RESUMO
PURPOSE: This systematic review aimed to evaluate the benefits and harms of fibrate therapy, alone or in combination with statins, in adult patients with type 2 diabetes (T2D). METHODS: A comprehensive search was conducted in six databases, from inception to January 27, 2022. Clinical trials that compared fibrate therapy with other lipid-lowering interventions or placebo were included. Outcomes of interest comprised cardiovascular (CV) events, complications of T2D, metabolic profile, and adverse events. Random-effects meta-analyses were performed to estimate mean differences (MD) and risk ratios (RR), alongside 95% confidence intervals (CI). RESULTS: A total of 25 studies were included, six comparing fibrates against statins, 11 against placebo, and eight evaluating the combination of fibrates with statins. Overall risk of bias was rated as moderate, and most outcomes rendered low confidence per GRADE approach. Fibrates showed reduction of serum triglycerides (TGs) (MD -17.81, CI -33.92 to -1.69) and a marginal increase of high-density lipoprotein cholesterol (HDL-c) (MD: 1.60, CI 0.29 to 2.90) in adults with T2D, but no differences were found in CV events when compared to statin therapy (RR 0.99, CI 0.76 to 1.09). When used in combination with statins, no major differences were exhibited regarding lipid profile and CV outcomes. Adverse events were comparable between fibrate and statin monotherapies (e.g., RR of 1.03 for rhabdomyolysis, and 0.90 for gastrointestinal events). CONCLUSIONS: Fibrate therapy in patients with T2D results in a marginal improvement of TGs and HDL-c but without reducing the risk of CV events and mortality. Their use should be reserved for very specific scenarios after a deliberative dialogue between patients and clinicians regarding their benefits and harms.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Inibidores de Hidroximetilglutaril-CoA Redutases , Adulto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Ácidos Fíbricos/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , HDL-Colesterol , Triglicerídeos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controleRESUMO
Due to the emergence of multidrug-resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at alternative molecular targets. The aim of the current study was to evaluate the capacity of three different series of synthetic compounds to inhibit the Candida glabrata enzyme denominated 3-hydroxy-methyl-glutaryl-CoA reductase and thus affect ergosterol synthesis and yeast viability. Compounds 1c (α-asarone-related) and 5b (with a pyrrolic core) were selected as the best antifungal candidates among over 20 synthetic compounds studied. Both inhibited the growth of fluconazole-resistant and fluconazole-susceptible C. glabrata strains. A yeast growth rescue experiment based on the addition of exogenous ergosterol showed that the compounds act by inhibiting the mevalonate synthesis pathway. A greater recovery of yeast growth occurred for the C. glabrata 43 fluconazole-resistant (versus fluconazole-susceptible) strain and after treatment with 1c (versus 5b). Given that the compounds decreased the concentration of ergosterol in the yeast strains, they probably target ergosterol synthesis. According to the docking analysis, the inhibitory effect of 1c and 5b could possibly be mediated by their interaction with the amino acid residues of the catalytic site of the enzyme. Since 1c displayed higher binding energy than α-asarone and 5b, it is the best candidate for further research, which should include structural modifications to increase its specificity and potency. The derivatives could then be examined with in vivo animal models using a therapeutic dose. IMPORTANCE Within the context of the COVID-19 pandemic, there is currently an epidemiological alert in health care services due to outbreaks of Candida auris, Candida glabrata, and other fungal species multiresistant to conventional antifungals. Therefore, it is important to propose alternative molecular targets, as well as new antifungals. The three series of synthetic compounds herein designed and synthesized are inhibitors of ergosterol synthesis in yeasts. Of the more than 20 compounds studied, two were selected as the best antifungal candidates. These compounds were able to inhibit the growth and synthesis of ergosterol in C. glabrata strains, whether susceptible or resistant to fluconazole. The rational design of antifungal compounds derived from clinical drugs (statins, fibrates, etc.) has many advantages. Future studies are needed to modify the structure of the two present test compounds to obtain safer and less toxic antifungals. Moreover, it is important to carry out a more in-depth mechanistic approach.
