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In the present study, the effects of the acetylcholinesterase (AChE) enzyme inhibitor rivastigmine (RIVA) on spike-wave discharges (SWDs), memory impairment, anxiety-like behavior, and the transient receptor potential vanilloid 1 (TRPV1) gene expression were investigated in genetic absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. After tripolar electrodes were implanted on the WAG/Rij rats' skulls, single doses of 0.125, 0.25, 0.5, 1, and 2 mg/kg RIVA were intraperitoneally (i.p.) administered, and electrocorticogram (ECoG) recordings of SWDs were recorded for three hours before and after injections. Additionally, once significant doses were determined in acute studies, WAG/Rij rats were administered low-dose (0.5 mg/kg) and high-dose (2 mg/kg) of RIVA for 21 consecutive days and SWDs were recorded. Learning-memory abilities (Y-maze test), anxiety-like behavior (elevated plus maze test), and TRPV1 gene expression were determined and compared in 8-month-old WAG/Rij and age-matched Wistar rats. Acute RIVA administration dose-dependently reduced the total number of SWDs and was even entirely inhibited at 1 and 2 mg/kg RIVA doses. On the other hand, long-term high-dose RIVA administration increased the total number of SWDs. Long-term high-dose RIVA treatment reduced learning-memory and anxiety-like behavior in WAG/Rij rats, while only anxiety-like behavior decreased in Wistar rats. TRPV1 gene expression increased in WAG/Rij rats and decreased in Wistar rats with long-term RIVA administration. These data indicate that the sudden increase of acetylcholine (ACh) causes a significant decrease in absence seizures. In contrast, prolonged maintenance of ACh elevation causes an increase in absence seizures, probably by altering the expression of channels such as TRPV1., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests. Ethics Approval: The study was performed by the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The experimental protocol was approved by Ondokuz Mayıs University Animal Experiments Local Ethics Committee (Approval No: 2022/08)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alzheimer's disease (AD) affects millions of people worldwide. The most commonly used drugs are acetylcholinesterase inhibitors, i.e., donepezil, galantamine and rivastigmine, which increase levels of acetylcholine. However, the exact efficacy and safety of acetylcholinesterase inhibitors in the treatment of AD is still unclear. The main objective of the current study was to determine the exact safety and efficacy profile of acetylcholinesterase inhibitors in the treatment of AD by conducting a systematic review and meta-analysis of clinical trials according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We conducted a web-based literature search of PubMed and clinical trial websites using relevant keywords. Data were extracted from eligible records and pooled as mean difference (MD) or risk ratio (RR) values with their 95% confidence interval (95% CI) using Review Manager software (v. 5.3 for Windows). Heterogeneity was calculated using χ2 and I2 tests. The standard mean difference (SMD) was -0.33 [-0.52, -0.13] for donepezil, -0.48 [-0.58, -0.38] for galantamine and -0.65 [-1.06, -0.23] for rivastigmine, indicating a significant effect of these drugs on cognitive outcomes. Here we show the significant effects of all available acetylcholinesterase inhibitors on cognitive function in patients with AD. However, further studies are needed to draw valid conclusions about the effects of acetylcholinesterase inhibitors on functional outcomes and adverse events.

Introduction: Cholinesterase inhibitors, along with memantine, are the mainstay of symptomatic treatment for AD (Alzheimer's disease); however, these medications are typically administered orally, which can be difficult for people with AD and their caregivers., Areas Covered: In this drug profile and narrative review, the authors trace the development of the new FDA-approved transdermal donepezil. The authors discuss the studies showing its bioequivalence with the oral formulation, including two double-blinded placebo controlled non-inferiority trials. The authors also compare the patch to the only other transdermal cholinesterase inhibitor on the market, rivastigmine, and highlight the potential advantages and disadvantages between these two treatments., Expert Opinion: While the patch is bio-equivalent, it is rather large and may not be affordable for some patients. In addition, there is no high dose (e.g. 23 mg) equivalent. Nevertheless, transdermal donepezil will be useful for people with AD and their caregivers, given its effectiveness and potential convenience.

Background: Anticholinergic toxicity is commonly encountered in the emergency department. However, the availability of physostigmine, a central acetylcholinesterase inhibitor used to reverse anticholinergic delirium, has been significantly limited due to national drug shortages in the United States. Several articles have explored the viability of rivastigmine as an alternative treatment in these patients., Case Report: A 33-year-old man presented to the emergency department after a suspected suicide attempt. The patient was found with an empty bottle of diphenhydramine at the scene. On arrival, he was tachycardic and delirious, with dilated and nonreactive pupils and dry skin. As the clinical picture was highly suggestive of anticholinergic toxicity, the patient was treated with oral rivastigmine at a starting dose of 4.5 mg to reverse his anticholinergic delirium. Although a repeat dose was required, his delirium resolved without recurrence. Why Should an Emergency Physician Be Aware of This? Oral rivastigmine has been applied successfully here and in other case reports to reverse anticholinergic delirium with the benefit of prolonged agitation control. Emergency physicians may consider this medication in consultation with a specialist, with initial doses starting at 4.5-6 mg, if encountering anticholinergic delirium when physostigmine is not available., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia. The early diagnosis of AD is an important factor for the control of AD progression. Electroencephalography (EEG) can be used for early diagnosis of AD. Acetylcholinesterase inhibitors (AChEIs) are also used for the amelioration of AD symptoms. In this systematic review, we reviewed the effect of different AChEIs including donepezil, rivastigmine, tacrine, physostigmine, and galantamine on EEG patterns in patients with AD., Methods: PubMed electronic database was searched and 122 articles were found. After removal of unrelated articles, 24 articles were selected for the present study., Results: AChEIs can decrease beta, theta, and delta frequency bands in patients with AD. However, conflicting results were found for alpha band. Some studies have shown increased alpha frequency, while others have shown decreased alpha frequency following treatment with AChEIs. The only difference was the type of drug., Conclusions: We found that studies reporting the decreased alpha frequency used donepezil and galantamine, while studies reporting the increased alpha frequency used rivastigmine and tacrine. It was suggested that future studies should focus on the effect of different AChEIs on EEG bands, especially alpha frequency in patients with AD, to compare their effects and find the reason for their different influence on EEG patterns. Also, differences between the effects of AChEIs on oligodendrocyte differentiation and myelination may be another important factor. This is the first article investigating the effect of different AChEIs on EEG patterns in patients with AD., (© 2023. Fondazione Società Italiana di Neurologia.)

