Microemulsions as topical delivery vehicles for the anti-melanoma prodrug, temozolomide hexyl ester (TMZA-HE)

A prodrug, temozolomide acid hexyl ester (TMZA-HE), was identified as a skin-deliverable congener for temozolomide (TMZ) to treat skin cancers. Poor solubility and instability of TMZA-HE rendered a serious challenge for formulation of a topical preparation. Microemulsions (ME) were chosen as a potential vehicle for TMZA-HE topical preparations. ME systems were constructed with either oleic acid (OA) or isopropyl myristate (IPM) as the oil phase and tocopheryl (vitamin E) polyethylene glycol 1000 succinate (VE-TPGS) as a surfactant. Topical formulations of OA and IPM ME systems demonstrated beneficial solubilising ability and provided a stable environment for the prodrug, TMZA-HE. Significant differences between the microstructures of OA and IPM ME systems were revealed by freeze fracture electron microscopy (FFEM) and different loading abilities and permeation potencies between the two systems were also identified. In permeation studies, IPM ME systems, with inclusion of isopropyl alcohol (IPA) as a co-surfactant, significantly increased TMZA-HE permeation through silicon membranes and rat skin resulting in less drug retention within the skin, while OA ME systems demonstrated higher solubilising ability and a higher concentration of TMZA-HE retained within the skin. Therefore IPM ME systems are promising for transdermal delivery of TMZA-HE and OA ME systems may be a suitable choice for a topical formulation of TMZA-HE. © 2007 The Authors.

Skin delivery potency and antitumor activities of temozolomide ester prodrugs

Clinical trials have shown temozolomide to be an effective agent for treatment of malignant melanoma. In order to investigate its suitability for delivery via the skin, a series of temozolomide esters was synthesized as prodrugs. In vitro assays demonstrated temozolomide, temozolomide acid and the hexyl ester equi-effective against selected cancer cell lines. The susceptibility of the esters to enzyme hydrolysis and their effectiveness for application to the skin were investigated. The esters effectively diffuse through rat skin and the hexyl ester demonstrated profound potency for penetrating through skin. Topical application of 5% (w/v) hexyl ester in DMSO solution on a mouse model demonstrated a significant inhibition of tumor growth. These results suggest that temozolomide esters could be an effective alternative to temozolomide in the treatment of skin cancer. © 2005 Elsevier Ireland Ltd. All rights reserved.

Permeability characteristics of temozolomide and its ester and amide products through rat and human skin.

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

Induction of protein degradation in skeletal muscle by a phorbol ester involves upregulation of the ubiquitin-proteasome proteolytic pathway

Although muscle atrophy is common to a number of disease states there is incomplete knowledge of the cellular mechanisms involved. In this study murine myotubes were treated with the phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA) to evaluate the role of protein kinase C (PKC) as an upstream intermediate in protein degradation. TPA showed a parabolic dose-response curve for the induction of total protein degradation, with an optimal effect at a concentration of 25 nM, and an optimal incubation time of 3 h. Protein degradation was attenuated by co-incubation with the proteasome inhibitor lactacystin (5 μM), suggesting that it was mediated through the ubiquitin-proteasome proteolytic pathway. TPA induced an increased expression and activity of the ubiquitin-proteasome pathway, as evidenced by an increased functional activity, and increased expression of the 20S proteasome α-subunits, the 19S subunits MSS1 and p42, as well as the ubiquitin conjugating enzyme E214k, also with a maximal effect at a concentration of 25 nM and with a 3 h incubation time. There was also a reciprocal decrease in the cellular content of the myofibrillar protein myosin. TPA induced activation of PKC maximally at a concentration of 25 nM and this effect was attenuated by the PKC inhibitor calphostin C (300 nM), as was also total protein degradation. These results suggest that stimulation of PKC in muscle cells initiates protein degradation through the ubiquitin-proteasome pathway. TPA also induced degradation of the inhibitory protein, I-κBα, and increased nuclear accumulation of nuclear factor-κB (NF-κB) at the same time and concentrations as those inducing proteasome expression. In addition inhibition of NF-κB activation by resveratrol (30 μM) attenuated protein degradation induced by TPA. These results suggest that the induction of proteasome expression by TPA may involve the transcription factor NF-κB. © 2005 Elsevier Inc. All rights reserved.

