Electrochemical Acetylcholinesterase Sensors for Anti-Alzheimer's Disease Drug Determination.

Neurodegenerative diseases and Alzheimer's disease (AD), as one of the most common causes of dementia, result in progressive losses of cholinergic neurons and a reduction in the presynaptic markers of the cholinergic system. These consequences can be compensated by the inhibition of acetylcholinesterase (AChE) followed by a decrease in the rate of acetylcholine hydrolysis. For this reason, anticholinesterase drugs with reversible inhibition effects are applied for the administration of neurodegenerative diseases. Their overdosage, variation in efficiency and recommendation of an individual daily dose require simple and reliable measurement devices capable of the assessment of the drug concentration in biological fluids and medications. In this review, the performance of electrochemical biosensors utilizing immobilized cholinesterases is considered to show their advantages and drawbacks in the determination of anticholinesterase drugs. In addition, common drugs applied in treating neurodegenerative diseases are briefly characterized. The immobilization of enzymes, nature of the signal recorded and its dependence on the transducer modification are considered and the analytical characteristics of appropriate biosensors are summarized for donepezil, huperzine A, rivastigmine, eserine and galantamine as common anti-dementia drugs. Finally, the prospects for the application of AChE-based biosensors in clinical practice are discussed.

In-depth analysis of data from the RAS-ALS study reveals new insights in rasagiline treatment for amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: In 2016, we concluded a randomized controlled trial testing 1 mg rasagiline per day add-on to standard therapy in 252 amyotrophic lateral sclerosis (ALS) patients. This article aims at better characterizing ALS patients who could possibly benefit from rasagiline by reporting new subgroup analysis and genetic data. METHODS: We performed further exploratory in-depth analyses of the study population and investigated the relevance of single nucleotide polymorphisms (SNPs) related to the dopaminergic system. RESULTS: Placebo-treated patients with very slow disease progression (loss of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R] per month before randomization of ≤0.328 points) showed a per se survival probability after 24 months of 0.85 (95% confidence interval = 0.65-0.94). The large group of intermediate to fast progressing ALS patients showed a prolonged survival in the rasagiline group compared to placebo after 6 and 12 months (p = 0.02, p = 0.04), and a reduced decline of ALSFRS-R after 18 months (p = 0.049). SNP genotypes in the MAOB gene and DRD2 gene did not show clear associations with rasagiline treatment effects. CONCLUSIONS: These results underline the need to consider individual disease progression at baseline in future ALS studies. Very slow disease progressors compromise the statistical power of studies with treatment durations of 12-18 months using clinical endpoints. Analysis of MAOB and DRD2 SNPs revealed no clear relationship to any outcome parameter. More insights are expected from future studies elucidating whether patients with DRD2CC genotype (Rs2283265) show a pronounced benefit from treatment with rasagiline, pointing to the opportunities precision medicine could open up for ALS patients in the future.

The effects of different acetylcholinesterase inhibitors on EEG patterns in patients with Alzheimer's disease: A systematic review.

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.

Patterns of use of symptomatic treatments for Alzheimer's disease dementia (AD).

BACKGROUND: Symptomatic treatment for Alzheimer's disease (AD) dementia could temporarily slow symptom worsening and improve the quality of life for both AD dementia patients and their caregivers. A comprehensive evaluation of symptomatic treatment patterns using recent data for newly diagnosed AD dementia has not been performed and compared across different countries. METHODS: The drug name, time to the first therapy, duration, discontinuation or switches were described in newly diagnosed AD dementia patients in two databases (a major U.S. health plan [US] and UK-Clinical Practice Research Datalink [CPRD GOLD]). This analysis included patients with newly diagnosed AD dementia in 2018-2019, who initiated symptomatic AD drug therapy, with ≥ 1 year baseline period and ≥ 1 year of follow-up. RESULTS: Over median follow-ups of 698 and 645 days, 63% and 65% of AD dementia patients used symptomatic treatments, with 34% and 77% newly initiating therapy, constituting analytic samples of 7637 patients in the US database and 4470 patients in the CPRD, respectively. The median time to the first therapy was 14 days for US and 49 days for CPRD; donepezil ranked the as most frequently used (69% vs 61%), followed by memantine (19% vs 28%) in the US database and CPRD, respectively. Median time on first therapy was 213 and 334 days, and 30% and 12% of patients proceeded to a second treatment in the US and CPRD databases, respectively. CONCLUSION: Approximately two thirds of newly diagnosed AD dementia patients utilized approved symptomatic treatment. Time on first therapy was relatively short (< 1 year) and the majority did not move to a second therapy, highlighting the need for better adherence and persistence to existing AD symptomatic therapies and the need for additional therapies to alleviate the significant burden of AD dementia.

