Use Of Acetylcholinesterase Inhibitors Research Articles

Patients with dementia: prevalence and type of drug-drug interactions.

Patients with Alzheimer's disease (AD) and other dementias are more frequently exposed to polymedication, mainly due to the presence of comorbidities, are particularly vulnerable to drug-related problems, and present greater risk of adverse effects due to drug-drug interactions (DDIs). To assess the prevalence of clinically relevant interactions in dementia patients using a routine database, we describe the most frequent interactions and risk factors associated with them to facilitate specific interventions and programs to prevent and minimize them. An observational, descriptive, and cross-sectional study that included patients with AD and other types of dementia (n = 100, 64% female) was conducted to identify potential DDI in their treatment using the Lexi-Interact/Lexicomp® database. A total of 769 drugs were prescribed, involving 190 different active ingredients; 83% of the treatments included five or more drugs. DDI occurred in 87% of the patients, of which 63.2% were female. A total of 689 DDIs were found, grouped in 448 drug pairs, with a mean of 6.9 ± 7.1 (range, 0-31) DDIs per patient, and 680 DDIs were considered clinically relevant. It was observed that 89.8% of the DDIs had a moderate level of severity, 23.5% had a good level of relevance, and pharmacodynamic-based DDIs accounted for 89.5%. The drugs most frequently involved in DDIs were quetiapine (24.5%) and acetylsalicylic acid (10%). A total of 97 DDIs were detected between the acetylcholinesterase inhibitors (AChEIs), and the remaining drugs were administered concomitantly. One of the most frequent DDIs was between AChEIs and beta-blocking agents (n = 29, 4.3%). The most important factors that showed the strongest association with the presence of drug interactions were the use of AChEIs (p = 0.01) and the total number of drugs (p = 0.014) taken by the patient. Patients with dementia present increased risk of DDIs. Among the most common drugs are psychotropic drugs, which are involved in pharmacodynamic interactions caused by the concomitant use of CNS-targeted drugs. The results highlight the difficulty to evaluate DDIs in clinical practice due to polymedication and variety of comorbidities. Therefore, it is important to review their treatment and consider metabolism inhibition or induction, and potentially P450 substrate overlapping.

Pharmacological inhibition of acetylcholinesterase improves the locomotion defective phenotype of a SCA3 C. elegans model.

Inhibition of acetylcholinesterase (AChE) is a common used treatment option for Alzheimer's disease. However, there has been limited research on the potential use of AChE inhibitors for the treatment of Machado-Joseph disease (MJD)/Spinocerebellar Ataxia 3 (SCA3), in spite of the positive results using AChE inhibitors in patients with other inherited ataxias. MJD/SCA3, the most common form of dominant Spinocerebellar Ataxia worldwide, is caused by an expansion of the polyglutamine tract within the ataxin-3 protein, and is characterized by motor impairments. Our study shows that administration of the AChE inhibitor neostigmine is beneficial in treating the locomotion defective phenotype of a SCA3/MJD model of C. elegans and highlights the potential contribution of AChE enzymes to mutant ataxin-3-mediated toxicity.

Early intervention and adding effective doses of EGb761 like Ginkgo extract slow down dementia progression: insights to the neurovascular unit.

Dementia is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and functional deterioration. Pharmacological interventions play a crucial role in managing dementia symptoms and potentially slowing down disease progression. This study aimed to investigate the impact of pharmacological interventions, including acetylcholinesterase inhibitors (AChEIs), memantine, and Gingko extract, on the progression of dementia, with a specific focus on mild cognitive impairment (MCI), Alzheimer's disease (AD), and non-Alzheimer dementias. A total of 547 participants out of 3,547 cases in a specific dataset followed by the same author, including healthy controls, individuals with MCI, AD, and non-Alzheimer dementias, were included in this study. The follow-up duration was up to 211 months, allowing for a minimum 3 visits comprehensive assessment of disease progression. The treatment approaches included AChEIs, memantine, and combination therapy, with variations in the starting time for these treatments based on the dementia type. The use of AChEIs and memantine showed efficacy in improving cognitive function and overall function in individuals with MCI, AD, and non-AD dementias. Combination therapy EGb761 like Gingko extract with AChEIs and/or Memantine demonstrated a slower progression compared to AChEIs alone in individuals with prodromal dementia (MCI) and AD. The starting time for memantine and combination therapy was earlier in non-AD dementia cases compared to AD dementia cases and prodromal dementia. Pharmacological interventions, particularly the use of AChEIs and memantine, can have a positive impact on cognitive function and overall function in individuals with dementia. The combination of AChEIs with EGb761 like Gingko extract may provide additional benefits in slowing down disease progression in AD cases. Early recognition and accurate classification of MCI subtypes are crucial, and the use of EGb761 like Gingko extract is recommended for symptomatic treatment. Future personalized risk predictions based on biomarker constellations may further enhance the multi-target treatment approaches of MCI and different dementia types.