Assuntos
COVID-19 , Candida glabrata , Acil Coenzima A , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida glabrata/metabolismo , Farmacorresistência Fúngica , Ergosterol/metabolismo , Ácidos Fíbricos/metabolismo , Fluconazol/metabolismo , Fluconazol/farmacologia , Humanos , Hidroximetilglutaril-CoA Redutases/química , Hidroximetilglutaril-CoA Redutases/metabolismo , Testes de Sensibilidade Microbiana , Pandemias , Pirróis/metabolismo , Pirróis/farmacologiaRESUMO
El objetivo de este estudio fue evaluar con microto-mografía los poros existentes entre el cemento de resina, poste de fibra y paredes del conducto en los distintos tercios radiculares en premolares inferio-res. Se utilizaron 15 premolares inferiores unirra-diculares humanos recientemente extraídos. Se les realizó el tratamiento endodóntico, y se obturó con conos de gutapercha y cemento endodóntico a base de resina. Una vez desobturados se procedió a la ce-mentación de los postes. Cada muestra se posicionó en un accesorio personalizado y se escaneó utilizan-do un Microtomógrafo. Con el software CTAn v.1.12 (Bruker-microCT) se analizaron las microtomografías para obtener el volumen de interés (VOI) que permi-tió calcular el área de superficie (mm2) y volumen de cada poro (mm3) entre la dentina y el poste a nivel co-ronal, medio y apical. Los datos fueron analizados me-diante las pruebas estadísticas de Friedman o ANOVA de medidas repetidas. El volumen de los poros entre los tres tercios radiculares mediante la prueba de Friedman, encontró una diferencia global significativa (F = 30,00; p < 0,05). El tercio en donde los poros presentaron un mayor volumen (mm3) fue el tercio coronal (mediana: 0,29250), seguido por los tercios medio (mediana: 0,03200), y apical (mediana: 0,00140). La comparación de la superficie de los poros entre los 3 tercios brindó un resultado análogo al de la comparación del volumen. La mayor superficie (mm2) correspondió al tercio coronal (media ± DE = 1,66377 ± 0,27175), seguido por los tercios medio (media ± DE = 1,16210 ± 0,20343) y apical (media ± DE = 0,41074 ± 0,12641). La microtomografía permitió realizar un análisis cuantitativo y cualitativo de los poros en toda la muestra, sin deterioro de la misma. Se puede concluir que el tercio coronal presenta más poros que el tercio apical con la técnica de cementación utilizada. En cuanto a la superficie y volumen de los poros, los resultados encontrados son similares a los reporta-dos por diversos autores (AU)
The aim of this study was to evaluate with microtomography the existing pores between the resin cement, fiber post and canal walls in the different in thirds of the canal, in single-root lower premolars. Fifteen recently extracted human single root lower premolars were used, endodontically treated, and filled with gutta-percha cones and resin-based endodontic cement. Once unfilled, the posts were cemented. Each sample was positioned on a custom fixture and scanned using a Microtomograph. Each sample was evaluated using CTAn v.1.12 software (Bruker-microCT) to obtain the surface area (mm2), volume of interest (mm3) of each pore between dentin and post at the coronal, middle and apical levels. Data were analyzed using Friedman's tests or repeated measures ANOVA. The volume of the pores between the three root thirds using the Friedman test, a significant global difference was found (F = 30.00; p < 0.05). The third in which the pores presented a greater volume (mm3) was the coronal third (means: 0.29250), followed by the middle (means: 0.03200) and apical (means: 0.00140) thirds. The comparison of the pore surface between the 3 thirds gave an analogous result to that of the volume comparison. The largest surface area (mm2) corresponded to the coronal third (mean ± SD 1.66377 ± 0.27175), followed by the middle (mean ± 1.16210 ± 0.20343) and apical (mean ± 0.41074 ± 0.12641) thirds.Microtomography allowed a quantitative and qualitative analysis of the pores in the entire sample without deterioration. It can be concluded that the coronal third has more pores than the apical third with the cementation technique used. Regarding the surface and volume of the pores, the results found are similar to those reported by various authors (AU)