The nitric oxide-donating pravastatin derivative, NCX 6550 [(1S-[1α(βS*, δS*), 2α, 6α, 8β-(R*), 8aα]]-1,2,6,7,8,8a-hexahydro-β, δ, 6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphtalene-heptanoic acid 4-(nitrooxy)butyl ester)], reduces splenocyte adhesion and reactive oxygen species generation in normal and atherosclerotic mice

Statins possess anti-inflammatory effects that may contribute to their ability to slow atherogenesis, whereas nitric oxide (NO) also influences inflammatory cell adhesion. This study aimed to determine whether a novel NO-donating pravastatin derivative, NCX 6550 [(1S-[1∝(ßS*,dS*),2∝,6a∝,8ß-(R*),8a∝]]-1,2,6,7,8,8a-hexahydro-ß,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-heptanoic acid 4-(nitrooxy)butyl ester)], has greater anti-inflammatory properties compared with pravastatin in normal and atherosclerotic apolipoprotein E receptor knockout (ApoE-/-) mice. C57BL/6 and ApoE-/- mice were administered pravastatin (40 mg/kg), NCX 6550 (48.5 mg/kg), or vehicle orally for 5 days. Ex vivo studies assessed splenocyte adhesion to arterial segments and splenocyte reactive oxygen species (ROS) generation. NCX 6550 significantly reduced splenocyte adhesion to artery segments in both C57BL/6 (8.8 ± 1.9% versus 16.6 ± 6.7% adhesion; P < 0.05) and ApoE-/- mice (9.3 ± 2.9% versus 23.4 ± 4.6% adhesion; P < 0.05) concomitant with an inhibition of endothelial intercellular adhesion molecule-1 expression. NCX 6550 also significantly reduced phorbol 12-myristate 13-acetate-induced ROS production that was enhanced in isolated ApoE-/- splenocytes. Conversely, pravastatin had no significant effects on adhesion in normal or ApoE-/- mice but reduced the enhanced ROS production from ApoE-/- splenocytes. In separate groups of ApoE-/- mice, NCX 6550 significantly enhanced endothelium-dependent relaxation to carbachol in aortic segments precon-tracted with phenylephrine (-logEC50, 6.37 ± 0.37) compared with both vehicle-treated (-logEC50, 5.81 ± 0.15; P < 0.001) and pravastatin-treated (-logEC50, 5.57 ± 0.45; P < 0.05) mice. NCX 6550 also significantly reduced plasma monocyte chemoattractant protein-1 levels (648.8 pg/ml) compared with both vehicle (1191.1 pg/ml; P < 0.001) and pravastatin (847 ± 71.0 pg/ml; P < 0.05) treatment. These data show that NCX 6550 exerts superior anti-inflammatory actions compared with pravastatin, possibly through NO-related mechanisms.

Ester Balfour, 65 year old running in marathon

General note: Title and date provided by Bettye Lane.

Síntese, aplicação e avaliação do efeito do teor de fósforo da celulose fosfatada em argamassa de alvenaria com aditivo comercial a base de hidroxi-etil-metil celulose (HEMC)

Generally, cellulose ethers improves mortar properties such as water retention, workability and setting time, along with adherence to the substrate. However, a major disadvantage of the addition of cellulose ethers in mortars is the delay in hydration of the cement. In this paper a cellulose phosphate (Cp) was synthesized water soluble and has been evaluated the effect of their incorporation into mortar based on Portland cement. Cellulose phosphate obtained was characterized by spectrophotometry Fourier transform infrared (FTIR), X-ray diffraction (XRD), elemental analysis and scanning electron microscopy (SEM). Mortar compositions were formulated with varying phosphorus content in cellulose and cellulose phosphate concentrations, when used in partial or total replacement of the commercial additive based hydroxyethyl methyl cellulose (HEMC). The mortars formulated with additives were prepared and characterized by: testing in the fresh state (consistency index, water retention, bulk density and air content incorporated) and in the hardened state (absorption by capillarity, density, flexural and compression strength). In mixtures the proportion of sand:cement of 1:5 (v / v) and factor a / c = 1.31 and water were held constant. Overall, the results showed that the celluloses phosphates employed in mortars added acted significantly when partially substituting the commercial additive. With regard to consistency index, water retention and bulk density in the fresh state and absorption by capillarity and bulk density apparent in the hardened state, showed no appreciable differences as compared to the commercial additive. The incorporated air content in the fresh state reduced markedly, but did not affect other properties. The mortars with cellulose phosphate, partially replacing the commercial additive showed an improvement of the properties of flexural strength and compressive strength

Development and scale-up studies of bio-based poly(ester-amide)s

Plastics are polymers of conventional and extensive use in our day-to-day life. This is due to their light weight, adaptability to different uses and low prices. A downside of such extensive use is the environmental pollution arising from plastic production and disposal. Indeed, many commodity polymers are produced from non-renewable resources while other do not bio-degrade after their end-of-life disposal. Consequently, the ideal polymer comes from renewable raw materials and bio-degrades after its disposal, meaning that it would do little or no harm to the environment from the beginning to the end of its life cycle. In this thesis project a class of bio-based and bio-degradable co-polymers, namely poly(ester-amide)s, was investigated because of their tunable mechanical and bio-degradation properties as well as their renewable origin. Such polymers were synthetized and characterized thermically and mechanically. Furthermore, a scale-up procedure was developed and applied to one polymer and processing trials were made with the material obtained after scale-up.

