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BACKGROUND: This study investigates the potential of eleven 1H-1,2,3-triazol-1,4-naphthoquinone conjugates as virulence factor inhibitors (like Pyocyanin) and their affinity for PhzM, a crucial enzyme for Pyocyanin biosynthesis in Pseudomonas aeruginosa infections. METHODS: A straightforward synthetic pathway enabled the production of these compounds, which were characterized and structurally confirmed through spectroscopic analyses. Evaluation of their impact on PhzM thermal stability identified promising candidates for PhzM binders. RESULTS: Concentration-response behavior elucidated their binding affinity, revealing them as the first reported micromolar affinity ligands for PhzM. Structure-activity relationship analysis emphasized the role of specific molecular moieties in binding affinity modulation, paving the way for future advanced inhibitors' development. CONCLUSION: These findings highlight the potential of naphthoquinone-triazole derivatives as leads for novel therapeutics against P. aeruginosa infections.
Assuntos
Antibacterianos , Testes de Sensibilidade Microbiana , Naftoquinonas , Pseudomonas aeruginosa , Piocianina , Triazóis , Naftoquinonas/farmacologia , Naftoquinonas/química , Naftoquinonas/síntese química , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Piocianina/antagonistas & inibidores , Piocianina/biossíntese , Piocianina/metabolismo , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia , Triazóis/metabolismo , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Estrutura Molecular , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Humanos , Relação Dose-Resposta a DrogaRESUMO
BACKGROUND: Hyperkalemia leads to suboptimal use of evidence-based therapies in patients with heart failure (HF). Therefore, we aimed to assess whether new potassium binders are effective and safe to promote medical optimization in patients with HF. METHODS: MEDLINE, Cochrane, and Embase were searched for randomized controlled trials (RCTs) that reported outcomes after initiation of Patiromer or Sodium Zirconium Cyclosilicate (SZC) versus placebo in patients with HF at high risk of hyperkalemia development. Risk ratios (RR) with 95% confidence intervals (CI) were pooled with a random effects model. Quality assessment and risk of bias were performed according to Cochrane recommendations. RESULTS: A total of 1432 patients from 6 RCTs were included, of whom 737 (51.5%) patients received potassium binders. In patients with HF, potassium binders increased the use of renin-angiotensin-aldosterone inhibitors (RR 1.14; 95% CI 1.02-1.28; p = 0.021; I2 = 44%) and reduced the risk of hyperkalemia (RR 0.66; 95% CI 0.52-0.84; p < 0.001; I2 = 46%). The risk of hypokalemia was significantly increased in patients treated with potassium binders (RR 5.61; 95% CI 1.49-21.08; p = 0.011; I2 = 0%). There was no difference between groups in all-cause mortality rates (RR 1.13; 95% CI 0.59-2.16; p = 0.721; I2 = 0%) or in adverse events leading to drug discontinuation (RR 1.08; 95% CI 0.60-1.93; p = 0.801; I2 = 0%). CONCLUSION: The use of new potassium binders Patiromer or SZC in patients with HF at risk for hyperkalemia increased the rates of medical therapy optimization with renin-angiotensin-aldosterone inhibitors and reduced the incidence of hyperkalemia, at the cost of an increased prevalence of hypokalemia.
Assuntos
Insuficiência Cardíaca , Hiperpotassemia , Hipopotassemia , Humanos , Hiperpotassemia/tratamento farmacológico , Hiperpotassemia/etiologia , Potássio , Hipopotassemia/complicações , Renina/farmacologia , Renina/uso terapêutico , Aldosterona/farmacologia , Aldosterona/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Sistema Renina-Angiotensina , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Angiotensinas/farmacologia , Angiotensinas/uso terapêuticoRESUMO
Cyclin-Dependent Kinase 2 (CDK2) and Vascular-Endothelial Growth Factor Receptor 2 (VEGFR2) are promising targets for the design of novel inhibitors in anticancer therapeutics. In a recent work, our group designed a set of potential dual inhibitors predicted to occupy an allosteric back pocket near the active site of both enzymes, but their dynamic and unbinding behavior was unclear. Here, we used molecular dynamics (MD) and metadynamics (meta-D) simulations to study two of these virtual candidates (herein called IQ2 and IQ3). Their binding mode was predicted to be similar to that observed in LQ5 and BAX, well-known back-pocket binders of CDK2 and VEGFR2, respectively, including H-bonding with critical residues such as Leu83/Cys113 and Asp145/Asp190 (but excepting H-bonding with Glu51/Glu111) in CDK2/VEGFR2, correspondingly. Likewise, while LQ5 and BAX unbound through the allosteric channel as expected for type-IIA inhibitors, IQ2 and IQ3 unbound via the ATP channel (except for CDK2-IQ2) as expected for type-I½A inhibitors. Interestingly, a C-C single/double bond difference between IQ2/IQ3, respectively, resulted associated with differences in the AS/T loop flexibility observed for CDK2. These insights will help developing scaffold modifications during an optimization stage, serving as a starting point to develop dual kinase inhibitors in challenging biological targets with a promising anticancer potential.Communicated by Ramaswamy H. Sarma.
