Deformable Nanovesicles Synthesized through an Adaptable Microfluidic Platform for Enhanced Localized Transdermal Drug Delivery.

Phospholipid-based deformable nanovesicles (DNVs) that have flexibility in shape offer an adaptable and facile method to encapsulate diverse classes of therapeutics and facilitate localized transdermal delivery while minimizing systemic exposure. Here we report the use of a microfluidic reactor for the synthesis of DNVs and show that alteration of input parameters such as flow speeds as well as molar and flow rate ratios increases entrapment efficiency of drugs and allows fine-tuning of DNV size, elasticity, and surface charge. To determine the ability of DNV-encapsulated drug to be delivered transdermally to a local site, we synthesized, characterized, and tested DNVs carrying the fluorescently labeled hydrophilic bisphosphonate drug AF-647 zoledronate (AF647-Zol). AF647-Zol DNVs were lyophilized, resuspended, and applied topically as a paste to the calvarial skin of mice. High-resolution fluorescent imaging and confocal microscopy revealed significant increase of encapsulated payload delivery to the target tissue-cranial bone-by DNVs as compared to nondeformable nanovesicles (NVs) or aqueous drug solutions. Interestingly, NV delivery was not superior to aqueous drug solution. Our studies show that microfluidic reactor-synthesized DNVs can be produced in good yield, with high encapsulation efficiency, reproducibility, and stability after storage, and represent a useful vehicle for localized transdermal drug delivery

Cultural adaptation, reliability and validity of the Brazilian version Independent Living Skills Survey (ILSS-BR/P) with schizophrenic patients for schizophrenia

BACKGROUND: There is a strong association between good psychosocial functioning and the ability to carry out everyday tasks in patients with schizophrenia. Valid instruments become increasingly necessary to evaluate the performance of these patients in independent living activities. OBJECTIVE: To adapt and assess the psychometric properties of the Brazilian version of the Independent Living Skills Survey (ILSS-BR/P) in patients with schizophrenia. METHODS: Reliability was assessed with test-retest, interrater and internal consistency. Furthermore, construct, discriminant and concurrent validity were assessed. RESULTS: Fifty patients were included in the interrater study, with an agreement of 64.4% between responses and an Intraclass Correlation (ICC) ranged from 0.80-0.99. Forty-six patients participated in the test-retest, with an ICC ranged from 0.84-0.94 and an agreement of 44.3%. The internal consistency was good (0.23-0.98). Hundred and sixty patients participated in the validation. Regarding to the discriminant validity, female patients presented a higher performance in the overall score and five subscales compared with men. The concurrent validity confirmed the specificity of the dimensions of the scale, comparing the ILSS with the PANSS, Calgary, CGI, GAF, WHOQOL and the Rosenberg Self-Esteem. DISCUSSION: The ILSS-BR/P is a valid and reliable research instrument to assess social functioning in patients with schizophrenia.CONTEXTO: Existe uma forte associação entre um bom funcionamento psicossocial e a habilidade de realizar tarefas diárias em pacientes com esquizofrenia. Instrumentos válidos tornam-se cada vez mais necessários para avaliar o desempenho desses pacientes nas atividades de vida independente. OBJETIVO: Avaliar as propriedades psicométricas do Inventário de Habilidades de Vida Independente - versão do paciente (ILSS-BR/P) em portadores de esquizofrenia. MÉTODOS: Confiabilidade foi avaliada pelo teste-reteste, entre observadores e consistência interna. Além disso, a validade de construto, discriminante e concorrente, foi avaliada. RESULTADOS: Cinquenta pacientes foram incluídos no estudo entre observadores, com 64,4% de concordância entre as respostas e uma variação de 0,80-0,99 do Coeficiente de Correlação Intraclasses (ICC). Quarenta e seis pacientes participaram do teste-reteste, e o ICC variou de 0,84-0,94, com 44,3% de concordância. A consistência interna apresentou bom resultado (0,23-0,98). Cento e sessenta pacientes participaram da validação. Na validade discriminante, as mulheres apresentaram desempenho superior no escore global e em cinco subescalas quando comparadas aos homens. A validade concorrente confirmou a especificidade das dimensões da escala, comparando a ILSS com a PANSS, Calgary, CGI, GAF, WHOQOL e Autoestima de Rosemberg. CONCLUSÃO: A ILSS-BR/P é um instrumento de pesquisa válido e confiável para avaliar o funcionamento social desses pacientes.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo (UNIFESP) Departamento de Psiquiatria PROESQUniversidade Federal de São Paulo (UNIFESP) Department of PsychiatryUNIFESP, Depto. de Psiquiatria PROESQUNIFESP, Department of PsychiatrySciEL

A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer's disease mouse model.

