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1.
Medicine (Baltimore) ; 100(22): e25833, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087826

RESUMO

ABSTRACT: The current status of the diagnosis and management of poststroke aphasia (PSA) in China is unknown.To analyze the physicians' strategy and knowledge about the management of PSA in clinical practice and the needs for standardization of diagnosis and treatment.This survey was conducted in March-August 2019 at 32 tertiary hospitals in 16 provinces/municipalities in China. The attending physicians from the Neurology and Neuro-rehabilitation/Rehabilitation Departments were included. The online questionnaire inquired about patient information, physicians' diagnosis and treatment behavior for PSA, and physicians' understanding of PSA.A total of 236 physicians completed the survey. Regarding PSA assessment, 99.2% of the physicians reported using medical history and physical examination, 93.2% reported using neuroimaging, and 76.3% reported using dedicated scales. Most physicians used a combination of drug and non-drug treatment. Neuro-regenerators/cerebral activators and anti-dementia drugs were the most common pharmacotherapies; butylphthalide, edaravone, and memantine were most frequently prescribed. Six months poststroke was rendered as a spontaneous language recovery period, and a ≥6-month treatment for PSA was suggested by many physicians. The lack of standardized treatment regimen/clinical guidelines and the limited number of approved drugs for PSA were the primary challenges encountered by physicians during practice. The majority of the physicians agreed with the necessity of guidelines or consensus for the diagnosis and treatment of PSA.The knowledge gaps exist among physicians in China regarding the assessment and management of PSA. The improved awareness of the available guidelines/consensus could improve the performance of the physicians.


Assuntos
Afasia/etiologia , Afasia/terapia , Conhecimentos, Atitudes e Prática em Saúde , Médicos/estatística & dados numéricos , Acidente Vascular Cerebral/complicações , Afasia/diagnóstico , Afasia/reabilitação , China , Inibidores da Colinesterase/uso terapêutico , Humanos , Fármacos Neuroprotetores/uso terapêutico , Médicos/psicologia , Padrões de Prática Médica
2.
Molecules ; 26(8)2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33920326

RESUMO

Neurodegenerative diseases (ND), including Alzheimer's (AD) and Parkinson's Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Dopaminérgicos/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Antiparkinsonianos/síntese química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Inibidores da Colinesterase/síntese química , Ensaios Clínicos como Assunto , Simulação por Computador , Dopaminérgicos/síntese química , Desenho de Fármacos , Antagonistas de Aminoácidos Excitatórios/síntese química , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica , Humanos , Fármacos Neuroprotetores/síntese química , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Sirtuínas/antagonistas & inibidores , Sirtuínas/genética , Sirtuínas/metabolismo
3.
ACS Chem Neurosci ; 12(8): 1328-1342, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33797877

RESUMO

Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3ß and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and ß-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Glicogênio Sintase Quinase 3 beta , Humanos , Ligantes , Monoaminoxidase/metabolismo
4.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803769

RESUMO

The aggregation of amyloid ß (Aß) peptides and deposition of amyloid plaques are implicated in the pathogenesis of Alzheimer's disease (AD). Therefore, blocking Aß aggregation with small molecules has been proposed as one therapeutic approach for AD. In the present study, a series of ranitidine analogs containing cyclic imide isosteres were synthesized and their inhibitory activities toward Aß aggregation were evaluated using in vitro thioflavin T assays. The structure-activity relationship revealed that the 1,8-naphthalimide moiety provided profound inhibition of Aß aggregation and structural modifications on the other parts of the parent molecule (compound 6) maintained similar efficacy. Some of these ranitidine analogs also possessed potent inhibitory activities of acetylcholinesterase (AChE), which is another therapeutic target in AD. These ranitidine analogs, by addressing both Aß aggregation and AChE, offer insight into the key chemical features of a new type of multi-target directed ligands for the pharmaceutical treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Ranitidina/síntese química , Ranitidina/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Bovinos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Imidas/química , Ligantes , Agregados Proteicos/efeitos dos fármacos , Ranitidina/química
5.
Chem Biol Interact ; 342: 109489, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33905740

