clinicians should be aware of the potential increased risk associated with donepezil. There is a need to examine the comparative risk of malignant arrhythmias among AChEIs users in real-world practice; this may have important implications with regards to changes in AChEI prescribing patterns.

Pisa syndrome induced by switching of a choline-esterase inhibitor treatment from donepezil to galantamine: a case report.

BACKGROUND: Pisa syndrome (PS) is characterized by an abnormally sustained posture, with flexion of the body and head to one side and slight rotation of the trunk. Although PS most commonly arises as an adverse effect of antipsychotic drugs, choline-esterase inhibitors (ChEIs) are also sometimes known to induce PS. Despite the fact that the precise mechanism remains unclear, cholinergic-dopaminergic imbalance has been considered as a possible pathophysiologic mechanism underlying the genesis of PS. CASE PRESENTATION: We hereby report the case of a 60-year-old woman with Alzheimer's disease who presented with the signs of PS after her treatment was switched to galantamine, a type of ChEI, even though she had received donepezil, another type of ChEI, for 5 years without any complications. To the best of our knowledge, this is the first report of PS associated with treatment switch from one to another type of ChEI. Galantamine, but not other ChEIs, can enhance striatal dopamine release through allosteric modulation of the nicotinic acetylcholine receptor, and has weaker muscarinic effects than donepezil. Therefore, we propose two novel hypotheses to explain the development of PS, as follows; galantamine, which enhances dopamine release, can induce imbalance of dopamine levels in the striatum of patients with dementia, resulting in PS, and the weaker muscarinic effects of the drug could be one of the factors predisposing to the development of PS. CONCLUSION: The present case suggests that treatment with galantamine is associated with a higher risk of development of PS than that with other ChEIs, such as donepezil, despite the pharmacological profile of galantamine as a dopamine modulator. Also, this report provides novel insight into another plausible mechanism underlying the development of PS, besides cholinergic-dopaminergic imbalance, namely, dopamine imbalance in the striatum with muscarinic-nicotinic imbalance.

An update on the utility and safety of cholinesterase inhibitors for the treatment of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders with a prevalence in the US of about 5.7 million in 2018. With the disease burden projected to increase dramatically in the coming years, it is imperative to review the current available treatment regimens for their safety and utility. The cholinesterase inhibitors (ChEIs) have continued to play a pivotal role in managing the symptoms and possibly slowing the rate of progression of AD since 1993. Owing to their being a mainstay in the treatment of AD, the safety and efficacy of prescribing these drugs needs to be reviewed often, especially with the approval of new formulations and doses.Areas covered: The three ChEIs currently approved by the FDA are donepezil, rivastigmine and galantamine. This article will review the safety and tolerability of these ChEIs and analyze the potential disease modifying properties of these drugs. The authors have reviewed all recent literature including review articles, meta-analyzes, clinical trials and more.Expert opinion: These ChEIs differ subtly in their mechanisms of action, in their tolerability and safety and FDA-approved indications. All are considered first-line, symptomatic treatments of the various phases of AD and may even have potentially disease-modifying effects.

Inducción de manía por inhibidores de la colinesterasa: evidencia empírica a través de datos observacionales / Mania induced by cholinesterase inhibitors: empirical evidence from observational data

OBJETIVOS: Evaluar si los inhibidores de la colinesterasa pueden inducir manía, y determinar si este efecto puede estar relacionado con estados u otras características previas de los pacientes. MÉTODO: Se realizó una revisión sistemática, incluyendo artículos publicados en ISI Web of Knowledge y PubMed, desde enero de 1990 a marzo de 2018, siguiendo criterios PRISMA. RESULTADOS: De 326 estudios identificados, se incluyeron en la revisión 16. En los casos comunicados hay una correlación entre la introducción de un inhibidor de la colinesterasa y la aparición de un episodio maníaco/hipomaníaco. El riesgo parece ser mayor si el paciente tiene antecedentes de trastorno afectivo y si está tomando medicación antidepresiva. CONCLUSIONES: Los inhibidores de la colinesterasa pueden inducir manía en algunos pacientes. Más estudios son necesarios para una mejor comprensión de este fenómeno; se deben tomar precauciones al prescribir estos fármacos en pacientes de riesgo