Background: Two classes of medications are used to treat Alzheimer's disease (AD); donepezil, galantamine, and rivastigmine are acetylcholinesterase inhibitors, and memantine is a non-competitive antagonist of the N-methyl-D-aspartate receptor. Although these are typically taken orally, there are transdermal therapeutic systems (TTSs) commercially available for rivastigmine and donepezil. The transdermal route has been preferable for guardians/caregivers due to ease of use, reduced side effects, and improved adherence to therapy., Objective: The study aimed to obtain knowledge of the properties of these drugs and to search for patents relating to the TTS for AD using the Espacenet platform., Methods: The search terms were "rivastigmine AND transdermal AND skin delivery AND Alzheimer's", changing the drugs "memantine", "donepezil", and "galantamine", between January 2015 and January 2022. Title and abstract were used to choose patents., Results: TTSs present some limit factors in terms of absorption due to skin physiology and the size of the molecules with established limits of percutaneous penetration (molecular mass of 500 g/mol and log P of 5). We found 1, 4, 4, and 2 patents for galantamine, rivastigmine, donepezil, and memantine, respectively. Galantamine TTS seems to be more challenging due to the molecular mass of 287.35 g/mol and logP of 1.8. The permeator of absorption is necessary. Memantine, rivastigmine, and donepezil present logP of 3.28, 2.3, and 4.27 and molecular weights of 179.30, 250.34, and 415.96 g/mol, respectively., Conclusion: TTSs are primarily effective for delivering small molecules. The use of absorption enhancers and irritation mitigators can be necessary to enhance the performance. The development of these technologies is essential for the convenience of patients and caregivers., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Alzheimer's disease (AD) treatment includes both non-pharmacological and pharmacological approaches. Current pharmacological approaches include symptomatic and disease-modifying therapies (DMTs). In Japan, DMTs have not yet been approved for treating AD; however, four drugs are currently available for symptomatic therapies, including cholinesterase inhibitors (ChEIs) such as donepezil for mild-to-severe dementia, galantamine and rivastigmine for mild-to-moderate dementia, and memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, for moderate-to-severe dementia. In this review, we describe the use of four symptomatic anti-AD drugs in clinical practice for AD.

The Corpus Callosum (CC) is an important structure that includes the majority of fibers connecting the two brain hemispheres. Several neurodegenerative diseases may alter CC size and morphology leading to its atrophy and malfunction which may play a role in the pathological manifestations found in these diseases. The purpose of the current study is to determine any possible changes in CC size in patients suffering from Alzheimer's disease. The Study also investigated the effect of acetylcholinesterase inhibitors (AChEIs) on the size of CC and its association with improvement in the Alzheimer disease severity scores. Midsagittal size of CC were recorded prospectively from 439 routine T1-weighted MRI brain images in normal individuals. The internal skull surface was measured to calculate CC/ internal skull surface ratio. Two groups of patients were studied: 300 (150 male / 150 female) were healthy subjects and 130 (55 males / 75 females) had Alzheimer disease. Out of the 130 Alzheimer disease pateints, 70 patients were treated with Donepezil or Rivastigmine or both. The size of the CC was measured based on T1-weighted MRI images after the treatment to investigate any possible improvement in CC size. The mean surface area of CC in controls was 6.53±1.105 cm2. There was no significant difference between males and females (P < 0.627), and CC/ internal skull surface ratio was 4.41±0.77%. Patients with mild or severe Alzheimer disease showed a significant reduction in CC size compared to healthy controls. Treating mild Alzheimer patients with either Donepezil or Rivastigmine exerts a comparable therapeutic effect in improving the CC size. There was more improvement in the size of CC in patients with severe Alzheimer disease by using combined therapy of Donepezil and Rivastigmine than using single a medication. we measured the mean size of the various portions of the corpus callosum in normal individuals and Alzheimer patients before and after taking Donepezil and Rivastigmine. Alzheimer patients have pronounced reduction in CC which is corrected after taking Donepezil and Rivastigmine leading to remarkable improvement in Alzheimer disease severity scores., Competing Interests: NO authors have competing interests

Objective: Acetylcholinesterase inhibitors (AChEIs) are used off-label, in both adult and pediatric patients, to help further neuro-recovery after traumatic brain injury (TBI). Evidence is limited and piecemeal. This review describes how TBI affects the cholinergic system and consolidates evidence supporting or refuting the use of AChEIs following TBI., Methods: NCBI MEDLINE search included all articles published through March 2021 on AChEI use in acute and post-acute adult TBI rehabilitation (treatment began <90 days or ≥90 days since injury, respectively), and in pediatric TBI rehabilitation. Further, we checked ClinicalTrials.gov for ongoing trials using AChEIs for TBI rehabilitation in the United States., Results: 27 original articles from NCBI Medline, published through March 2021, were included. The use of AChEIs following TBI in acute and post-acute rehabilitation settings, in both adult and pediatric patients, along with medication side effects, is discussed., Conclusions: Most studies showed benefits with only moderate effect sizes because of small sample sizes. Reported side effects are minimal and stop soon after AChEIs is discontinued. Conclusions are limited by paucity of research; but fortunately, a large randomized controlled trial is ongoing, and more are needed to truly determine the efficacy of AChEIs in helping with recovery from TBI.

Dementia is one of the leading causes of death and disability in older population. Previous reports have shown that antidementia medications are associated with longer survival; nonetheless, the prevalence of their use and the compliance with them are quite different worldwide. There is hardly any available information about the pharmacoepidemiology of these drugs in the Eastern-European region; we aimed to analyze the use of cholinesterase inhibitors (ChEis) for the treatment of dementia to provide real-life information from the Eastern European region. All medical and medication prescription reports of the in- and outpatient specialist services collected in the NEUROHUN database in Hungary were analyzed between 2013 and 2016. Survival, adherence, and persistence values were calculated. 8803 patients were treated with ChEis during the study period, which was only 14.5% of the diagnosed demented patients. The survival of treated patients (more than 4 years) was significantly longer than patients without ChEi treatment (2.50 years). The best compliance was observed with rivastigmine patch. Choosing the appropriate medication as soon as possible after the dementia diagnosis may lead to increased life expectancy., (© 2021. The Author(s).)

Background: Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer's disease (AD) are sparse., Objective: We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients., Methods: We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles., Results: Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD., Conclusion: Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD.