Assuntos
Simulação de Dinâmica Molecular , Quinase 2 Dependente de Ciclina/química , Ligação Proteica , Sítios de LigaçãoRESUMO
A total of 1,296 broiler chicken were housed, distributed in a completely randomized design with 6 treatments and 6 repetitions. The treatments consisted of a control diet formulated with corn considered adequate and without the addition of adsorbent, a diet formulated with corn naturally contaminated with mycotoxin (CCM) and four diets formulated with CCM and added with different commercial adsorbents. At the end of the first week and at 21 days of age of the birds, it was observed that the control diet resulted in greater (p < 0.05) live weight and weight gain in relation to the inclusion of CCM. The relative weight of the liver was lower for the control group compared to the groups receiving a diet with CCM and CCM + ads D. The relative weight of the proventriculus and cloacal bursa was lower for the control group compared to those who received a diet with CCM + ads B and CCM + ads C. There was no significant effect (p > 0.05) of the diets on the analysis of serum biochemistry and the occurrence of fatty and hydropic degeneration in the liver of broilers. The use of adsorbents can mitigate the harmful effects of mycotoxins, however, these products have specific binding capacity to the type of mycotoxin present in food.
A total of 1,296 broiler chicken were housed, distributed in a completely randomized design with 6 treatments and 6 repetitions. The treatments consisted of a control diet formulated with corn considered adequate and without the addition of adsorbent, a diet formulated with corn naturally contaminated with mycotoxin (CCM) and four diets formulated with CCM and added with different commercial adsorbents. At the end of the first week and at 21 days of age of the birds, it was observed that the control diet resulted in greater (p < 0.05) live weight and weight gain in relation to the inclusion of CCM. The relative weight of the liver was lower for the control group compared to the groups receiving a diet with CCM and CCM + ads D. The relative weight of the proventriculus and cloacal bursa was lower for the control group compared to those who received a diet with CCM + ads B and CCM + ads C. There was no significant effect (p > 0.05) of the diets on the analysis of serum biochemistry and the occurrence of fatty and hydropic degeneration in the liver of broilers. The use of adsorbents can mitigate the harmful effects of mycotoxins, however, these products have specific binding capacity to the type of mycotoxin present in food.
RESUMO
A total of 1,296 broiler chicken were housed, distributed in a completely randomized design with 6 treatments and 6 repetitions. The treatments consisted of a control diet formulated with corn considered adequate and without the addition of adsorbent, a diet formulated with corn naturally contaminated with mycotoxin (CCM) and four diets formulated with CCM and added with different commercial adsorbents. At the end of the first week and at 21 days of age of the birds, it was observed that the control diet resulted in greater (p < 0.05) live weight and weight gain in relation to the inclusion of CCM. The relative weight of the liver was lower for the control group compared to the groups receiving a diet with CCM and CCM + ads D. The relative weight of the proventriculus and cloacal bursa was lower for the control group compared to those who received a diet with CCM + ads B and CCM + ads C. There was no significant effect (p > 0.05) of the diets on the analysis of serum biochemistry and the occurrence of fatty and hydropic degeneration in the liver of broilers. The use of adsorbents can mitigate the harmful effects of mycotoxins, however, these products have specific binding capacity to the type of mycotoxin present in food.(AU)
Assuntos
Animais , Alimentos Formulados/análise , Galinhas/fisiologia , Fumonisinas/efeitos adversos , Ração Animal/toxicidade , Zea mays/microbiologia , Micotoxinas/efeitos adversosRESUMO
A total of 1,296 broiler chicken were housed, distributed in a completely randomized design with 6 treatments and 6 repetitions. The treatments consisted of a control diet formulated with corn considered adequate and without the addition of adsorbent, a diet formulated with corn naturally contaminated with mycotoxin (CCM) and four diets formulated with CCM and added with different commercial adsorbents. At the end of the first week and at 21 days of age of the birds, it was observed that the control diet resulted in greater (p < 0.05) live weight and weight gain in relation to the inclusion of CCM. The relative weight of the liver was lower for the control group compared to the groups receiving a diet with CCM and CCM + ads D. The relative weight of the proventriculus and cloacal bursa was lower for the control group compared to those who received a diet with CCM + ads B and CCM + ads C. There was no significant effect (p > 0.05) of the diets on the analysis of serum biochemistry and the occurrence of fatty and hydropic degeneration in the liver of broilers. The use of adsorbents can mitigate the harmful effects of mycotoxins, however, these products have specific binding capacity to the type of mycotoxin present in food.
