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Acute intoxication with cholinesterase inhibiting organophosphates (OP) can produce life-threatening cholinergic crisis and status epilepticus (SE). Survivors often develop long-term neurological consequences, including spontaneous recurrent seizures (SRS) and impaired cognition. Numerous studies implicate OP-induced neuroinflammation as a pathogenic mechanism contributing to these chronic sequelae; however, little is known about the inflammatory phenotype of innate immune cells in the brain following acute OP intoxication. Thus, the aim of this study was to characterize the natural history of microglial and astrocytic inflammatory phenotypes following acute intoxication with the OP, diisopropylfluorophosphate (DFP). Adult male and female Sprague-Dawley rats were administered a single dose of DFP (4 mg/kg, sc) followed by standard medical countermeasures. Within minutes, animals developed benzodiazepine-resistant SE as determined by monitoring seizures using a modified Racine scale. At 1, 3, 7, 14, and 28 d post-exposure (DPE), neuroinflammation was assessed using translocator protein (TSPO) positron emission tomography (PET) and magnetic resonance imaging (MRI). In both sexes, we observed consistently elevated radiotracer uptake across all examined brain regions and time points. A separate group of animals was euthanized at these same time points to collect tissues for immunohistochemical analyses. Colocalization of IBA-1, a marker for microglia, with iNOS or Arg1 was used to identify pro- and anti-inflammatory microglia, respectively; colocalization of GFAP, a marker for astrocytes, with C3 or S100A10, pro- and anti-inflammatory astrocytes, respectively. We observed shifts in the inflammatory profiles of microglia and astrocyte populations during the first month post-intoxication, largely in hyperintense inflammatory lesions in the piriform cortex and amygdala regions. In these areas, iNOS+ proinflammatory microglial cell density peaked at 3 and 7 DPE, while anti-inflammatory Arg1+ microglia cell density peaked at 14 DPE. Pro- and anti-inflammatory astrocytes emerged within 7 DPE, and roughly equal ratios of C3+ pro-inflammatory and S100A10+ anti-inflammatory astrocytes persisted at 28 DPE. In summary, microglia and astrocytes adopted mixed inflammatory phenotypes post-OP intoxication, which evolved over one month post exposure. These activated cell populations were most prominent in the piriform and amygdala areas and were more abundant in males compared to females. The temporal relationship between microglial and astrocytic responses suggests that initial microglial activity may influence delayed, persistent astrocytic responses. Further, our findings identify putative windows for inhibition of OP-induced neuroinflammatory responses in both sexes to evaluate the therapeutic benefit of anti-inflammation in this context.

Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T2 measures obtained from brain magnetic resonance imaging (MRI) scans provide quantitative metrics of brain injury and therapeutic efficacy. Adult male Sprague Dawley rats were imaged on a 7T MRI scanner at 3, 7 and 28 days post-exposure to DFP or vehicle (VEH) with or without treatment with the standard of care antiseizure drug, midazolam (MDZ); a novel antiseizure medication, allopregnanolone (ALLO); or combination therapy with MDZ and ALLO (DUO). Our results show that mean T2 values in DFP-exposed animals were: (1) higher than VEH in all volumes of interest (VOIs) at day 3; (2) decreased with time; and (3) decreased in the thalamus at day 28. Treatment with ALLO or DUO, but not MDZ alone, significantly decreased mean T2 values relative to untreated DFP animals in the piriform cortex at day 3. On day 28, the DUO group showed the most favorable T2 characteristics. This study supports the utility of T2 mapping for longitudinally monitoring brain injury and highlights the therapeutic potential of ALLO as an adjunct therapy to mitigate chronic morbidity associated with acute OP intoxication.

Introduction: With an increasing prevalence, dementia is one of the most disabling diseases among the elderly. Impaired cognitive function and behavioral and psychological symptoms predispose patients to medication non-adherence, resulting in increased morbidity, mortality, and healthcare costs. The aim of this study was to estimate the prevalence of non-adherence to antidementia medications and to identify the main predictors. Methods: A population-based registry study was conducted in 2022 in Castile and Leon, Spain. A total of 17,563 patients with dementia were included. The medication possession ratio (MPR) was used as an indirect method to measure adherence. The cut-off point for determining that a patient was nonadherent was 80% of MPR. Multivariate logistic regression was used to identify predictors of nonadherence based on sociodemographic and health-related variables. Results: In 2022, 6.2% of the population over 80 years old used antidementia medications. Of these patients, 70% were women, 28.15% were institutionalized, and over 90% were polymedicated and had multiple prescribers. The most used medicines were donepezil (43.49%), rivastigmine (36.84%), and memantine (30.7%). The combined use of an acetylcholinesterase inhibitor plus memantine was relevant (13.33%). Men were less adherent than women, and the prevalence of non-adherence decreased with age. The medication associated with the highest prevalence of non-adherence was rivastigmine (19%), followed by donepezil (17%) and memantine (13.23%). Institutionalized patients (13%) and patients on combination therapy (13.29%) had the lowest prevalence of non-adherence. Protective factors against non-adherence include institutionalization, polymedication, use of memantine or combination therapy, and comorbid mental illness. Conclusions: In Castile and Leon, one in six patients were non-adherent to antidementia medications. Younger male patients with cardiometabolic disease are more likely to be non-adherent to antidementia medications. On the other hand, institutionalization is a protective factor against non-adherence, but still 10% of nursing home patients are non-adherent to antidementia medications. [ABSTRACT FROM AUTHOR]

(1) Background: Lippia sidoides Cham is a Brazilian aromatic plant rich in phenolic compounds. In traditional medicine, its leaves are used to treat diseases of the Central Nervous System such as stress and anxiety. This study evaluates the capacity of the aqueous extract of L. sidoides as an anticonvulsant, anticholinesterase and antihemolytic agent. (2) Methods: The extract was obtained from the leaves using water as a solvent, then dried in a spray dryer. The anticonvulsant effect was evaluated in zebrafish models using the pentylenetetrazol (PTZ) method. The anticholinesterase effect was determined using the acetylcholinesterase enzyme and physostigmine as a positive control. The antihemolytic action was evaluated by exposing erythrocytes to different concentrations of NaCl in the presence and absence of the extract. (3) Results: The anticonvulsant effect was observed at a concentration of 400 mg/kg, delaying convulsive crises. In the anticholinesterase assay, a dose-dependent action and variation in the effect over time were observed, demonstrating a reversible effect of the extract. For the osmotic fragility test, the extract showed satisfactory results, providing cellular protection across all variations of NaCl concentration. (4) Conclusions: These results demonstrate the promising potential of L. sidoides extract for the development of drugs that act in the treatment of diseases that affect the Central Nervous System. [ABSTRACT FROM AUTHOR]

Background: Both Alzheimer's disease (AD) and deliriogenic medications increase the risk of delirium in older adults. This study examined the association between delirium and the subsequent monthly use of anticholinergic, sedative, and opioid medications in the 1 year after delirium in older adults with AD. Methods: This comparative interrupted time series analysis involved adults (aged 65 years and older) with a diagnosis of AD initiating on cholinesterase inhibitors (ChEIs) based on 2013–2017 Medicare data. Separate patient‐level segmented regression models were used for each outcome to evaluate changes in the cumulative anticholinergic burden (CAB), sedative load, and opioid load after the delirium/index event using a 12‐month baseline and follow‐up period among patients who had a delirium event and those without delirium (control group). Propensity score‐based stabilized weights were utilized to balance baseline factors in the delirium and control groups. Results: The study included 80,019 older adults with AD with incident ChEI use; 17.11% had delirium. There was an immediate decline in monthly CAB after the delirium event (mean estimate −0.86, p‐value: 0.01) compared to the control group. A similar decline was observed when examining the sedative load (−0.06, p‐value: 0.002) after the delirium event. However, there was no decline in opioid load (−0.50, p‐value: 0.18). In the long term, CAB (0.13; p‐value: <0.0001), sedative load (0.01; p‐value: <0.001), and opioid load (0.07; p‐value: 0.006) increased over the 1‐year post‐delirium period in the delirium group compared to those without delirium. Conclusion: This study found the burden of deliriogenic medications over the 1‐year follow‐up showed increasing trends in older adults with AD, even though there was some level shift in CAB and sedative load after the delirium event. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is characterized by cholinergic dysfunction, making the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) critical for improving cholinergic neurotransmission. However, the development of effective dual inhibitors remains challenging. Objective: This study aims to synthesize and evaluate novel pyridazine-containing compounds as potential dual inhibitors of AChE and BuChE for AD treatment. Methods: Ten novel pyridazine-containing compounds were synthesized and characterized using IR, 1H NMR, and 13C NMR. The inhibitory activities against AChE and BuChE were assessed in vitro, and pharmacokinetic properties were explored through in silico ADME studies. Molecular dynamics simulations were performed for the most active compound. Results: Compound 5 was the most potent inhibitor, with IC50 values of 0.26 µM for AChE and 0.19 µM for BuChE, outperforming rivastigmine and tacrine, and showing competitive results with donepezil. Docking studies revealed a binding affinity of −10.21 kcal/mol to AChE and −13.84 kcal/mol to BuChE, with stable interactions confirmed by molecular dynamics simulations. In silico ADME studies identified favorable pharmacokinetic properties for compounds 5, 8, and 9, with Compound 5 showing the best activity. Conclusions: Compound 5 demonstrates strong potential as a dual cholinesterase inhibitor for Alzheimer's disease, supported by both in vitro and in silico analyses. These findings provide a basis for further optimization and development of these novel inhibitors. [ABSTRACT FROM AUTHOR]