Acetylcholinesterase (AchE), hydrolase enzyme, regulates the hydrolysis of acetylcholine neurotransmitter in the neurons. AchE is found majorly in the central nervous system at the site of cholinergic neurotransmission. It is involved in the pathophysiology of Alzheimer's diseasecausing dementia, cognitive impairment, behavioral and psychological symptoms. Recent findings involved the inhibition of AchE that could aid in the treatment of Alzheimer's. Many drugs of different classes are being analyzed in the clinical trials and examined for their potency. Drugs that are used in the treatment of Alzheimer's disease are donepezil, galantamine, tacrine, rivastigmine showing major adverse effects. To overcome this, researchers work on novel drugs to elicit inhibition. This review comprises many hybrids and non-hybrid forms of heteroaromatic and nonheteroaromatic compounds that were designed and evaluated for AchE inhibition by Ellman's method of assay. These novel compounds may assist future perspectives in the discovery of novel moieties against Alzheimer's disease by the inhibition of AchE., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The current study focuses on development of nasal mucoadhesive microspheres for nose-to-brain delivery of rivastigmine for Alzheimer treatment. A systematic development was employed for optimization of the formulation and process parameters influential on the quality attributes of the microspheres. The risk assessment study revealed major influence of the polymer concentration (ethylcellulose: chitosan), the concentration of surfactant solution (polyvinyl alcohol), and stirring speed as the critical factors for optimization of the microspheres. These factors were systematically optimized using Box-Behnken design and microspheres were evaluated for the particle size, entrapment efficiency, and in vitro drug release as the response variables. The optimized microspheres containing 4.4% wt/vol polymers, 1% wt/vol surfactant, and stirring speed at 1500 rpm showed particle size of 19.9 µm, entrapment efficiency of 77.8%, and drug release parameters as T 80% of 7.3 h. The surface modification of microspheres was performed with lectin by carbodiimide activation reaction and confirmed by difference in surface charge before and after chemical functionalization by zeta potential measurement which was found to be - 25.7 mV and 20.5 mV, respectively. Ex vivo study for bioadhesion strength evaluation on goat nasal mucosa indicated a significant difference (p < 0.001) between the plain (29%) and lectin functionalized microspheres (64%). In vivo behavioral and biochemical studies in the rats treated with lectin functionalized microspheres showed markedly better memory-retention vis-à-vis test and pure drug solution treated rats (p < 0.001). In a nutshell, the present studies showed successful development of nasal microspheres for enhanced brain delivery of rivastigmine for Alzheimer's treatment., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Alzheimer's disease (AD), the most common cause of adult-onset dementia is characterized by a progressive decline of cognitive functions accompanied by behavioral manifestations. The main class of drugs currently used for the treatment of AD are acetylcholinesterase/cholinesterase inhibitors (ChE-Is). The first ChE-I licensed for symptomatic treatment of AD was tacrine. The ChE-Is currently available in the market are donepezil, rivastigmine and galantamine as tacrine is no longer in use, due to its hepatotoxicity. According to mechanism of action the ChE-Is are classified as short-acting or reversible agents such as tacrine, donepezil, and galantamine, as intermediate-acting or pseudo-irreversible agent such as rivastigmine. Overall, the efficacy of the three ChE-Is available in the market is similar and the benefit of administration of these compounds is mild and may not be clinically significant. Due to gastrointestinal side effects of these drugs, medicinal chemistry and pharmaceutical delivery studies have investigated solutions to improve the pharmacological activity of these compounds. In spite of the limited activity of ChE-Is, waiting for more effective approaches, these drugs still represent a pharmacotherapeutic resource for the treatment of AD. Other approaches in which ChE-Is were investigated is in their use in combination with other classes of drugs such as cholinergic precursors, N-methyl-d-aspartate (NMDA) receptor antagonists and antioxidant agents. After many years from the introduction in therapy of ChE-Is, the combination with other classes of drugs may represent the chance for a renewed interest of ChE-Is in the treatment of adult-onset dementia disorders., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Alzheimer's disease (AD) is a gradually growing irreversible illness of the brain that almost affects every fifth person (aged > 80 years) in the world. World Health Organization (WHO) also revealed that the prevalence of this disease will enhance (upto double) significantly upto 2030. The poor cholinergic transmission at the synapse is considered to be one of the main reasons behind the progression and occurrence of this disorder. Natural inhibitors of acetylcholine (ACh) such as galanthamine and rivastigmine are used commercially in the treatmentof AD. The biomolecules such assesquiterpenes, possess a great structural diversity and are responsible for a plethora of pharmacological properties. The potential of various sesquiterpenes as anticholinesterase has been reviewed in this article. For this purpose, the various databases, mainly PubMed, Scopus, and Web of Science were investigatedwith different keywords such as "sesquiterpenes+acetylcholinesterase" and "sesquiterpenes+cholinesterase+inhibitors" in the surveyed time frame (2010-2020). A vast literature was evident in the last decade, which affirms the potential of various sesquiterpenes in the improvement of cholinergic transmission by inhibiting the AChE. After data analysis, it was found that 12 compounds out of a total of 58 sesquiterpenes were reported to possess IC 50 < 9μM and can be considered as potential candidates for the improvement of learning and memory. Sesquiterpene is an important category of terpenoids, found to possess a large spectrum of biological activities. The outcome of the review clearly states that sesquiterpenes (such as amberboin, lipidiol,etc) from herbs could offer fresh, functional compounds for possible prevention and treatment of AD.

Background: Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders., Methods: This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale., Results: After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration., Conclusion: Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function., Trial Registration: UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr&#95;view.cgi?recptno=R000029744.

Dementia is the major cause of mortality and morbidity in older adults, with Alzheimer's disease (AD) being the most common cause. AD has a significant impact on economic and psychosocial status. Cholinesterase inhibitors (ChEIs) are currently the mainstay in the management of AD. Rivastigmine is the only ChEI that inhibits both acetylcholinesterase and butyrylcholinesterase enzymes in the brain. This dual inhibition makes it potentially more effective for AD patients. Its availability as both a transdermal formulation and oral capsule, may improve adherence rates and care giver satisfaction compared with other ChEIs. To date, the data from randomized clinical trials and post marketing observational studies have shown evidence for an impact on cognitive functions in AD with good safety and tolerability.

Background: Pneumonia is an inflammatory condition induced by infection of the lungs and is frequently a cause of morbidity and mortality among patients with Alzheimer's disease (AD). Some studies have shown an association between acetylcholinesterase inhibitor use and elevated pneumonia risk., Objective: The purpose of this study was to perform a comparative analysis of the number of reported pneumonia cases in individuals prescribed rivastigmine relative to the number of reported cases by patients using other therapeutics including over-the-counter drugs and other AD therapeutics, as reported to the FDA Adverse Event Reporting System (FAERS) database., Methods: A disproportionality analysis was conducted to investigate the association between using rivastigmine and risk of pneumonia. Age, gender, dosage, temporality, and geographic distribution of reported cases were also assessed., Results: Patients prescribed rivastigmine were more likely to report pneumonia as an adverse event than many drugs except galantamine. Males were found to be 46% more likely than females to report pneumonia as an adverse event while likelihood of pneumonia diagnosis increases 3-5-fold in patients older than 65 years of age., Conclusion: The observed elevated frequency of aspiration pneumonia in patients prescribed rivastigmine may be due to an induced cholinergic crisis that is selective for the medulla oblongata, resulting in gastrointestinal distress, impaired swallowing, heightened salivation, and labored breathing. The observed elevated frequency of infectious pneumonia in patients prescribed rivastigmine may also be linked to overstimulation of neurons in the medulla oblongata and downstream suppression of localized inflammatory responses.

Background: Dementia is one of the strongest predictors of admission to a 24-hour care facility among older people, and 24-hour care is the major cost of Alzheimer's disease (AD)., Objective: The aim of this study was to evaluate the association of early start of anti-dementia medication and other predisposing factors with 2-year risk of transition to 24-hour care in the nationwide cohort of Finnish AD patients., Methods: This was a retrospective, non-interventional study based on individual-level data from Finnish national health and social care registers. The incident cohort included 7,454 AD patients (ICD-10, G30) comprised of two subgroups: those living unassisted at home (n = 5,002), and those receiving professional home care (n = 2,452). The primary outcome was admission to a 24-hour care facility. Exploratory variables were early versus late anti-dementia medication start, sociodemographic variables, care intensity level, and comorbidities., Results: Early anti-dementia medication reduced the risk of admission to 24-hour care both in patients living unassisted at home, with a hazard ratio (HR) of 0.58 (p < 0.001), and those receiving professional home care (HR, 0.84; p = 0.039). Being unmarried (HR, 1.69; p < 0.001), having an informal caregiver (HR, 1.69; p = 0.003), or having a diagnosis of additional neurological disorder (HR, 1.68; p = 0.006) or hip fracture (HR, 1.61; p = 0.004) were associated with higher risk of admission to 24-hour care in patients living unassisted at home., Conclusion: To support living at home, early start of anti-dementia medication should be a high priority in newly diagnosed AD patients.