Assuntos
Porosidade , Técnica para Retentor Intrarradicular , Cimentação/instrumentação , Microtomografia por Raio-X , Dente Pré-Molar , Análise de Variância , Cimentos de Resina , Imageamento Tridimensional/métodos , Ácidos FíbricosRESUMO
En los últimos años resulta de elección la utilización de postes de fib ra en la rehabilitación de piezas endodónticamente tratadas. La adhesión entre poste, agente cementante y dentina radicular permitiría lograr una retención de la estructura dentro de las paredes del conducto. El objetivo de este estudio fue comparar la resistencia adhesiva en los tercios cervical, medio y apical, entre la dentina del conducto radicular y el cemento adhesivo utilizado en la cementación de postes de fibra. Se utilizaron 30 premolares inferiores uniradiculares humanos, recientemente extraídos, se realizaron los tratamientos endodónticos, se desobturaron y realizaron las preparaciones con la fresa conformadora número 3 para la cementación de postes White Post DC especial número 3 con cemento Paracore utilizando el protocolo adhesivo del mismo sistema. Las muestras fueron incluidas en acrílico cristal, cortadas en forma perpendicular al eje mayor de la pieza con una máquina de corte y por último se procedió a medir los valores de adhesión de los postes a la superficie interna de los conductos en los tres tercios con la prueba push-out mediante una máquina de ensayo universal. Los resultados arrojaron que las resistencias (media +- DE, MPa) en los tercios cervical, medio y apical, fueron 8,74 +- 3,12, 9,38 +- 2,29 y 11,11 +- 2,95, respectivamente. En el tercio apical se registró mayor resistencia. Considerando las limitaciones de esta investigación, se puede concluir que la cementación de postes de fibra con cementos resinosos, presenta mayores valores en el tercio apical y menores en el tercio cervical del conducto radicular con técnica de Push-out (AU)
Assuntos
Resistência à Tração , Técnica para Retentor Intrarradicular , Resistência à Flexão , Dente Pré-Molar , Cimentação/métodos , Adesivos Dentinários , Colo do Dente , Cavidade Pulpar , Ácidos FíbricosRESUMO
En los últimos años, se ha reportado en la literatura científica un declive en la calidad seminal. La significancia biológica de ese evento podría estar relacionada con la reducción en la fertilidad masculina o con el aumento del riesgo de enfermedades en la descendencia. La occidentalización en el estilo de vida, caracterizado por el aumento del peso corporal, el sedentarismo, el uso de cigarrillo, la ingesta de alimentos ricos en grasas y sodio y la reducción en la ingesta de alimentos fuente de fibras y antioxidantes, pudieran estar implicados en esos resultados. A su vez, cambios en el estilo de vida, que conduzcan a una reducción de peso corporal, de la ingesta de grasa y sodio, a un mejor estado antioxidante y a un aumento de la ingesta de fibra, se han asociado a mejores parámetros seminales. Por lo tanto, la alimentación basada en plantas o vegetariana, podría ser una estrategia válida para mejorar el estado nutricional y la salud masculina.
In recent years, a decline in seminal quality has been reported in the scientific literature. The biological significance of this event could be related to the reduction in male fertility or the increased risk of diseases in the offspring. Westernization in lifestyle, characterized by increased body weight, sedentary lifestyle, cigarette use, intake of foods high in fat and sodium and reduced intake of food sources of fiber and antioxidants, may be involved in these changes. Modifications in lifestyle, which lead to a reduction in body weight, fat and sodium intake, a better antioxidant status and an increase in fiber intake, have been associated with better seminal parameters. Therefore, plant-based or vegetarian food could be a valid strategy to improve nutritional status and male health.