Background and Objective: As dementia progresses, people living with dementia may take high-risk, unnecessary, or ineffective medicines. Cholinesterase inhibitors (ChEIs) may have benefit in some people with dementia; however, up to one third are continued when no longer necessary or safe. Our aim was to co-design a consult patient decision aid (CPtDA) to support shared decision making between healthcare professionals and consumers about continuing or deprescribing ChEIs. Methods: A systematic process was employed to design and test the CPtDA prototype. First, a steering group composed of healthcare professionals and a consumer representative was assembled. Guided by the International Patient Decision Aids Standards, the steering group defined the CPtDA's purpose, scope, and target audience and drafted the prototype for further testing. Interviews with consumers and healthcare professionals were conducted to gain feedback on the content, format, structure, comprehensibility and usability of the CPtDA prototype. Results: After the steering group developed the CPtDA prototype, interviews were conducted with 11 consumers and six healthcare professionals. The content and format of the decision aid were improved iteratively over three rounds after consolidating the feedback at each round. The main changes included rewording the purpose of the decision aid and simplifying its layout and format. Participants reported that the decision aid is comprehensible and may be useful in practice. Conclusions: Limited available resources guide shared decision making about deprescribing. This study resulted in a co-designed and alpha-tested CPtDA for people living with dementia and carers to help them review the ongoing need for their ChEIs. Further research is needed to explore using the CPtDA in practice to support people living with dementia and their carers engage in the shared decision-making process about continuing or deprescribing their ChEIs. Our co-designed CPtDA could help people living with dementia and their carers review their goals of care alongside their healthcare professional. This may prompt conversations about appropriately using ChEIs and increase the uptake of deprescribing. [ABSTRACT FROM AUTHOR]

Objective: synthesize thioacetamide-thiazole as key pharmacophore possessing acetylcholinesterase (AChE) inhibitory activity. Methods: Thirteen compounds (IIIa–IIIm) were synthesized by preparing differently substituted aminothiazoles and subsequently evaluated for AChE inhibitory and antioxidant activity. Results and Discussion: Compound (IIIk) (IC50 = 1.99 µM) exhibits promising AChE inhibitory activity amongvarious derivatives of the series. The antioxidant potential of synthesized compounds were determined by DPPH assay (IC50 = 1.10 to 15.45 µM). Compound (IIIk) exhibited the utmost antioxidant activity with IC50 = 1.10 µM. Further molecular docking, drug-likeness, and ADMET predictions of all synthesized compounds were also assessed with computational methods. The results unequivocally supported the in vitro studies of all derivatives by displaying good docking score with binding pocket of PDB4EY7. Conclusions: The study concluded that compound (IIIk) emerged as potential lead compound as AChE inhibitor for the development of new compounds as anti-Alzheimer's candidates. [ABSTRACT FROM AUTHOR]

Background: Cholinesterase inhibitors (ChEIs) are prescribed for Alzheimer's disease (AD) and sometimes for mild cognitive impairment (MCI) without knowing underlying pathologies and its effect on cognition. We investigated the frequency of ChEI prescriptions in amyloid-negative MCI and their association with cognitive changes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Methods: We included participants with amyloid positron emission tomography (PET)-negative MCI from the ADNI. We analyzed the associations of ChEI use with cognitive changes, brain volume, and cerebrospinal fluid (CSF) total tau (t-tau), hyperphosphorylated tau181 (p-tau181), and p-tau181/t-tau ratio. Results: ChEIs were prescribed in 27.4% of amyloid PET-negative MCI and were associated with faster cognitive decline, reduced baseline hippocampal volume and entorhinal cortical thickness, and a longitudinal decrease in the frontal lobe cortical thickness. Conclusions: The association between ChEI use and accelerated cognitive decline may stem from underlying pathologies involving reduced hippocampal volume, entorhinal cortical thickness and faster frontal lobe atrophy. We suggest that ChEI use in amyloid PET-negative MCI patients might need further consideration, and studies investigating the causality between ChEI use and cognitive decline are warranted in the future. [ABSTRACT FROM AUTHOR]

Purpose Neuromuscular blocking agents (NMBAs) are commonly used during surgery, and restoring neuromuscular function at the end of surgery is vital in preventing complications of residual paralysis. Recent guidelines from the American Society of Anesthesiology recommend using sugammadex over neostigmine; however, sugammadex is significantly more expensive than neostigmine and may increase drug expenditure for pharmacy departments. This review summarizes evidence evaluating sugammadex dose adjustments and the potential of these dose adjustments to lead to cost savings for pharmacy departments. Summary We found evidence suggesting that the manufacturer-recommended sugammadex dose may not be needed in many patients and that dosing based on an adjusted body weight or based on depth of neuromuscular blockade may lead to lower sugammadex usage. Combining sugammadex with neostigmine could also decrease the dose of sugammadex required. We have highlighted the importance of objective neuromuscular monitoring to guide sugammadex dosing and evaluation for residual neuromuscular blockade. Cost savings for pharmacy departments may be realized by these alternative dosing strategies and/or vial-splitting practices. Conclusion Implementing practices related to sugammadex vial splitting and dose adjustment based on body weight and depth of neuromuscular blockade shows potential benefits in terms of sugammadex cost savings. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We aimed to assess the impact of cholinesterase inhibitors (ChEIs) and memantine on cognition, major adverse cardiovascular events (MACE) and mortality in dementia with Lewy bodies (DLB). METHODS: A total of 1,095 incident DLB patients from the Swedish Registry on cognitive/dementia disorders were included. Using an inverse probability of treatment weighting, the effect of initiating ChEI or memantine within 90 days of DLB diagnosis and nonuse was evaluated on cognitive trajectories and risks of MACE and death. RESULTS: The use of ChEIs significantly slowed cognitive decline at follow‐ups (Mini‐Mental State Examination [MMSE] ‐0.39 points/y; 95% confidence interval [CI], ‐0.96 to 0.18) compared to memantine (‐2.49 points/y; ‐4.02 to ‐0.97) and nonuse (‐2.50 points/y; ‐4.28 to ‐0.73). Treatment groups did not differ in MACE events. ChEI use was associated with lower risk of death in the first year after DLB diagnosis (adjusted hazard ratio [HR] 0.66, 95% CI 0.46, 0.94). DISCUSSION: Our findings illuminate the potential benefits of ChEI treatment in DLB patients. Highlights: Cholinesterase inhibitors slow cognitive decline over a 5‐year follow‐up period when compared to both memantine treatment and nonuse in patients with dementia with Lewy bodies.Cholinesterase Inhibitors reduce risk of mortality within the initial year, but this effect is not sustained after 1 year in patients with dementia with Lewy bodies. [ABSTRACT FROM AUTHOR]