Melhoria da atenção ao pré-natal e puerpério na ESF 09 - Vila Ester, em São Borja-RS

A Melhoria da atenção ao pré-natal e puerpério é fundamental para observar precocemente transtornos que podem afetar a saúde do binômio mãe e filho, e assegurar uma gestação segura e o nascimento de uma criança saudável. Uma assistência humanizada e qualificada no período gestacional e pós-parto é essencial para diminuir os índices de mortalidade, além de contribuir para maior liberdade, segurança e qualidade de vida destas gestantes e seus familiares. Este trabalho teve como objetivo melhorar a atenção ao pré-natal e puerpério praticada na ESF 09, em São Borja, RS. É o relato de uma intervenção de 16 semanas com ações desenvolvidas em quatro eixos de trabalho: organização e gestão do serviço, monitoramento e avaliação das ações, qualificação da prática clínica e engajamento público. Após os quatro meses, houve a avaliação do período com a qualificação e reordenamento das ações para incorporação das mesmas na rotina da unidade. Como principal resultado tivemos um aumento da cobertura e da qualidade do pré-natal. Foram identificadas 25 gestantes no território, e, dessas, 17 foram cadastradas para acompanhamento local, proporcionando uma cobertura global de 68%, além da incorporação da avaliação de risco para morbimortalidade e de atividades educativas coletivas nas ações cotidianas, trabalhando com promoção de saúde para as várias linhas de cuidado da atenção primária. A qualificação do programa resultou, também, na melhoria dos registros na unidade, e refletiu numa melhoria geral das demais ações programáticas. Para o serviço e para a comunidade, este trabalho trouxe resultados positivos: melhora nos atendimentos, qualificação dos profissionais, atividades educativas realizadas por todos os profissionais, além de um atendimento mais humanizado e integral, resultando num melhor cuidado à população como um todo, e não apenas atendimento às suas demandas clínicas.

Melhoria da Atenção à Saúde do Idoso na UBS Ana Ester Correa Pinto, São Borja/RS

Resumo SCHMITZ, Viviane Martins. Melhoria da atenção à saúde do idoso na UBS Ana Ester Correa Pinto, SÃO BORJA/RS. 2015. 100f. Trabalho de Conclusão de Curso (Curso de Especialização em Saúde da Família) - Departamento de Medicina Social, Faculdade de Medicina, Universidade Federal de Pelotas, Pelotas, 2015. A Organização Pan-Americana de Saúde define envelhecimento como “um processo sequencial, individual, acumulativo, irreversível, universal, não patológico, de deterioração de um organismo maduro, próprio a todos os membros de uma espécie, de maneira que o tempo o torne menos capaz de fazer frente ao estresse do meio-ambiente e, portanto, aumente sua possibilidade de morte”. Em condições de sobrecarga como, por exemplo, doenças, acidentes e estresse emocional, pode ocasionar uma condição patológica que requeira assistência - senilidade. Cabe ressaltar que certas alterações decorrentes do processo de senescência podem ter seus efeitos minimizados pela assimilação de um estilo de vida mais ativo. O presente trabalho tem como objetivo ampliar a cobertura da atenção à saúde do idoso, melhorar a qualidade da atenção e a promoção a saúde do idoso na ESF 12 Ana Ester Correa Pinto em São Borja/RS. A intervenção ocorreu durante 12 semanas, entre março a maio de 2015, neste período a população da área era de 3.395 pessoas, 1.013 famílias, sendo 433 a população de idosos. Reorganizamos a equipe, capacitamos os profissionais, cadastramos os idosos, os acamados e com dificuldade de locomoção. Obtivemos apoio dos gestores e a adesão da comunidade. Atingimos uma cobertura 23,1% idosos ficando abaixo do esperado, mas realizado de forma integral. Foi realizada a Avaliação Multidimensional Rápida a todos os participantes, rastreamos os idosos para Hipertensão Arterial Sistêmica (HAS) e Diabetes, solicitamos exames complementares periódicos aos idosos hipertensos e/ou diabéticos, avaliamos a necessidade de atendimento odontológico, avaliação de rede social e presença de indicadores de fragilização na velhice. Realizamos visita domiciliar a 100% dos idosos acamados e/ou com problemas de locomoção. Fortalecemos o vinculo com a comunidade e com os demais serviços: NASF, CRAS, farmácia básica e gestores. Durante a intervenção nenhum usuário faltou à consulta, aumentou à demanda dos idosos na ESF e a participação nos grupos de ioga, atividade física, HIPERDIA e com a nutricionista, estabelecendo assim uma rotina de hábitos saudáveis na vida dos idosos. Observamos à promoção da saúde, a prevenção de doenças crônicas, a provisão equânime de apoio comunitário e de cuidados paliativos e de longo prazo, por meio da reorientação no atendimento ao idoso, considerando suas opiniões e preferências, fortalecendo o vinculo usuário-equipe de saúde e a continuidade da assistência. Palavras-chave: Saúde da Família; Atenção Primária à Saúde; Saúde do Idoso; assistência domiciliar; Saúde Bucal.