Assuntos
Humanos , Masculino , Dieta , Análise do Sêmen , Comportamento Alimentar , Ácidos Fíbricos , Fertilidade , Vegetarianos , Alimentos , Estado Nutricional , Risco , Ingestão de Alimentos , Saúde do Homem , Comportamento Sedentário , Produtos do Tabaco , Estilo de Vida , AntioxidantesRESUMO
BACKGROUND: A considerable amount of randomized controlled trials (RCTs) have been published on statins and/or fibrates for diabetic retinopathy, a clinical condition associated with high social and economic burden. Adherence to the CONSORT statement items is imperative to ensure transparency and reproducibility in clinical research. The aim of this study is to assess the reporting quality and the adherence to CONSORT of RCTs assessing statins and/or fibrates for diabetic retinopathy. METHODS: We conducted a critical appraisal study at Discipline of Evidence-based Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo (Unifesp). A sensitive literature search was performed to identify all relevant RCTs, with no time or language limits. Two authors independently evaluated the reporting quality of the selected RCTs using the CONSORT statement as a standard. RESULTS: Thirteen reports of RCTs were included in this study. The adherence of the reports to CONSORT items ranged from 24% to 68%. The median score was 11 (interquartile range (IQR) 8 to 13). When analyzed separately, the methods sections of the reports had a median of three items (IQR 2 to 4) judged adherent to the methods items of CONSORT (items 3 to 12). The most underreported items were those related to trial design, title and abstract, allocation concealment, implementation of the randomization sequence, and blinding. Other important items, such as the one related to the description of the inclusion criteria, also had low adherence. CONCLUSIONS: The overall adherence to the CONSORT checklist items was poor, especially in the items related to the methods section. RCT reports on statins and/or fibrates for diabetic retinopathy must be optimized to avoid reporting biases and to improve transparency and reproducibility.
Assuntos
Lista de Checagem/normas , Confiabilidade dos Dados , Retinopatia Diabética/tratamento farmacológico , Ácidos Fíbricos/uso terapêutico , Fidelidade a Diretrizes/normas , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Projetos de Pesquisa/normas , Retinopatia Diabética/diagnóstico , Ácidos Fíbricos/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Resultado do TratamentoRESUMO
Abstract Evidence from observational studies have found a relationship between serum cholesterol and diabetic retinopathy (DR). Apart of the assumption that cholesterolemic control has benefits for patients with diabetes with or without retinopathy, the effects of lipid-lowering drugs have not been properly mapped and critically assessed so far. The objective of this study was to evaluate the effects of statins and/or fibrates on prevention and progression of DR. We conducted a Systematic review of randomized controlled trials (RCTs) following the Cochrane Handbook for Systematic Reviews of Interventions and reported in accordance to PRISMA Statement. GRADE approach was used to summarize the certainty of the evidence. Eight RCTs that fulfilled our eligibility criteria were included, assessing the effects of fibrates (n = 4), statins (n = 3) and fibrate plus statins (n = 1) for therapy (n = 8) or prevention (n = 4) of DR. Overall, the main concern regarding risk of bias assessment was due to incomplete outcome data because high rate of losses in five RCTs. Furthermore, the risk of reporting bias was rated unclear due the lack of previously published protocol in seven RCTs. Fibrates seemed to be associated with a 45% risk reduction of macular edema incidence (Relative Risk 0.55, 95% confidence interval of 0.38 to 0.81, 1309 participants, 2 RCTs, I2 = 0%, low certainty of the evidence). The certainty of evidence for other outcomes was also very low or low, and we are uncertain regarding the effects of fibrates for DR. Overall, adverse events seemed to be similar between fibrate and placebo, but again based on the width of the confidence intervals, an important increase of adverse events cannot be rule out. The