Consumption of drugs for Alzheimer's disease on the Brazilian private market.

OBJECTIVE: To analyze the consumption of drugs for Alzheimer's disease on the Brazilian private market and its geographical distribution from 2014 to 2020. METHODS: National data from the Brazilian National System of Controlled Product Management were used, regarding sales of donepezil, galantamine, rivastigmine, and memantine from January 2014 to December 2020. Sales data were used as a proxy for drug consumption and expressed as defined daily dose/1,000 inhabitants/year at national, regional, federative unit and microregion levels. RESULTS: Drug consumption went from 5,000 defined daily doses/1,000 inhabitants, in 2014, to more than 16,000/1,000 inhabitants, in 2020, and all federative units showed positive variation. The Brazilian Northeast had the highest cumulative consumption in the period but displayed microregional disparities while the North region had the lowest consumption. Donepezil and memantine were the most consumed drugs, with the highest growth in consumption from 2014 to 2020. CONCLUSION: The consumption of medicines indicated to treat Alzheimer's disease tripled in Brazil between 2014 and 2020, which may relate to the increase in the prevalence of the disease in the country, greater access to health services, and inappropriate use. This challenges managers and healthcare providers due to population aging and the increased prevalence of chronic-degenerative diseases.

Prevalence of treated patients with Alzheimer's disease: current trends and COVID-19 impact.

BACKGROUND: There are few updated studies on the prevalence and management of Alzheimer's disease (AD), which could be underdiagnosed or undertreated. The COVID-19 pandemic may have worsened the deficiencies in the diagnosis and treatment of these patients. Electronic medical records (EMR) offer an opportunity to assess the impact and management of medical processes and contingencies in the population. OBJECTIVE: To estimate AD prevalence in Spain over a 6-year period, based on treated patients, according to usual clinical practice. Additionally, to describe the management of AD-treated patients and the evolution of that treatment during the 2020 COVID-19 pandemic. METHODS: Retrospective study using the Spanish IQVIA EMR database. Patients treated with donepezil, galantamine, rivastigmine, and/or memantine were included in the study. Annual AD prevalence (2015-2020) was estimated and extrapolated to the national population level. Most frequent treatments and involved specialties were described. To assess the effect of COVID-19, the incidence of new AD cases in 2020 was calculated and compared with newly diagnosed cases in 2019. RESULTS: Crude AD prevalence (2015-2020) was estimated at 760.5 per 100,000 inhabitants, and age-standardized prevalence (2020) was 664.6 (male 595.7, female 711.0). Monotherapy was the most frequent way to treat AD (86.2%), in comparison with dual therapy (13.8%); rivastigmine was the most prescribed treatment (37.3%), followed by memantine (36.4%) and donepezil (33.0%). Rivastigmine was also the most utilized medication in newly treated patients (46.7%), followed by donepezil (29.8%), although donepezil persistence was longer (22.5 vs. 20.6 months). Overall, donepezil 10 mg, rivastigmine 9.5 mg, and memantine 20 mg were the most prescribed presentations. The incidence rate of AD decreased from 148.1/100,000 (95% confidence interval [CI] 147.0-149.2) in 2019 to 118.4/100,000 (95% CI 117.5-119.4) in 2020. CONCLUSIONS: The obtained prevalence of AD-treated patients was consistent with previous face-to-face studies. In contrast with previous studies, rivastigmine, rather than donepezil, was the most frequent treatment. A decrease in the incidence of AD-treated patients was observed during 2020 in comparison with 2019, presumably due to the significant impact of the COVID-19 pandemic on both diagnosis and treatment. EMR databases emerge as valuable tools to monitor in real time the incidence and management of medical conditions in the population, as well as to assess the health impact of global contingencies and interventions.

Efficacy of donepezil plus hydrogen-oxygen mixture inhalation for treatment of patients with Alzheimer disease: A retrospective study.

