9 research outputs found
AS (IM) POSSIBILIDADES NO MERCADO DE TRABALHO BRASILEIRO AOS REFUGIADOS
RESUMO: As transformaçÔes societĂĄrias tem promovido uma sociedade de mercado que obriga centenas de milhares de pessoas a viver a realidade migratĂłria, em especial, com caracterĂsticas de refugiado. Essa reflexĂŁo teĂłrica - bibliogrĂĄfica buscarĂĄ refletir sobre como ocorre a inserção desses refugiados (migrantes em situação de guerras religiosas, Ă©tnicas e polĂticas) no mercado de trabalho no Brasil. PropĂ”e-se realizar reflexĂ”es, bem como contextualizaçÔes sobre a representatividade dos refugiados na sociedade brasileira. Concluiu-se que estes sujeitos sĂŁo funcionais ao sistema, na medida em que grande parte passam a se inserir na informalidade, reforçando a precariedade das relaçÔes e condiçÔes de trabalho estabelecidas
REFUGIADOS E POLĂTICAS SOCIAIS: dilemas e realidades no sĂ©culo XXI
RESUMO: Este trabalho realiza um resgate histĂłrico do avanço nas legislaçÔes acerca dos refugiados, destacando a convenção de Genebra 1951 - relativa ao Estatuto dos Refugiados, o Protocolo de Nova Iorque (1967), a Declaração de Cartagena, 1984, e a Lei Brasileira de 1997 (Lei Federal no. 9.474/97). Em seguida realizam-se problematizaçÔes acerca das condiçÔes de vida e do acesso ĂĄs polĂticas sociais aos refugiados. SerĂŁo elencadas polĂticas vinculadas ao acesso Ă moradia, assistĂȘncia social, educação e trabalho. Com base no estudo identificou-se que as expressĂ”es da questĂŁo social permeiam a vida destes sujeitos e que as polĂticas sociais sĂŁo uma das principais formas de subsistĂȘncia e formação aos refugiados
Prophylactic evaluation of verubecestat on disease- and symptom-modifying effects in 5XFAD mice.
Introduction: Alzheimer\u27s disease (AD) is the most common form of dementia. Beta-secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been under-investigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for Late-Onset Alzheimer\u27s Disease (MODEL-AD) Preclinical Testing Core (PTC) Drug Screening Pipeline.
Methods: 5XFAD mice were administered verubecestat ad libitum in chow from 3 to 6 months of age, prior to the onset of significant disease pathology. Following treatment (6 months of age), in vivo imaging was conducted with 18F-florbetapir (AV-45/Amyvid) (18F-AV45) and 18-FDG (fluorodeoxyglucose)-PET (positron emission tomography)/MRI (magnetic resonance imaging), brain and plasma amyloid beta (AÎČ) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with the pharmacokinetic data.
Results: Prophylactic verubecestat treatment resulted in dose- and region-dependent attenuations of 18F-AV45 uptake in male and female 5XFAD mice. Plasma AÎČ40 and AÎČ42 were also dose-dependently attenuated with treatment. Across the dose range evaluated, side effects including coat color changes and motor alterations were reported, in the absence of cognitive improvement or changes in 18F-FDG uptake.