AIMS: To evaluate if cholinesterase inhibitors can induce mania, and if so to determine if this effect could be related to pre-existing conditions and other patient characteristics. METHODS: A systematic review was conducted that included articles published in PubMed and ISI Web of Knowledge from January 1990 to March 2018, following PRISMA guidelines. RESULTS: From a total of 326 studies found, 16 were included in the review. In the reported cases, there was a correlation between the introduction of a cholinesterase inhibitor and the development of a manic/ hypomanic episode. The risk appears to be higher if the patient had a history of affective disorder and if he/she was taking antidepressant medication. CONCLUSIONS: Cholinesterase inhibitors may induce mania in some patients. Further studies are needed for a better understanding of this phenomenon. Care should be taken when prescribing these drugs in specific patients

Risk of rhabdomyolysis with donepezil compared with rivastigmine or galantamine: a population-based cohort study.

BACKGROUND: Donepezil, rivastigmine and galantamine are popular cholinesterase inhibitors used to manage the symptoms of Alzheimer disease and other dementias; regulatory agencies in several countries warn about a possible risk of rhabdomyolysis with donepezil, based on information from case reports. Our goal was to investigate the 30-day risk of admission to hospital with rhabdomyolysis associated with initiating donepezil versus other cholinesterase inhibitors. METHODS: We conducted a retrospective cohort study in Ontario, Canada, from 2002 to 2017. Participants were adults aged 66 years or older with a newly dispensed prescription for donepezil compared with rivastigmine or galantamine. The primary outcome was hospital admission with rhabdomyolysis (assessed using hospital diagnostic codes) within 30 days of a new prescription of a cholinesterase inhibitor. Odds ratios were estimated using logistic regression, with inverse probability of treatment weights calculated from propensity scores. RESULTS: The average age in our 2 groups was 81.1 years, and 61.4% of our population was female. Donepezil was associated with a higher risk of hospital admission with rhabdomyolysis compared with rivastigmine or galantamine (88 events in 152 300 patients [0.06%] v. 16 events in 68 053 patients [0.02%]; weighted odds ratio of 2.21, 95% confidence interval [CI] 1.52-3.22). Most hospital admissions with rhabdomyolysis after donepezil use were not severe, and no patient was treated with acute dialysis or mechanical ventilation. INTERPRETATION: Initiating donepezil is associated with a higher 30-day risk of admission to hospital with rhabdomyolysis compared with initiating rivastigmine or galantamine. The proportion of patients who develop severe rhabdomyolysis within 30 days of initiating donepezil is very low.

Correlation of CSF- and MRI-Biomarkers and Progression of Cognitive Decline in an Open Label MCI Trial.

BACKGROUND: In several randomized controlled trials (RCT) acetylcholinesterase-inhibitors (AChE-I) were tested in patients with mild cognitive impairment (MCI) but were ineffective in delaying disease progression as determined by neuropsychological testing only. Here we present data from an open label observational extension of a multicenter RCT in order to assess if biomarkers are providing useful additional information about a drug's efficacy. We followed 83 amnestic MCI patients and performed correlational analyses of Aß 1-42 and total-Tau in the cerebrospinal fluid (CSF), hippocampal and amygdala volume at baseline, the total duration of blinded and open label AChE-I treatment and the outcome 24 months after inclusion into the RCT. Twelve out of 83 amnestic MCI (14%) had progressed to Alzheimer's disease (AD). Overall, worsening and disease progression as measured by the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) and Clinical Dementia Rating (CDR) did not correlate with the duration of AChE-I treatment. However, a specific multidimensional biomarker profile at baseline indicated more reliably than cognitive testing alone progression to AD. We conclude that pharmacological RCTs testing symptomatic treatment effects in MCI should include biomarker assessment.

Galantamine and Computerized Cognitive Behavioral Therapy for Cocaine Dependence: A Randomized Clinical Trial.