Potential cardioprotective effects of acetylcholinesterase inhibitors in patients with Alzheimer's disease

Abstract Background In patients with mild to moderate Alzheimer's disease (AD), acetylcholinesterase inhibitors (AChE-I) are commonly employed to improve cognitive function. They increase the amount of acetylcholine (ACh) in the neuronal synapses, but bradycardia, cardiac electrical conduction blocks and hypotension due to muscarinic M2 receptor stimulation are potential side effects. However, whether these "side effects" could play a potential protective effect on cardiovascular (CV) events is not yet well defined. Purpuses To evaluate potential beneficial cardiac effects of AChE-Is in patients with AD, in terms of reduction of major adverse cardiovascular events (MACEs). Methods We conducted a retrospective, monocentric, observational cohort study in patients referred to our hospital. Two groups were considered: the interventional group included AD patients treated with AChE-I. The control group enrolled a cohort of subjects matched for age and comorbidities, recruited between caregivers of intervention group subjects that were cognitively unimpaired and not taking AchE-I. The primary endpoint was a composite of hospitalization for heart failure (HF), non-fatal acute myocardial infarction (AMI), myocardial revascularization, hospitalization for cardiovascular (CV) causes, cardiovascular mortality and occurrence of stroke and/or TIA during total 5 year follow-up period (MACEs). Secondary endpoints were each individual component of the primary end point, total deaths, non-cardiovascular death and incidence of pacemaker implant. Results 221 AD patients treated with AChE-I (91 with Donepezil, 130 with Rivastigmine) were included in intervention group and 221 non-AD patients in control group. Groups were homogeneous in terms of age, gender and main cardiovascular risk factors, except for family history of cardiovascular diseases (CVD), which was more frequent in control group. During a median follow-up of 3.1 years the primary endpoint occurred in 24 patients in intervention group (2.1 per 100 patient-years) compared to 56 patients in the control group (5.0 per 100 patient-years). Therefore, AChE-I therapy resulted a protective factor from primary endpoint (HR 0.48, 95% CI 0.24-0.95; p= 0.036). Even not significant, the difference was mainly driven by myocardial revascularization (3.2% in intervention group vs 6.8% in controls) and hospitalization for heart failure (4.5% in intervention group vs 14.5% in controls). Non-CVD mortality was significantly higher in treatment group (13,6% in intervention group vs 2,7% in controls). No significant difference was observed between groups in terms of other secondary outcomes. Conclusions Among patients with AD, use of AChE-I may be protective for CV outcomes, especially reducing HF hospitalisation and myocardial revascularization.Kaplan-Meier of cumulative MACEsNumber of Event/Years

Psychiatric Adverse Events of Acetylcholinesterase Inhibitors in Alzheimer's Disease and Parkinson's Dementia: Systematic Review and Meta-Analysis.

The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined. We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer's dementia and Parkinson's dementia. A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29-3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33-2.82; p=0.0006; insomnia: OR 1.55, 95% CI 1.25-1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23-2.06, p=0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine. Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia. The study was pre-registered on PROSPERO (CRD42021258376).

Potential Cardiologic Protective Effects of Acetylcholinesterase Inhibitors in Patients With Mild to Moderate Dementia

In patients with mild to moderate dementia, acetylcholinesterase inhibitors (AChE-I) are used to improve cognitive functions, but bradycardia, conduction abnormalities, and hypotension are possible side effects because of the peripheral muscarinic M2 receptor stimulation. This study aimed to evaluate the main cardiologic clinical outcomes in patients with dementia who are on AChE-I. In this retrospective, monocentric, observational cohort study, 2 groups were considered: (1) patients with dementia because of the typical and atypical forms of Alzheimer disease treated with AChE-I and (2) cognitively unimpaired, matched control group. The primary end point was a composite of cardiovascular death, nonfatal acute myocardial infarction, myocardial revascularization, occurrence of stroke and/or transient ischemic attacks, and hospitalization for heart failure occurring during a mean of 3.1years of follow-up. The secondary end points were each individual component of the primary end point, total mortality, noncardiovascular death, and incidence of pacemaker implant. Each group included 221 patients who were homogeneous in terms of age, gender, and main cardiovascular risk factors. Major adverse cardiovascular events occurred in 24 patients with dementia (2.1 per 100 patient-years) compared with 56 in control group (5.0 per 100 patient-years), p=0.036. Even if not significant, the difference was mainly driven by myocardial revascularization (3.2% vs 6.8%) and hospitalization for heart failure (4.5% vs 14.5%). As expected, noncardiovascular mortality was significantly higher in the treatment group (13.6% vs 2.7% p=0.006). No significant difference between the groups was observed in terms of other secondary outcomes. In conclusion, in patients with dementia, the use of AChE-I may be protective for cardiovascular outcomes, especially in reducing heart failure hospitalization and myocardial revascularization.

