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

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

Endophytic fungi: a potential source for drugs against central nervous system disorders.

Neuroprotection is one of the important protection methods against neuronal cells and tissue damage caused by neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and multiple sclerosis. Various bioactive compounds produced by medicinal plants can potentially treat central nervous system (CNS) disorders. Apart from these resources, endophytes also produce diverse secondary metabolites capable of protecting the CNS. The bioactive compounds produced by endophytes play essential roles in enhancing the growth factors, antioxidant defence functions, diminishing neuroinflammatory, and apoptotic pathways. The efficacy of compounds produced by endophytic fungi was also evaluated by enzymes, cell lines, and in vivo models. Acetylcholine esterase (AChE) inhibition is frequently used to assess in vitro neuroprotective activity along with cytotoxicity-induced neuronal cell lines. Some of drugs, such as tacrine, donepezil, rivastigmine, galantamine, and other compounds, are generally used as reference standards. Furthermore, clinical trials are required to confirm the role of these natural compounds in neuroprotection efficacy and evaluate their safety profile. This review illustrates the production of various bioactive compounds produced by endophytic fungi and their role in preventing neurodegeneration.

Advances on Therapeutic Strategies for Alzheimer's Disease: From Medicinal Plant to Nanotechnology.

Alzheimer's disease (AD) is a chronic dysfunction of neurons in the brain leading to dementia. It is characterized by gradual mental failure, abnormal cognitive functioning, personality changes, diminished verbal fluency, and speech impairment. It is caused by neuronal injury in the cerebral cortex and hippocampal area of the brain. The number of individuals with AD is growing at a quick rate. The pathology behind AD is the progress of intraneuronal fibrillary tangles, accumulation of amyloid plaque, loss of cholinergic neurons, and decrease in choline acetyltransferase. Unfortunately, AD cannot be cured, but its progression can be delayed. Various FDA-approved inhibitors of cholinesterase enzyme such as rivastigmine, galantamine, donepezil, and NDMA receptor inhibitors (memantine), are available to manage the symptoms of AD. An exhaustive literature survey was carried out using SciFinder's reports from Alzheimer's Association, PubMed, and Clinical Trials.org. The literature was explored thoroughly to obtain information on the various available strategies to prevent AD. In the context of the present scenario, several strategies are being tried including the clinical trials for the treatment of AD. We have discussed pathophysiology, various targets, FDA-approved drugs, and various drugs in clinical trials against AD. The goal of this study is to shed light on current developments and treatment options, utilizing phytopharmaceuticals, nanomedicines, nutraceuticals, and gene therapy.

Pharmacotherapy of Alzheimer's disease: an overview of systematic reviews.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia. In this umbrella systematic review (SR), we summarized the efficacy of different pharmacological interventions in improving cognitive function in patients with AD. METHODS: A systematic search was performed through the PubMed, Scopus, Embase, and Cochrane databases for SRs of studies assessing the efficacy of pharmacological interventions versus placebo in improving cognitive function in AD or mild cognitive impairment due to AD. The risk of bias (RoB) was assessed using the Risk of Bias in SRs (ROBIS) tool. RESULTS: Out of 1748 articles found through the database survey, 33 SR articles were included. These studies assessed effects of immunotherapy, cholinesterase inhibitors (ChEIs), memantine, statins, lithium, nonsteroidal anti-inflammatory drugs (NSAIDs), antidiabetic agents, Cerebrolysin, RAS-targeting antihypertensive drugs (ARBs and ACEIs), psychostimulants, glycogen synthase kinase 3 (GSK-3) inhibitors, melatonin, and herbal medications on cognitive function in AD patients. There was no notable overall RoB in 18 studies (54.5%), the RoB in 14 studies (42.4%) was high, and in one study (3.0%) it was unclear. CONCLUSIONS: The use of ChEIs, including rivastigmine, galantamine, and donepezil, as well as memantine has demonstrated a positive impact on improving cognitive outcomes of AD patients, but no considerable effects were found for immunotherapies. Melatonin, statins, antihypertensive drugs, antidiabetic agents, Cerebrolysin, psychostimulants, and some herbal drugs such as Danggui-Shaoyao-San and Ginkgo biloba seem to be effective in improving cognitive function of AD patients, but the evidence in this regard is limited.