We describe here the results from the testing of a small molecule first-in-class apolipoprotein E4 (ApoE4)-targeted sirtuin1 (SirT1) enhancer, A03, that increases the levels of the neuroprotective enzyme SirT1 while not affecting levels of neurotoxic sirtuin 2 (SirT2) in vitro in ApoE4-transfected cells. A03 was identified by high-throughput screening (HTS) and found to be orally bioavailable and brain penetrant. In vivo, A03 treatment increased SirT1 levels in the hippocampus of 5XFAD-ApoE4 (E4FAD) Alzheimer's disease (AD) model mice and elicited cognitive improvement while inducing no observed toxicity. We were able to resolve the enantiomers of A03 and show using in vitro models that the L-enantiomer was more potent than the corresponding D-enantiomer in increasing SirT1 levels. ApoE4 expression has been shown to decrease the level of the NAD-dependent deacetylase and major longevity determinant SirT1 in brain tissue and serum of AD patients as compared to normal controls. A deficiency in SirT1 level has been recently implicated in increased tau acetylation, a dominant post-translational modification and key pathological event in AD and tauopathies. Therefore, as a novel approach to therapeutic development for AD, we targeted identification of compounds that enhance and normalize brain SirT1 levels

Adaptação cultural, validade e confiabilidade da versão brasileira do Inventário de Habilidades de Vida Independente: versão do paciente (ILSS-BR/P), na esquizofrenia

BACKGROUND: There is a strong association between good psychosocial functioning and the ability to carry out everyday tasks in patients with schizophrenia. Valid instruments become increasingly necessary to evaluate the performance of these patients in independent living activities. OBJECTIVE: To adapt and assess the psychometric properties of the Brazilian version of the Independent Living Skills Survey (ILSS-BR/P) in patients with schizophrenia. METHODS: Reliability was assessed with test-retest, interrater and internal consistency. Furthermore, construct, discriminant and concurrent validity were assessed. RESULTS: Fifty patients were included in the interrater study, with an agreement of 64.4% between responses and an Intraclass Correlation (ICC) ranged from 0.80-0.99. Forty-six patients participated in the test-retest, with an ICC ranged from 0.84-0.94 and an agreement of 44.3%. The internal consistency was good (0.23-0.98). Hundred and sixty patients participated in the validation. Regarding to the discriminant validity, female patients presented a higher performance in the overall score and five subscales compared with men. The concurrent validity confirmed the specificity of the dimensions of the scale, comparing the ILSS with the PANSS, Calgary, CGI, GAF, WHOQOL and the Rosenberg Self-Esteem. DISCUSSION: The ILSS-BR/P is a valid and reliable research instrument to assess social functioning in patients with schizophrenia.CONTEXTO: Existe uma forte associação entre um bom funcionamento psicossocial e a habilidade de realizar tarefas diárias em pacientes com esquizofrenia. Instrumentos válidos tornam-se cada vez mais necessários para avaliar o desempenho desses pacientes nas atividades de vida independente. OBJETIVO: Avaliar as propriedades psicométricas do Inventário de Habilidades de Vida Independente - versão do paciente (ILSS-BR/P) em portadores de esquizofrenia. MÉTODOS: Confiabilidade foi avaliada pelo teste-reteste, entre observadores e consistência interna. Além disso, a validade de construto, discriminante e concorrente, foi avaliada. RESULTADOS: Cinquenta pacientes foram incluídos no estudo entre observadores, com 64,4% de concordância entre as respostas e uma variação de 0,80-0,99 do Coeficiente de Correlação Intraclasses (ICC). Quarenta e seis pacientes participaram do teste-reteste, e o ICC variou de 0,84-0,94, com 44,3% de concordância. A consistência interna apresentou bom resultado (0,23-0,98). Cento e sessenta pacientes participaram da validação. Na validade discriminante, as mulheres apresentaram desempenho superior no escore global e em cinco subescalas quando comparadas aos homens. A validade concorrente confirmou a especificidade das dimensões da escala, comparando a ILSS com a PANSS, Calgary, CGI, GAF, WHOQOL e Autoestima de Rosemberg. CONCLUSÃO: A ILSS-BR/P é um instrumento de pesquisa válido e confiável para avaliar o funcionamento social desses pacientes

A 6-month randomized controlled trial to test the efficacy of a lifestyle intervention for weight gain management in schizophrenia