RESUMO

The development of multi-target-directed ligands (MTDLs) may improve complex central nervous system diseases such as Alzheimer's disease (AD). Here, a series of 7-O-1, 2, 3-triazole hesperetin derivatives was evaluated for their inhibition of cholinesterase, anti-neuroinflammatory, and neuroprotective activity. Among the hesperetin derivatives, compound a8 (7-O-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)hesperetin) possessed excellent anti-butyrylcholinesterase activity (IC50 = 3.08 ± 0.29 µM) and exhibited good anti-neuroinflammatory activity (IC50 = 2.91 ± 0.47 µM) against NO production through remarkably blocking the NF-κB signaling pathway and inhibiting the phosphorylation of P65. In addition, a8 showed a remarkable neuroprotective effect and lacked neurotoxicity up to 50 µM concentration. Furthermore, possessing significant self-mediated Aß1-42 aggregation inhibitory activity, chelated biometals and reduced ROS production were found in compound a8. In the bi-directional transport assay, a8 exhibited a blood-brain barrier penetrating ability. In this study, the Morris water maze task showed that compound a8 significantly improved the learning and memory impairment of the scopolamine-induced AD mice model. Results highlighted the potential of compound a8 to be a potential MTDL for the development of anti-AD agents.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Hesperidina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Triazóis/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Descoberta de Drogas , Hesperidina/síntese química , Hesperidina/metabolismo , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/metabolismo , Óxido Nítrico/antagonistas & inibidores , Ligação Proteica , Ratos , Fator de Transcrição RelA/metabolismo , Triazóis/síntese química , Triazóis/metabolismo
6.
Emerg Med Clin North Am ; 39(2): 307-322, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33863461

RESUMO

Chronic brain failure, also known as dementia or major neurocognitive disorder, is a syndrome of progressive functional decline characterized by both cognitive and neuropsychiatric symptoms. It can be conceptualized like other organ failure syndromes and its impact on quality of life can be mitigated with proper treatment. Dementia is a risk factor for delirium, and their symptoms can be similar. Patients with dementia can present with agitation that can lead to injury. Logic and reason are rarely successful when attempting to redirect someone with advanced dementia. Interactions that offer a sense of choice are more likely to succeed.


Assuntos
Demência/diagnóstico , Transtornos Neurocognitivos/diagnóstico , Idoso , Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Delírio/diagnóstico , Demência/tratamento farmacológico , Demência/etiologia , Diagnóstico Diferencial , Medicina de Emergência , Humanos , Incidência , Memantina/uso terapêutico , Competência Mental , Transtornos Neurocognitivos/tratamento farmacológico , Transtornos Neurocognitivos/etiologia , Testes Neuropsicológicos , Dor/diagnóstico , Prevalência , Agitação Psicomotora/prevenção & controle
7.
Neurology ; 96(17): e2220-e2230, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33741639

RESUMO

OBJECTIVE: To investigate whether cholinesterase inhibitors (ChEIs) are associated with slower cognitive decline in Alzheimer dementia and decreased risk of severe dementia or death. METHODS: Patients with Alzheimer dementia from the Swedish Dementia Registry starting on ChEIs within 3 months of the dementia diagnosis were included and compared to nontreated patients with Alzheimer dementia. In a propensity score-matched cohort, the association between ChEI use and cognitive trajectories assessed by Mini-Mental State Examination (MMSE) scores was examined with a mixed model, and severe dementia (MMSE score <10) or death as an outcome was assessed with Cox proportional hazards models. RESULTS: The matched cohort included 11,652 ChEI users and 5,826 nonusers. During an average of 5 years of follow-up, 255 cases developed severe dementia, and 6,055 (35%) died. ChEI use was associated with higher MMSE score at each visit (0.13 MMSE points per year; 95% confidence interval [CI] 0.06-0.20). ChEI users had a 27% lower risk of death (0.73, 95% CI 0.69-0.77) compared with nonusers. Galantamine was associated with lower risk of death (0.71, 95% CI 0.65-0.76) and lower risk of severe dementia (0.69, 95% CI 0.47-1.00) and had the strongest effect on cognitive decline of all the ChEIs (0.18 MMSE points per year, 95% CI 0.07-0.28). CONCLUSIONS: ChEIs are associated with cognitive benefits that are modest but persist over time and with reduced mortality risk, which could be explained partly by their cognitive effects. Galantamine was the only ChEI demonstrating a significant reduction in the risk of developing severe dementia. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with Alzheimer dementia ChEIs decrease long-term cognitive decline and risk of death and that galantamine decreases the risk of severe dementia.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/mortalidade , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/mortalidade , Estudos de Coortes , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Modelos de Riscos Proporcionais , Tempo
8.
Eur J Med Chem ; 216: 113320, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33652356