A total of 1,296 broiler chicken were housed, distributed in a completely randomized design with 6 treatments and 6 repetitions. The treatments consisted of a control diet formulated with corn considered adequate and without the addition of adsorbent, a diet formulated with corn naturally contaminated with mycotoxin (CCM) and four diets formulated with CCM and added with different commercial adsorbents. At the end of the first week and at 21 days of age of the birds, it was observed that the control diet resulted in greater (p < 0.05) live weight and weight gain in relation to the inclusion of CCM. The relative weight of the liver was lower for the control group compared to the groups receiving a diet with CCM and CCM + ads D. The relative weight of the proventriculus and cloacal bursa was lower for the control group compared to those who received a diet with CCM + ads B and CCM + ads C. There was no significant effect (p > 0.05) of the diets on the analysis of serum biochemistry and the occurrence of fatty and hydropic degeneration in the liver of broilers. The use of adsorbents can mitigate the harmful effects of mycotoxins, however, these products have specific binding capacity to the type of mycotoxin present in food.
RESUMO
A total of 1,296 broiler chicken were housed, distributed in a completely randomized design with 6 treatments and 6 repetitions. The treatments consisted of a control diet formulated with corn considered adequate and without the addition of adsorbent, a diet formulated with corn naturally contaminated with mycotoxin (CCM) and four diets formulated with CCM and added with different commercial adsorbents. At the end of the first week and at 21 days of age of the birds, it was observed that the control diet resulted in greater (p < 0.05) live weight and weight gain in relation to the inclusion of CCM. The relative weight of the liver was lower for the control group compared to the groups receiving a diet with CCM and CCM + ads D. The relative weight of the proventriculus and cloacal bursa was lower for the control group compared to those who received a diet with CCM + ads B and CCM+ ads C. There was no significant effect (p > 0.05) of the diets on the analysis of serum biochemistry and the occurrence of fatty and hydropic degeneration in the liver of broilers. The use of adsorbents can mitigate the harmful effects of mycotoxins, however, these products have specific binding capacity to the type of mycotoxin present in food.(AU)
Assuntos
Animais , Galinhas/fisiologia , Micotoxinas/análise , Micotoxinas/química , Zea mays , FumonisinasRESUMO
The incorporation of nanomaterials in binders in the paving area has been studied to improve the mechanical behavior of asphalt mixtures. However, asphalt mixture compounds are susceptible to leaching and deposition in the environment. In this context, this research aimed to investigate the toxic effect of two leachate extracts from asphalt mixtures nanomodified with 2% carbon nanotube and 3% organophilic nanoclay, compared to conventional mixture, using Daphnia magna and Landoltia punctata as test organisms. The nanomaterials were characterized to confirm morphology, stability and effective diameter. Extracts were chemically characterized using the Fourier-Transform Infrared Spectroscopy (FTIR) technique, which indicated presence of functional groups of the asphalt binder in greater intensity in the leachate from conventional mixture. Acute toxicity with D. magna indicated EC50,48h of 83.5 ± 6.2 mL/L for leachate extract from conventional mixture, 306.0 ± 87.6 mL/L for leachate extract from mixture with nanoclay and 464.8 ± 32.1 mL/L for leachate extract from mixture with carbon nanotube. No leachate caused significant chronic toxicity. As for L.punctata, concentrations that caused 50% growth inhibition were 127.5 mL/L for the leachate extract from mixture with carbon nanotube, 196.9 mL/L for the leachate extract from mixture with nanoclay and 205 mL/L for the leachate extract from conventional mixture. For these test organisms, there is no evidence of negative impacts directly associated with the use of the present nanomaterials in asphalt mixtures. The incorporation of these nanos may also reduce the acute toxicity of the mixtures.