The use of antidementia therapy in non-dementia cognitive disorders associated with COVID-19

IntroductionThe new coronavirus infection causes severe damage to the human body. One of the most serious complication is cognitive impairment.According to a meta-analysis by Maxime Taquet et al. (2021), which assessed neurological and psychiatric outcomes among 236,379 patients diagnosed with COVID-19, 1.7% of participants over 65 years of age were diagnosed with dementia.In a US online survey of 1,500 people (Sarah Ballou et al., 2020), about half reported difficulty concentrating on any task after experiencing COVID-19.It was also found that there is a decrease in the speed of reactions and problem-solving (Jeffrey D. Pyne et al., 2021).There are a number of studies that present the evidence-based efficacy of acetylcholinesterase (AChE) inhibitors in dementia prevention.However, in accordance with clinical guidelines for cognitive disorders in the elderly, anti-dementia drugs are not used at the stage of mild to moderate cognitive impairment (Ministry of Health of the Russian Federation, 2020).ObjectivesThe use of AChE inhibitors in cognitive impairments that do not reach the degree of dementia.MethodsResearch data from open sources.ResultsThe development of early cholinergic deficiency correlates with the development of cognitive impairment, while acetylcholine has a pronounced neuroplastic effect and increases the number of neurons (Gabriela Dumitrita Stanciu et al., 2019).In a double-blind, placebo-controlled study, a positive effect of rivastigmine was found in patients with mild to moderate cognitive impairment. The study’s results show that rivastigmine treatment (3, 6, 9 mg/day) for six months increases brain activity of the hippocampus in the control group by 32,5%. Rivastigmine prevented the clinical progression of symptoms of cognitive impairment and caused activation of some parts of the cerebral cortex (Nagaendran Kandiah et al., 2017).In a study by Wolfson C. et al. (2002), it was found that rivastigmine can slow down the development of cognitive impairment for at least six months in patients with mild to moderate massive cognitive dysfunction. Subjects treated with 1 to 21 mg per day for 7 to 12 weeks got more favorable ADAS-cog scores for the six months after treatment. While those who took the drug in doses of 6 to 12 mg showed a more pronounced positive effect compared to the placebo group.The Luca Rozzini in 2006 conducted a study based on 59 subjects with mild cognitive impairment. 15 subjects received both neuropsychological examination and acetylcholinesterase inhibitors. As a result, the remaining subjects were behind in terms of abstract thinking and behavioral symptoms, in comparison with a combined treatment group.ConclusionsIt is advisable to conduct further studies on the effectiveness of AChE inhibitors to prevent the progression of mild to moderate cognitive impairment and their transition to dementia.Disclosure of InterestNone Declared

Impact of concomitant acetylcholinesterase inhibitor use on the pharmacokinetic profile of pimavanserin in patients with dementia‐related psychosis: Modeling data from the phase 3 HARMONY study