combination statin/fibrate did not seem to have benefit for visual acuity but is likely that further studies can modify this estimate since the current evidence is limited. Adverse events and quality of life were not measured or reported. Concluding, this study found eight RCTs, with limited methodological quality, that assessed the effects of fibrates and/or statins for DR. Based on these findings, we are uncertain about the effects of statins for DR. Fibrates seemed to reduce the incidence of macular edema (low certainty evidence) without increase adverse events (low to very low certainty evidence). Number of Protocol registration PROSPERO CRD42016029746. (AU)
Assuntos
Metanálise , Inibidores de Hidroximetilglutaril-CoA Redutases , Retinopatia Diabética , Ácidos FíbricosRESUMO
The objective of this study was to ascertain the influence of different dietary fiber sources and the usage of xylanase on diet of commercial layers and their influence on productive performance, egg quality, and digestive organ biometry. A total of 864 Lohmann® White hens was fed diets with three different fiber sources (wheat bran, soybean hull, or coffee husk) with or without xylanase inclusion (concentration of 160,000 BXU/g) in a 3×2 factorial arrangement, with six replicates of 24 birds each, from 25 to 44 weeks of age. There were no interactions between dietary fiber and xylanase inclusion. The enzyme supplementation did not influence any parameters evaluated. There were dietary fiber effects on body weight gain, viability, egg weight, eggshell quality, yolk pigmentation, and liver and gizzard relative weights. Wheat bran, soybean hull, and coffee husk can be used in laying hen diets without detrimental effect on productive performance. The enzyme used had no effect on the performance and eggshell quality of laying hens.(AU)
Assuntos
Animais , Xilanos/análise , Galinhas/fisiologia , Ovos/análise , Ácidos Fíbricos/análise , Trato Gastrointestinal/enzimologiaRESUMO
Ursodeoxycholic acid is the first-line therapy for primary biliary cholangitis. However, a subset of patients fail to show biochemical response. For these patients, adjuvant therapies are warranted. Obeticholic acid was conditionally approved as a second-line drug. Evidence is building up in favor of fibrates, which are available for off-label use.
Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Colagogos e Coleréticos/uso terapêutico , Colangite/tratamento farmacológico , Ácidos Fíbricos/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Ácido Quenodesoxicólico/efeitos adversos , Ácido Quenodesoxicólico/uso terapêutico , Colagogos e Coleréticos/efeitos adversos , Colangite/diagnóstico , Colangite/mortalidade , Quimioterapia Combinada , Ácidos Fíbricos/efeitos adversos , Humanos , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/mortalidade , Uso Off-Label , Resultado do Tratamento , Ácido Ursodesoxicólico/efeitos adversosRESUMO
ABSTRACT Fibrates are drugs used for the treatment of hypertriglyceridemia and for the prevention of atherosclerosis. Three drugs in the fibrate class, ciprofibrate, fenofibrate and bezafibrate, were chosen for this study because their raw materials are readily available and because scientific publications on these compounds is limited. To evaluate their intrinsic stability, the drugs were exposed to a test condition (temperature, oxidation, UV light exposure, hydrolysis at different pH values and metal ions in solution) and then were subjected to analysis by HPLC. The samples were run on a C18 column, with a flow rate of 1.0 mL min-1 in a mobile phase consisting of methanol: 0.01 % phosphoric acid v/v (80:20), with variable detection wavelengths in the UV spectra. The analysis methodology showed satisfactory performance parameters. The three drugs were very unstable, degrading in each of the conditions evaluated. The test conditions of acid and basic hydrolysis showed the most significant degradation. The results demonstrated that the drugs in this class are unstable. Based on these experimentally determined degradation kinetics, it is easy to understand and emphasize the importance of the lack of liquid dosage forms on the market for fibrates because of their instability.