Assuntos
Araceae , Daphnia , Animais , Hidrocarbonetos , Extratos VegetaisRESUMO
Hyperphosphatemia is a common complication in patients with chronic kidney disease (CKD), particularly in those requiring renal replacement therapy. The importance of controlling serum phosphate has long been recognized based on observational epidemiological studies that linked increased phosphate levels to adverse outcomes and higher mortality risk. Experimental data further supported the role of phosphate in the development of bone and cardiovascular diseases. Recent advances in our understanding of the mechanisms involved in phosphate homeostasis have made it clear that the serum phosphate concentration depends on a complex interplay among the kidneys, intestinal tract, and bone, and is tightly regulated by a complex endocrine system. Moreover, the source of dietary phosphate and the use of phosphate-based additives in industrialized foods are additional factors that are of particular importance in CKD. Not surprisingly, the management of hyperphosphatemia is difficult, and, despite a multifaceted approach, it remains unsuccessful in many patients. An additional issue is the fact that the supposedly beneficial effect of phosphate lowering on hard clinical outcomes in interventional trials is a matter of ongoing debate. In this review, we discuss currently available treatment approaches for controlling hyperphosphatemia, including dietary phosphate restriction, reduction of intestinal phosphate absorption, phosphate removal by dialysis, and management of renal osteodystrophy, with particular focus on practical challenges and limitations, and on potential benefits and harms.
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RESUMO A escassez dos recursos florestais integrada à necessidade de aquisição de produtos mais ecológicos demanda o uso de outros tipos de biomassa, além da madeira no setor construtivo. Diante disso, o mesocarpo do dendê - resíduo oriundo da agroindústria e com grande potencial de utilização para desenvolvimento de novos materiais - surge como alternativa na elaboração de painéis lignocelulósicos em substituição ao MDF (medium density fiberboard) convencionalmente utilizado. Dessa forma, o presente trabalho demonstrou a viabilidade da produção e a integridade estrutural desse tipo de painel na fabricação de elementos construtivos a serem empregados na construção civil, mediante estudo comparativo entre suas propriedades com as de painéis de MDF. A metodologia consistiu na realização de ensaios de caracterização dos painéis, por meio da determinação de suas propriedades físicas (absorção de água, inchamento e densidade) e mecânicas (resistência à flexão e módulo de elasticidade), além da morfologia dos painéis produzidos, mediante a técnica de microscopia eletrônica de varredura (MEV), análise química (por meio do espectro de infravermelho com transformada de Fourier) e térmica, por meio de curvas termogravimétricas e derivada. Dos resultados obtidos, tem-se que a produção desses painéis sem aglutinantes, obtidos pela incorporação do mesocarpo de dendê, agrega valor à cadeia produtiva do dendê, além de surgir como alternativa aos desafios inerentes à produção tradicional dos painéis de madeira e, consequentemente, como opção de elemento construtivo a ser integrado à construção civil.
ABSTRACT The lack of forest resources integrated with the need of purchasing more environmentally friendly products requires the use of other types of biomass besides wood in the construction sector. Therefore, the dendê mesocarp - waste arising from the agro-industry and with great use potential in developing new materials - is an alternative in the preparation of lignocellulosic panels to replace MDF (Medium Density Fiberboard), that is conventionally used. Thus, this work demonstrated the feasibility of the production and the structural integrity of this type of panel in the manufacture of building blocks to be used in civil construction through a comparative study of their properties with the MDF panels. The methodology consists in performing characterization tests in panels through determining their physical (water absorption, swelling and density) and mechanical (flexion resistance and modulus of elasticity) properties, besides analysing the morphology of the panels produced by the Scanning Electron Microscopy (MEV) technique, performing a chemical (via infrared spectrum Fourier transform) and thermal analysis through derived thermogravimetric curves. The results obtained suggest that the production of these panels without a binder, obtained by the incorporation of dendê mesocarp, adds value to the production chain of dendê, in addition to emerge as an alternative to the challenges inherent to the traditional production of wood panels and, consequently, is considered as an option of a constructive element to be integrated with the construction.