AbstractBackgroundPimavanserin is a selective serotonin modulator with inverse agonist/antagonist activity at the 5HT2A receptor, and to a lesser extent at the 5HT2C receptor. Pimavanserin efficacy and safety were evaluated in patients with dementia‐related psychosis (DRP) in the phase 3 HARMONY study. Many patients with DRP receive acetylcholinesterase inhibitors (AChEIs) to treat their dementia. This analysis evaluated the pharmacokinetic (PK) profile of pimavanserin in patients receiving concomitant AChEIs using data from HARMONY.MethodsHARMONY was a randomized discontinuation study in patients with DRP. Patients received open‐label pimavanserin, 34 mg daily with flexible dosing (20 mg) based on tolerability, for 12 weeks, and those with sustained response were randomized into the 26‐week double‐blind period where they continued their pimavanserin or switched to placebo. PK samples were collected at baseline and weeks 12, 13, 22, and 38 (or end of treatment). Individual Bayesian estimates of pimavanserin apparent clearance (CL/F) and apparent volume of distribution (V/F) were obtained using a previously developed population PK model for patients with/without concomitant AChEIs. Steady‐state area under the plasma concentration‐time curve (AUC) and maximum drug concentration (Cmax) were computed for pimavanserin doses normalized to 34 mg daily.Results158/337 (46.9%) patients in HARMONY had concomitant AChEI use (donepezil, galantamine, rivastigmine). In patients with/without AChEI use, CL/F and V/F showed no apparent differences between groups. Covariate testing found no statistically significant effect (α = 0.05) of AChEI use on CL/F or V/F. Minimal differences in predicted steady‐state pimavanserin exposures were observed between patients with concomitant AChEI use and those without (Table 1); median Cmax was 8.4% higher (with AChEI: 57.9 ng/mL; without AChEI: 53.4 ng/mL) and median AUC was 9.2% higher (with AChEI: 1328.9 ng × h/mL; without AChEI: 1216.5 ng × h/mL).ConclusionsConcomitant AChEIs had no significant effect on the PK parameters of pimavanserin. Differences in exposure measures (Cmax and AUC) between groups were negligible (&lt;10%). These results suggest that concomitant AChEI use does not have a clinically relevant impact on the PK profile of pimavanserin.

Efficacy of Acetylcholinesterase Inhibitors on Cognitive Function in Alzheimer's Disease. Review of Reviews.

Alzheimer’s disease (AD) is the most common form of dementia over the age of 65. It is estimated that 115.4 million people will be affected by AD by 2050. Acetylcholinesterase inhibitors (AChEI) are the only available and approved treatment for AD. The aim of the present study was to analyse the evidence on the efficacy of the AChEI in the treatment of cognitive symptoms of Alzheimer’s disease. For that purpose, a review of review of the systematic reviews (SRs) on this topic was carried out by Web of Science, PubMed, and The Cochrane Library, among others, were searched until 24 September 2021. Thirteen of the 1773 articles evaluated the efficacy of AChEI on cognitive function and/or general condition and/or behavioural disturbances of patients with mild to moderate AD. Methodological quality and risk of bias were rated using the ROBIS scale. The quality of the identified studies was high for nine of them, unclear for two, and finally only in two of the 13 studies did we detect low quality. Overall, AChEI showed very low efficacy in improving cognition in patients with mild to moderate AD. Better results were obtained in improving global state, with donepezil being the most effective treatment. No improvements in behavioural disturbances were found. Few high-quality reviews provide clear evidence of the effects of AChEI on cognition, global change, behaviour, and mortality. The data suggest that AChEI stabilize or slow cognitive deterioration, improving global status. In addition, data indicate that the use of AChEI decreases mortality in patients with mild to moderate AD. However, there is no evidence that they improve patient behaviour. Donepezil is the best therapeutic alternative at a dose of 10 mg/day.

Current Pharmacological and Emerging Non-pharmacological Treatments in Slowing the Progression of Mild Cognitive Impairment: A Literature Review

Introduction: MCI is considered as a prodromal stage between normal cognitive aging and dementia given its potential to develop into various forms of dementia, most notably Alzheimer’s disease (AD). This translates to a need for effective pharmacological and non-pharmacological treatments to prevent the progression of MCI and subsequently slowing AD onset. This review aims to discuss the effectiveness of pharmacological and non-pharmacological interventions in slowing MCI progression. Methods: A literature search was conducted using the PubMed database for randomized controlled trials (RCTs) examining the effectiveness of interventions with individuals with MCI. Keywords included “mild cognitive impairment”, “drug”, “treatment”, and “randomized controlled trials”. Articles were evaluated on criteria relevant to the review’s purpose. Results: Studies on different pharmacological and non-pharmacological interventions demonstrated promising results in slowing the progression of MCI into dementia. Acetylcholinesterase inhibitors (AChEIs) display favourable results on multiple cognitive assessments when compared to placebo. Non-pharmacological interventions, such as diet supplementation or exercise, also have the potential in improving performance in a multitude of cognitive domains. Discussion: In multiple RCTs, AChEIs displayed effectiveness in alleviating cognitive impairment associated with MCI, but only temporarily with some adverse effects. Given the difficulty in determining a clear use of AChEIs on slowing the progression of MCI, additional research is needed. Non-pharmacological interventions have also displayed effectiveness without risk of adverse drug effects. Literature regarding multimodal approaches combining both pharmacological and non-pharmacological interventions is a novel area of research, and these studies have suggested positive additive effects. Conclusion: Pharmacological and non-pharmacological interventions for slowing the progression of MCI display promising results. More studies are needed to determine which treatment plans, whether pharmacological, non-pharmacological, or a combination of the two, will prove to be the most effective for individuals with MCI.