It is of vital importance to patients and physicians, as well as administrators and drug regulators, that the treatment for a disease has been shown to be safe and clinically meaningful in long-term use. Recent literature has highlighted 3 major categories of arguments for and against modification of the underlying disease process in Alzheimer's disease (AD): pathophysiology, biomarkers and data from clinical trials. We argue that the Alzheimer's arena is over-reliant on theories of disease modification based solely on brain positron emission tomography (PET) imaging and blood biomarkers of tau and Aß peptides. Here, we instead focus on a historically-grounded empirical criterion from other fields of medicine to overcome the weak interpretations of short Alzheimer's trials: survival time (ST). Our analysis has identified 3 key points. First, if anti-amyloid therapies are AD-modifying treatments, then we argue that they should increase ST more than the standard "symptomatic" care with memantine and acetylcholinesterase inhibitors. Second, we question memantine and cholinesterase inhibitors being labeled simply as "symptomatic" Alzheimer's drugs since long-term use of them can produce disease modification, that is, increase ST. Third, we make a case for memantine or cholinesterase inhibitors being used as controls in clinical trials with amyloid-lowering and other drugs, and argue against their current under-use in care of Alzheimer's patients. [ABSTRACT FROM AUTHOR]

Introduction: For over 25 years, cholinesterase inhibitors (ChEIs) have been the main symptomatic treatment for Alzheimer’s disease (AD). Several meta-analyses have supported their effectiveness in various neurocognitive, functional, and behavioral aspects of amnestic AD. Over 86% of cases of the logopenic variant of primary progressive aphasia (lvPPA), also named language variant AD, are caused by a similar pathologic process than AD, yet no study has examined the efficacy of ChEIs in this AD variant. We aimed to explore the efficacy of ChEIs in the treatment of lvPPA by comparing their evolution on the MMSE, and other functional and behavioral parameters, to that of treated amnestic AD patients. Methods: A retrospective chart review was performed in 45 patients with lvPPA and 52 patients with amnestic AD. Both groups were similar in terms of age, level of education, and onset of symptoms. Drug history and MMSE scores, as well as functional (activities of daily living [ADLs] and instrumental activities of daily living [IADLs]), neurocognitive and neuropsychiatric symptoms were collected on several time points before and after the introduction of ChEIs. Data were analyzed using ANOVA and a generalized linear mixed model. Results: Patients with lvPPA showed a similar trajectory of decline than amnestic AD patients on serial MMSEs up to 12–24 months after the introduction of ChEIs. There was a significant impact on ADLs but not IADLs and neuropsychiatric symptoms remained stable over time. Conclusion: This study provides preliminary evidence for efficacy of ChEIs in patients with lvPPA and suggests similar benefits to those seen in amnestic AD patients, hence reassuring patients and their physicians. [ABSTRACT FROM AUTHOR]

Objective: Alzheimer's disease (AD), affecting over 55 million people globally, poses a substantial public health challenge. Early diagnosis and appropriate treatment are vital to slowing its progression and enhancing patient quality of life. The fixed-dose combination of citicoline with rivastigmine emerges as a promising strategy AD treatment. Methods: A real-time Delphi consensus was reached with the participation of 11 Mexican experts. Results: The combination offers neuroprotective benefits, enhancing neuronal regeneration and reducing glutamate levels linked to neuronal damage in AD. These effects translate into improved cognitive function and delayed cognitive decline in AD. Conclusions: The Mexican Consensus for the Combined Management of AD endorses this fixed-dose combination of rivastigmine with citicoline as a new therapeutic perspective. Its efficacy and safety make it a valuable option for the treatment of this neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Objectives: Pharmacological and non‐pharmacological interventions are mostly designed for patients with early Alzheimer's disease (AD) dementia. Long‐term case management and planning for the remainder of life with disability require an estimation of the survival duration. Methods: This cohort study utilized data from the National Health Insurance Research Database, Taiwan, to identify incident cases of mild‐to‐moderate AD dementia diagnosed from 2000 to 2002, followed through December 31, 2017. A multivariate Cox proportional hazards regression model was constructed to compare the independent effects of age, sex, and comorbidities on all‐cause mortality risk. Cumulative survival rates and survival times were estimated. Results: A total of 5258 incident cases were identified, all treated with cholinesterase inhibitors after diagnosis confirmation by an expert committee. During the 15‐year follow‐up period, 4331 deaths occurred. The 1‐, 3‐, 5‐, 10‐, and 15‐year cumulative survival rates were 95, 92, 67, 37, and 18, respectively. The median (95% CI) survival time after diagnosis was 7.69 (7.46–7.90) years overall, 6.37 (6.06–6.65) years in men, and 8.81 (8.49–9.12) years in women. After stratification by age and number of comorbidities, the median survival time ranged from 13.72 (ages 40–64) to 5.29 (ages ≥ 80) years among those without comorbidities. For those with ≥ 3 comorbidities, the median survival times decreased to 6.43 for individuals diagnosed at ages 40–64 and to 2.98 years for those diagnosed at age 80 or older. Conclusions: This nationwide, large, long‐term cohort study provided survival rates and durations from diagnosis to death, varying by sex, age group, and presence/number of comorbidities. This information can serve as a foundation for further cost‐effectiveness studies on new treatments, and may aid clinicians, patients, and families in shared decision‐making and advance personalized care planning for early dementia cases. [ABSTRACT FROM AUTHOR]

Synthesis and properties of tetrahydroxy substituted zinc phthalocyanine is reported. UV–Visible spectrum for the aggregation properties of the compound and fluorescence properties were examined by excitation, emission spectra. This complex was an inhibitor of butyrylcholinesterase (BChE), α-Gly, α-Amy, and acetylcholinesterase (AChE) enzymes for tetra- hydroxy phthalocyaninato zinc (II) 3 with IC50 values of 49.18 μM for α-Amy, 110.85 μM for BChE, 35.13 μM for α-glycosidase and 54.63 μM for AChE, respectively. On the otherside, within the scope of computational study, in vitro activity behavior and states of the related complex, which cannot be explained experimentally, were evaluated at atomic level. The pharmacodynamics properties of the complex (3) were elucidated by molecular docking against four target enzymes, AChE, BChE, α-Gly and α-Amy. After that, its potential drug candidate was investigated based on its pharmacokinetic properties with help of in silico-ADMET analysis. As a result of all the applications, a desired goal in medicinal chemistry was to develop new, reliable and safe cholinesterase and α-glycosidase inhibitors with high efficacy. [ABSTRACT FROM AUTHOR]

This research aimed to create and optimize a transethosomal patch containing Rivastigmine Hydrogen Tartarate, a cholinesterase inhibitor, for the symptomatic management of Alzheimer's disease that would reduce drug loading and patch size. Transethosomes are elastic vesicles made up of phospholipids, ethanol, and edge activator. Transethosomes of Rivastigmine were prepared by cold method, which were then incorporated into a transdermal adhesive patch prepared by solvent casting method. The transethosomes were optimised using the central composite design. The optimized transethosomes showed low vesicle size, good entrapment efficiency and enhanced transdermal flux. The electron microscopy revealed that the vesicles were uniform and sphere-shaped, also the vesicle surface was found to be smooth. Rivastigmine Hydrogen Tartarate was released slowly in the study, and the mechanism of drug release followed the Korsemeyer-Peppas model. Transethosomal formulation showed significant increase in the steady state flux to 2.18 times than the pure drug solution. Also, the transethosomal patch showed significant increase in the steady state flux to 1.55 times than the conventional patch. Based on the results, Rivastigmine Hydrogen Tartarate loaded transethosomal patch was the best formulation since it provided long-term drug release. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is one of the most devastating chronic health problems of the last few decades. Unfortunately, current treatment and care options for AD are insufficient, making it a prominent topic for drug discovery studies. Currently, AD drug development studies have focused on the strategy of multitarget directed ligands (MTDLs). Following this strategy, we designed new ChE inhibitors with additional antioxidant and metal chelator effects. In this research, we designed and synthesized novel eight N'-(4-oxo-4H-chromen-3-yl)methylene propanehydrazide derivatives. We then evaluated the inhibition potency of all final compounds for cholinesterase enzymes. Among them, (6f) (IC50 AChE=16.91 µM) was found to be the most potent acetylcholinesterase inhibitor. Additionally, (6d) (IC50's AChE=26.91 µM and BChE=47.94 µM) exhibited dual cholinesterase inhibitor activity. Moreover, we investigated all title compounds for their antioxidant (DPPH, ORAC) and metal chelator activities. According to the ORAC-FL results, all the compounds exhibited good antioxidant activity ranging from 4.082 to 16.715 Trolox equivalents. We also observed chelator effects of all compounds for Cu(II), Fe(II), and Zn(II) ions at varying rates. Furthermore, we assessed the in-silico physicochemical parameters of the compounds to evaluate their drug-likeness or druggability. [ABSTRACT FROM AUTHOR]