Iranian thyme honey plays behavioral, cellular and molecular important roles as an amazing preventive and therapeutic agent in the brain of Alzheimer's rat model.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with neuronal loss in the hippocampus. Our aim was to evaluate the effects of Iranian thyme honey (single dose: 2 gr/kg) vs rivastigmine (0.3 mg/kg) in vivo on spatial memory and in vitro on important parameters of oxidative stress as well as quantitative and qualitative studies of hippocampal neurons of AD rat models with this design that 30 days after oral administration of 17 mg/kg AlCl3, 20 AD rats were received that underwent a 6-weeks therapeutic period and another 20 rats underwent a 6-weeks preventive period and also 20 rats were as controls. Y-Maze test was performed to show memory deficiency as well as TBARS and FRAP assays to measure malondialdehyde (MDA) and total antioxidant, respectively. In addition, H&E staining was also done for cell counting and morphological changes. We observed that AD rats with hippocampal damage had more significant errors during the Y-maze test than the control and other rats. Likewise, MDA and neurodegeneration increased in the AD group while in all preventive and therapeutic group's especially Iranian thyme honey, they decreased and conversely, total antioxidant and number of normal cells elevated and healthy neurons were observed in all parts of the hippocampus and cortex. Our results despite the limitations showed the powerful antioxidant properties and cytoprotective effects of Iranian thyme honey vs rivastigmine on hippocampal neurons that consequently enhanced memory and if advanced diagnostic tests in human clinical patients show other more pronounced effects, we have certainly started a key and targeted strategy.

Differential neuroprotective effect of curcuminoid formulations in aluminum chloride-induced Alzheimer's disease.

Alzheimer's disease (AD) is a slowly progressive brain degenerative disorder which gradually impairs memory, thinking, and ability to perform easy routine tasks. This degenerative disorder mainly targets the elderly people and has imposed an endemic burden on society. Hence, there is a crucial need to investigate the efficacious herbal pharmacotherapies that can effectively mitigate and prevent the pathological hallmarks of AD. The current study aims to explore the potential efficacy of curcuminoid-rich extract (CRE) and its ternary complex (TC). Experimental rodents were administered with AlCl3 (300 mg/kg) to induce AD and treated with rivastigmine, curcuminoid crude extract, CRE, and TC orally for three consecutive weeks. Neurobehavioral, biochemical, and histopathological studies were performed from the last week of the study period. The mRNA expression of different pathological biomarkers was estimated by RT-qPCR analysis. The results of the study suggested that CRE and TC significantly improved the behavioral, biochemical parameters and acetylcholinesterase inhibitory activity in treatment groups. Histological analysis was also carried out indicating that the neurodegenerative changes and neuronal loss were stabilized by CRE and TC supplementation. CRE and TC supplementation remarkably downregulated the interleukin-1α, tumor necrosis factor-α, interleukin-1ß, acetylcholinesterase, and ß-secretase pathological gene expression. Hence, it was concluded that CRE and TC may act as promising candidates in the prevention of AD via numerous underlying signaling pathways.

The Dose and Duration-dependent Association between Melatonin Treatment and Overall Cognition in Alzheimer's Dementia: A Network Meta- Analysis of Randomized Placebo-Controlled Trials.

BACKGROUND: While Alzheimer's dementia (AD) has a prevalence as high as 3-32% and is associated with cognitive dysfunction and the risk of institutionalization, no efficacious and acceptable treatments can modify the course of cognitive decline in AD. Potential benefits of exogenous melatonin for cognition have been divergent across trials. OBJECTIVE: The current network meta-analysis (NMA) was conducted under the frequentist model to evaluate the potential beneficial effects of exogenous melatonin supplementation on overall cognitive function in participants with AD in comparison to other FDA-approved medications (donepezil, galantamine, rivastigmine, memantine, and Namzaric). METHODS: The primary outcome was the changes in the cognitive function [measured by mini-mental state examination (MMSE)] after treatment in patients with Alzheimer's dementia. The secondary outcomes were changes in the quality of life, behavioral disturbance, and acceptability (i.e., drop-out due to any reason and rate of any adverse event reported). RESULTS: The current NMA of 50 randomized placebo-controlled trials (RCTs) revealed the medium-term lowdose melatonin to be associated with the highest post-treatment MMSE (mean difference = 1.48 in MMSE score, 95% confidence intervals [95% CIs] = 0.51 to 2.46) and quality of life (standardized mean difference = -0.64, 95% CIs = -1.13 to -0.15) among all of the investigated medications in the participants with AD. Finally, all of the investigated exogenous melatonin supplements were associated with similar acceptability as was the placebo. CONCLUSION: The current NMA provides evidence for the potential benefits of exogenous melatonin supplementation, especially medium-term low-dose melatonin, in participants with AD.