Importance: Altough disease-modifying factors such as malnutrition and diet have been associated with Alzheimer's disease (AD), little is known about the effects of pharmacological therapies on the nutritional status of AD patients., Objective: To evaluate the nutritional status, prealbumin, and albumin serum levels and several anthropometric measurements in patients with probable moderate-stage AD, with and without rivastigmine drug treatment., Study Design: A cross-sectional study., Setting and Participants: 34 patients were included, 17 with rivastigmine treatment and 17 without pharmacological treatment, over 60 years of both sexes., Measurements: The nutritional status was evaluated using the Mini Nutritional Assessment (MNA). Albumin and prealbumin (transthyretin) levels and anthropometric evaluation were assessed using standard methods., Results: A polarity of malnutrition was detected in the untreated group. According to the MNA survey, the risk of malnutrition is higher without rivastigmine treatment (p = 0.0001). There are a less loss of appetite, less psychological stress, greater mobility and independence in those patients receiving rivastigmine (p = 0.003, 0.008, 0.016 and 0.018, respectively). The body mass index does not show a statistical difference, however, categorizing it for older adults, this index was improved in those receiving rivastigmine (p = 0.016). The serum levels of albumin and prealbumin showed no significant statistical difference between the groups., Conclusion: Rivastigmine treatment shows a protective effect on malnutrition in patients with moderate-stage AD., Competing Interests: The authors declare that there is no conflict of interest for the publication of this work; no financial or material assistance was received from any company, especially those that have the patent or commercial use of rivastigmine. The data used to support the findings of this study are available from the corresponding author upon request.

Background: Transdermal patches are convenient to use, especially in Rotkreuz ZG Rotkreuz ZG patients with Alzheimer's disease (AD)-associated dementia. However, various identified risks of errors in administering the patches cannot be disregarded. Patient Reminder Cards (PRCs, included a Medication record sheet [MRS]) have been recently introduced as a risk minimisation tool to prevent incorrect patch use (IU)., Objectives: This study aimed to assess the effectiveness of PRCs to prevent IU and to investigate the dose titration pattern of rivastigmine patches in a real-world setting., Methods: This multinational, observational, 11-month study included patients with AD currently using rivastigmine patches (4.6 mg/day, 9.5 mg/day, 13.3 mg/day) accompanied by a caregiver. Study outcomes were IU, including multiple patch use (MPU), incorrect patch placement, other IUs, perceived usefulness of the PRCs, and titration patterns of the patches., Results: Of the total 614 patients included, most were aged ≥ 65 years and had mild-to-moderate AD. Before and during the study, 27.7% and 18.0% of patients reported IU, respectively. Most patients used MRS, and 73.5% rated it 'helpful' and reported lower rates of IU than those who reported it 'not helpful' (13.9%-16.5% vs. 20.2%). Overall, 141 patients had dose titrations, with 75.8% being up-titrated from 4.6 mg/day to 9.5 mg/day after a mean duration of 58 days. Safety findings were consistent with the established profile for the rivastigmine patch., Conclusion: PRC was effective as a risk minimisation tool in limiting the inappropriate use of rivastigmine patches. The majority of patients requiring dose-change were up-titrated to 9.5 mg/day patches., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Dementia with Lewy bodies (DLB) is the second most common dementia. Features of DLB include postganglionic cardiac sympathetic denervation and autonomic instability. Rivastigmine therapy, an acetylcholinesterase inhibitor, is widely used in the primary treatment of DLB; however, the cardiovascular safety and tolerability of transdermal rivastigmine needs to be reviewed., Objective: To evaluate whether transdermal rivastigmine has an effect on blood pressure, heart rate, and electrocardiography measurements., Materials and Methods: A total of 722 patients diagnosed with dementia were retrospectively screened. Fifty-seven of 98 DLB patients who received transdermal rivastigmine treatment with available serial electrocardiography and blood pressure measurements were included in the study. Baseline and follow-up measurements were compared for patients on the 9.5 to 13.3 mg/d rivastigmine dose for at least 4 weeks., Results: The mean age of the patients was 80.77±6.04, and the majority were women (63%). A total of 8 cases with bradycardia and 5 with orthostatic hypotension were detected during follow-up, and rivastigmine patch was stopped in one of those 8 patients due to symptomatic bradycardia. Nonetheless, there was no difference between baseline and follow-up measurements of the patients, including heart rate, cardiac rhythm, electrocardiographic intervals, blood pressure, pulse pressure, and postural blood pressure changes., Conclusions: Transdermal rivastigmine therapy is not associated with arrhythmogenic or hypotensive effects in the elderly patients with DLB. However, when prescribing transdermal rivastigmine, physicians should pay attention to newly emerging orthostatic hypotension during the follow-up in these patients.

Background: Rivastigmine is an acetylcholine esterase inhibitor which is commonly used as therapy for dementia in Alzheimer's disease and Parkinson's disease (PD). Recently, a randomized controlled trial demonstrated a positive effect of rivastigmine on gait function in nondemented PD patients. Disturbed gait is a shared hallmark of PD and ataxias., Objectives: We hypothesized that the effect of rivastigmine could be translated to spinocerebellar ataxia (SCA) improving gait function., Method: Five patients with SCA type 3 were treated with transdermal rivastigmine for 8 weeks. The patients were monitored using the Scale for the Assessment and Rating of Ataxia (SARA) and an electronic walkway system (GAITRite®)., Results: Gait function was not changed by treatment, but 4 patients who continued treatment for 8 weeks showed improved coordination of extremities. The SARA sum score, which was 7.6 ± 2.2 at baseline, had dropped by 1.5 ± 1.9 after 4 weeks and by 2.1 ± 1.4 after 8 weeks., Conclusions: Contrary to our hypothesis, we observed no improvement of gait parameters as assessed by SARA and GAIT-Rite®, but coordination abilities were improved. Rivastigmine was well tolerated, but known side effects of rivastigmine, such as deterioration of asthma, may appear. Further trials in larger cohorts are needed to confirm our findings., (© 2020 S. Karger AG, Basel.)

Aims: We investigated anticholinergic medicines use among older adults initiating dementia medicines., Methods: We used Pharmaceutical Benefits Scheme dispensing claims to identify patients who initiated donepezil, rivastigmine, galantamine or memantine between 1 January 2013 and 30 June 2017 (after a period of ≥180 days with no dispensing of these medicines) and remained on therapy for ≥180 days (n = 4393), and dispensed anticholinergic medicines in the 180 days before and after initiating dementia medicines. We further examined anticholinergic medicines prescribed by a prescriber other than the one initiating dementia medicines., Results: One-third of the study cohort (1439/4393) was exposed to anticholinergic medicines up to 180 days before or after initiating dementia medicines. Among patients exposed to anticholinergic medicines, 46% (659/1439) had the same medicine dispensed before and after initiating dementia medicines. The proportion of patients dispensed anticholinergic medicines increased by 2.5% (95% confidence interval [CI]: 1.3-3.7) after initiating dementia medicines. Antipsychotics use increased by 10.1% (95% CI: 7.6-12.7) after initiating dementia medicines; driven by increased risperidone use (7.3%, 95% CI: 5.3-9.3). Nearly half of patients dispensed anticholinergic medicines in the 180 days after (537/1133), were prescribed anticholinergic medicines by a prescriber other than the one initiating dementia medicines., Conclusion: Use of anticholinergic medicines is common among patients initiating dementia medicines and this occurs against a backdrop of widespread campaigns to reduce irrational medicine combinations in this vulnerable population. Decisions about deprescribing medicines with questionable benefit among patients with dementia may be complicated by conflicting recommendations in prescribing guidelines., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Non-Alzheimer's dementias constitute 30% of all dementias and present with major cognitive and behavioral disturbances. Cholinesterase inhibitors improve memory by increasing brain acetylcholine levels and are approved symptomatic therapies for Alzheimer's disease (AD). They have also been investigated in other types of dementias with potential cholinergic dysfunction. There is compelling evidence for a profound cholinergic deficit in Lewy Body dementia (LBD) and Parkinson's disease dementia (PDD), even to a greater extent than AD. However, this deficit is difficult to objectivize in vascular dementia (VaD) given the increased comorbidity with AD. Furthermore, there is minimal to no evidence for cholinergic loss in frontotemporal dementia (FTD). Although cholinesterase inhibitors showed significant improvement in cognitive, behavioral, and functional measures in both LBD and PDD clinical trials, only rivastigmine is approved for PDD, due to the heterogeneity of the scales used, the duration of trials, and the limited sample sizes impacting data interpretation. Similarly, the interpretation of findings in VaD trials are limited by the lack of pre-defined inclusion criteria for 'pure VaD' and the wide heterogeneity of patients enrolled with respect to location and extent of cerebrovascular disease. In FTD patients, cholinesterase inhibitors were mostly associated with worsening of cognitive and behavioral symptoms. In non-AD dementias, cholinesterase inhibitors were well tolerated, with increased reports of mild to moderate cholinergic side effects and a non-significant trend for increased cardio and cerebrovascular events with rivastigmine in VaD, justifying their cautious use on a case-by-case basis, especially when there is evidence for cholinergic deficit.