To investigate the clinical effect of donepezil combined with hydrogen-oxygen mixture inhalation in the treatment of patients with Alzheimer disease (AD), a total of 273 AD patients admitted to our hospital from March 2018 to March 2022 were retrospectively analyzed and assigned into an observation group (n = 138) and a control group (n = 135) according to the different treatment that they received. The control group was treated with donepezil tablets, while the observation group was treated with donepezil tablets combined with hydrogen-oxygen mixture inhalation. The scores of mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA), Alzheimer's Disease Assessment Scale-Cognition, activity of daily living scale (ADL) and the P300 event-related potential were compared between the 2 groups. After treatment, MMSE score, MoCA score, and ADL score in both groups increased after treatment (P < .01), while the improvement in the observation group was more significant than that in the control group (P < .001 for MMSE, P = .003 for MoCA, and P = .013 for ADL). The scores of Alzheimer's Disease Assessment Scale-Cognition in the observation group decreased after treatment (P < .05), while the improvement in the observation group was more significant than that in the control group (P = .005). After treatment, the latency of P300 in both groups was shortened (P < .01), and the improvement in the observation group was more significant than that in the control group (P < .001). The amplitude of the observation group increased after treatment (P < .01), and the improvement of the observation group was significant than that of the control group (P = .007). The clinical efficacy of donepezil combined with hydrogen-oxygen mixture inhalation in the treatment of AD is better than that of donepezil alone, which is worthy of further study.

Effect of Acetylcholinesterase Inhibitors on Cerebral Perfusion and Cognition: A Systematic Review.

BACKGROUND: Perfusion imaging has the potential to identify neurodegenerative disorders in a preclinical stage. However, to correctly interpret perfusion-derived parameters, the impact of perfusion modifiers should be evaluated. OBJECTIVE: In this systematic review, the impact of acute and chronic intake of four acetylcholinesterase inhibitors (AChEIs) on cerebral perfusion in adults was investigated: physostigmine, donepezil, galantamine, and rivastigmine. RESULTS: Chronic AChEI treatment results in an increase of cerebral perfusion in treatment-responsive patients with Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease dementia in the frontal, parietal, temporal, and occipital lobes, as well as the cingulate gyrus. These effects appear to be temporary, dose-related, and consistent across populations and different AChEI types. On the contrary, further perfusion decline was reported in patients not receiving AChEIs or not responding to the treatment. CONCLUSION: AChEIs appear to be a potential perfusion modifier in neurodegenerative patients. More research focused on quantitative perfusion in both patients with and without a cholinergic deficit is needed to draw conclusions on whether AChEI intake should be considered when analyzing perfusion data.

The measured CSF/plasma donepezil concentration ratio but not individually measured CSF and plasma concentrations significantly increase over 24 h after donepezil treatment in patients with Alzheimer's disease.

BACKGROUND: The acetylcholinesterase inhibitor donepezil is administered as a treatment for Alzheimer's disease (AD). However, the appropriate donepezil dosage is still a matter of debate. METHODS: Forty AD patients receiving 10 mg/day of donepezil were randomly divided into four groups based on the time of plasma and cerebrospinal fluid (CSF) sampling: 6 h (n = 5), 12 h (n = 12), 18 h (n = 6) and 24 h (n = 17) after donepezil administration. High-performance liquid chromatography measured the donepezil concentration in plasma samples and CSF samples collected at 4-time points. RESULTS: Plasma and CSF levels among the groups were not significantly different. Conversely, the CSF/plasma donepezil concentration ratio considerably increased in the 24 h group compared to the 6 h (p < 0.005) and 12 h (p < 0.05) groups. CONCLUSION: The measurement of the CSF/plasma donepezil concentration ratio could be used to better evaluate the optimal dose of donepezil.

Ozanimod in the Treatment of Ulcerative Colitis: Initial Real-World Data From a Large Tertiary Center.

Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon and rectum. Long-term therapy is generally required to achieve and maintain disease control.1 In May 2021 the US Food and Drug Administration approved the use of ozanimod in patients with moderate to severe UC. We describe the first report of the use of ozanimod in real-world clinical practice.

Monoamine-oxidase Type B Inhibitors and Cognitive Functions in Parkinson's Disease: Beyond the Primary Mechanism of Action.