Background: Clinical trial findings on cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) are inconclusive, offering limited support for their MCI treatment. Given that nearly half of amnestic MCI cases lack cerebral amyloid-β (Aβ) deposition, a hallmark of Alzheimer's disease; this Aβ heterogeneity may explain inconsistent results. Objective: This study aimed to assess whether Aβ deposition moderates ChEI effects on amnestic MCI cognition. Methods: We examined 118 individuals with amnestic MCI (ages 55–90) in a longitudinal cohort study. Baseline and 2-year follow-up assessments included clinical evaluations, neuropsychological testing, and multimodal neuroimaging. Generalized linear models were primarily analyzed to test amyloid positivity's moderation of ChEI effects on cognitive change over 2 years. Cognitive outcomes included Mini-Mental Status Examination score, the total score of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery, and Clinical Dementia Rating-sum of boxes. Results: The analysis found no significant ChEI use x amyloid positivity interaction for all cognitive outcomes. ChEI use, irrespective of Aβ status, was associated with more cognitive decline over the 2-year period. Conclusions: Aβ pathology does not appear to moderate ChEI effects on cognitive decline in MCI. [ABSTRACT FROM AUTHOR]

The article describes the case of a 79-year old Caucasian man who was treated with donepezil after developing a pruritic erythematous maculopapular eruption at the application site of rivastigmine transdermal patches, which was used to treat his Lewy body disease. The patient's skin lesions did not regress after antihistaminic treatment with cetirizine. A Naranjo scale assessment showed the high probability of the relation of cutaneous adverse effects with rivastigmine transdermal patches.

Aim: Postoperative sore throat (POST) is a commonly encountered and significant complication following anesthesia, which can adversely affect the quality of a patient's recovery. Many factors contribute to the development of POST. Controlled hypotension (CH) is a surgical technique used to reduce blood flow, improve visibility, and shorten procedure time by safely lowering blood pressure. In this study, we aimed to investigate the effects of CH on POST, coughing, hoarseness, and vomiting in patients undergoing surgery in a supine position with a fixed endotracheal cuff pressure. Material and Method: A total of 124 patients, aged between 18 and 65 years, classified as American Society of Anesthesiologists (ASA) class I-II and scheduled for elective surgical procedures, were included in the study. The patients were divided into two groups: Group N (n=65), consisting of normotensive individuals, and Group H (n=59), which included patients subjected to CH. In both groups, the endotracheal cuff pressure was manually set to 25 cmH2O using a cuff pressure manometer. CH was achieved in Group H by administering glyceryl trinitrate (nitroglycerin) infusion, maintaining the mean arterial pressure (MAP) within the range of 55-65 mmHg. Patients were assessed for POST, coughing, hoarseness, and vomiting at postoperative 15 minutes, 2, 6, 12, and 24 hours. Results: Demographic data, smoking status, ASA scores, surgical and anesthesia durations were similar between the groups. Statistically significant differences were observed between the groups in the numeric rate scores (NRS) for throat pain at 15 minutes and 2 hours, as well as hoarseness scores at 2 and 6 hours. The groups were similar regarding vomiting rates and cough scores. Conclusion: In this study investigating the impact of CH on sore throat, we observed an increased incidence of POST and hoarseness in patients subjected to CH. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder, in which there is a progressive deterioration of intellectual and social functions, memory loss, personality changes and inability for self-care, and has become the fourth leading cause of death in developed countries. Pathogenesis of AD, there is a progressive deposition of β-amyloid (Aβ)- peptide in the hippocampal and cerebral cortical regions. This deposition is associated with the presence of neurofibrillary tangles (NFTs) and senile plaques. The senile plaques deposited between the neurons consist mainly protein β amyloid. Neurofibrillary tangles deposited inside the neurons fabricated from Tau protein. Diagnosing Alzheimer's requires careful medical evaluation thorough medical history, mental status testing, physical and neurological examination tests (such as blood tests and brain imaging), two classes of medications approved to treat AD. Cholinesterase inhibitors: Donepezil, Rivastigmine, Galantamine, NMDA receptor antagonists: Memantine. The major goal in designing nanoparticles as a delivery system are to control particle size, surface property and release of pharmacologically active agents in order to achieve the site-specific action of the drug at the therapeutic optimum rate and dose regimen of the agent to the CNS, but also the ability of the agent to access the relevant target site within the CNS. Many strategies have been developed to deliver the drug into brain by crossing the BBB: chemical delivery systems, magnetic drug targeting or drug carrier systems such as antibodies, liposomes or nanoparticles. Among those, nanoparticles have got a great concentration as the potential targeted drug delivery systems in the brain recently. [ABSTRACT FROM AUTHOR]

Abstract Background Cholinesterase inhibitors (ChEIs) are prescribed for Alzheimer’s disease (AD) and sometimes for mild cognitive impairment (MCI) without knowing underlying pathologies and its effect on cognition. We investigated the frequency of ChEI prescriptions in amyloid-negative MCI and their association with cognitive changes in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Methods We included participants with amyloid positron emission tomography (PET)-negative MCI from the ADNI. We analyzed the associations of ChEI use with cognitive changes, brain volume, and cerebrospinal fluid (CSF) total tau (t-tau), hyperphosphorylated tau181 (p-tau181), and p-tau181/t-tau ratio. Results ChEIs were prescribed in 27.4% of amyloid PET-negative MCI and were associated with faster cognitive decline, reduced baseline hippocampal volume and entorhinal cortical thickness, and a longitudinal decrease in the frontal lobe cortical thickness. Conclusions The association between ChEI use and accelerated cognitive decline may stem from underlying pathologies involving reduced hippocampal volume, entorhinal cortical thickness and faster frontal lobe atrophy. We suggest that ChEI use in amyloid PET-negative MCI patients might need further consideration, and studies investigating the causality between ChEI use and cognitive decline are warranted in the future.

Abstract Alzheimer’s disease is the most prevalent neurodegenerative disorder characterized by significant memory loss and cognitive impairments. Studies have shown that the expression level and activity of the butyrylcholinesterase enzyme increases significantly in the late stages of Alzheimer’s disease, so butyrylcholinesterase can be considered as a promising therapeutic target for potential Alzheimer’s treatments. In the present study, a novel series of 2,4-disubstituted quinazoline derivatives (6a–j) were synthesized and evaluated for their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes, as well as for their antioxidant activities. The biological evaluation revealed that compounds 6f, 6h, and 6j showed potent inhibitory activities against eqBuChE, with IC50 values of 0.52, 6.74, and 3.65 µM, respectively. These potent compounds showed high selectivity for eqBuChE over eelAChE. The kinetic study demonstrated a mixed-type inhibition pattern for both enzymes, which revealed that the potent compounds might be able to bind to both the catalytic active site and peripheral anionic site of eelAChE and eqBuChE. In addition, molecular docking studies and molecular dynamic simulations indicated that potent compounds have favorable interactions with the active sites of BuChE. The antioxidant screening showed that compounds 6b, 6c, and 6j displayed superior scavenging capabilities compared to the other compounds. The obtained results suggest that compounds 6f, 6h, and 6j are promising lead compounds for the further development of new potent and selective BuChE inhibitors.