Introduction: Rivastigmine is a cholinesterase inhibitor, approved for the treatment of mild-to-moderate dementia of Alzheimer's type. This study assessed the short- and long-term effectiveness and safety of rivastigmine in patients with mild-to-moderate Alzheimer's disease (AD) in a real-world clinical setting in Taiwan., Methods: This was a 48-week, single-arm, open-label, prospective, observational, post-marketing surveillance, multicenter study. The primary outcomes were change from baseline to week 48 in the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scores. One-year persistence to treatment, effect on activities of daily living, and incidence of adverse events (AEs) were also assessed., Results: Overall, 151 patients were enrolled in the study, of which 91 (60.26%) completed this study. At the end of the study, the mean rivastigmine dose received by the patients was 6.59 mg/day. At week 48, the changes in mean [standard deviation (SD)] MMSE and CDR scores in the intent-to-treat (ITT) population from baseline were - 1.00 (3.8; p = 0.0344) and 0.07 (0.29; p = 0.0403), respectively. The most frequently reported AEs by preferred term were dizziness (12.58%) and nausea (9.27%). No new or unexpected AEs were observed, and 30 (20.13%) patients in the ITT population were on rivastigmine therapy for 1 year without treatment discontinuation., Conclusion: Despite the low 1-year persistence rate, rivastigmine showed a stabilizing effect on declining cognition in patients with mild-to-moderate AD in a real-world scenario. Rivastigmine is well tolerated at 6.0-9.0 mg/day with no unexpected safety concerns., Funding: Novartis Co. Ltd., Taipei, Taiwan.

Introduction: The benefits of pharmacological therapy with anti-dementia drugs are not yet fully demonstrated and there is even a lack of publications describing their use profile. The present work sought to determine the prescription patterns of anti-dementia drugs in a Colombian population., Patients and Methods: Descriptive cross-sectional study. Through a systematized database of 3.5 million affiliates to the Colombian health system, patients with uninterrupted dispensing of anti-dementia drugs between August-October/2016 were selected. Sociodemographic, pharmacological and comedication variables were analyzed. The costs of the therapies were estimated from the reference price of the medicines., Results: We identified 8372 patients with a mean age of 79.5 ± 8.7 years and 65.3% (n = 5471) were women. The most widely used medication was rivastigmine (69.6%), mainly in transdermal presentation, followed by memantine (31.4%). In general, the average dose administered per day was lower than the defined daily dose. Only 568 patients (6.7%) used combination therapy. 84.3% of patients (n = 7061) used some additional medication and 54.2% (n = 4535) had another neurologic medication. The cost per 1000 inhabitants/day of rivastigmine was 3.47 USD and for memantine 0.30 USD., Conclusion: Patients with anti-dementia drugs are using them at doses lower than those defined and they present an important frequency of comorbidities and comedications.

Objective: To perform a cost-effectiveness analysis of donepezil and rivastigmine therapy for mild and moderate Alzheimer's disease (AD) from the perspective of the Brazilian Unified Health System., Method: A hypothetical cohort of 1,000 individuals of both sexes, aged >65 years, and diagnosed with AD was simulated using a Markov model. The time horizon was 10 years, with 1-year cycles. A deterministic and probabilistic sensitivity analysis was performed., Results: For mild AD, the study showed an increase in quality-adjusted life years (QALYs) of 0.61 QALY/21,907.38 Brazilian reais (BRL) for patients treated with donepezil and 0.58 QALY/BRL 24,683.33 for patients treated with rivastigmine. In the moderate AD group, QALY increases of 0.05/BRL 27,414.96 were observed for patients treated with donepezil and 0.06/BRL 34,222.96 for patients treated with rivastigmine., Conclusions: The findings of this study contradict the standard of care for mild and moderate AD in Brazil, which is based on rivastigmine. A pharmacological treatment option based on current Brazilian clinical practice guidelines for AD suggests that rivastigmine is less cost-effective (0.39 QALY/BRL 32,685.77) than donepezil. Probabilistic analysis indicates that donepezil is the most cost-effective treatment for mild and moderate AD.

Background: To treat patients with bipolar disorders (BPD) during the acute phase, the standard procedure is to administer lithium or sodium valproate. To further optimize treatment, acetylcholinesterase inhibitors such as donepezil and galantamine have gained increased interest, though with conflicting results. In the present randomized, double-blind, placebo-controlled clinical trial, we investigated whether, and to what extent, adjuvant rivastigmine might improve symptoms of mania in patients with BPD during the acute manic phase., Methods: A total of 70 patients with BPD in an acute state of mania (mean age 33.8 years; 24% females) took part in this study. After a thorough clinical interview, standard treatment consisted of 20mg/kg/day of sodium valproate; next, patients were randomly assigned either to the adjuvant rivastigmine or to the placebo condition. The study duration was 24 days. The dose of rivastigmine was 1.5 mg for the first 7 days and 3 mg from day 8 to day 24. Experts blind to the patients' study condition rated patients' mania scores, symptom severity, and symptom improvements at baseline (except symptom improvements) and 4, 8, 12, and 24 days after the beginning of this study., Results: Symptoms of mania improved over time, but more so in the adjuvant rivastigmine compared to the placebo condition. Greater improvements were observed from day 8 on., Conclusions: The pattern of results from the present randomized, placebo-controlled, double-blind study suggests that adjuvant rivastigmine, a cholinesterase inhibitor, improved symptoms of mania among a larger sample of inpatients with BPD and in the acute manic state. However, the improvements were modest, and the results should be replicated and above all balanced against side effects., (© 2019 S. Karger AG, Basel.)