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs mental ability development and interrupts neurocognitive function. This neuropathological condition is depicted by neurodegeneration, neural loss, and development of neurofibrillary tangles and Aß plaques. There is also a greater risk of developing AD at a later age for people with cardiovascular diseases, hypertension and diabetes. In the biomedical sciences, effective treatment for Alzheimer's disease is a severe obstacle. There is no such treatment to cure Alzheimer's disease. The drug present in the market show only symptomatic relief. The cause of Alzheimer's disease is not fully understood and the blood-brain barrier restricts drug efficacy are two main factors that hamper research. Stem cell-based therapy has been seen as an effective, secure, and creative therapeutic solution to overcoming AD because of AD's multifactorial nature and inadequate care. Current developments in nanotechnology often offer possibilities for the delivery of active drug candidates to address certain limitations. The key nanoformulations being tested against AD include polymeric nanoparticles (NP), inorganic NPs and lipid-based NPs. Nano drug delivery systems are promising vehicles for targeting several therapeutic moieties by easing drug molecules' penetration across the CNS and improving their bioavailability. In this review, we focus on the causes of the AD and their treatment by different approaches.


Assuntos
Doença de Alzheimer/terapia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Animais , Biomarcadores/metabolismo , Barreira Hematoencefálica/metabolismo , Inibidores da Colinesterase/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Nanopartículas/uso terapêutico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Transplante de Células-Tronco
9.
J Nutr Health Aging ; 25(3): 340-346, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33575726

RESUMO

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.


Assuntos
Doença de Alzheimer/fisiopatologia , Inibidores da Colinesterase/uso terapêutico , Desnutrição/complicações , Avaliação Nutricional , Estado Nutricional/fisiologia , Rivastigmina/uso terapêutico , Idoso , Inibidores da Colinesterase/farmacologia , Estudos Transversais , Feminino , Humanos , Masculino , Rivastigmina/farmacologia
10.
J Med Chem ; 64(4): 1844-1855, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33570950

RESUMO

The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/uso terapêutico , Indanos/uso terapêutico , Nootrópicos/uso terapêutico , Piperidinas/uso terapêutico , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Cristalografia por Raios X , Cães , Desenho de Fármacos , Feminino , Humanos , Indanos/síntese química , Indanos/metabolismo , Cinética , Masculino , Camundongos Endogâmicos ICR , Estrutura Molecular , Nootrópicos/síntese química , Nootrópicos/metabolismo , Piperidinas/síntese química , Piperidinas/metabolismo , Ligação Proteica , Ratos Sprague-Dawley , Escopolamina , Relação Estrutura-Atividade
11.
Mayo Clin Proc ; 96(2): 350-362, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33549256

RESUMO

OBJECTIVE: To evaluate the association between the use of cholinesterase inhibitors (ChEIs) and incident cardiovascular events (CVEs) among older patients with Alzheimer disease (AD). PATIENTS AND METHODS: This retrospective cohort study was conducted with a new-user design and active-comparator design. The data source was the 2005-2014 Full Population file from the Health and Welfare Database in Taiwan. Patients were included if they were aged 50 years or older and had been diagnosed with AD between January 1, 2006, and December 31, 2010. The association between ChEI use and the risk of CVEs was investigated in patients with AD. Among the ChEI users, the risk of CVEs was further compared between patients with different cumulative doses and different ChEI treatment strategies. The propensity score method, which included matching and inverse probability of treatment weighting, was used to balance the potential confounders. A Cox proportional hazards model with competing risks was used to estimate the hazard ratio of CVEs. RESULTS: The study included 6070 patients with AD. After covariate adjustment, ChEI users had a significantly lower risk of CVEs than nonusers (hazard ratio, 0.57; 95% CI, 0.51 to 0.62). Among ChEI users, patients with a high cumulative dose had a significantly lower risk of CVEs than those with a low cumulative dose (hazard ratio, 0.82; 95% CI, 0.70 to 0.96). CONCLUSION: The use of ChEIs was associated with a decreased risk of incident CVEs among patients with AD. The cardioprotective effect of ChEIs showed a dose-response relationship.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Inibidores da Colinesterase/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Inibidores da Colinesterase/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos , Taiwan/epidemiologia
12.
BMC Neurol ; 21(1): 61, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568083

RESUMO

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


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Marcha/efeitos dos fármacos , Rivastigmina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Cognição/efeitos dos fármacos , Feminino , Humanos , Masculino , Estudos Prospectivos , Análise e Desempenho de Tarefas
13.
J Nat Med ; 75(2): 372-380, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33411157