Discussion: Prophylactic treatment with verubecestat resulted in attenuated amyloid plaque deposition when treatment was initiated prior to significant pathology in 5XFAD mice. At the same dose range effective at attenuating AÎČ levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODEL-AD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for early-stage AD
The panicolytic-like effect of fluoxetine in the elevated T-maze is mediated by serotonin-induced activation of endogenous opioids in the dorsal periaqueductal grey
Serotonin (5-HT), opioids and the dorsal periaqueductal grey (DPAG) have been implicated in the pathophysiology of panic disorder. In order to study 5-HT-opioid interaction, the opioid antagonist naloxone was injected either systemically (1 mg/kg, i.p.) or intra-DPAG (0.2 mu g/0.5 mu L) to assess its interference with the effect of chronic fluoxetine (10 mg/kg, i.p., daily for 21 days) or of intra-DPAG 5-HT (8 mu g/0.5 mu L). Drug effects were measured in the one-escape task of the rat elevated T-maze, an animal model of panic. Pretreatment with systemic naloxone antagonized the lengthening of escape latency caused by chronic fluoxetine, considered a panicolytic-like effect that parallels the drug's therapeutic response in the clinics. Pretreatment with naloxone injected intra-DPAG antagonized both the panicolytic effect of chronic fluoxetine as well as that of 5-HT injected intra-DPAG. Neither the performance of the inhibitory avoidance task in the elevated T-maze, a model of generalized anxiety nor locomotion measured in a circular arena was affected by the above drug treatments. These results indicate that the panicolytic effect of fluoxetine is mediated by endogenous opioids that are activated by 5-HT in the DPAG. They also allow reconciliation between the serotonergic and opioidergic hypotheses of panic disorder pathophysiology.CAPESCNPqFundacao de Amparo ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas de Ribeirao Preto (FAEPA
Serotonin-1A receptors in the dorsal periaqueductal gray matter mediate the panicolytic-like effect of pindolol and paroxetine combination in the elevated T-maze
The beta-adrenergic blocker and 5-HT(1A) receptor antagonist pindolol has been combined with selective serotonin reuptake inhibitors (SSRIs) in patients with depressive and anxiety disorders to shorten the onset of the clinical action and/or increase the proportion of responders. The results of a previous study have shown that pindolol potentiates the panicolytic effect of paroxetine in rats submitted to the elevated T-maze (ETM). Since reported evidence has implicated the 5-HT(1A) receptors of the dorsal periaqueductal gray matter (DPAG) in the panicolytic effect of antidepressants, rats treated with pindolol (5.0 mg/kg, i.p.) and paroxetine (1.5 mg/kg, i.p.) received a previous intra-DPAG injection of the selective 5-HT(1A) antagonist, WAY-100635 (0.4 mu g) and were submitted to the ETM. Pretreatment with WAY-100635 reversed the increase in escape latency, a panicolytic effect, determined by the pindolol-paroxetine combination. These results implicate the 5-HT(1A) receptors of the DPAG in the panicolytic effect of the pindolol-paroxetine combination administered systemically. They also give further preclinical support for the use of this drug combination in the treatment of panic disorder. (C) 2011 Elsevier Ireland Ltd. All rights reserved.CNPq, BrazilCNPqFAEP
Activity of eftozanermin alfa plus venetoclax in preclinical models and patients with acute myeloid leukemia
Activation of apoptosis in malignant cells is an established strategy for controlling cancer and is potentially curative. To assess the impact of concurrently inducing the extrinsic and intrinsic apoptosis-signaling pathways in acute myeloid leukemia (AML), we evaluated activity of the TRAIL receptor agonistic fusion protein eftozanermin alfa (eftoza; ABBV-621) in combination with the B-cell lymphoma protein-2 selective inhibitor venetoclax in preclinical models and human patients. Simultaneously stimulating intrinsic and extrinsic apoptosis-signaling pathways with venetoclax and eftoza, respectively, enhanced their activities in AML cell lines and patient-derived ex vivo/in vivo models. Eftoza activity alone or plus venetoclax required death receptor 4/5 (DR4/DR5) expression on the plasma membrane but was independent of TP53 or FLT3-ITD status. The safety/tolerability of eftoza as monotherapy and in combination with venetoclax was demonstrated in patients with relapsed/refractory AML in a phase 1 clinical trial. Treatment-related adverse events were reported in 2 of 4 (50%) patients treated with eftoza monotherapy and 18 of 23 (78%) treated with eftoza plus venetoclax. An overall response rate of 30% (7/23; 4 complete responses [CRs], 2 CRs with incomplete hematologic recovery, and 1 morphologic leukemia-free state) was reported in patients who received treatment with eftoza plus venetoclax and 67% (4/6) in patients with myoblasts positive for DR4/DR5 expression; no tumor responses were observed with eftoza monotherapy. These data indicate that combination therapy with eftoza plus venetoclax to simultaneously activate the extrinsic and intrinsic apoptosis-signaling pathways may improve clinical benefit compared with venetoclax monotherapy in relapsed/refractory AML with an acceptable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT03082209.</p