Background: Rivastigmine is a cholinesterase inhibitor, approved for the treatment of mild-to-moderate dementia of Alzheimer's type., Objective: To explore the efficacy and safety of the maximal tolerated dose of rivastigmine capsules in Chinese patients with mild-to-moderate Alzheimer's disease (AD)., Methods: The study was a multicenter, open-label, single-arm, phase IV clinical study in mild-to-moderate drug-naïve AD patients treated with rivastigmine capsules. The primary endpoint was the changes in the total scores of Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) from baseline to week 16. Secondary endpoints included changes in the scores of the following assessment scales and safety: Alzheimer's Disease Cooperative Study; Activities of Daily Living; Mini-Mental Status Examination (MMSE); Neuropsychiatry Index (NPI), and Caregiver Burden Inventory., Results: 222 patients were enrolled. Of these, 136 (75.1%) patients received and maintained the effective dose (≥6 mg/d) of rivastigmine for at least 4 weeks. The ADAS-Cog scale score improved in rivastigmine-treated patients at week 16 compared with baseline (p < 0.001) by 2.0 (95% CI: -3.0 to -1.1) points, which met the pre-defined superiority criteria. NPI-10 and NPI-12 scores improved by 3.6 and 4.0 points at week 16 (p = 0.001, p < 0.001), respectively. A total of 107 patients (59.1%) experienced adverse effects (AEs) during the study; common AEs included nausea (20.5%), vomiting (16.6%), anorexia (7.8%), dizziness (7.7%), and diarrhea (7.2%)., Conclusion: This was the first phase IV study on rivastigmine in mainland China. The study preliminarily demonstrated that rivastigmine capsules showed good tolerability and efficacy in mild-to-moderate AD patients with the maximal tolerated dose.

The present study aimed to evaluate the role of rivastigmine against the effect of a single unilateral botulinum toxin-A (BTX-A) injection on the bone and bone marrow of adult albino rats 4 weeks after injection. Twenty-four Wistar albino rats were divided into four equal groups: group I, which received distilled water; group II, which received rivastigmine (0.3 mg/kg daily, intraperitoneally for 4 weeks); group III, which received BTX-A (4 IU in 0.2 mL physiological saline) single dose, intramuscularly; and group IV, which received BTX-A + rivastigmine. The results revealed that BTX-A induced a significant decrease in the calcium level with a significant increase in the phosphorus, alkaline phosphatase, C-reactive protein, and tumor necrosis factor α levels in serum. Furthermore, a significant increase in malondialdehyde with a significant decrease in reduced glutathione activities in both bone and bone marrow. Histologically, a distortion and thinning out of the compact bone and trabeculae of cancellous bone of the rat femur in the BTX-A group with an increase in adipocytes in adjacent bone marrow were detected. Immunohistochemically, Cluster of Differentiation 68 (CD68) showed a significant increase in both osteoclasts and bone marrow macrophage. Rivastigmine treatment could relieve the toxic effects induced by BTX-A. In conclusion, rivastigmine has a protective effect against the hazardous effects of BTX-A on bone and bone marrow.

Purpose: The increasing prevalence of Alzheimer's disease (AD) demands more effective drugs, which are still unclear. The aim of this study is to compare the effectiveness of six drugs, such as donepezil, rivastigmine, galantamine, memantine, huperzine-A, and tacrine, in senior AD patients and identify the most effective one to improve patients' cognitive function., Methods: A system of search strategies was used to identify relevant studies including randomized controlled trials and clinical controlled trials evaluating the efficacy of six drugs in patients with AD. We updated relevant studies that were published before March 2018 as full-text articles. Using Bayesian network meta-analysis (NMA), we ranked cognitive ability objectively based on Mini-Mental State Examination (MMSE). Pairwise and NMAs were sequentially performed for the efficacy of drugs compared to each drug or control group through the trials included., Results: Among the 35 trials included, no obvious heterogeneity ( I 2 =0.0%, P =0.583) was revealed according to the pooled data for cognition in NMA and the mean difference (MD) of memantine (MD=1.7, 95% CI: 0.73, 2.8) showed that the memantine was significantly efficacious in the treatment group in terms of MMSE. Followed by galantamine, huperzine-A, rivastigmine, tacrine, and donepezil., Conclusion: As the first NMA comparing the major drugs in market for AD, our study suggests that memantine might have a more significant benefit on cognition than other five drugs available., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Cholinesterase inhibitors (ChEIs) are the mainstays of symptomatic treatment of Alzheimer's disease (AD); however, their efficacy is limited, and their use was associated with deaths in some groups of patients. The aim of the current study was to assess the impact of the long-term use of ChEIs on mortality in patients with AD. This observational, longitudinal study included 1171 adult patients with a diagnosis of AD treated with donepezil or rivastigmine. Each patient was observed for 24 months or until death. The cognitive and functional assessments, the use of ChEIs, memantine, antipsychotics, antidepressants, and anxiolytics were recorded. The total number of deaths at the end of the observational period was 99 (8.45%). The patients who had received rivastigmine treatment were at an increased risk of death in the follow-up period. The higher risk of death in the rivastigmine group remained significant in multivariate Cox regression models.

Background: Delirium is a common clinical syndrome defined as alterations in attention with an additional disturbance in cognition or perception, which develop over a short period of time and tend to fluctuate during the course of the episode. Delirium is commonly treated in hospitals or community settings and is often associated with multiple adverse outcomes such as increased cost, morbidity, and even mortality. The first-line intervention involves a multicomponent non-pharmacological approach that includes ensuring effective communication and reorientation in addition to providing reassurance or a suitable care environment. There are currently no drugs approved specifically for the treatment of delirium. Clinically, however, various medications are employed to provide symptomatic relief, such as antipsychotic medications and cholinesterase inhibitors, among others., Objectives: To evaluate the effectiveness and safety of cholinesterase inhibitors for treating people with established delirium in a non-intensive care unit (ICU) setting., Search Methods: We searched ALOIS, which is the Cochrane Dementia and Cognitive Improvement Group's Specialised Register, on 26 October 2017. We also cross-checked the reference lists of included studies to identify any potentially eligible trials., Selection Criteria: We included randomised controlled trials, published or unpublished, reported in English or Chinese, which compared cholinesterase inhibitors to placebo or other drugs intended to treat people with established delirium in a non-ICU setting., Data Collection and Analysis: We used the standard methodological procedures expected by Cochrane. The primary outcomes were duration of delirium, severity of delirium, and adverse events. The secondary outcomes were use of rescue medications, persistent cognitive impairment, length of hospitalisation, institutionalisation, mortality, cost of intervention, leaving the study early, and quality of life. For dichotomous outcomes, we calculated the risk ratio (RR) with 95% confidence intervals (CIs); for continuous outcomes we calculated the mean difference (MD) with 95% CIs. We assessed the quality of evidence using GRADE to generate a 'Summary of findings' table., Main Results: We included one study involving 15 participants from the UK. The included participants were diagnosed with delirium based on the Confusion Assessment Method (CAM) criteria. Eight males and seven females were included, with a mean age of 82.5 years. Seven of the 15 participants had comorbid dementia at baseline. The risk of bias was low in all domains.The study compared rivastigmine with placebo. We did not find any clear differences between the two groups in terms of duration of delirium (MD -3.6, 95% CI -15.6 to 8.4), adverse events (nausea, RR 0.30, 95% CI 0.01 to 6.29), use of rescue medications (RR 0.13, 95% CI 0.01 to 2.1), mortality (RR 0.10, 95% CI 0.01 to 1.56), and leaving the study early (RR 0.88, 95% CI 0.07 to 11.54). Evidence was not available regarding the severity of delirium, persistent cognitive impairment, length of hospitalisation, cost of intervention, or other predefined secondary outcomes.The quality of evidence is low due to the very small sample size., Authors' Conclusions: There is insufficient evidence to support or refute the use of cholinesterase inhibitors for the treatment of delirium in non-ICU settings. No clear benefits or harms associated with cholinesterase inhibitors were observed when compared with placebo due to the lack of data. More trials are required.