Based on my work as a clinical neurologist with more than 50 years of experience in caring for patients with Alzheimer's disease (AD), I focus, in this review article, on the disease's two fundamental aspects for the doctor: diagnosis and treatment. The 1984 diagnostic criteria had been stable for more than a quarter of a century when it was replaced in 2011. Since then, there have been many discoveries, especially of biomarkers that have a heavy impact on the diagnosis of AD. Recently, AD biomarkers have become available in plasma, which certainly will cause a major change in the diagnosis of biological AD, a term that still needs care and information to society before being used in clinical practice. Three monoclonal antibodies against β-amyloid peptide have also been recently approved, and two of these have shown a small but statistically significant effect on clinical outcome. These monoclonal antibodies have had a greater effect on the reduction of amyloid plaques in the brain assessed by positron emission tomography (PET), and on the concentration of biomarkers in the cerebrospinal fluid (β-amyloid peptide with 42 amino acids and hyperphosphorylated tau protein) than in the neuropsychological and functional assessments. Even this small clinical effect will be encouraging for the development of new research, particularly helped by the greater ease of diagnosis and monitoring of the evolution of AD pathophysiology with plasma biomarkers. Recently, new diagnostic criteria for AD were presented by the Alzheimer's Association, causing controversy about their use in clinical practice.

In this study, heterocyclic compounds containing a benzothiophene scaffold were designed and synthetized, and their inhibitory activity against cholinesterases (ChE) and the viability of SH-SY5Y cells have been evaluated. Benzothiophenes 4a–4i and benzothiophene-chalcone hybrids 5a–5i were tested against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing interesting structure–activity relationships. In general, benzothiophene–chalcone hybrids from series 5 proved to be better inhibitors of both enzymes, with compound 5f being the best AChE inhibitor (IC50 = 62.10 μM) and compound 5h being the best BChE inhibitor (IC50 = 24.35 μM), the last one having an IC50 similar to that of galantamine (IC50 = 28.08 μM), the reference compound. The in silico ADME profile of the compounds was also studied. Molecular docking calculations were carried out to analyze the best binding scores and to elucidate enzyme–inhibitors' interactions. [ABSTRACT FROM AUTHOR]

Piper baccatum is a woody climber and grows throughout the tropics mostly in Southeast Asia such as Thailand, Malaysia, Singapore, and Indonesia. The studies on essential oil composition and anticholinesterase activities were performed, along with molecular docking of all components. The essential oil was obtained by hydrodistillation and analyzed by GC-FID and GC-MS, while anticholinesterase activity was assessed using Ellman method. A total of 14 components were identified, representing 98.1% of the total composition of the essential oil. The major identified components were β-caryophyllene (30.7%), camphene (22.1%), eucalyptol (14.9%), γ-muurolene (6.9%), and α-pinene (5.3%). A moderate inhibitory effect was observed for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values of 80.5 and 96.4 μg/mL, respectively. Molecular docking studies of P. baccatum components with AChE and BChE revealed binding energy ranges of -5.6 to -8.5 Kcal/mol and -5.2 to -7.8 Kcal/mol, respectively, predominantly involving hydrophobic interactions with active site residues. Notably, β-caryophyllene and γ-muurolene exhibited superior binding energy profiles with both AChE and BChE compared to other components. The docking results underscore the potential of P. baccatum essential oil components as cholinesterase inhibitors, with implications for applications in food, aromatherapy, and pharmaceutical industries. The identified components, particularly β-caryophyllene and γ-muurolene, showcase promising attributes for further exploration in developing therapeutic interventions targeting cholinesterase-related conditions. This essential oil in general could be potentially used as a cholinesterase inhibitor with possible applications in food, aromatherapy, and pharmaceutical industries. [ABSTRACT FROM AUTHOR]

In an effort to develop new and effective therapeutic agents for Alzheimer's disease, a series of hydrazone derivatives bearing piperidine rings have been designed and synthesized. The chemical structures of the compounds were characterized by various spectroscopic techniques. In vitro antioxidant and cholinesterase activities of the compounds were evaluated. Among the compounds, N12 exhibited the most antioxidant activity in all methods (CUPRAC, FRAP, DPPH, ABTS). In vitro acetylcholinesterase (AChE) activity results of the compounds showed good IC50 values between 14.124 ± 0.084 and 49.680 ± 0.110 µM were obtained (IC50 = 38.842 ± 0.053 µM for Donepezil). Among the compounds, N7 and N6 are much more effective derivatives than the standard compound donepezil with IC50 values of 14.124 ± 0.084 and 17.968 ± 0.072 µM, respectively. In vitro, butyrylcholinesterase (BChE) inhibition values of the compounds were between 13.505 ± 0.025 and 52.230 ± 0.027 μm. Among the compounds, N6 has the highest BChE inhibition with an IC50 value of 13.505 μm in the series. The cytotoxicity and AChE inhibitory activity of the compounds on SH‐SY5Y cell lines were also evaluated. Kinetic studies were also performed to determine the behavior of the compounds as competitive or noncompetitive inhibitors. The binding modes of N6, which was determined to be highly effective according to in vitro analyses, with AChE and BChE were investigated using molecular docking studies, and the stability of the complexes was determined by molecular dynamics simulations. These findings indicated that AChE and BChE enzymes maintained their overall structural stability and compactness during interactions with compound N6. [ABSTRACT FROM AUTHOR]

BACKGROUND: Postoperative delirium in patients receiving head and neck surgery is a pressing concern, affecting morbidity, mortality, and healthcare costs. With an aging population and about 65,000 new head and neck cancer diagnoses per year in the United States, surgery remains a primary treatment modality, regardless of age. OBJECTIVES: This article offers an educational overview of postoperative delirium management in patients receiving head and neck surgery, summarizing incidence, etiology, pathophysiology, diagnostic tests, treatment, complications, and risk factors. METHODS: A narrative literature review of articles published in the past 10 years was conducted to consolidate information on postoperative delirium in patients receiving head and neck surgery. FINDINGS: Postoperative delirium is characterized by acute, fluctuating cognitive dysfunction within 30 days after surgery, with incidence ranging from 11% to 26%. Pathophysiology is multifactorial, and pharmacologic options are limited because of side effects and varying effectiveness. Nonpharmacologic management focuses on addressing underlying causes and early mobilization. Reducing postoperative delirium risk necessitates interprofessional, systemwide collaboration. [ABSTRACT FROM AUTHOR]

Cholinesterase inhibitors (ChEIs) insecticide poisoning is a serious global health concern that results in hundreds of thousands of fatalities each year. Although inhibition of the cholinesterase enzyme is the main mechanism of ChEI poisoning, oxidative stress is considered the mechanism underlying the related complications. The study aimed to assess the oxidative status of the patients with ChEI insecticide poisoning and the role of L-carnitine as adjuvant therapy in their management. Human studies on the efficacy and safety of L-carnitine in treating insecticide poisoning are limited despite its growing research interest as a safe antioxidant. This prospective study was conducted on eighty patients with acute ChEIs insecticide poisoning admitted to Alexandria Poison Center, Alexandria Main University Hospital, Egypt. Patients were allocated into two equal groups randomly. The L-carnitine (LC) group received the conventional treatment (atropine & toxogonin) and LC and the standard treatment (ST) group received the standard treatment only. Outcome measures were fatality rate, the total administered dose of atropine & toxogonin, length of hospital stay, and the requirement for ICU admission or mechanical ventilation. The study results revealed that malondialdehyde (MDA) significantly decreased in the LC group. Cholinesterase enzyme levels increased significantly after treatment in the LC group than in the ST group. The LC group needed lower dosages of atropine and toxogonin than the ST group. Also, the LC group showed no need for ICU admission or mechanical ventilation. The study concluded that LC can be considered a promising adjuvant antioxidant treatment in acute ChEIs pesticide poisoning. [ABSTRACT FROM AUTHOR]