Assuntos
Fenofibrato/análise , Bezafibrato/análise , Cinética , Ácidos Fíbricos/análise , Hipertrigliceridemia , Cromatografia Líquida de Alta Pressão/métodos , Ácidos Fíbricos/classificaçãoRESUMO
Ovine pregnancy toxaemia is a metabolic disorder affecting sheep in their last 6 weeks of pregnancy as a result of their inability to maintain adequate energy homoeostasis. Different alternative treatments are available with variable results. The aim of this research was to evaluate a peroxisome proliferator-activated receptor alpha (PPARα) stimulant as an alternative to treat clinical pregnancy toxaemia. Thirty-three adult sheep, with known gestation date and carrying a single foetus, were fasted from day 130 of gestation until animals showed clinical disease. From that moment onwards, sheep were treated during 6 days with three different therapeutic alternatives: 10 mg/kg of 2-methyl-2-phenoxy-propionic acid; 10 mg/kg of 2-methyl-2-phenoxy-propionic acid + 100 mL of propylene glycol oral; or 100 mL of propylene glycol oral. Glycaemia and serum ß-hydroxybutyrate (BHOB) were determined daily. Liver biopsies were taken at day 130 of gestation, at the beginning and end of treatments and at 5 days postpartum, evaluating the extent and degree of the steatosis lesion. Even though in sheep treated with 2-methyl-2-phenoxy-propionic acid, serum concentrations of glucose and BHOB recovered more slowly, we conclude that 2-methyl-2-phenoxy-propionic acid alone or combined with propylene glycol can be used as an alternative to effectively treat fatty liver, and therefore pregnancy toxaemia.
Assuntos
Ácidos Fíbricos/uso terapêutico , PPAR alfa/agonistas , Pré-Eclâmpsia/veterinária , Propilenoglicol/uso terapêutico , Doenças dos Ovinos/tratamento farmacológico , Ácido 3-Hidroxibutírico/sangue , Administração Oral , Animais , Glicemia/análise , Feminino , Ácidos Fíbricos/administração & dosagem , Pré-Eclâmpsia/tratamento farmacológico , Gravidez , Propilenoglicol/administração & dosagem , OvinosRESUMO
Antecedentes: Las dislipidemias, ya sea un aumento en los niveles de colesterol LDL y/o una disminución en las cifras de colesterol HDL, son muy relevantes para el desarrollo de la enfermedad cardiovascular ateroesclerótica, siendo el colesterol HDL bajo la dislipidemia más frecuente en la población chilena. Con respecto al colesterol HDL bajo y los tri -glicéridos elevados, los fibratos, agonistas del receptor nuclear PPAR-a que modula la transcripción de genes involucrados en el metabolismo de lípidos, representan una importante alternativa de manejo farmacológico de las dislipidemias. Sin embargo, estudios clínicos recientes no han sido concluyentes con respecto a su beneficio real sobre el control de la ateroesclerosis cuando se usan combinados con estatinas. Objetivo: Evaluar el impacto de la administración de fibratos sobre el metabolismo del colesterol HDL y la función antioxidante del plasma usando el ratón como modelo experimental. Metodología: Los ratones de la cepa C57BL/6 fueron tratados con ciprofibrato al 0,2% en dieta control durante 7 días. Luego del tratamiento, se analizaron los niveles de colesterol plasmático y triglicéridos, la expresión hepática de proteínas claves involucradas en el metabolismo de colesterol HDL, el contenido de colesterol hepático, la secreción de colesterol biliar y el daño oxidativo y la función antioxidante plasmática. Resultados: El tratamiento con ciprofibrato disminuyó significativamente los niveles de triglicéridos plasmáticos y la expresión hepática del receptor de HDL SR-BI, efecto que se correlacionó con un aumento en el tamaño de las partículas de HDL, pero no en los niveles de colesterol HDL. Además, el ciprofibrato disminuyó los niveles proteicos de los transportadores de colesterol ABCG1 y ABCG8, aunque no modificó ABCA1, en conjunto con una reducción del contenido hepático de colesterol y un aumento en la secreción de colesterol hacia la bilis. Finalmente, el uso de este hipolipemiante mejoró la función antioxidante del plasma, aunque se detectó un aumento en el daño nitrosativo de las proteínas plasmáticas. Conclusión: Este estudio ha permitido obtener nueva información sobre el efecto metabólico y funcional de la administración de fibratos en ratones, lo cual podría ayudar comprender los resultados de estudios clínicos recientes que han usado esta clase de hipolipemiantes en humanos.