Elderly patients with Alzheimer's disease (AD) and other dementias are at high risk of polypharmacy and excessive polypharmacy for common coexisting medical conditions. Polypharmacy increases the risk of drug-drug and drug-disease interactions in these patients who may not be able to communicate early symptoms of adverse drug events. Three acetylcholinesterase inhibitors (ACHEIs) have been approved for AD: donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne). They are also used off-label for other causes of dementia such as Lewy body and vascular dementia. We here report evidence from the literature that ACHEI treatment, prescribed for cognitive impairment, can reduce the load of medications in patients with AD by also addressing cardiovascular, gastrointestinal, and other comorbidities. Using one drug to address multiple symptoms can reduce costs and improve medication compliance.

Objectives: To evaluate the clinical evidence for traditional medicines (TMs) used in East Asia on measures of cognition in Alzheimer disease, determine the effect sizes at different time points for the TMs and pharmacotherapies, and assess the tolerability of the TMs., Methods: We searched 12 databases in English, Chinese, and Japanese for eligible randomised controlled trials that compared orally administered TMs with pharmacotherapy and reported cognitive outcomes. Meta-analyses were conducted for Alzheimer's Disease Assessment Scale-cognitive subscale and/or Mini-Mental State Examination (MMSE). Mean differences and 95% confidence intervals were calculated to evaluate treatment effects., Results: Thirty randomised controlled trials met inclusion criteria. Twenty-nine compared TMs with donepezil. Single studies provided comparisons with galantamine, rivastigmine, or memantine. There were no significant differences between the TM and donepezil groups at 12 or 24 weeks for Alzheimer's Disease Assessment Scale-cognitive subscale or MMSE. Improvements over baseline were significant for MMSE at 12 and 24 weeks within the TM and donepezil groups and remained significant at 1 year. Effect sizes were reduced in the 3 double-blind studies. At 24 weeks, donepezil 10 mg/d generally produced greater improvements in MMSE than 5 mg/d. Tolerability reporting was incomplete and inconsistent between studies., Conclusions: The results suggested that the clinical benefits of the TMs were not less than donepezil at comparable time points, with both groups showing improvements. However, lack of blinding in most studies and other design and measurement issues are likely to have resulted in overestimation of effect sizes in both groups. Further well-designed studies are needed., (Copyright © 2017 John Wiley & Sons, Ltd.)

Importance: New therapeutic approaches for Alzheimer disease (AD) are needed., Objective: To assess whether idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild to moderate AD., Design, Setting, and Participants: Three randomized clinical trials that included 2525 patients aged 50 years or older with mild to moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites). The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017., Interventions: Idalopirdine (10, 30, or 60 mg/d) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3)., Main Outcomes and Measures: Primary end point in all 3 studies: change in cognition total score (range, 0-70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog); key secondary end points: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores. Dose group efficacy required a significant benefit over placebo for the primary end point and 1 or more key secondary end points. Safety data and adverse event profiles were recorded., Results: Among 2525 patients randomized in the 3 trials (mean age, 74 years; mean baseline ADAS-Cog total score, 26; between 62% and 65% of participants were women), 2254 (89%) completed the studies. In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, -0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, -0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, -0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, -0.55 [95% CI, -1.45 to 0.36]). Treatment-emergent adverse events occurred in between 55.4% and 69.7% of participants in the idalopirdine groups vs between 56.7% and 61.4% of participants in the placebo groups., Conclusions and Relevance: In patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment. These findings do not support the use of idalopirdine for the treatment of AD., Trial Registration: clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654.

Background: The impact of adverse effects of drugs for dementia on the risk of hospitalization has not been much studied despite the impact of hospitalizations on cognitive decline., Objective: To determine if the main adverse effects of cholinesterase inhibitors and memantine may be associated with excess of hospitalization and to quantify the subsequent impact on healthcare expenditures., Methods: A representative sample of the French national health insurance beneficiaries aged 65 and older and suffering from dementia were included and followed from 2007 to 2014. Binary logit models for longitudinal data (GEE estimation technique) were used to estimate the excess of hospitalization events related to the adverse effects of anti-dementia drugs and then to derive the additional costs of hospitalizations for the public health insurance fund., Results: In total, 7,668 patients were followed, generating 111,133 individual observations over the 8-year period. Treated patients were hospitalized significantly more than non-treated patients (adjusted Odd Ratio (OR) = 1.08, 95% confidence interval (95% CI) = [1.02 to 1.13], p = 0.004), mainly with cholinesterase inhibitors for cardiac (OR = 1.21, 95% CI = [1.01 to 1.46], p = 0.034) and gastrointestinal events (OR = 1.43, 95% CI = [1.01-2.05], p = 0.045), especially with rivastigmine. When extrapolated to the entire population, this corresponded to an annual additional cost of € 55,000., Conclusion: Prescription of antidementia drugs, more specifically rivastigmine, increases the risk of hospitalizations via their cardiac and gastrointestinal adverse effects and lead to additional health care expenditures. Even though these results must be confirmed, they may encourage cautious consideration of the balance between benefits and harms before a prescription is given.

Objective: To investigate quantitative positron emission tomography (PET) findings and to study whether the cholinergic function differs between respondents to cholinergic medication versus nonrespondents., Setting: Outpatient clinic and university PET imaging center., Participants: We studied 17 subjects for more than 1 year after at least moderate traumatic brain injury. Ten of the subjects were respondents and 7 nonrespondents to cholinergic medication., Design: Cholinergic function was assessed with [methyl-C] N-methylpiperidyl-4-acetate-PET (C-MP4A-PET), which reflects the activity of the acetylcholinesterase (AChE) enzyme. The subjects were PET scanned twice: without medication and after a 4-week treatment with rivastigmine 1.5 mg twice a day., Measures: Regional cerebral AChE activity was measured with PET., Results: At baseline Statistical Parametric Mapping analyses showed significantly lower AChE activity in respondents bilaterally in the frontal cortex as compared with nonrespondents. Region of interest (ROI) analysis revealed that the difference was most pronounced in the lateral frontal cortex (-9.4%, P = .034) and anterior cingulate (-6.0%, P = .049). After rivastigmine treatment, AChE activity was notably lower throughout the cortex in both respondents and nonrespondents, without significant differences between them., Conclusion: Our study suggests that frontal cholinergic dysfunction is associated with the clinical response to cholinergic stimulation in patients with traumatic brain injury.