Symptoms of cognitive impairment are rather common since the early stage of Parkinson's disease (PD); they aggravate with disease progression and may lead to dementia in a significant proportion of cases. Worsening of cognitive symptoms in PD patients depends on the progression of subcortical dopaminergic damage as well as the involvement of other brain neurotransmitter systems in cortical and subcortical regions. Beyond the negative impact on disability and quality of life, the presence and severity of cognitive symptoms may limit adjustments of dopamine replacement therapy along the disease course. This review focuses on the consequences of the administration of monoamine-oxidase type Binhibitors (MAOB-I) on cognition in PD patients. Two drugs (selegiline and rasagiline) are available for the treatment of motor symptoms of PD as monotherapy or in combination with L-DOPA or dopamine agonists in stable and fluctuating patients; a further drug (safinamide) is usable in fluctuating subjects solely. The results of available studies indicate differential effects according to disease stage and drug features. In early, non-fluctuating patients, selegiline and rasagiline ameliorated prefrontal executive functions, similarly to other dopaminergic drugs. Benefit on some executive functions was maintained in more advanced, fluctuating patients, despite the tendency of worsening prefrontal inhibitory control activity. Interestingly, high-dose safinamide improved inhibitory control in fluctuating patients. The benefit of high-dose safinamide on prefrontal inhibitory control mechanisms may stem from its dual mechanism of action, allowing reduction of excessive glutamatergic transmission, in turn secondary to increased cortical dopaminergic input.

Comparative efficacy and safety of monoamine oxidase type B inhibitors plus channel blockers and monoamine oxidase type B inhibitors as adjuvant therapy to levodopa in the treatment of Parkinson's disease: a network meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: The monoamine oxidase type B inhibitors plus channel blockers (MAO-BIs plus) are a new class of antiparkinsonian drug with additional mechanisms of action for their property as ion channel blockers. The present study aimed to compare the efficacy and safety of MAO-BIs plus and conventional MAO-BIs, as well as their corresponding doses, as adjuvant therapy to levodopa in the treatment of Parkinson's disease (PD). METHOD: Randomized controlled trials enrolling PD patients treated with selegiline, rasagiline, safinamide or zonisamide as adjuvant therapy to levodopa were identified. Bayesian network meta-analysis was conducted. RESULTS: Thirty-one randomized controlled trials comprising 7142 PD patients were included. Compared with levodopa monotherapy, the combination therapy of MAO-BIs and levodopa was significantly more effective, with a mean difference of 2.74 (1.26-4.18) on the Unified Parkinson's Disease Rating Scale (UPDRS) III score change for selegiline, 2.67 (1.45-3.87) for safinamide, 2.2 (0.98-3.64) for zonisamide and 2.04 (1.24-2.87) for rasagiline. No significant difference was detected amongst MAO-BIs. The surface under the cumulative ranking results showed that safinamide 100 mg and rasagiline 1 mg ranked first in improving UPDRS III and UPDRS II, respectively. Zonisamide 100 mg ranked first in reducing OFF time. For safety outcomes, rasagiline was associated with a higher incidence of adverse events than placebo and safinamide. MAO-BIs plus had a higher probability of being safer agents compared to conventional MAO-BIs. CONCLUSIONS: Monoamine oxidase type B inhibitors plus, conventional MAO-BIs and the corresponding doses are similar in efficacy in PD treatment. MAO-BIs plus might be safer than conventional MAO-BIs. Head-to-head comparisons are needed for further investigation.

In vitro assessment of the binding and functional responses of ozanimod and its plasma metabolites across human sphingosine 1-phosphate receptors.