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ABSTRACT The aim of this study was to evaluate binding potential of Mulva neglecta mucilage (MNM) with subsequent comparison to PVP K30. Eight batches of Diclofenac sodium tablets were prepared by wet granulation technique keeping different concentrations (4, 6, 8 & 10% w/w) of Mulva neglecta mucilage (extracted from leaves of Mulva neglecta) and PVP K30 as standard binder. The granules of formulated batches showed bulk density (g/mL) 0.49 ± 0.00 to 0.57 ± 0.00, tapped density (g/mL) 0.59 ± 0.01 to 0.70 ± 0.01, Carr's index 09.27 ± 0.95 to 19.65 ± 0.59, Hausner's ratio 1.12 ± 0.00 to 1.24 ± 0.01 and angle of repose 30.37 ± 2.90 °C to 36.86 ± 0.94 °C. Tablets were compressed to hardness 7.50 to 7.95 kg/cm2. The tablets showed 0.39 ± 0.02 to 0.39 ± 0.01% friability and 7:20 to 14:00 min disintegration time. Granules and post-compression evaluation revealed that parameters assessed were all found to be within the pharmacopoeial limits. The results (hardness, disintegration and dissolution) proved that Mulva neglecta mucilage has better binding capacity for preparation of uncoated tablet dosage form as compared to PVP K30. Among all the formulations, MN-1 to MN-4 showed slow release as compared to PV-1 to PV-4 and thereby Mulva neglecta mucilage exhibited satisfactory drug release phenomenon tablets of diclofenac sodium.
RESUMO O objetivo deste estudo foi avaliar o potencial de ligação de mucilagem de Mulva neglecta (MNM), com posterior comparação ao PVP K30. Oito lotes de comprimidos de diclofenaco de sódio foram preparados pela técnica de granulação úmida, mantendo diferentes concentrações (4, 6, 8 e 10% w/w) de mucilagem de Mulva neglecta (extraída de folhas de Mulva neglecta) e PVP K30 como ligante padrão. Os grânulos de lotes formulados mostraram densidade aparente (g/mL) 0.49 ± 0.00-0.57 ± 0.00, densidade compactada (g/mL) 0.59 ± 0.01-0.70 ± 0.01, índice de Carr 09.27 ± 0.95-19.65 ± 0.59, a relação de Hausner 1.12 ± 0.00-1.24 ± 0.01 e ângulo de repouso 30.37 ± 2.90 °C a 36.86 ± 0.94 °C. Os comprimidos foram prensados à dureza de 7.50-7.95 kg/cm2. Os comprimidos apresentaram 0.39 ± 0.02-0.39 ± 0.01% friabilidade e 7:20-14:00 min de tempo de desintegração. A avaliação de grânulos e pós-compressão revelou que todos os parâmetros estavam dentro dos limites da farmacopeia. Os resultados (dureza, desintegração e dissolução) provaram que a mucilagem de Mulva neglecta tem maior capacidade de ligação na preparação da forma de dosagem de comprimido não revestido em relação à PVP K30. Entre todas as formulações, MN-1 e MN-4 mostraram liberação lenta em comparação com PV-1 e PV-4 e, assim, a mucilagem de Mulva neglecta exibiu liberação do fármaco satisfatória para os comprimidos de diclofenaco de sódio.
Assuntos
Malva , Mucilagem Vegetal/classificação , Comprimidos , Diclofenaco/análogos & derivadosRESUMO
Se determinó la influencia de los componentes de la receta y la temperatura sobre algunas propiedades de pasta de pescado, obtenida a partir del picadillo de pescado tratado térmicamente. Entre las propiedades estudiadas se encuentran: dureza, representada por el grado de penetración, capacidad de enlace de agua, representada por la pérdida de aguay parámetros sensoriales del producto. También se analizó el efecto de la sustitución de la harina de trigo por otros ligantes como el almidón de yuca y de maíz. Los resultados indican que la elevación del contenido de proteínas y/o carbohidratos provoca un endurecimiento del producto y una disminución de pérdida de agua. El aumento de la temperatura ocasiona, a su vez, endurecimiento de la textura y aumento de pérdida de agua. Los resultados demuestran que existe estrecha correlación entre la dureza y la pérdida de agua. Es posible sustituir la harina de trigo, usada como ligante en la producción de pastas de pescado, por almidón de yuca o de maíz sin cambios significativos en los parámetros físico-químicos y sensoriales del producto analizado.