Adverse Drug Reactions of Acetylcholinesterase Inhibitors in Older People Living with Dementia: A Comprehensive Literature Review.

The rising of global geriatric population has contributed to increased prevalence of dementia. Dementia is a neurodegenerative disease, which is characterized by progressive deterioration of cognitive functions, such as judgment, language, memory, attention and visuospatial ability. Dementia not only has profoundly devastating physical and psychological health outcomes, but it also poses a considerable healthcare expenditure and burdens. Acetylcholinesterase inhibitors (AChEIs), or so-called anti-dementia medications, have been developed to delay the progression of neurocognitive disorders and to decrease healthcare needs. AChEIs have been widely prescribed in clinical practice for the treatment of Alzheimer’s disease, which account for 70% of dementia. The rising use of AChEIs results in increased adverse drug reactions (ADRs) such as cardiovascular and gastrointestinal adverse effects, resulting from overstimulation of peripheral cholinergic activity and muscarinic receptor activation. Changes in pharmacokinetics (PK), pharmacodynamics (PD) and pharmacogenetics (PGx), and occurrence of drug interactions are said to be major risk factors of ADRs of AChEIs in this population. To date, comprehensive reviews in ADRs of AChEIs have so far been scarcely studied. Therefore, we aimed to recapitulate and update the diverse aspects of AChEIs, including the mechanisms of action, characteristics and risk factors of ADRs, and preventive strategies of their ADRs. The collation of this knowledge is essential to facilitate efforts to reduce ADRs of AChEIs.

Antimuscarinic Cascade Across Individual Cholinesterase Inhibitors in Older Adults with Dementia.

Acetylcholinesterase inhibitors (AChEIs) have been associated with an increased risk of starting antimuscarinic treatment to treat overactive bladder (OAB)-an example of a prescribing cascade. Limited comparative data exist regarding the prescribing cascade of antimuscarinics across individual AChEIs in older adults with dementia. This study examined the association between individual AChEI use and antimuscarinic cascade in older adults with dementia. We conducted a new user retrospective cohort study from January 2005 to December 2018 using data from the TriNetX electronic medical record database, a federated electronic medical records network in the US. The cohort included patients 65 years or older with a diagnosis of dementia using AChEIs (donepezil, galantamine, or rivastigmine). Individual AChEIs were identified with index dates from 1 January 2006 to 31 June 2018, with a 1-year washout period. The study excluded patients with any antimuscarinic use and OAB diagnosis 1 year before the AChEI index date. The primary outcome of interest was the prescription of antimuscarinics within 6 months of the AChEI index date. A Cox proportional hazard model was used to assess the association between individual incident AChEI use and antimuscarinic prescribing cascade after controlling for several covariates. The study included 47,059 older adults with dementia who were incident users of AChEIs. Most of these patients were initiated with donepezil (83.1%), followed by rivastigmine (12.3%) and galantamine (4.6%). Overall, 8.16% of the study cohort had incident OAB diagnosis or antimuscarinic prescription. Antimuscarinics were initiated by 1725 (3.7%) older adults with dementia within 6 months of AChEI prescription, and cascade varied widely across individual agents-donepezil (3.9%), rivastigmine (2.6%), and galantamine (2.9%). Cox proportional hazard analyses revealed that donepezil users had an increased risk of receiving antimuscarinics (adjusted hazard ratio 1.55, 95% confidence interval 1.31-1.83) compared with rivastigmine. The findings were consistent in sensitivity analyses. This study found that donepezil use is more likely to lead to antimuscarinic cascade than rivastigmine. Future studies are needed to determine the potential consequences of this cascade in dementia.

Prescribing cholinesterase inhibitors in mild cognitive impairment-Observations from the Alzheimer's Disease Neuroimaging Initiative.