Ozanimod is approved in multiple countries for the treatment of adults with either relapsing multiple sclerosis or moderately to severely active ulcerative colitis. Ozanimod is metabolized in humans to form seven active plasma metabolites, including two major active metabolites CC112273 and CC1084037, and an inactive metabolite. Here, the binding and activity of ozanimod and its metabolites across human sphingosine 1-phosphate receptors were determined. Binding affinity was assessed in Chinese hamster ovary cell membranes expressing recombinant human sphingosine 1-phosphate receptors 1 and 5 via competitive radioligand binding using tritium-labeled ozanimod; selectivity via functional potency assessment was performed using [35S]-guanosine-5'-(γ-thio)-triphosphate binding assays. Receptor internalization was assessed in human embryonic kidney 293 cells overexpressing sphingosine 1-phosphate receptor 1-green fluorescent protein and Chinese hamster ovary cells overexpressing sphingosine 1-phosphate receptor 5-hemagglutinin via fluorescence activated cell sorting. Functional activity was assessed in primary cultures of human astrocytes via phosphorylation assays. Ozanimod and its functionally active metabolites bound to the same sites within sphingosine 1-phosphate receptors 1 and 5, with metabolites displaying the same selectivity profile as ozanimod. Agonism at sphingosine 1-phosphate receptor 1 induced receptor internalization, whereas sphingosine 1-phosphate receptor 5 did not. Ozanimod, CC112273, and CC1084037 elicited functional intracellular signaling in human astrocytes, pharmacologically characterized to be mediated by sphingosine 1-phosphate receptor 1. The active plasma metabolites of ozanimod bound to sphingosine 1-phosphate receptors 1 and 5 and displayed similar pharmacologic profiles as their parent compound, likely contributing to clinical efficacy in patients with relapsing multiple sclerosis or moderately to severely active ulcerative colitis.

Effects of monotherapy with a monoamine oxidase B inhibitor on motor symptoms in Parkinson's disease are dependent on frontal function.

BACKGROUND: Monotherapy with monoamine oxidase B (MAO-B) inhibitors enhances the level of endogenous dopamine in treatment for Parkinson's disease (PD) and provides some benefits. Certain neuropsychiatric functions are also regulated by central dopaminergic activity. AIM: To investigate the relationship of the efficacy of monotherapy with MAO-B inhibitors on motor symptoms in PD with baseline cognitive function. PATIENTS AND METHODS: Outcomes were examined for 27 consecutive drug-naïve PD patients who received initial treatment with a MAO-B inhibitor (selegiline: 11, rasagiline: 16). Selegiline was titrated to an optimal dose. The dose of rasagiline was fixed at 1 mg/day. Motor symptoms were assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III before treatment and after the efficacy reached a plateau within 19 weeks after drug initiation, and the % improvement in motor symptoms was calculated. Pre-treatment cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB). Correlations of % improvement in motor symptoms and baseline cognitive assessments were examined using Spearman correlation coefficients and multiple regression analysis. RESULTS: In all patients, the mean % improvement in motor symptoms was 46.5% (range 0-83.3%). Spearman correlation coefficients showed the % improvement in motor symptoms was correlated with FAB (r = 0.631, p < 0.001). In multiple regression analysis with patient background factors as independent variables, only FAB was associated with improvement in motor symptoms in the MAO-B group. CONCLUSION: Better FAB scores predict a significant improvement in motor symptoms with treatment with MAO-B inhibitors, suggesting high activity of endogenous dopamine.

Combination of Donepezil and Memantine Attenuated Cognitive Impairment Induced by Mixed Endocrine-Disrupting Chemicals: an In Silico Study.

Little is known about the effects of endocrine-disrupting chemicals (EDCs) and the combination of memantine and donepezil on the pathogenesis of cognitive impairment. Here, we aimed to identify in silico the molecular mechanisms of the combination of memantine and donepezil that combat cognitive impairment induced by nine common EDCs using GeneMania, AutoDock Vina, Metascape, SwissADME, MIENTURNET, and miRNAsong. We observed that the mixture of memantine and donepezil had therapeutic effects on mixed EDC-induced cognitive impairment via five genes (TNF, ACHE, BAX, IL1B, and CASP3). With ACHE and TNF, donepezil and memantine both had a high docking score, respectively. The predominant connections among five mutual genes were physical interactions (77.6%). The major pathways associated with memantine and donepezil countering cognitive impairment generated by mixed EDCs were discovered to be "AGE-RAGE signaling pathway in diabetic complications," "pro-survival signaling of neuroprotectin D1," and "non-alcoholic fatty liver disease." The miRNAs and transcription factors implicated in memantine and donepezil protecting against mixed EDCs were hsa-miR-128-3p and hsa-miR-34a-5p, NFKB1, NFKB2, IRF8, and E2F4. The sponges' tertiary structure predictions for two major miRNAs were provided. The physicochemical and pharmacokinetic properties of memantine and donepezil highlighted the need for a therapeutic combination of these medications to treat cognitive impairment.