Foi determinada a influência dos componentes da formulação e da temperatura sobre algumas propriedades da pasta de pescado, obtida de picadinho de pescado, tratado termicamente. Entre as propriedades avaliadas encontram-se: dureza, representada pelo grau de penetração, a capacidade de retenção da água, representada pela perda da água e parâmetros sensoriais do produto. Além, foi analisada a substituição da farinha de trigo por outros agentes de ligação tais como amido de mandioca e amido do milho. Os resultados refletem que a elevação do conteúdo de proteínas e/ou carboidratos provoca um endurecimento do produto e uma redução das perdas da água. O aumento da temperatura provoca o endurecimento da textura e o aumento das perdas de água. Os resultados mostram que existe uma forte correlação entre a dureza e a perda de água. A farinha de trigo, utilizada como agente de ligação na produção da pasta de pescado, pode ser substituída pelo amido de mandioca ou pelo amido do milho, sem alterações significativas nos parâmetros físico-químicos e sensoriais dos produtos analisados.
The influence of the recipe components and the temperature on some fish paste properties obtained from heat treated minced fish was evaluated. Hardness, represented by the degree of penetration, water binding capacity, represented by water loss, and sensory parameters of the product were tested. The replacement of wheat flour by other binders as cassava starch or corn starch was also analyzed. The results indicate that the increase of protein and/or carbohydrates causes hardening of the product and water loss reduction. The increase in the temperature of processing causes hardening of texture and water loss increases. The results show that there is close correlation between hardness and water loss. Replacing the wheat flour used as a binder in the production of fish paste can be performed through cassava starch or corn starch without significant changes in sensory and physico-chemical parameters of the product.
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Increased cardiovascular morbidity and mortality has been associated with the hyperphosphatemia seen in patients with end-stage chronic kidney disease (CKD). Oral phosphate binders are prescribed in these patients to prevent intestinal absorption of dietary phosphate and reduce serum phosphate. In prospective observational cohorts they have shown to decrease all-cause and cardiovascular mortality risk. Different problems have been associated with currently available phosphate binders as positive calcium balance and impaired outcomes with calcium-based phosphate binders or increased costs with non-calcium-based phosphate binders. Iron-based phosphate binders represent a new class of phosphate binders. Several iron-based phosphate binders have undergone testing in clinical trials. Ferric citrate (JTT-751) and sucroferric oxyhydroxide (PA21) are the two iron-based binders that have passed to the clinical field after being found safe and effective in decreasing serum phosphate. Iron from ferric citrate is partially absorbed compared to sucroferric oxyhydroxide. Ferric citrate usage could result in an important reduction in erythropoiesis-stimulating agent (ESA) and IV iron usage, resulting in significant cost savings. Sucroferric oxyhydroxide was effective in lowering serum phosphorus in dialysis patients with similar efficacy to sevelamer carbonate, but with lower pill burden, and better adherence. Ferric citrate may be more suited for the treatment of chronic hyperphosphatemia in CKD patients requiring iron supplements but its use may have been hampered by potential aluminum overload, as citrate facilitates its absorption; sucroferric oxyhydroxide may be more suited for hyperphosphatemic CKD patients not requiring iron supplementation, with low pill burden.
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BACKGROUND: Mineral bone disorder (MBD) is an early complication of chronic kidney disease (CKD), with complex interactions in the bone-kidney-energy axis. These events lead to impaired bone remodelling, which in turn is associated with cardiovascular disease. Recently, we reported on a positive effect of phosphate binder treatment on bone remodelling markers and a reduction in serum FGF-23 levels in predialysis-CKD patients. The goal of the present study of this trial was to examine the effects of phosphate binders on energy-regulating hormones and Wnt pathway. METHODS: In this present post hoc analysis of the above randomized, open-label, 8-week trial, which compared the effects of increasing doses of sevelamer-HCl or calcium acetate on various CKD-MBD parameters in 40 normophosphatemic CKD Stage 3-4 patients, we measured serum sclerostin, Dickkopf-1, leptin, adiponectin and serotonin concentrations. RESULTS: Serum sclerostin, Dickkopf-1 and leptin were elevated at baseline despite normal calcium, phosphorus levels and daily urinary phosphorus excretion. There were significant and positive correlations between sclerostin and FGF-23, as well between leptin and Dickkopf-1. Treatment with both phosphate binders led to a significant decrease in phosphate overload. However, sevelamer-HCl, but not with calcium acetate, led to a significant decrease in serum FGF-23, sclerostin and leptin, and to a significant increase in bone alkaline phosphatase levels. CONCLUSIONS: Early stages of CKD are associated with an impairment of the Wnt pathway, as reflected by elevated sclerostin, and a dysregulation of energy-regulating hormones. Many of these disturbances can be ameliorated by phosphate binder treatment, more with sevelamer-HCl than with calcium acetate.