IntroductionAnalyses of off‐label use of acetylcholinesterase inhibitors (AChEIs) in mild cognitive impairment (MCI) has produced mixed results. Post hoc analyses of observational cohorts, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), have reported deleterious effects in AChEI‐treated subjects (AChEI+). Here, we used neuroimaging biomarkers to determine whether AChEI+ subjects had a greater rate of neurodegeneration than untreated (AChEI–) subjects while accounting for baseline differences.MethodsWe selected 121 ADNI MCI AChEI+ subjects and 151 AChEI– subjects with a magnetic resonance imaging (MRI) scan; 82 AChEI+ and 110 AChEI– also had a fluorodeoxyglucose (FDG) scan. A subset (83 AChEI+ and 98 AChEI–) had cerebrospinal fluid (CSF) or amyloid positron emission tomography (PET) assessment for amyloid positivity. Linear regression models were used to compare the effect of treatment on changes in Mini‐Mental State Examination and Clinical Dementia Rating‐Sum of Boxes scores. We used standard regression in SPM (for baseline) and the SPM toolbox sandwich estimator, SwE (for longitudinal) for comparisons of AChEI+ and AChEI– FDG PET and MRI data.ResultsAt baseline, the AChEI+ group had significantly reduced cortical gray matter density (GMD) and more hypometabolism than AChEI– subjects. The greater rate of atrophy and hypometabolic changes over time in AChEI+ compared to AChEI– subjects did not survive correction for baseline differences. AChEI+ participants were more likely to be amyloid‐positive and have lower GMD and FDG standardized uptake value ratio than AChEI– at baseline. AChEI+ subjects showed greater atrophy over time, which remained significant after controlling for amyloid status.DiscussionOur data suggest that the observed differences in rates of cognitive decline, atrophy, and hypometabolism are likely the result of significant baseline differences between the groups. Furthermore, the data indicate no treatment effect of AChEI (positive of negative), rather that physicians prescribe AChEI to subjects who present with more severe clinical impairment. This alone may account for the negative effect seen previously in the ADNI population of AChEI use among MCI subjects.

Perspective on Acetylcholinesterase: A Potential Target for Alzheimer’s Disease Intervention

Background: Alzheimer's disease (AD) is an unexplained progressive degenerative brain disease; it accounts for 60-70% of dementia cases worldwide, has an estimated global incidence of 24.3 million, and is associated with deterioration of the central nervous system. Acetylcholinesterase (AChE) is an enzyme that catalyzes the breakdown of acetylcholine to acetate and choline. It is also the potential target of most of the clinically used drugs for the treatment of AD. The degeneration of cholinergic neurons and the loss of neural transmission are the main reasons for the decline of cognitive ability in AD patients. Objective: In recent years, the development of targeted drugs in AD has made significant achievements. The global impact of AD continues to grow, and as a result, the focus of disease-modifying therapies remains elusive. The role of treatment is not limited to pharmacology but involves many factors, such as the psychological, social, and economic aspects of the patient and family. AChE is an important target in AD to consider the use of AChE inhibitors in patients with mild to moderate AD, even though the costs are high and no other direct progress has been made. Although there are many AChE inhibitors, there is no selective potent inhibitor for AChE. There is still a need to address human AChE structure, provide key insights into key protein-ligand interactions, and provide the basis for molecular modeling and structure-based drug design. Conclusion: In this review, we briefly introduce the clinical characteristics of AD, the development of crystal structure, and the latest research on AD. In recent years, the development of different strategies for amyloid-β, BACE1, and type-1 interferon receptor alpha-1 has attracted great attention. There is an urgent need to further characterize available instrumental compounds to explore the use of new selectivity and key protein-ligand interactions in AD. In the past few decades, great progress has been made in the treatment of AD, but AD is still one of the world's problems, and the inability to cure AD, indicates that there is an urgent need for new treatments.

PMH31 RISK OF FALLS AND FRACTURES ASSOCIATED WITH CONCOMITANT USE OF ACETYLCHOLINESTERASE INHIBITORS AND ATYPICAL ANTIPSYCHOTICS AMONG OLDER ADULTS WITH DEMENTIA

Acetylcholinesterase inhibitors (AChEIs) may counteract the anticholinergic properties of certain atypical antipsychotics (AAs) and thereby affect the adverse outcomes in dementia patients. This study evaluated the risk of falls and fractures due to the concomitant use of AChEIs and AAs (classified as high-level versus low-level anticholinergic) among older adults with dementia.