Real-world effects of anti-dementia treatment on mortality in patients with Alzheimer´s dementia.

To examine the real-world effects of the cholinesterase inhibitors (AChEI) on all-cause mortality. A nationwide, retrospective cohort study. Participants were diagnosed with incident AD in Denmark from January 1, 2000 to December 31, 2011 with follow-up until December 31, 2012. A total of 36,513 participants were included in the current study with 22,063 deaths during 132,426 person-years of follow-up. At baseline, patients not treated with AChEI (n = 28,755 [9961 males (35%)]) had a mean age ±â€…standard deviation (SD) of 80.33 ±â€…7.98 years (78.97 ±â€…8.26 for males and 81.04 ±â€…7.98 for females), as compared to 79.95 ±â€…7.67 (78.87 ±â€…7.61 for males and 80.61 ±â€…7.63 for females) in the group exposed at baseline. Patients treated with AChEI had a beneficial hazard ratio (HR) of 0.69, 95% confidence interval (CI) (0.67-0.71) for all-cause mortality as compared to patients not treated, with donepezil (HR 0.80, 95% CI [0.77-0.82]) and galantamine (HR 0.93,95% CI [0.89-0.97]) having beneficial effects on mortality rate as compared to non-treatment, whereas rivastigmine (HR 0.99, 95% CI [0.95-1.03]) was associated with a mortality rate comparable to non-treatment with AChEI. Patients were primarily exposed to donepezil (65.8%) with rivastigmine (19.8%) and galantamine (14.4%) being used less often. These findings underscore the effect of AChEI on not only reducing speed of cognitive decline but also directly prolonging life, which could result in changes in treatment recommendation for when to stop treatment.

Design, synthesis and biological evaluation of a new series of arylidene indanones as small molecules for targeted therapy of non-small cell lung carcinoma and prostate cancer.

In an attempt to identify small molecules for targeted therapy of non-small cell lung carcinoma (NSCLC) and prostate cancer (PCa), new arylidene indanones (1-10) were synthesized via the Claisen-Schmidt condensation of 5,6-methylenedioxy-1-indanone with p-substituted benzaldehyde. Compounds 1-10 were assessed for their cytotoxic effects on human lung adenocarcinoma (A549) and human pancreatic ductal carcinoma (PANC-1) cells as well as human normal lung fibroblast (CCD-19Lu) and human normal pancreatic ductal epithelial (hTERT-HPNE) cells. Among them, compounds 2, 4 and 10 were more effective on A549 and PANC-1 cells than cisplatin. Compounds 1 and 9 also showed more potent cytotoxic activity towards PANC-1 cells than cisplatin. In vitro assays were performed to assess their effects on DNA synthesis, apoptosis, caspase-3, mitochondrial membrane potential, intracellular calcium levels, morphological changes in cancer cells. Furthermore, all compounds were investigated for their inhibitory effects on cathepsin L (CatL) and cathepsin D (CatD). Compounds 2 and 4 exerted potent anti-NSCLC action through caspase-independent apoptosis induced by an increase in intracellular calcium level and correspondingly the disruption of the ΔΨm. These compounds also caused apoptotic morphological alterations in A549 cells. Compound 4 also inhibited both cathepsins but its inhibitory potency on CatL was more significant. Based on in vitro mechanistic assays, compound 4 was identified as a promising anticancer agent for targeted therapy of NSCLC. On the other hand, the marked anti- PCa activity of compound 1 mediated by apoptotic cell death is also noteworthy, but further enzymatic assays are required to elucidate its main mechanism of action.

Anti-Dementia Drug Persistence Following Donepezil Initiation Among Alzheimer's Disease Patients in Japan: LIFE Study.