Background: The simultaneous use of dementia medications and anticholinergic medications occurs frequently. Cholinesterase inhibitors and anticholinergic medications likely counteract one another, potentially exposing patients to medications with decreased benefit, more adverse effects, and higher cost of care. We identified the rate of concurrent prescriptions of cholinesterase inhibitors/memantine with anticholinergics in an urban hospital setting with a large Asian and Pacific Islander population., Methods: This study is a retrospective review of patients hospitalized from 1 January 2006 to 31 December 2010 at a general hospital who simultaneously received US Food and Drug Administration-approved dementia medications (galantamine, rivastigmine, donepezil, and/or memantine) and anticholinergics., Results: Overall, 304 patients receiving cholinesterase inhibitors/memantine also received anticholinergics. Of these patients, 64.1% were given high-potency anticholinergic medications, and 35.9% received medium-potency medications. Indications for the use of anticholinergic medication were urological (17.8%), gastrointestinal excluding nausea (32.6%), nausea (10.2%), psychiatric (7.9%), and other (31.6%). Asian patients received the combination of cholinesterase inhibitors/memantine and anticholinergics less frequently than Native Hawaiian or Caucasian patients (8.4% vs 12.2% and 13.3%, respectively; χ 2  = 16.04, degrees of freedom = 2, P < 0.0003)., Conclusions: Simultaneous prescribing of cholinesterase inhibitors, memantine, and anticholinergic medications was significantly less common than in previous studies, with some ethnic variability. The less frequent occurrence of concurrent medications in the Asian population may be because of variations in the rate of indications or in tolerability for anticholinergic medications among the population., (© 2017 Japanese Psychogeriatric Society.)

Aim: To evaluate the therapeutic effects of switching from one acetylcholinesterase inhibitor (ChEI), donepezil, galantamine or rivastigmine, to another in Alzheimer's disease patients., Methods: We retrospectively enrolled 171 Alzheimer's disease patients, whose ChEI medication was changed. The patients were evaluated on three major aspects of dementia - cognitive, affective and activities of daily living (ADL) measures - at 6 months (M) before the drug switch, at the time of drug switch (baseline), and at 3 M and 6 M after the drug switch., Results: The doses of the three ChEI were significantly lower at 6 M after the switch compared with the pre-switch doses. Improvements in apathy were found at 3 M when switching from donepezil to galantamine, but not to rivastigmine, but this switch had adverse effects on ADL. Improvements in cognitive scores at 3 M were also found when switching from galantamine to rivastigmine, but not to donepezil. However, both of these changes improved Abe's Behavioral and Psychological Symptoms of Dementia scores (ABS), except ADL. Switching from rivastigmine to donepezil worsened ABS at 6 M, but preserved cognitive and ADL scores., Conclusions: The present study suggests that despite a relatively lower dose of ChEI after the switch, switching from donepezil or rivastigmine preserved cognitive functions for at least 6 M. Switching from galantamine to rivastigmine improved Mini-Mental State Examination and ABS at 3 M, but did not improve ADL scores. Geriatr Gerontol Int 2017; 17: 1843-1848., (© 2017 Japan Geriatrics Society.)

Objective: To date, data regarding the efficacy of acetylcholinesterase inhibitors in preventing postoperative delirium (POD) are inconsistent and conflicting. Older individuals with cognitive dysfunction are thought to show POD more frequently. Our aim was to study the effectiveness of rivastigmine prophylaxis on the incidence, severity, and risk factors for POD in older patients with cognitive impairment undergoing hip fracture surgery., Methods: Of 62 older patients with cognitive impairment about to undergo surgery after a hip fracture, 31 were randomly assigned to receive a rivastigmine patch from 3 days before to 7 days after the operation (Group I), and the other 31 did not receive a rivastigmine patch (Group II). The two groups were compared with regard to incidence and severity of delirium on postoperative days 2 or 3 and 7. Multivariate logistic regression analysis was performed to assess factors associated with POD., Results: Postoperative delirium occurred in five Group I patients and 14 Group II patients (p = 0.013). The mean severity of delirium in the two groups as determined by the Delirium Rating Scale was 2.2 and 6.2 respectively (p = 0.033). The odds ratio for POD was 0.259 (95% CI: 0.074-0.905, p = 0.034) after adjusting for American Society of Anesthesiologists score (p = 0.058), age (p = 0.203), and gender (p = 0.560). There were no rivastigmine-related perioperative complications., Conclusion: Perioperative rivastigmine patch application could reduce the occurrence of POD in older patients with low cognitive status. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Aim: To investigate whether the inhibitory rate of serum butyrylcholinesterase (BuChE) activity in Japanese patients with Alzheimer's disease is correlated with cognitive function, behavioral symptoms and caregiver burden., Methods: A total of 61 patients with mild to moderately severe Alzheimer's disease who were not undergoing cholinesterase enzyme inhibitor/memantine combinatorial treatment received a rivastigmine (18 mg) patch for 24 weeks. The rate of inhibition of BuChE was correlated with scores obtained on cognitive (Mini-Mental State Examination), behavioral (the Japanese version of the modified Crichton Geriatric Behavioral Rating Scale [CGBRS] and Vitality Index [VI]) and burden (the Japanese version of Zarit Burden Inventory [ZBI]) scales; and the Clinical Global Impression of Change scale., Results: The serum BuChE activity showed a significant decrease after 24 weeks compared with baseline (P < 0.001). Overall, significant effects were found in the Mini-Mental State Examination score, VI score and modified CGBRS score. We then divided patient groups into a high inhibitory rate (≥40%) group and a low inhibitory rate (<40%) group; there were significant improvements in the Mini-Mental State Examination score, VI score and modified CGBRS score in both groups. However, favorable results were seen in cooperation, restlessness and leisure on modified CGBRS subscales in the high inhibitory rate group (P < 0.001, P = 0.007, P < 0.001, respectively), and rehabilitation and other activities on VI subscales in the high inhibitory rate group (P = 0.005) compared with those in the low inhibitory rate group., Conclusions: Demonstrable significant improvements in behavioral symptoms, such as low cooperation, restlessness or low activities in patients with Alzheimer's disease, were achieved on inhibition of BuChE at a rate of 40% or more. Geriatr Gerontol Int 2017; 17: 1306-1312., (© 2016 Japan Geriatrics Society.)

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.

Background/objectives: Post-marketing comparative trials describe medication use patterns in diverse, real-world populations. Our objective was to determine if differences in rates of adherence and tolerability exist among new users to acetylcholinesterase inhibitors (AChEI's)., Design: Pragmatic randomized, open label comparative trial of AChEI's currently available in the United States., Setting: Four memory care practices within four healthcare systems in the greater Indianapolis area., Participants: Eligibility criteria included older adults with a diagnosis of possible or probable Alzheimer's disease (AD) who were initiating treatment with an AChEI. Participants were required to have a caregiver to complete assessments, access to a telephone, and be able to understand English. Exclusion criteria consisted of a prior severe adverse event from AChEIs., Intervention: Participants were randomized to one of three AChEIs in a 1:1:1 ratio and followed for 18 weeks., Measurements: Caregiver-reported adherence, defined as taking or not taking study medication, and caregiver-reported adverse events, defined as the presence of an adverse event., Results: 196 participants were included with 74.0% female, 30.6% African Americans, and 72.9% who completed at least twelfth grade. Discontinuation rates after 18 weeks were 38.8% for donepezil, 53.0% for galantamine, and 58.7% for rivastigmine (P = .063) in the intent to treat analysis. Adverse events and cost explained 73.1% and 25.4% of discontinuation. No participants discontinued donepezil due to cost. Adverse events were reported by 81.2% of all participants; no between-group differences in total adverse events were statistically significant., Conclusions: This pragmatic comparative trial showed high rates of adverse events and cost-related non-adherence with AChEIs. Interventions improving adherence and persistence to AChEIs may improve AD management., Trial Registration: Clinicaltrials.gov: NCT01362686 (https://clinicaltrials.gov/ct2/show/NCT01362686)., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

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.