The Efficacy and Safety of Alzheimer's Disease Therapies: An Updated Umbrella Review.

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

Chemical and genetic rescue of in vivo progranulin-deficient lysosomal and autophagic defects.

In 2006, GRN mutations were first linked to frontotemporal dementia (FTD), the leading cause of non-Alzheimer dementias. While much research has been dedicated to understanding the genetic causes of the disease, our understanding of the mechanistic impacts of GRN deficiency has only recently begun to take shape. With no known cure or treatment available for GRN-related FTD, there is a growing need to rapidly advance genetic and/or small-molecule therapeutics for this disease. This issue is complicated by the fact that, while lysosomal dysfunction seems to be a key driver of pathology, the mechanisms linking a loss of GRN to a pathogenic state remain unclear. In our attempt to address these key issues, we have turned to the nematode, Caenorhabditis elegans, to model, study, and find potential therapies for GRN-deficient FTD. First, we show that the loss of the nematode GRN ortholog, pgrn-1, results in several behavioral and molecular defects, including lysosomal dysfunction and defects in autophagic flux. Our investigations implicate the sphingolipid metabolic pathway in the regulation of many of the in vivo defects associated with pgrn-1 loss. Finally, we utilized these nematodes as an in vivo tool for high-throughput drug screening and identified two small molecules with potential therapeutic applications against GRN/pgrn-1 deficiency. These compounds reverse the biochemical, cellular, and functional phenotypes of GRN deficiency. Together, our results open avenues for mechanistic and therapeutic research into the outcomes of GRN-related neurodegeneration, both genetic and molecular.

Design, development and in-vitro/in-vivo evaluation of intranasally delivered Rivastigmine and N-Acetyl Cysteine loaded bifunctional niosomes for applications in combinative treatment of Alzheimer's disease.

The present investigation explores the potential of novel dual drug-loaded niosomes for nasal delivery of Rivastigmine (RIV) and N-Acetyl Cysteine (NAC) to the brain. The dual niosomes showed a particle size of 162.4 nm and % entrapment efficiencies of 97.7% for RIV and 85.9% for NAC. The niosomes were statistically validated using Box-Behnken experimental design (BBD) with good significance. Ultrastructural and chemical characterization of the niosomes using various analytical techniques like Fourier Transform Infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), Transmission electron microscopy (TEM) showcased drug-excipient compatibility and robust stability of 6 months in a liquid state at 4-8 °C. The dual drug-loaded niosomes showed a sustained drug release pattern up to 2 days. Acetylcholinesterase (AChE) and DPPH (1, 1-diphenyl-2- picrylhydrazyl) enzyme inhibition assays showed a better combinative effect than the free drug solutions. A 2-day nasal permeation proved the effectiveness and biocompatibility of the niosomes. In-vivo pharmacokinetic and organ biodistribution studies revealed a better drug profile and greater distribution of the niosomes in the brain compared to other organs, thereby indicating a direct nose-to-brain delivery of the niosomes.

Acetylcholinesterase Inhibitory Potential of Various Sesquiterpene Analogues for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) is a gradually growing irreversible illness of the brain that almost affects every fifth person (aged > 80 years) in the world. World Health Organization (WHO) also revealed that the prevalence of this disease will enhance (upto double) significantly upto 2030. The poor cholinergic transmission at the synapse is considered to be one of the main reasons behind the progression and occurrence of this disorder. Natural inhibitors of acetylcholine (ACh) such as galanthamine and rivastigmine are used commercially in the treatmentof AD. The biomolecules such assesquiterpenes, possess a great structural diversity and are responsible for a plethora of pharmacological properties. The potential of various sesquiterpenes as anticholinesterase has been reviewed in this article. For this purpose, the various databases, mainly PubMed, Scopus, and Web of Science were investigatedwith different keywords such as "sesquiterpenes+acetylcholinesterase" and "sesquiterpenes+cholinesterase+inhibitors" in the surveyed time frame (2010-2020). A vast literature was evident in the last decade, which affirms the potential of various sesquiterpenes in the improvement of cholinergic transmission by inhibiting the AChE. After data analysis, it was found that 12 compounds out of a total of 58 sesquiterpenes were reported to possess IC50 < 9µM and can be considered as potential candidates for the improvement of learning and memory. Sesquiterpene is an important category of terpenoids, found to possess a large spectrum of biological activities. The outcome of the review clearly states that sesquiterpenes (such as amberboin, lipidiol,etc) from herbs could offer fresh, functional compounds for possible prevention and treatment of AD.