RESUMO

Four unknown stilbenoids, including one dimer, namely 4'-methoxy-scirpusin A (5) and three monomeric stilbene glycosides, namely piceatannol-3'-O-[2''-(3,5-dihydroxy-4-methoxybenzoyl)]-ß-D-glucopyranoside (13), piceatannol-3'-O-(2''-galloyl)-ß-D-glucopyranoside (14) and piceatannol-3'-O-(6″-p-coumaroyl)-ß-D-glucopyranoside (16) together with 15 described compounds, were isolated from the ethyl acetate fraction of the ethanol extract of roots of Rheum lhasaense based on the guidance of the inhibitory effect on acetylcholinesterase. The structures of the unknown compounds were established by combined spectroscopic analysis and comparing their spectral data with compounds with similar structures. Some selected components were also investigated for their inhibitory abilities on acetylcholinesterase (AChE), indicating that compound 13 may be responsible for higher inhibitory activity of the ethyl acetate fraction on AChE.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Raízes de Plantas/química , Rheum/química , Estilbenos/uso terapêutico , Inibidores da Colinesterase/farmacologia , Estilbenos/farmacologia
14.
Clin Drug Investig ; 41(2): 177-182, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33484469

RESUMO

OBJECTIVE: Combined therapy of memantine or acetylcholinesterase inhibitors, with cholinergic precursors such as citicoline, can be effective in Alzheimer's disease. Indeed, they are able to increase the intrasynaptic levels of acetylcholine more than the single drug. Our aim was to evaluate the efficacy and safety of oral citicoline plus memantine plus rivastigmine in patients with Alzheimer's disease. METHODS: This was a multi-centric, retrospective case-control study conducted in Italian Centers for Cognitive Impairment and Dementia on consecutive patients aged 65 years or older affected with Alzheimer's disease. Overall, 104 patients were recruited (27% male, mean age 76.04 ± 4.92 years); 41 (39.42%) treated with citicolin 1000 mg/day given orally + memantine + rivastigmine (Cases) and 63 (60.58%) treated with memantine + rivastigmine (Controls). At baseline (T0), month 6 (T1) and month 12 (T2), cognitive functions were assessed by the Mini Mental State Examination (MMSE), functional dependence by basal Activities (ADL) and Instrumental Activities of Daily Living (IADL), comorbidity by the Cumulative Illness Rating Scale (CIRS), mood by the Geriatric Depression Scale (GDS), and behavioural disturbances by the Neuropsychiatric Inventory (NPI). Adverse events were reported during the study. RESULTS: The difference in MMSE score was not significant when comparing the two groups at T0, T1 or T2. However, in the case group, the MMSE total score showed a statistically significant difference at T0 versus T1 (13.63 ± 2.46 vs. 14.17 ± 2.24; p = 0.008), and at T0 versus T2 (13.63 ± 2.46 vs. 14.32 ± 2.53; p = 0.002). In the control group, no statistical differences were found at baseline (T0), T1 and T2. ADL, IADL, GDS and NPI total score did not improve during the study in either the case or the control group. CONCLUSIONS: In our study we observed absence of a statistically significant difference between case and control groups for the MMSE total scores. However, in the case group in the MMSE total scores, there was a statistically significant increase between the baseline and the end of the study.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Citidina Difosfato Colina/uso terapêutico , Memantina/administração & dosagem , Rivastigmina/uso terapêutico , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Inibidores da Colinesterase/uso terapêutico , Cognição/efeitos dos fármacos , Comorbidade , Feminino , Humanos , Itália , Masculino , Estudos Retrospectivos
15.
Br J Anaesth ; 126(3): 700-705, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33317802