Pharmacokinetic, pharmacodynamic, and transcriptomic analysis of chronic levetiracetam treatment in 5XFAD mice: A MODELâAD preclinical testing core study
Abstract Introduction Hyperexcitability and epileptiform activity are commonplace in Alzheimer's disease (AD) patients and associated with impaired cognitive function. The antiâseizure drug levetiracetam (LEV) is currently being evaluated in clinical trials for ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of our studies was to establish a pharmacokinetic/pharmacodynamic (PK/PD) relationship with LEV in an amyloidogenic mouse model of AD to enable predictive preclinical to clinical translation, using the rigorous preclinical testing pipeline of the Model Organism Development and Evaluation for LateâOnset Alzheimer's Disease Preclinical Testing Core. Methods A multiâtier approach was applied that included quality assurance and quality control of the active pharmaceutical ingredient, PK/PD modeling, positron emission tomography/magnetic resonance imaging (PET/MRI), functional outcomes, and transcriptomics. 5XFAD mice were treated chronically with LEV for 3 months at doses in line with those allometrically scaled to the clinical dose range. Results Pharmacokinetics of LEV demonstrated sex differences in Cmax, AUC0ââ, and CL/F, and a dose dependence in AUC0ââ. After chronic dosing at 10, 30, 56Â mg/kg, PET/MRI tracer 18FâAV45, and 18Fâfluorodeoxyglucose (18FâFDG) showed specific regional differences with treatment. LEV did not significantly improve cognitive outcomes. Transcriptomics performed by nanoString demonstrated drugâ and doseârelated changes in gene expression relevant to human brain regions and pathways congruent with changes in 18FâFDG uptake. Discussion This study represents the first report of PK/PD assessment of LEV in 5XFAD mice. Overall, these results highlighted nonâlinear kinetics based on dose and sex. Plasma concentrations of the 10Â mg/kg dose in 5XFAD overlapped with human plasma concentrations used for studies of mild cognitive impairment, while the 30 and 56Â mg/kg doses were reflective of doses used to treat seizure activity. Postâtreatment gene expression analysis demonstrated LEV doseârelated changes in immune function and neuronalâsignaling pathways relevant to human AD, and aligned with regional 18FâFDG uptake. Overall, this study highlights the importance of PK/PD relationships in preclinical studies to inform clinical study design. Highlights Significant sex differences in pharmacokinetics of levetiracetam were observed in 5XFAD mice. Plasma concentrations of 10 mg/kg levetiracetam dose in 5XFAD overlapped with human plasma concentration used in the clinic. Drugâ and doseârelated differences in gene expression relevant to human brain regions and pathways were also similar to brain regionâspecific changes in 18Fâfluorodeoxyglucose uptake
Prophylactic evaluation of verubecestat on diseaseâ and symptomâmodifying effects in 5XFAD mice
Abstract Introduction Alzheimer's disease (AD) is the most common form of dementia. Betaâsecretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been underâinvestigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for LateâOnset Alzheimer's Disease (MODELâAD) Preclinical Testing Core (PTC) Drug Screening Pipeline. Methods 5XFAD mice were administered verubecestat ad libitum in chow from 3 to 6 months of age, prior to the onset of significant disease pathology. Following treatment (6 months of age), in vivo imaging was conducted with 18Fâflorbetapir (AVâ45/Amyvid) (18FâAV45) and 18âFDG (fluorodeoxyglucose)âPET (positron emission tomography)/MRI (magnetic resonance imaging), brain and plasma amyloid beta (AÎČ) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with the pharmacokinetic data. Results Prophylactic verubecestat treatment resulted in doseâ and regionâdependent attenuations of 18FâAV45 uptake in male and female 5XFAD mice. Plasma AÎČ40 and AÎČ42 were also doseâdependently attenuated with treatment. Across the dose range evaluated, side effects including coat color changes and motor alterations were reported, in the absence of cognitive improvement or changes in 18FâFDG uptake. Discussion Prophylactic treatment with verubecestat resulted in attenuated amyloid plaque deposition when treatment was initiated prior to significant pathology in 5XFAD mice. At the same dose range effective at attenuating AÎČ levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODELâAD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for earlyâstage AD