Assuntos
Acetatos/farmacologia , Biomarcadores/sangue , Doenças Ósseas/metabolismo , Metabolismo Energético/fisiologia , Poliaminas/farmacologia , Insuficiência Renal Crônica/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Adiponectina/sangue , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas/tratamento farmacológico , Proteínas Morfogenéticas Ósseas/sangue , Compostos de Cálcio/farmacologia , Quelantes/farmacologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Marcadores Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/tratamento farmacológico , Serotonina/sangue , SevelamerRESUMO
With the purpose of evaluating the behavior of different polymers employed as binders in small-diameter pellets for oral administration, we prepared formulations containing paracetamol and one of the following polymers: PVP, PEG 1500, hydroxypropylmethylcellulose and methylcellulose, and we evaluated their different binding properties. The pellets were obtained by the extrusion/spheronization process and were subsequently subjected to fluid bed drying. In order to assess drug delivery, the United States Pharmacopeia (USP) apparatus 3 (Bio-Dis) was employed, in conjunction with the method described by the same pharmacopeia for the dissolution of paracetamol tablets (apparatus 1). The pellets were also evaluated for granulometry, friability, true density and drug content. The results indicate that the different binders used are capable of affecting production in different ways, and some of the physicochemical characteristics of the pellets, as well as the dissolution test, revealed that the formulations acted like immediate-release products. The pellets obtained presented favorable release characteristics for orally disintegrating tablets. USP apparatus 3 seems to be more adequate for discriminating among formulations than the basket method.
Com a finalidade de se avaliar o comportamento de diferentes polímeros empregados como aglutinantes em pellets de pequeno diâmetro para uso oral foram preparadas formulações contendo paracetamol e um dos seguintes polímeros: PVP, PEG 1500, hidroxipropilmetilcelulose e metilcelulose por apresentarem diferentes propriedades aglutinantes. Os pellets foram obtidos pelo processo de extrusão/esferonização e secagem em leito fluidizado. Para avaliar a liberação do fármaco, empregou-se o método 3 da Farmacopeia Americana, também conhecido como Bio-Dis e o método preconizado pela mesma farmacopeia para comprimidos de paracetamol. Os pellets foram avaliados, ainda, com relação à granulometria, friabilidade, densidade verdadeira e teor. Os resultados indicaram que os diferentes aglutinantes empregados são capazes de afetar a produção e algumas das características físico-químicas dos pellets e o ensaio de dissolução revelou que as formulações comportam-se como produtos de liberação imediata. Os pellets obtidos apresentaram características de liberação favoráveis para a obtenção de comprimidos de liberação instantânea. O aparato 3 da Farmacopeia Americana demonstrou ser um método com melhor capacidade discriminatória entre as formulações, quando comparado com o método da cesta.
Assuntos
/análise , Implantes de Medicamento , Dissolução/classificação , Polímeros/classificação , LigantesRESUMO
Metformin hydrochloride (MH) is an oral hypoglycemic agent and a high-dose drug that has poor flow and compression properties. In this study, the feasibility of developing adequate, low cost 500mg tablets of metformin hydrochloride by wet granulation was tested with several binders (Starch / PVP K30®; Starch1500® /PVP K30®, PVP K30® and PVP K90®) in a simple tablet press of the type used in small pharmaceutical laboratories. The drug powder was tested for ability to flow, by determining Carr?s Index (CI) and the Hausner ratio (HR). Differential scanning calorimetry and thermogravimetric analysis were carried out on isolated MH and 1:1 (w/w) binary mixtures with the excipients. The size distribution, friability, flow properties and drug content of the granules were analyzed, as were the hardness, friability, disintegration, dissolution and uniformity of the dosage form. The drug powder showed CI > 22% and HR > 1.25, characteristic of a poor flow powder, and no significant incompatibilities with the excipients. All the granules showed adequate flow properties and were suitable for pressing into tablets, all of which complied with pharmacopeial specifications. The starch /PVP K30® and starch 1500®/PVP K30® mixtures were best for producing 500 mg MH tablets.