Objective: In our study, we researched the chemical composition of Linaria corifolia Desf. We also tested in vitro antioxidant, and anticholinesterase activities of different extracts, and compounds from L. corifolia. Methods: We isolated from ethyl acetate and n-butanol extracts of L. corifolia aerial parts. We used various spectroscopic methods. We also compared the results with data in the literature. This allowed us to determine the structure of the compounds. We used different spectroscopic methods and comparisons with literature data to determine the structure of the compounds. We evaluated the antioxidant activities of 20% aqueous methanol, ethyl acetate, and n-butanol extracts using DPPH, ABTS Radical Scavenging Effect, and CUPRAC Assay, and also examined total phenol and flavonoid contents. We used Ellman's method to find the cholinesterase inhibitor activities of the extracts, and isolated compounds. Results: We isolated 6 compounds in ethyl acetate and n-butanol extracts. These compounds have terpenoid (iridoid glycosides), and phenolics (flavonoid, and phenylpropanoid structures). We isolated linariin and acteoside (verbascoside) from ethyl acetate. We isolated antirrhinoside, 6-ß-Hydroxyantirrhide, catalpol, and aucubin from n-butanol extract. The ethyl acetate extract was most active in all antioxidant methods due to its high phenolic content. In contrast to phenolic content, n-butanol extract had more flavonoids. The ethyl acetate extract had higher acetylcholinesterase inhibitory activity at 200 and 400 μg/ml. Linariin had the highest acetylcholinesterase inhibitory effect among the pure compounds. The extracts and pure compounds inhibited butyrylcholinesterase less than acetylcholinesterase. Conclusion: The isolated compounds are new compounds for the L. corifolia plant. The plant's cholinesterase inhibitor activity was investigated for the first time. We found low anti-acetylcholinesterase and butyrylcholinesterase activities. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Health Sciences / Sağlık Bilimleri Dergisi is the property of Erciyes Universitesi Saglik Bilimleri Dergisi and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Dysregulation of oligodendrocyte progenitor cell (OPC) recruitment and oligodendrocyte differentiation contribute to failure of remyelination in human demyelinating diseases such as multiple sclerosis (MS). Deletion of muscarinic receptor enhances OPC differentiation and remyelination. However, the role of ligand-dependent signaling versus constitutive receptor activation is unknown. We hypothesized that dysregulated acetylcholine (ACh) release upon demyelination contributes to ligand-mediated activation hindering myelin repair. Following chronic cuprizone (CPZ)-induced demyelination (male and female mice), we observed a 2.5-fold increase in ACh concentration. This increase in ACh concentration could be attributed to increased ACh synthesis or decreased acetylcholinesterase-/butyrylcholinesterase (BChE)-mediated degradation. Using choline acetyltransferase (ChAT) reporter mice, we identified increased ChAT-GFP expression following both lysolecithin and CPZ demyelination. ChAT-GFP expression was upregulated in a subset of injured and uninjured axons following intraspinal lysolecithin-induced demyelination. In CPZ-demyelinated corpus callosum, ChAT-GFP was observed in Gfap+ astrocytes and axons indicating the potential for neuronal and astrocytic ACh release. BChE expression was significantly decreased in the corpus callosum following CPZ demyelination. This decrease was due to the loss of myelinating oligodendrocytes which were the primary source of BChE. To determine the role of ligand-mediated muscarinic signaling following lysolecithin injection, we administered neostigmine, a cholinesterase inhibitor, to artificially raise ACh. We identified a dose-dependent decrease in mature oligodendrocyte density with no effect on OPC recruitment. Together, these results support a functional role of ligand-mediated activation of muscarinic receptors following demyelination and suggest that dysregulation of ACh homeostasis directly contributes to failure of remyelination in MS. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common cause of dementia. Management of AD is dynamic and multidisciplinary, involving pharmacological and non-pharmacological interventions to manage patient's symptoms, prevent clinical decline and improve quality of life. This study aims to evaluate the standard of patient care provided for the management of AD. Patients and methods: This was a retrospective clinical audit of patients in Brunei Darussalam, with the International Classification of Disease and related health problems, tenth revision (ICD-10) diagnosis of AD between 2019 and 2020. Results: There was a total of 168 patients (68 males, 100 females). Their mean age was 79.5 years. Only half of the patients (n = 84) were advised on measures to take to slow down the progression of the disease, and less than half (49.1%) of eligible patients were offered cognitive stimulation therapy. 51.8% (n = 87) were referred to occupational therapists for assessment of activities of daily living. 113 patients (67.3%) were started on cognitive enhancers; of these, 92 were continued on these medications. Donepezil was the most common drug prescribed (n = 78). Only 44.2% (n = 50) of the 113 patients were maximized on their cognitive enhancer dose. 84.1% had documented follow-up evaluations on the effect of cognitive enhancers. 88 (52.4%) patients had behavioural and psychological symptoms of dementia (BPSD), of whom 64 (72.7%) received treatment, with quetiapine (n = 33, 51.6%) being the most prescribed drug. Conclusions: There are still gaps between guidelines and practice; more effort is needed to improve achieving the standards of care for the management of AD in Brunei Darussalam. [ABSTRACT FROM AUTHOR]

Copyright of Gyermekgyógyászat is the property of Semmelweis Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Exploring novel frameworks for treating Alzheimer's disease is an ambitious objective. In this particular context, a range of asymmetric biscarbothioamide derivatives (3a–l) with varying substitutions have been meticulously designed and effectively synthesized. The newly synthesized compounds have all been definitively characterized using established spectroscopic techniques such as 1H-NMR, 13C-NMR, FT-IR, and elemental analysis. In vitro, all the derivatives (3a–l) were evaluated to assess their inhibitory potential against cholinesterase enzymes (acetylcholinesterase, AChE, and butyrylcholinesterase, BChE). The outcomes demonstrated that these derivatives were potent and exhibited selectivity in inhibiting AChE, except for compounds 3b and 3e, which specifically inhibited BChE, showcasing varying degrees of KI values. Significantly, compounds 3j (KIs of 11.91 ± 2.25 nM for AChE and 77.76 ± 8.02 nM for BChE) and 3h (KIs of 14.73 ± 2.30 nM for AChE and 59.54 ± 6.20 nM for BChE) emerged as the most potent dual inhibitors of AChE and BChE within the series, respectively, with KI constants even lower than those of the standard drug tacrine (KIs of 68.70 ± 5.39 nM for AChE and 111.60 ± 10.52 nM for BChE). Furthermore, their potential scavenging activity against DPPH and ABTS radicals was evaluated. To further validate the experimental findings, molecular docking studies were performed in silico to ascertain the binding modes of these compounds with the active pockets of AChE and BChE enzymes. [ABSTRACT FROM AUTHOR]

D-galactose has been reported to accelerate senescence in rodents, accompanied by a decline in learning and memory. We used a model of D-galactose-induced amnesia for the efficacy evaluation and pharmacologic studies of active compounds against Alzheimer’s disease (AD). DL0410 is a potent inhibitor against acetylcholinesterase (AChE) and, in the present study, the effect of DL0410 was evaluated in this model. We found that DL0410 could significantly improve the learning and memory of D-galactose induced aging mice in a series of behavioral tests: novel-object recognition test, nest-building test, Morris water maze test and step-through test. Pharmacologic studies were conducted from several aspects: the cholinergic system, mitochondrial respiration, oxidative stress, neuroinflammation, apoptosis and synaptic loss. The acetylcholine level and AChE activity were not altered by D-galactose but were slightly affected by DL0410 in the brain. DL0410 could significantly improve decreased mitochondrial respiration in the NADH chain and FADH2 chain, and protect mitochondrial ultrastructure. DL0410 reduced the accumulation of advanced glycation end products (AGEs) and malondialdehyde (MDA) and increase the total antioxidant capability of the brain via an increase in activity of catalase, glutathione peroxidase (GPx) and superoxide dismutase (SOD). RAGE expression was inhibited by DL0410, followed by the decreased activation of astrocytes and microglia. Subsequent phosphorylation of NF-κB was also reversed by DL0410, with lower expression of cyclooxygenase-2 (COX2) and iNOS. With respect to apoptosis, the activation of caspase 3 and cleavage of PARP were downregulated significantly by DL0410, after the inhibition of phosphorylation of JNK induced by inflammation and oxidative stress. Synaptic protection by DL0410 was also demonstrated. These data suggest that mitochondrial protection has a primary role in the ameliorating effect of DL0410 on the impaired learning and memory, oxidative stress, inflammation, apoptosis and synaptic loss induced by D-galactose. DL0410 is a promising candidate for the treatment of aging-related AD, and this study lays an important foundation for its further research and development. [ABSTRACT FROM AUTHOR]