Cardiac Magnetic Resonance Assessment Of Interstitial Myocardial Fibrosis And Cardiomyocyte Hypertrophy In Hypertensive Mice Treated With Spironolactone.

Nearly 50% of patients with heart failure (HF) have preserved LV ejection fraction, with interstitial fibrosis and cardiomyocyte hypertrophy as early manifestations of pressure overload. However, methods to assess both tissue characteristics dynamically and noninvasively with therapy are lacking. We measured the effects of mineralocorticoid receptor blockade on tissue phenotypes in LV pressure overload using cardiac magnetic resonance (CMR). Mice were randomized to l-nitro-ω-methyl ester (l-NAME, 3 mg/mL in water; n=22), or l-NAME with spironolactone (50 mg/kg/day in subcutaneous pellets; n=21). Myocardial extracellular volume (ECV; marker of diffuse interstitial fibrosis) and the intracellular lifetime of water (τic; marker of cardiomyocyte hypertrophy) were determined by CMR T1 imaging at baseline and after 7 weeks of therapy alongside histological assessments. Administration of l-NAME induced hypertensive heart disease in mice, with increases in mean arterial pressure, LV mass, ECV, and τic compared with placebo-treated controls, while LV ejection fraction was preserved (>50%). In comparison, animals receiving both spironolactone and l-NAME (l-NAME+S) showed less concentric remodeling, and a lower myocardial ECV and τic, indicating decreased interstitial fibrosis and cardiomyocyte hypertrophy (ECV: 0.43 ± 0.09 for l-NAME versus 0.25 ± 0.03 for l-NAME+S, P<0.001; τic: 0.42 ± 0.11 for l-NAME groups versus 0.12 ± 0.05 for l-NAME+S group). Mice treated with a combination of l-NAME and spironolactone were similar to placebo-treated controls at 7 weeks. Spironolactone attenuates interstitial fibrosis and cardiomyocyte hypertrophy in hypertensive heart disease. CMR can phenotype myocardial tissue remodeling in pressure-overload, furthering our understanding of HF progression.

Sinonasal Disorders In Hematopoietic Stem Cell Transplantation.

hematopoietic stem cell transplantation (HSCT) is associated with more respiratory infections due to immunosuppression. this study aimed to verify the frequency of rhinosinusitis after HSCT, and the association between rhinosinusitis and chronic graft vs. host disease (GVHD) and type of transplantation, clinical treatment, surgical treatment, and survival. this was a retrospective study in a tertiary university hospital. A total of 95 patients with hematological diseases undergoing HSCT between 1996 and 2011 were selected. chronic myeloid leukemia was the most prevalent disease. The type of transplant most often performed was the allogenic type (85.26%). The frequency of rhinosinusitis was 36%, with no difference between the autologous and the allogenic types. Chronic GVHD occurred in 30% of patients. Patients with GVHD had a higher frequency and recurrence of rhinosinusitis, in addition to more frequent need for endoscopic sinusectomy and decreased overall survival. there was a higher frequency of rhinosinusitis in HSCT and GVHD. The type of transplant does not appear to predispose to the occurrence of rhinosinusitis. GVHD seems to be an aggravating factor and requires a more stringent treatment.

Long-term Prospects For The Environmental Profile Of Advanced Sugar Cane Ethanol.

This work assessed the environmental impacts of the production and use of 1 MJ of hydrous ethanol (E100) in Brazil in prospective scenarios (2020-2030), considering the deployment of technologies currently under development and better agricultural practices. The life cycle assessment technique was employed using the CML method for the life cycle impact assessment and the Monte Carlo method for the uncertainty analysis. Abiotic depletion, global warming, human toxicity, ecotoxicity, photochemical oxidation, acidification, and eutrophication were the environmental impacts categories analyzed. Results indicate that the proposed improvements (especially no-til farming-scenarios s2 and s4) would lead to environmental benefits in prospective scenarios compared to the current ethanol production (scenario s0). Combined first and second generation ethanol production (scenarios s3 and s4) would require less agricultural land but would not perform better than the projected first generation ethanol, although the uncertainties are relatively high. The best use of 1 ha of sugar cane was also assessed, considering the displacement of the conventional products by ethanol and electricity. No-til practices combined with the production of first generation ethanol and electricity (scenario s2) would lead to the largest mitigation effects for global warming and abiotic depletion. For the remaining categories, emissions would not be mitigated with the utilization of the sugar cane products. However, this conclusion is sensitive to the displaced electricity sources.