Nutritional Status in Patients with Probable Alzheimer's Disease: Effect of Rivastigmine.

IMPORTANCE: Altough disease-modifying factors such as malnutrition and diet have been associated with Alzheimer's disease (AD), little is known about the effects of pharmacological therapies on the nutritional status of AD patients. OBJECTIVE: To evaluate the nutritional status, prealbumin, and albumin serum levels and several anthropometric measurements in patients with probable moderate-stage AD, with and without rivastigmine drug treatment. STUDY DESIGN: A cross-sectional study. SETTING AND PARTICIPANTS: 34 patients were included, 17 with rivastigmine treatment and 17 without pharmacological treatment, over 60 years of both sexes. MEASUREMENTS: The nutritional status was evaluated using the Mini Nutritional Assessment (MNA). Albumin and prealbumin (transthyretin) levels and anthropometric evaluation were assessed using standard methods. RESULTS: A polarity of malnutrition was detected in the untreated group. According to the MNA survey, the risk of malnutrition is higher without rivastigmine treatment (p = 0.0001). There are a less loss of appetite, less psychological stress, greater mobility and independence in those patients receiving rivastigmine (p = 0.003, 0.008, 0.016 and 0.018, respectively). The body mass index does not show a statistical difference, however, categorizing it for older adults, this index was improved in those receiving rivastigmine (p = 0.016). The serum levels of albumin and prealbumin showed no significant statistical difference between the groups. CONCLUSION: Rivastigmine treatment shows a protective effect on malnutrition in patients with moderate-stage AD.

Approach to Cognitive Impairment in Parkinson's Disease.

Cognitive dysfunction is common in Parkinson's disease (PD) and predicts poor clinical outcomes. It is associated primarily with pathologic involvement of basal forebrain cholinergic and prefrontal dopaminergic systems. Impairments in executive functions, attention, and visuospatial abilities are its hallmark features with eventual involvement of memory and other domains. Subtle symptoms in the premotor and early phases of PD progress to mild cognitive impairment (MCI) which may be present at the time of diagnosis. Eventually, a large majority of PD patients develop dementia with advancing age and longer disease duration, which is usually accompanied by immobility, hallucinations/psychosis, and dysautonomia. Dopaminergic medications and deep brain stimulation help motor dysfunction, but may have potential cognitive side effects. Central acetylcholinesterase inhibitors, and possibly memantine, provide modest and temporary symptomatic relief for dementia, although there is no evidence-based treatment for MCI. There is no proven disease-modifying treatment for cognitive impairment in PD. The symptomatic and disease-modifying role of physical exercise, cognitive training, and neuromodulation on cognitive impairment in PD is under investigation. Multidisciplinary approaches to cognitive impairment with effective treatment of comorbidities, proper rehabilitation, and maintenance of good support systems in addition to pharmaceutical treatment may improve the quality of life of the patients and caregivers.

Current Strategies and Novel Drug Approaches for Alzheimer Disease.

Alzheimer's Disease (AD) is a chronic, devastating dysfunction of neurons in the brain leading to dementia. It mainly arises due to neuronal injury in the cerebral cortex and hippocampus area of the brain and is clinically manifested as a progressive mental failure, disordered cognitive functions, personality changes, reduced verbal fluency and impairment of speech. The pathology behind AD is the formation of intraneuronal fibrillary tangles, deposition of amyloid plaque and decline in choline acetyltransferase and loss of cholinergic neurons. Tragically, the disease cannot be cured, but its progression can be halted. Various cholinesterase inhibitors available in the market like Tacrine, Donepezil, Galantamine, Rivastigmine, etc. are being used to manage the symptoms of Alzheimer's disease. The paper's objective is to throw light not only on the cellular/genetic basis of the disease, but also on the current trends and various strategies of treatment including the use of phytopharmaceuticals and nutraceuticals. Enormous literature survey was conducted and published articles of PubMed, Scifinder, Google Scholar, Clinical Trials.org and Alzheimer Association reports were studied intensively to consolidate the information on the strategies available to combat Alzheimer's disease. Currently, several strategies are being investigated for the treatment of Alzheimer's disease. Immunotherapies targeting amyloid-beta plaques, tau protein and neural pathways are undergoing clinical trials. Moreover, antisense oligonucleotide methodologies are being approached as therapies for its management. Phytopharmaceuticals and nutraceuticals are also gaining attention in overcoming the symptoms related to AD. The present review article concludes that novel and traditional therapies simultaneously promise future hope for AD treatment.