BACKGROUND: Donepezil is frequently used to treat Alzheimer's disease (AD) symptoms but is associated with early discontinuation. Determining the persistence rates of anti-dementia drug use after donepezil initiation may inform the development and improvement of treatment strategies, but there is little evidence from Japan. OBJECTIVE: To determine anti-dementia drug persistence following donepezil initiation among AD patients in Japan using insurance claims data. METHODS: Insurance claims data for AD patients with newly prescribed donepezil were obtained from 17 municipalities between April 2014 and October 2021. Anti-dementia drug persistence was defined as a gap of ≤60 days between the last donepezil prescription and a subsequent prescription of donepezil, another cholinesterase inhibitor, or memantine. Cox proportional hazards models were used to analyze the association between care needs levels and discontinuation. RESULTS: We analyzed 20,474 AD patients (mean age±standard deviation: 82.2±6.3 years, women: 65.7%). The persistence rates were 89.1% at 30 days, 79.4% at 90 days, 72.6% at 180 days, 64.5% at 360 days, and 58.3% at 540 days after initiation. Among the care needs levels, the hazard ratio (95% confidence interval) for discontinuation was 1.01 (0.94-1.07) for patients with support needs, 1.12 (1.06-1.18) for patients with low long-term care needs, and 1.31 (1.21-1.40) for patients with moderate-to-high long-term care needs relative to independent patients. CONCLUSION: Japanese AD patients demonstrated low anti-dementia drug persistence rates that were similar to those of other countries. Higher long-term care needs were associated with discontinuation. Further measures are needed to improve drug persistence in AD patients.

Ozanimod as a novel oral small molecule therapy for the treatment of Crohn's disease: The YELLOWSTONE clinical trial program.

BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate receptor modulator currently approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis, showed clinical, endoscopic, and histological benefit in the phase 2 STEPSTONE trial for Crohn's disease (CD). We aim to describe the trial design of the YELLOWSTONE phase 3 program evaluating the safety and efficacy of ozanimod in patients with moderately to severely active CD. METHODS: The YELLOWSTONE program consists of phase 3, randomized, double-blind, placebo-controlled induction (NCT03440372 and NCT03440385) and maintenance (NCT03464097) trials and an open-label extension (OLE) study (NCT03467958). Patients with inadequate response or intolerance to ≥1 CD treatment are randomized to receive daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo for 12 weeks during induction. Those who respond to ozanimod are rerandomized to continue ozanimod or placebo maintenance therapy for 52 weeks. Patients who do not meet criteria for maintenance, experience relapse during maintenance, or complete maintenance or ≥ 1 year of STEPSTONE are eligible for open-label treatment for up to 234 weeks. Efficacy endpoints include clinical, endoscopic, and histologic outcomes. RESULTS: Expected 2023 (induction studies), 2024 (maintenance study), and 2026 (OLE). CONCLUSION: YELLOWSTONE will provide pivotal phase 3 data on the safety and efficacy of ozanimod in patients with moderately to severely active CD using state-of-the-art methods, including centrally read endoscopic and histologic measurements, along with subjective assessments of symptom control based on the Crohn's Disease Activity Index. These studies could enable approval of ozanimod as a new CD therapy. CLINICAL TRIAL REGISTRATION NUMBERS: NCT03440372, NCT03440385, NCT03464097, NCT03467958.

Neuroprotective Function of Rasagiline and Selegiline, Inhibitors of Type B Monoamine Oxidase, and Role of Monoamine Oxidases in Synucleinopathies.

Synucleinopathies are a group of neurodegenerative disorders caused by the accumulation of toxic species of α-synuclein. The common clinical features are chronic progressive decline of motor, cognitive, behavioral, and autonomic functions. They include Parkinson's disease, dementia with Lewy body, and multiple system atrophy. Their etiology has not been clarified and multiple pathogenic factors include oxidative stress, mitochondrial dysfunction, impaired protein degradation systems, and neuroinflammation. Current available therapy cannot prevent progressive neurodegeneration and "disease-modifying or neuroprotective" therapy has been proposed. This paper presents the molecular mechanisms of neuroprotection by the inhibitors of type B monoamine oxidase, rasagiline and selegiline. They prevent mitochondrial apoptosis, induce anti-apoptotic Bcl-2 protein family, and pro-survival brain- and glial cell line-derived neurotrophic factors. They also prevent toxic oligomerization and aggregation of α-synuclein. Monoamine oxidase is involved in neurodegeneration and neuroprotection, independently of the catalytic activity. Type A monoamine oxidases mediates rasagiline-activated signaling pathways to induce neuroprotective genes in neuronal cells. Multi-targeting propargylamine derivatives have been developed for therapy in various neurodegenerative diseases. Preclinical studies have presented neuroprotection of rasagiline and selegiline, but beneficial effects have been scarcely presented. Strategy to improve clinical trials is discussed to achieve disease-modification in synucleinopathies.