RESUMO

BACKGROUND: Several studies have shown that cholinergic mechanisms play a pivotal role in the anti-nociceptive system by acting synergistically with morphine and reducing postoperative opioid consumption. In addition, the anti-cholinesterase drug physostigmine that increases synaptic acetylcholine concentrations has anti-inflammatory effects. METHODS: In this randomised placebo-controlled trial including 110 patients undergoing nephrectomy, we evaluated the effects of intraoperative physostigmine 0.5 mg h-1 i.v. for 24 h on opioid consumption, hyperalgesia, pain scores, and satisfaction with pain control. RESULTS: Physostigmine infusion did not affect opioid consumption compared with placebo. However, the mechanical pain threshold was significantly higher (2.3 [sd 0.3]) vs 2.2 [0.4]; P=0.0491), and the distance from the suture line of hyperalgesia (5.9 [3.3] vs 8.5 [4.6]; P=0.006), wind-up ratios (2.2 [1.5] vs 3.1 [1.5]; P=0.0389), and minimum and maximum postoperative pain scores at 24 h (minimum 1.8 [1.0] vs 2.4 [1.2]; P=0.0451; and maximum 3.2 [1.4] vs 4.2 [1.4]; P=0.0081) and 48 h (minimum 0.9 [1.0] vs 1.6 [1.1]; P=0.0101; and maximum 2.0 [1.5] vs 3.2 [1.6]; P=0.0029) were lower in the study group. Pain Disability Index was lower and satisfaction with pain control was higher after 3 months in the physostigmine group. CONCLUSIONS: In contrast to previous trials, physostigmine did not reduce opioid consumption. As pain thresholds were higher and hyperalgesia and wind-up lower in the physostigmine group, we conclude that physostigmine has anti-hyperalgesic effects and attenuates sensitisation processes. Intraoperative physostigmine may be a useful and safe addition to conventional postoperative pain control. CLINICAL TRIAL REGISTRATION: EudraCT number 2012-000130-19.


Assuntos
Analgésicos Opioides/administração & dosagem , Inibidores da Colinesterase/administração & dosagem , Hiperalgesia/prevenção & controle , Morfina/administração & dosagem , Dor Pós-Operatória/prevenção & controle , Assistência Perioperatória/métodos , Fisostigmina/administração & dosagem , Analgésicos Opioides/uso terapêutico , Anestesia Geral , Inibidores da Colinesterase/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/uso terapêutico , Nefrectomia , Fisostigmina/uso terapêutico , Estudos Prospectivos
16.
J Med Chem ; 64(1): 812-839, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33356266

RESUMO

The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Aß42/Aß40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.


Assuntos
Acetilcolinesterase/metabolismo , Antioxidantes/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Butirilcolinesterase/química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade , Distribuição Tecidual
18.
Artigo em Russo | MEDLINE | ID: mdl-33081459

RESUMO

Donepezil is the most commonly used drug of the group of cholinesterase inhibitors. It is recommended for tretament of Alzheimer's disease. Donepezil is also used to treat dementia in Lewy body disease, Parkinson's disease with dementia, and vascular dementia. In Russia, donepezil is not used as often, which is facilitated by the concern of doctors about the possibility of serious side-effects. Clinical studies demonstrate the safety and good tolerability of donepezil. Our study included 62 patients with dementia due to various neurodegenerative diseases (Alzheimer's disease, Lewy body disease, Parkinson's disease with dementia). Thirty-seven patients (59.7%) started to receive donepezil. Side-effects, including bradycardia, hypertension, aggressive behavior, increased tremor, were observed in 7 patients (18.9%). There was no correlation between the development of side-effects and polymorphisms of the CYP2D6 and MDR1 genes.


Assuntos
Donepezila , Indanos , Inibidores da Colinesterase/uso terapêutico , Donepezila/uso terapêutico , Humanos , Indanos/uso terapêutico , Piperidinas/uso terapêutico , Federação Russa
19.
BMC Infect Dis ; 20(1): 765, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066761

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), may lead to severe systemic inflammatory response, pulmonary damage, and even acute respiratory distress syndrome (ARDS). This in turn may result in respiratory failure and in death. Experimentally, acetylcholine (ACh) modulates the acute inflammatory response, a neuro-immune mechanism known as the inflammatory reflex. Recent clinical evidence suggest that electrical and chemical stimulation of the inflammatory reflex may reduce the burden of inflammation in chronic inflammatory diseases. Pyridostigmine (PDG), an ACh-esterase inhibitor (i-ACh-e), increases the half-life of endogenous ACh, therefore mimicking the inflammatory reflex. This clinical trial is aimed at evaluating if add-on of PDG leads to a decrease of invasive mechanical ventilation and death among patients with severe COVID-19. METHODS: A parallel-group, multicenter, randomized, double-blinded, placebo-controlled, phase 2/3 clinical trial to test the efficacy of pyridostigmine bromide 60 mg/day P.O. to reduce the need for invasive mechanical ventilation and mortality in hospitalized patients with severe COVID-19. DISCUSSION: This study will provide preliminary evidence of whether or not -by decreasing systemic inflammation- add-on PDG can improve clinical outcomes in patients with severe COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04343963 (registered on April 14, 2020).


Assuntos
Inibidores da Colinesterase/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Brometo de Piridostigmina/uso terapêutico , Adulto , Betacoronavirus/patogenicidade , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Humanos , Inflamação , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Respiração Artificial
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