Subchronic use of rivastigmine increases procognitive flexibility across multimodal behavioral tasks in healthy male rats.

Rivastigmine (RVT) is a reversible inhibitor of cholinesterase approved worldwide for the treatment of cognitive dysfunctions, especially in Alzheimer's disease. Most previous pre-clinical studies have examined the effects of RVT treatment in a wide variety of pathological research models. Nonetheless, the effects of this drug on sensorimotor gating, memory, and learning tasks in healthy subjects remains unclear. In this study, we investigate the procognitive effects of RVT treatment in healthy rats through sensorimotor gating evaluations (measured as prepulse inhibition of the acoustic startle reflex), active avoidance learning, and spatial memory learning in a radial maze. There is an increase in the amplitude of the startle reflex in RVT-treated rats compared to the control groups, whereas the latency remained constant. Sensorimotor gating values were also incremented compared to those values from controls. In active avoidance, rats treated with RVT learned faster to successfully perform the task compared to controls, but afterwards all groups exhibited virtually identical results. During the sessions in the radial maze, RVT-treated rats committed fewer errors in both the working and reference memory compared to controls. All in all, our results support the hypothesis that RVT treatment may entail procognitive effects in healthy subjects.

Cost-effectiveness analysis of the treatment of mild and moderate Alzheimer's disease in Brazil

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

Cost-effectiveness analysis of the treatment of mild and moderate Alzheimer's disease in Brazil.

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

Direct Asymmetric Reductive Amination for the Synthesis of (S)-Rivastigmine.

In this article we demonstrate how asymmetric total synthesis of (S)-rivastigmine has been achieved using direct asymmetric reductive amination as the key transformation in four steps. The route started with readily available and cheap m-hydroxyacetophenone, through esterification, asymmetric reductive amination, N-diphenylmethyl deprotection and reductive amination, to provide the final (S)-rivastigmine in 82% overall yield and 96% enantioselectivity. In the asymmetric reductive amination, catalysed by the iridium⁻phosphoramidite ligand complex and helped by some additives, the readily prepared 3-acetylphenyl ethyl(methyl)carbamate directly reductively coupled with diphenylmethanamine to yield the chiral amine product in 96% ee and 93% yield.

Paroxetine and rivastigmine mitigates adjuvant-induced rheumatoid arthritis in rats: Impact on oxidative stress, apoptosis and RANKL/OPG signals.

Rheumatoid arthritis (RA) is considered a form of inflammatory autoimmune disease with unknown etiology, but environmental and genetic causes are sharing. T-cells, B-cells, synovial cells, osteoclast, and chondrocytes are the main cell types in RA pathophysiology. The present study aimed to investigate the anti-rheumatic effects of paroxetine, a selective serotonin reuptake inhibitor (SSRI), and rivastigmine, acetyl choline esterase inhibitor (AChEI), in complete Freund's adjuvant (CFA)-induced RA. Adult female rats were categorized into five groups of eight rats each: normal control received vehicles only, RA control received CFA (0.4 ml, s.c) dexamethasone group (1 mg/kg/day, p.o), paroxetine group (10 mg/kg/day, i.p) and rivastigmine group (1 mg/kg/day, i.p). All treatments were administered for 13 consecutive days. Specific rheumatoid marker rheumatoid factor (RF), cartilage oligomeric protein (COMP) and matrix metalloproteinase-3 (MMP-3) were determined. Serum MDA and reduced GSH levels were investigated as oxidative stress biomarkers. IL-6, TNF-α, and monocyte chemotactic protein-1 (MCP-1) were also determined as inflammatory biomarkers. Tissue Receptor activator of nuclear factor kappa-B ligand/osteoprotegerin (RANKL/OPG) expression levels were detected using qRT-PCR. Paroxetine and rivastigmine significantly reduced RF, COMP, MMP-3, IL-6, TNF-α, and MCP-1 serum levels. Tested drugs also significantly reduced serum MDA and increased GSH levels. In addition, paroxetine and rivastigmine attenuated histopathological variations by reducing pannus formation and return synovial fluid near to normal. Administration of paroxetine or rivastigmine normalized caspase-3 and RANKL/OPG in CFA-induced RA. In conclusion, paroxetine and rivastigmine possess antirheumatoid effects in CFA-induced RA which is mediated through antioxidant, anti-inflammatory, antiapoptotic and modulation of RANKL/OPG expression levels.

Comparisons between traditional medicines and pharmacotherapies for Alzheimer disease: A systematic review and meta-analysis of cognitive outcomes.

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