OBJECTIVE: To examine whether galantamine, a cognitive-enhancing medication that is both acetylcholinesterase inhibitor and agonist at nicotinic acetylcholine receptors, is effective at improving cocaine use outcomes and cognitive functioning, alone and in combination with computerized cognitive behavioral therapy (CBT). METHOD: A 12-week, randomized 2 × 2, factorial trial was conducted to evaluate galantamine versus placebo (double-blind) and computerized CBT plus standard methadone treatment versus standard methadone treatment alone in a community-based methadone maintenance program (September 2009-April 2015). One hundred twenty individuals diagnosed with DSM-IV cocaine use disorder were randomly assigned to the following conditions: (1) galantamine (8 mg/d) plus standard methadone maintenance treatment (treatment as usual [TAU]), (2) placebo plus TAU, (3) galantamine plus computerized CBT plus TAU, or (4) placebo plus computerized CBT plus TAU; medication administration was supervised at the time of daily methadone dosing. The primary cocaine use outcome was change in percent days of abstinence over time. Number of cocaine-negative urine toxicology screens submitted and cognitive function were secondary outcomes. RESULTS: Random effect regression analysis indicated significant reductions in frequency of cocaine use over time, with significant treatment-by-time effects for both galantamine over placebo (F = 5.3, P = .02, d = 0.34) and computerized CBT over standard methadone treatment (F = 4.2, P = .04, d = 0.30) but no evidence of significant benefit of the combination over either treatment alone. Pretreatment to posttreatment comparisons of multiple indices of cognitive functioning, including sustained attention, indicated no benefit of galantamine over placebo. CONCLUSIONS: Findings suggest benefits of galantamine and computerized CBT for reducing cocaine use in this sample. Although galantamine did not improve measures of cognitive function in this sample, multiple measures of cognitive function were associated with cocaine use outcomes, underlining the significance of cognitive function in cocaine treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00809835.

Acetylcholinesterase inhibitors for treating dementia symptoms - a safety evaluation.

INTRODUCTION: The prevalence of Alzheimer's disease (AD) continues to rise, while treatment options for cognitive impairment are limited. Acetylcholinesterase inhibitors (AChEIs) aim to provide symptomatic benefit for cognitive decline, however these drugs are not without adverse events (AEs). The safety profile of each drug must be taken carefully into consideration before being prescribed, as new dosages and formulations have recently been approved. Areas covered: Donepezil, galantamine and rivastigmine are the three AChEIs approved for the treatment of varying stages of AD. Numerous clinical trials and post-marketing studies have evaluated the safety of these medications. This article will review the safety, efficacy and tolerability of these drugs in treating AD. Topics including pharmacovigilance databases, concomitant drug interactions, prescribing cascades, and treatment discontinuation are also covered. Expert opinion: AChEI use in those with mild, moderate or severe AD provide modest improvements in cognition, function and behavior. The pharmacological treatment of AD using AChEIs is associated with generally mild AEs. Differences in drug formulations should be taken into account when determining the most appropriate route of administration for each individual. Furthermore, discontinuation of AChEIs must be carefully monitored as it may be associated with worsening cognitive impairment.

Use of antidementia drugs and risk of pneumonia in older persons with Alzheimer's disease.

INTRODUCTION: Persons with Alzheimer's disease are at an increased risk of pneumonia, but the comparative risks during specific antidementia treatments are not known. We compared the risk of pneumonia in the use of donepezil, rivastigmine (oral, transdermal), galantamine and memantine. PATIENTS AND METHODS: We used data from a nationwide cohort of community-dwelling individuals diagnosed with Alzheimer's disease during 2005-2011 in Finland, who initiated monotherapy with acetylcholinesterase inhibitor or memantine (n = 65,481). The risk of hospitalization or death due to pneumonia was investigated with Cox proportional hazard models. RESULTS: The risk of pneumonia was higher in persons using rivastigmine patch (n = 9709) (adjusted hazard ratio (HR) 1.15, 95% confidence interval (CI) 1.04-1.27) and memantine (n = 11,024) (HR 1.59, 95% CI 1.48-1.71) compared with donepezil users (n = 26,416) whereas oral rivastigmine (n = 7384) (HR 1.08, 95% CI 0.98-1.19) and galantamine (n = 10,948) (HR 0.91, 95% CI 0.83-1.00) were not associated with an increased risk. These results did not change when adjusting for comorbid conditions, use of psychotropic drugs or with inverse probability of treatment weighting. DISCUSSION: The increased risk of pneumonia in this fragile group of aged persons should be taken into account. Memantine is associated with the highest risk in the comparison of antidementia drugs. KEY Message Pneumonia risk is increased in persons with Alzheimer's disease who use memantine or rivastigmine patches.