GC/MS analysis of Murraya koenigii (L.) Spreng. and Murraya paniculata (L.) Jacq. leaves revealed the identification of 73 components, with an evident greater contribution of monoterpenes hydrocarbons to their total volatiles. α-Pinene (37.5%) and β-caryophyllene (27.4%) were the most abundant compounds in M. koenigii leaves and β-phellandrene (40.7%) in M. paniculata leaves, using headspace. β-Phellandrene (33.7%) was the major constituent by M. koenigii leaves where germacrene D (23.8%), and δ-elemene (22.0%) were predominant in M. paniculata leaves, using steam distillation. M. koenigii leaves oil showed quite remarkable cholinesterase inhibitory activity, where oil of M. paniculata leaves showed strong inhibitory activity against AChE (IC50=13.2 ± 0.9 µg/mL) and BChE (IC50=5.1 ± 0.3 µg/mL). Germacrene D, α-zingiberene, and δ-elemene showed higher affinity to BChE than AChE as revealed from docking scores (S = −5.65 to −6.03 Kcal/mol) for BChE and (S = −5.56 to −6.25 Kcal/mol) for AChE. [ABSTRACT FROM AUTHOR]

Alzheimer's Diseases are one of the most serious brain condition affecting senior peoples. Improved cognitive disorders therapy, better behaviour and clinical diagnostic standard are recent breakthrough. Placebocontrolled, double--blind, Randomised, parallel group studies evaluating performance -based assessment of cognitive function, activities of daily living and behaviour have been used to clinically evaluate symptomatic treatment that focuses on cholinergic therapy. Patient of Alzheimer's disease are advised to use cholinesterase inhibitors, such as ntamine and tacrine, to address cognitive impairment. Antipsychotics, anxiolytics, antidepressants, mood stabilizer and hypnotics are used in treatment of behavioural disturbance. Evaluation in research and treatment of patients of Alzheimer's disease includes: Applying functional brain imaging techniques and evaluation of treatment efficacy. Development of new classes of medications works on different neurotransmitter systems, for the treatment of cognitive deficits and behavioural disturbance. [ABSTRACT FROM AUTHOR]

Background: Postoperative gastrointestinal dysfunction (POGD) commonly occurs following gastrointestinal (GI) surgery and is associated with specific anesthetic agents. Cholinesterase inhibitors employed for reversing neuromuscular blockade have been implicated in development of POGD. Sugammadex, a novel reversal agent, is linked with reduced POGD. However, there is a lack of comprehensive comparative review between these agents regarding their impact on POGD following GI surgery. This study aims to systematically review the effects of sugammadex on POGD compared to cholinesterase inhibitors following GI surgery. Methods: MEDLINE, EMBASE, and CENTRAL were searched as of July 2022 to identify articles comparing sugammadex with cholinesterase inhibitors in patients undergoing gastrointestinal surgery, specifically in relation to POGD. Secondary endpoints included length of hospital stay, readmission rates, pulmonary complications, and postoperative morbidity. Results: From 198 citations, 2 randomized controlled trials (RCTs) and 3 retrospective cohorts with 717 patients receiving sugammadex and 812 patients receiving cholinesterase inhibitors were included. Significantly lower rates of prolonged postoperative ileus (OR.44, 95% CI.25-.77, P <.05, I2 = 56%, low certainty evidence) was observed with sugammadex. No significant difference in any other outcome was observed. Narrative review of readmission data demonstrated no significant difference. Conclusion: The use of sugammadex following gastrointestinal surgery is associated with significantly lower rates of prolonged postoperative ileus compared to cholinesterase inhibitors. However, these do not translate into a significant reduction in length of stay, morbidity, or postoperative nausea and vomiting. Results are limited by the numer of studies included and missing data, more robust RCTs are needed before recommendations can be made. [ABSTRACT FROM AUTHOR]

In this study, the synthesis of N‐(5,6‐methylenedioxybenzothiazole‐2‐yl)‐2‐[(substituted)thio/piperazine]acetamide/propanamide derivatives (3a‐3k) and to investigate their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β‐secretase 1 (BACE‐1) inhibition activity were aimed. Mass, 1H NMR, and 13C NMR spectra were utilized to determine the structure of the synthesized compounds. Compounds 3b, 3c, 3f, and 3j showed AChE inhibitory activity which compound 3c (IC50 = 0.030 ± 0.001 µM) showed AChE inhibitory activity as high as the reference drug donepezil (IC50 = 0.0201 ± 0.0010 µM). Conversely, none of the compounds showed BChE activity. Compounds 3c and 3j showed the highest BACE‐1 inhibitory activity and IC50 value was found as 0.119 ± 0.004 µM for compound 3j whereas IC50 value was 0.110 ± 0.005 µM for donepezil, which is one of the reference substance. Molecular docking studies have been carried out using the data retrieved from the server of the Protein Data Bank (PDBID: 4EY7 and 2ZJM). Using in silico approach behavior active compounds (3c and 3j) and their binding modes clarified. [ABSTRACT FROM AUTHOR]

Introduction: At present, increasing reports from different aspects indicated that cholinesterase inhibitors (ChEIs) may be effective on improving neuropsychiatric and functional assessment scores in patients with Alzheimer disease (AD). However, no studies comprehensively and detailedly evaluated the effect of ChEIs on AD. The present analysis was designed to comprehensively evaluate the efficacy and safety of ChEIs for AD. Methods: Two independent researchers systematically reviewed 1096 searching records in PubMed, Embase, Cochrane Library, andWeb of Science from inception to 10 May 2023, and finally identified 12 randomized, double-blind, placebo-controlled trials with 6908 participants according to predetermined inclusion and exclusion criteria. The effects were assessed with standardized mean difference (SMD) or odds ratio (OR). The primary outcomes were the mean change and least squares (LS) mean change from baseline to endpoint of neuropsychiatric and functional assessment scores. The secondary outcome was adverse events of ChEIs when compared to placebo for patients with AD. All statistical analyses were performed using the standard statistical procedures provided in Review Manager 5.2 and and Stata 12.0. Results: Pooled analysis indicated that ChEIs significantly improved the assessment scores of the AD Assessment Scale (ADAS) (SMD -1.57; 95% CI: -2.64 to -0.51), Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus) (SMD -0.28; 95% CI: -0.41 to -0.15), the Neuropsychiatric Inventory (NPI) (both SMD -1.67; 95% CI: -2.88 to -0.47 for 10-tiem total score and SMD -1.83; 95% CI: -3.25 to -0.42 for 12-tiem total score), and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL) total score (SMD 2.44; 95% CI: 1.29-3.59), evaluated with mean change from baseline to endpoint. In addition, when evaluated with the LS mean change from baseline to endpoint, ChEIs significantly improved Mini-Mental State Examination (MMSE) total score, the Clinician Interview-Based Impression of Severity, CIBIC-Plus, ADCS-ADL total score, NPI, ADAS. Regarding to adverse events (AEs) of patients with AD, it indicated that compared to placebo, ChEIs did not increase the frequency of severe and serious AEs (fatal or nonfatal) as well as the incidence of death. Conclusions: Our analysis indicated that ChEIs treatment generally improved neuropsychiatric and functional assessment scores in patients with AD though opposite result was observed in Wechsler Memory Scale. ChEIs had an acceptable safety profile in patients with AD without increasing of any crucial adverse or outcomes. [ABSTRACT FROM AUTHOR]

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. 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. 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. [ABSTRACT FROM AUTHOR]