Background: Patients with schizophrenia have lower longevity than the general population as a consequence of a combination of risk factors connected to the disease, lifestyle and the use of medications, which are related to weight gain.Methods: A multicentric, randomized, controlled-trial was conducted to test the efficacy of a 12-week group Lifestyle Wellness Program (LWP). the program consists of a one-hour weekly session to discuss topics like dietary choices, lifestyle, physical activity and self-esteem with patients and their relatives. Patients were randomized into two groups: standard care (SC) and standard care plus intervention (LWP). Primary outcome was defined as the weight and body mass index (BMI).Results: 160 patients participated in the study (81 in the intervention group and 79 in the SC group). On an intent to treat analysis, after three months the patients in the intervention group presented a decrease of 0.48 kg (CI 95% - 0.65 to 1.13) while the standard care group showed an increase of 0.48 kg (CI 95% 0.13 to 0.83; p=0.055). At six-month follow-up, there was a significant weight decrease of -1.15 kg, (CI 95% -2.11 to 0.19) in the intervention group compared to a weight increase in the standard care group (+0.5 kg, CI 95% -0.42-1.42, p=0.017).Conclusion: in conclusion, this was a multicentric randomized clinical trial with a lifestyle intervention for individuals with schizophrenia, where the intervention group maintained weight and presented a tendency to decrease weight after 6 months. It is reasonable to suppose that lifestyle interventions may be important long-term strategies to avoid the tendency of these individuals to increase weight. Clinicaltrials.gov identifier: NCT01368406Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Eli Lilly do BrasilCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Ministry of EducationJanssen-CilagNovartisRocheConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundacao SafraFundacao ABRADSLundbeckEli Lilly laboratoryUniversidade Federal de São Paulo, Dept Psychiat, BR-04044000 São Paulo, BrazilUniv São Paulo, Med School, Dept & Inst Psychiat, BR-05403010 São Paulo, BrazilCAISM Ctr Atencao Integrada Saude Mental Irmandad, BR-04017030 São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Med, Div Endocrinol, BR-04039002 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, BR-04044000 São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Med, Div Endocrinol, BR-04039002 São Paulo, BrazilFAPESP: 2007/00464-6Web of Scienc

Deformable Nanovesicles Synthesized through an Adaptable Microfluidic Platform for Enhanced Localized Transdermal Drug Delivery

Phospholipid-based deformable nanovesicles (DNVs) that have flexibility in shape offer an adaptable and facile method to encapsulate diverse classes of therapeutics and facilitate localized transdermal delivery while minimizing systemic exposure. Here we report the use of a microfluidic reactor for the synthesis of DNVs and show that alteration of input parameters such as flow speeds as well as molar and flow rate ratios increases entrapment efficiency of drugs and allows fine-tuning of DNV size, elasticity, and surface charge. To determine the ability of DNV-encapsulated drug to be delivered transdermally to a local site, we synthesized, characterized, and tested DNVs carrying the fluorescently labeled hydrophilic bisphosphonate drug AF-647 zoledronate (AF647-Zol). AF647-Zol DNVs were lyophilized, resuspended, and applied topically as a paste to the calvarial skin of mice. High-resolution fluorescent imaging and confocal microscopy revealed significant increase of encapsulated payload delivery to the target tissue—cranial bone—by DNVs as compared to nondeformable nanovesicles (NVs) or aqueous drug solutions. Interestingly, NV delivery was not superior to aqueous drug solution. Our studies show that microfluidic reactor-synthesized DNVs can be produced in good yield, with high encapsulation efficiency, reproducibility, and stability after storage, and represent a useful vehicle for localized transdermal drug delivery

Nanoscale Extracellular Vesicle Analysis in Alzheimer’s Disease Diagnosis and Therapy

Diagnostic assays that leverage bloodborne neuron-derived (neuronal) nanoscale extracellular vesicles (nsEVs) as “windows into the brain” can predict incidence of Alzheimer’s Disease (AD) many years prior to onset. Beyond diagnostics, bloodborne neuronal nsEVs analysis may have substantial translational impact by revealing mechanisms of AD pathology; such knowledge could enlighten new drug targets and lead to new therapeutic approaches. The potential to establish three-dimensional nsEV analysis methods that characterize highly purified bloodborne nsEV populations in method of enrichment, cell type origin, and protein or RNA abundance dimensions could bring this promise to bear by yielding nsEV “omics” datasets that uncover new AD biomarkers and enable AD therapeutic development. In this review we provide a survey of both the current status of and new developments on the horizon in the field of neuronal nsEV analysis. This survey is supplemented by a discussion of the potential to translate such neuronal nsEV analyses to AD clinical diagnostic applications and drug development