PND60 ACETYLCHOLINESTERASE INHIBITOR - ASSOCIATED ANTIPSYCHOTIC PRESCRIBING CASCADE AMONG OLDER ADULTS WITH DEMENTIA

Acetylcholinesterase inhibitors (AChEIs) offer modest effect size for managing dementia symptoms; this may lead to exacerbation including behavioral and psychological symptoms of dementia (BPSD) thereby necessitating treatment with antipsychotics. This study evaluated the extent of prescribing cascade involving AChEIs and antipsychotics in older dementia patients. Using 2005-2018 TriNetX Electronic Medical Records (EMR), a nested case-control study was conducted in a cohort of AChEI users. The base cohort included patients aged ≥ 65 years with dementia, no use of AChEIs and antipsychotics between January – June 2005. Cases were those who initiated treatment with antipsychotics between July 2005 – December 2018. Incidence density sampling was used to match each case with 4 controls based on age and sex. Date of the first antipsychotic prescription formed the event date for cases. Primary exposure was incident prescription of AChEIs within 6 months before the event date. Conditional logistic regression model was used to evaluate the association between AChEI use and antipsychotic prescribing cascade after controlling for other risk factors. There were 16,413 cases and 65,609 matched controls. Cases were significantly more likely than controls to have incident AChEI exposure within 6 months preceding the event date (7.39% vs 0.43 %; p-value <.0001). Multivariable analyses revealed that incident AChEI exposure was significantly associated with higher odds of antipsychotic prescribing cascade, compared to non-use (OR =69.74; 95% CI, 54.48 - 89.28). Depression (OR =1.13; 95% CI, 1.08 -1.18), falls (OR =1.23; 95% CI, 1.15- 1.30), psychoses (OR =2.88; 95% CI, 2.66 -3.12), fluid and electrolyte disorders (OR =1.25; 95% CI, 1.19 - 1.31) and other neurological disorders (OR =1.08; 95% CI, 1.01- 1.16) were significantly associated with antipsychotic cascade. The finding of strong association between AChEI initiation and antipsychotic cascade suggests the need to focus on studying the impact of these cascades in the vulnerable dementia patients.

Post-treatment with Posiphen Reduces Endoplasmic Reticulum Stress and Neurodegeneration in Stroke Brain.

SummaryAcetylcholinesterase (AChE) inhibitors have protective and anti-inflammatory actions against brain injury, mediated by nicotinic α7 cholinergic receptor activation. The use of AChE inhibitors in patients is limited by systemic cholinergic side effects. Posiphen, a stereoisomer of the AChE inhibitor Phenserine, lacks AChE inhibitor activity. The purpose of this study is to determine the protective effect of Posiphen in cellular and animal models of stroke. Both Posiphen and Phenserine reduced glutamate-mediated neuronal loss in co-cultures of primary cortical cells and microglia. Phenserine-, but not Posiphen-, mediated neuroprotection was diminished by the nicotinic α7 receptor antagonist methyllycaconitine. Posiphen antagonized NMDA-mediated Ca++ influx, thapsigargin-mediated neuronal loss and ER stress in cultured cells. Early post-treatment with Posiphen reduced ER stress signals, IBA1 immunoreactivity, TUNEL and infarction in the ischemic cortex, as well as neurological deficits in stroke rats. These findings indicate that Posiphen is neuroprotective against stroke through regulating Ca++i and ER stress.

Association Between Acetylcholinesterase Inhibitors and Osteoporotic Fractures in Older Persons With Alzheimer's Disease

ObjectiveTo identify the association between the use of acetylcholinesterase inhibitors (AChEIs) and risk of osteoporotic fractures in older persons with Alzheimer's disease (AD). Design, Setting, and ParticipantsA nested case-control study was conducted using the Korean National Health Insurance Service-National Elderly Cohort database. Patients with AD who were newly diagnosed with osteoporotic fractures were identified as cases. Up to 3 controls were matched with cases according to age, sex, and duration of follow-up. MethodsParticipants were considered as exposed to AChEIs if they had been prescribed at least 1 AChEI during a period of 2 years before the index date. A conditional logistic regression was performed to estimate the adjusted odds ratios with 95% confidence intervals for the association between the use of AChEIs and osteoporotic fractures in patients with AD. We also examined the impact of dose, duration of treatment, and timing of exposure on the estimates of the association between the use of AChEIs and risk of osteoporotic fractures. ResultsThe study cohort comprised 45,006 patients diagnosed with AD, of which 9470 patients, including 2385 cases and 7085 controls, were available for the study. The mean ages (standard deviations) were 78.6 (6.9) years in the cases and 80.0 (6.9) years in the controls. Adjusted odds ratios for the association between the use of AChEIs and osteoporotic fractures in patients with AD was 1.18 (95% confidence interval 1.07–1.31). Conclusions and ImplicationsOur data indicated that the use of AChEIs was not associated with a reduced risk of osteoporotic fractures in patients with AD; in contrast, their use was associated with a mild increased risk of osteoporotic fractures. Thus, clinicians should consider the possibility of AChEIs-associated fractures among older persons with AD. Findings of this study will support shared decision making among prescribers, patients, and caregivers.