Cloridrato de metformina é um fármaco hipoglicemiante oral que apresenta propriedades pobres de fluxo e compressibilidade. Este trabalho teve como objetivo o desenvolvimento de comprimidos de baixo custo,após granulação por via úmida, contendo 500 mg de cloridrato de metformina e diferentes aglutinantes (F1-amido / PVP K30®; F2- Starch 1500® / PVP K30®, F3-PVP K30®, F4- PVP K90®) em máquinas de compressão de baixo desempenho usadas em laboratórios farmacêuticos de pequeno porte. As propriedades defluxo do fármaco foram analisadas através do índice de Carr (IC) e fator de Hausner (FH). Cloridrato de metformina e suas misturas binárias com os excipientes na relação 1:1 (m/m) foram analisadas por calorimetria diferencial por varredura e análise termogravimétrica. Os granulados foram analisados quanto a distribuição granulométrica, friabilidade, propriedades de fluxo e teor e os comprimidos em relação à dureza, friabilidade, desintegração, dissolução e uniformidade de conteúdo.O cloridrato de metformina apresentou IC > 22% e FH> 1,25, característicos de fluxo pobre e não apresentou incompatibilidades com os outros excipientes. Todos os granulados demonstraram adequadas propriedades de fluxo e facilidade no processo de compressão. Os comprimidos apresentaram conformidade com as especificações farmacopeicas. As misturas amido / PVPK30® e Starch 1500® / PVP K30® foram mais adequadas para produzir comprimidos de cloridrato de metformina 500 mg.
Assuntos
Composição de Medicamentos , Avaliação de Medicamentos , Metformina/farmacocinética , Preparações Farmacêuticas , ComprimidosRESUMO
O fósforo é um elemento fundamental no metabolismo celular e sua homeostase é mantida pelo sistema digestivo, remodelação óssea e rins. Uma dasprincipais alterações no metabolismo do fósforo, a hiperfosfatemia, pode se tornar uma situação de grave morbidade para pacientes com doença renalcrônica (DRC), sendo considerada atualmente uma responsável indireta pela alta taxa de mortalidade dessa população. Cerca de 60% dos pacientes em diálise apresentam níveis de fósforo elevados. O excesso de ingestão de fósforo, o uso inadequado de seus quelantes intestinais, a inadequação dialítica e o status da remodelação óssea compõem o caráter multifatorial da hiperfosfatemia, tornando seu tratamento um dilema ao nefrologista. Na fase não-dialítica, a restrição de fósforo é mais facilmente implementada já que normalmente os pacientes são orientados a ingerir reduzida quantidade de proteína, o que, conseqüentemente, acarreta uma diminuição no conteúdo de fósforo. Na fase dialítica, em função da elevada necessidade protéica, a restrição significativa de fósforo quase nunca pode ser empregada, o que na maioria das vezes, implica na utilização de quelantes de fósforo. Os quelantes devem ser ingeridos junto com a alimentação, de forma a permitir a melhor mistura com os alimentos. Dentre os tipos mais comumente utilizados estão os quelantes à base decálcio ou aqueles livres de cálcio ou metal, como o sevelamer. A dose de cálcio elementar proveniente de quelantes não deve exceder a 1500 mg/dia ou 2000 mg/dia, se considerado o cálcio da dieta. Pacientes com hipercalcemia não devem utilizar quelantes que contêm cálcio. Finalmente, é importanteressaltar que o sucesso do tratamento da hiperfosfatemia da DRC requer o envolvimento de toda a equipe multiprofissional, particularmente do nutricionista.
Phosphorus, an essential element for cell metabolism, has its homeostasis maintained in the body by the integrated actions of intestine, bone and kidneys.Hyperphosphatemia, mainly due to derangements in phosphorus metabolism, is a serious complication of chronic kidney disease (CKD) responsible for thehigh rates of mortality in this population. Elevated serum phosphorus is found in about 60% of the patients on maintenance dialysis. Several factors can contribute to hyperphosphatemia, including high phosphorus intake, inappropriate use of phosphate binders, poor dialysis efficiency and the bone turnover condition. For these reasons the treatment of hyperphosphatemia is still a challenge for nephrologists. In CKD stages 2 to 4 a low phosphorus intake is often achieved since dietary protein restriction, with consequent phosphorus reduction content is usually employed for these patients. In contrast, considering the elevated protein requirement of patients on dialysis it is not possible to reduce phosphorus intake in a significant manner without harmful consequences inthe nutritional status. Thus, the use of phosphate binders is always necessary for these patients. For better results, however, the binders must be takentogether with the meals to guarantee a satisfactory mixture with food. Calcium based phosphate binders or those binders free of calcium or metals such assevelamer are among the most used ones. Calcium intake provided by phosphate binders should not exceed 1500 mg/day or 2000 mg/day, considering the calcium provided by the diet. However, for patients with hypercalcemia, calcium based phosphate binders should be avoided. Finally, it is important to address that the success of the treatment relies on the involvement of all members of health care team in particular the nutritionist.