Objective: We aimed to examine the factors associated with treatment outcomes in patients with Alzheimer's disease (AD) after 1 year of acetylcholinesterase inhibitors (AChEI) treatment. Method: We obtained electronic medical records from a medical center in Southern Taiwan between January 2015 and September 2021. Participants aged ≥60 who were newly diagnosed with AD and had been prescribed AChEIs were included. Cognitive assessments were performed before the AChEIs were prescribed and at the 1 year follow‐up. Cognition progressors were defined as a Mini‐Mental State Examination decline of >3 or a Clinical Dementia Rating decline of ≥1 after 1 year of AChEI treatment. The relationship between the baseline characteristics and cognitive status after follow‐up was investigated using logistic regression analysis after adjusting for potential confounders. Results: A total of 1370 patients were included in our study (mean age, 79.86 ± 8.14 years). After adjustment, the body mass index (BMI) was found to be significantly lower in the progressor group [adjusted odds ratio (AOR): 0.970, 95% confidence intervals (95% CIs): 0.943 to 0.997, P = 0.033]. The usage of antipsychotics was significantly higher in the progressor group (AOR: 1.599, 95% CIs: 1.202 to 2.202, P = 0.001). The usage of benzodiazepine receptor agonists also tended to be significantly higher in the progressor group (AOR: 1.290, 95% CIs: 0.996 to 1.697, p = 0.054). Conclusion: These results suggest that patients with AD who receive 1 year of AChEI treatment and have a lower BMI or concurrent treatment with antipsychotics and benzodiazepine receptor agonists are more likely to suffer from cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Electroacupuncture (EA) has been reported to improve intestinal motility in mice with postoperative ileus (POI). Previous studies, however, have yielded heterogeneous results regarding the effect of EA on POI. Methods: Herein, a POI mouse model was constructed by intestinal manipulation. To evaluate the effect of EA treatment on colonic transit, the levels of inflammatory markers (macrophage inflammatory protein (MIP)-1α, interleukin (IL)-1β, IL-6, monocyte chemotactic protein (MCP)-1 and intercellular adhesion molecule (ICAM)-1) were detected by enzyme-linked immunosorbent assay (ELISA); immune cell infiltration was detected by immunohistochemical staining of myeloperoxidase (MPO), ectodysplasin (ED)-1 and ED-2, and the percentage of CD4+ interferon (IFN)-γ+ Th1 cells and IFN-γ secretion levels were determined. Activated Th1 cells and pentoxifylline, a cell differentiation inhibitor, were used to assess the role of Th1 cells in EA treatment of POI. Neostigmine administration and unilateral vagotomy were performed to confirm whether the effects of EA treatment on Th1 cells were mediated by the vagus nerve (VN). Results: The results revealed that EA treatment at ST36 improved POI, as indicated by a decreased level of inflammatory-related markers and immune cell infiltration and shortened colonic transit time. The activated Th1 cells abolished the effects of EA treatment on POI. The effects of EA treatment on POI were enhanced by stimulation of the VN along with a decreased level of Th1 cells, but these effects were abolished by vagotomy along with an increased percentage of Th1 cells; this result indicates that the VN mediates the role of Th1 cells in the effects of EA treatment of POI. Conclusion: Our findings showed that the effects of EA treatment of POI were mainly mediated by Th1 cells through the stimulation of the VN and inhibition of the inflammatory response. [ABSTRACT FROM AUTHOR]

In this paper, we developed a series of piperic acid (PA) analogs with the aim of overcoming the limitations associated with the natural products for the management of Alzheimer's disease (AD). A comprehensive SAR study was performed to enhance cholinesterase inhibition of PA. The acetylcholinesterase inhibition and its kinetic data suggested 6j as the lead molecule (AChE IC50 = 2.13 ± 0.015 µM, BChE = 28.19 ± 0.20%), in comparison to PA (AChE = 7.14 ± 0.98%) which was further selected for various biological studies in AD models. 6j, exhibited interaction with the peripheral anionic site of AChE, BBB permeability (Pe = 7.98), and antioxidant property (% radical scavenging activity = 35.41 ± 1.09, 2.43 ± 1.65, for 6j and PA at 20 M μ , respectively). The result from the metal chelation study suggests that 6j did not effectively chelate iron. The molecular modeling studies suggested that 6j could effectively interact with Ser293, Phe295, Arg296, and Tyr34 of AChE. In the cell-based cytotoxicity studies, 6j exhibited cytocompatibility at the different tested concentrations. The acute toxicity data on mice suggested that compound 6j had no renal and hepatotoxicity at 500 mg/kg. Moreover, 6j could effectively reverse scopolamine-induced amnesia by improving spatial and cognitive memory in mice. The above results strongly suggest that compound 6j may act as a novel multi-targeted lead for AD therapy. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder, in which there is a progressive deterioration of intellectual and social functions, memory loss, personality changes and inability for self-care, and has become the fourth leading cause of death in developed countries. Pathogenesis of AD, there is a progressive deposition of ß-amyloid (Aß)- peptide in the hippocampal and cerebral cortical regions. This deposition is associated with the presence of neurofibrillary tangles (NFTs) and senile plaques. The senile plaques deposited between the neurons consist mainly protein ß amyloid. Neurofibrillary tangles deposited inside the neurons fabricated from Tau protein. Diagnosing Alzheimer's requires careful medical evaluation thorough medical history, mental status testing, physical and neurological examination tests (such as blood tests and brain imaging), two classes of medications approved to treat AD. Cholinesterase inhibitors: Donepezil, Rivastigmine, Galantamine, NMDA receptor antagonists: Memantine. The major goal in designing nanoparticles as a delivery system are to control particle size, surface property and release of pharmacologically active agents in order to achieve the site-specific action of the drug at the therapeutic optimum rate and dose regimen of the agent to the CNS, but also the ability of the agent to access the relevant target site within the CNS. Many strategies have been developed to deliver the drug into brain by crossing the BBB: chemical delivery systems, magnetic drug targeting or drug carrier systems such as antibodies, liposomes or nanoparticles. Among those, nanoparticles have got a great concentration as the potential targeted drug delivery systems in the brain recently. [ABSTRACT FROM AUTHOR]

IntroductionWith an increasing prevalence, dementia is one of the most disabling diseases among the elderly. Impaired cognitive function and behavioral and psychological symptoms predispose patients to medication non-adherence, resulting in increased morbidity, mortality, and healthcare costs. The aim of this study was to estimate the prevalence of non-adherence to antidementia medications and to identify the main predictors.MethodsA population-based registry study was conducted in 2022 in Castile and Leon, Spain. A total of 17,563 patients with dementia were included. The medication possession ratio (MPR) was used as an indirect method to measure adherence. The cut-off point for determining that a patient was nonadherent was 80% of MPR. Multivariate logistic regression was used to identify predictors of nonadherence based on sociodemographic and health-related variables.ResultsIn 2022, 6.2% of the population over 80 years old used antidementia medications. Of these patients, 70% were women, 28.15% were institutionalized, and over 90% were polymedicated and had multiple prescribers. The most used medicines were donepezil (43.49%), rivastigmine (36.84%), and memantine (30.7%). The combined use of an acetylcholinesterase inhibitor plus memantine was relevant (13.33%). Men were less adherent than women, and the prevalence of non-adherence decreased with age. The medication associated with the highest prevalence of non-adherence was rivastigmine (19%), followed by donepezil (17%) and memantine (13.23%). Institutionalized patients (13%) and patients on combination therapy (13.29%) had the lowest prevalence of non-adherence. Protective factors against non-adherence include institutionalization, polymedication, use of memantine or combination therapy, and comorbid mental illness.ConclusionsIn Castile and Leon, one in six patients were non-adherent to antidementia medications. Younger male patients with cardiometabolic disease are more likely to be non-adherent to antidementia medications. On the other hand, institutionalization is a protective factor against non-adherence, but still 10% of nursing home patients are non-adherent to antidementia medications.

Background: The cholinergic system regulates a variety of structures on the ocular surface and maintains homeostasis. Therefore, dysregulation of cholinergic activity could impact lacrimal and conjunctival function. Consequently, exposure of the ocular surface to chemical agents, including pesticides such as acetylcholinesterase inhibitors, which interact closely with the ocular surface and anterior segment, could affect ocular homeostasis. In this study, we assess alterations in the ocular surface in workers exposed to organophosphate pesticides. Methods: A cross-sectional study was conducted involving 39 participants (23 controls and 16 cases exposed to agrochemicals). The ocular surface of all subjects was assessed using the Schirmer test, TBUT, conjunctival impression cytology, and the Q16 neurotoxicity and ocular symptoms questionnaire by Donate. Results: Conjunctival hyperemia, impression cytology and Schirmer test were found to be altered in the workers exposed to cholinesterase inhibitor pesticides. Conclusion: These findings suggest that ocular surface alterations can be seen in organophosphate pesticide exposure, and that lacrimal hypersecretion could be an ocular biomarker for detecting pesticide effects before adverse clinical effects occur.