Acetylcholinesterase Inhibitors Are Associated with Reduced Fracture Risk among Older Veterans with Dementia.

Acetylcholinesterase inhibitors (AChEIs) have been noted to increase bone density and quality in mice. Human studies are limited but suggest an association with improved bone healing after hip fracture. We examined the relationship between AChEI use and fracture risk in a national cohort of 360,015 male veterans aged 65 to 99 years with dementia but without prior fracture using Veterans Affairs (VA) hospital, Medicare, and pharmacy records from 2000 to 2010. Diagnosis of dementia, any clinical fracture (excluding facial and digital), comorbidities, and medications were identified using ICD-9 and drug class codes. Cox proportional hazard models considering AChEI use as a time-varying covariate and adjusting for fall and fracture risk factors compared the time-to-fracture in AChEI users versus non-AChEI users. Potential confounders included demographics (age, race, body mass index), comorbidities associated with fracture or falls (diabetes, lung disease, stroke, Parkinson's, seizures, etc.) and medications associated with fracture or falls (bisphosphonates, glucocorticoids, androgen deprivation therapy [ADT], proton pump inhibitors [PPIs], selective serotonin receptor inhibitors [SSRIs], etc.). Competing mortality risk was considered using the methods of Fine and Gray. To account for persistent effects on bone density or quality that might confer protection after stopping the medication, we completed a secondary analysis using the medication possession ratio (MPR) as a continuous variable in logistic regression models and also compared MPR increments of 10% to minimal/no use (MPR 0 to <0.10). Among older veterans with diagnosis of dementia, 20.1% suffered a fracture over an average of 4.6 years of follow-up. Overall, 42.3% of the cohort were prescribed AChEIs during the study period. The hazard of any fracture among AChEI users compared with those on other/no dementia medications was significantly lower in fully adjusted models (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.75-0.88). After considering competing mortality risk, fracture risk remained 18% lower in veterans using AChEIs (HR = 0.82; 95% CI 0.76-0.89). © 2019 American Society for Bone and Mineral Research. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.

PND66 ASSESSING THE POTENTIALLY INAPPROPRIATE USE OF ACETYLCHOLINESTERASE INHIBITORS IN ELDERLY PATIENTS WITH PARKINSON DISEASE USING KOREA NATIONAL HEALTH INSURANCE CLAIMS DATA

Motor-related symptoms of patients with Parkinson's disease (PD) are caused by the decrease of dopamine (DA) in the midbrain. Decrease in DA induces imbalance between DA and acetylcholine (ACh), leading to an increase in the relative Ach level, which in turn contributes to motor symptoms again. Therefore, administration of acetylcholinesterase inhibitor (ACHEI), which inhibits the degradation of ACh, to PD patients should be avoided as it may exacerbate the imbalance between DA and Ach. However, a lot of PD patients are using ACHEI for the treatment of cognitive symptoms. Thus, we aimed to analyze the actual use of ACHEI in elderly patients with PD in Korea. PD patients were defined as those having at least one claim record with a diagnosis of PD (ICD-10 codes: G20-21) from 2016 Health Insurance Review and Assessment Service (HIRA) - Adult Patients Sample (APS) data, composed of 20% random sample of patient aged 65 and over in Korea. ACHEI users were defined as those with at least one prescription record of donepezil, rivastigmine or galantamine. Demographic characteristics were compared between ACHEI users and non-users. Of 24,524 PD patients identified from the 2016 HIRA-APS data, 8,928 patients (36%) were ACHEI users. ACHEI use increased with age (25% in 65-74, 42% in 75-84, and 49% in 85 and over, p <0.0001). The use of ACHEI was more common in women (38%) than men (34%, p <0.0001). Medical Aid beneficiaries (40%) tended to use ACHEI more than National Health Insurance beneficiaries (36%, p <0.0001). The use of ACHEI among PD patients in Korea is high. In-depth analysis should be conducted to identify factors affecting ACHEI prescribing in PD patients and to establish effective strategy to avoid potentially inappropriate use of ACHEI at clinical and the national level.