Background: Increased serum levels of LDL cholesterol and/or decreased values of HDL cholesterol are very relevant for atherosclerotic cardiovascular disease. Low HDL cholesterol is the most prevalent dyslipidemia in the Chilean population. Regarding reduced HDL cholesterol and high triglyceride levels, fibrates, nuclear receptor PPAR-a agonists that modulate transcription of genes involved in lipid metabolism, represent an important alternative for pharmacological management of dyslipidemia. However, recent clinical studies have been inconclusive with respect to their real benefit on atherosclerosis when used in combination with statins. Aim: To evaluate the impact of fibrate administration on HDL cholesterol metabolism and antioxidant plasma functionality using the mouse as experimental model. Methodology: Using wild-type C57BL/6 mice, ciprofibrate was administered at 0.2% in chow diet for 7 days. After treatment, plasma cholesterol and triglycerides levels, hepatic expression of key proteins involved in HDL cholesterol metabolism, liver cholesterol content, biliary cholesterol secretion, and plasma oxidative damage and antioxidant function were analyzed. Results: Ciprofibrate treatment significantly decreased plasma triglycerides levels and hepatic HDL receptor SR-BI expression. This latter finding was associated with increased HDL particle size, without changes in HDL cholesterol levels. Furthermore, ci-profibrate decreased hepatic expression of cholesterol transporters ABCG1 and ABCG8, but not ABCA1, which correlated with reduced liver cholesterol content and increased biliary cholesterol secretion. Fina-lly, fibrate therapy improved plasma antioxidant func-tion, even though increased nitrosative plasma protein damage was detected. Conclusion: This study has provided new information on metabolic and functional effects derived from fibrate use in mice and it may help to better understand recent clinical findings using this lipid-lowering drug class in humans.
Assuntos
Animais , Camundongos , Ácidos Fíbricos/farmacologia , Hipoglicemiantes/farmacologia , HDL-Colesterol/efeitos dos fármacos , Triglicerídeos/sangue , Colesterol/análise , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais , Receptores Ativados por Proliferador de Peroxissomo , HDL-Colesterol/metabolismo , Fígado/efeitos dos fármacos , Fígado/química , Camundongos Endogâmicos C57BLRESUMO
A sixty-one year old white female was referred to the Dermatology Department to treat an ingrown nail in the inner corner of the left hallux. Examination of the entire nail unit showed the presence of xanthonychia in the outer corner besides thickening and increase in the transverse curvature of the nail plate. Dermoscopy and nuclear magnetic resonance of the free edge of the nail plate detected characteristic signs of onychomatricoma, a diagnosis that was later confirmed by anatomopathological exam.
Assuntos
Humanos , Anticolesterolemiantes/uso terapêutico , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Ácidos Fíbricos/uso terapêutico , Lipoproteínas HDL/sangue , Niacina/uso terapêutico , Doença das Coronárias/sangue , Doença das Coronárias/mortalidade , Doença das Coronárias/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Infarto do Miocárdio/sangue , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/prevenção & controle , Oxazolidinonas/uso terapêutico , Quinolinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Compostos de Sulfidrila/uso terapêuticoRESUMO
OBJECTIVES: Panax ginseng, Camellia sinensis and bezafibrate were compared for their lipid-lowering, antioxidant and anti-inflammatory properties as potential agents to prevent nonalcoholic fatty liver disease and its progression to nonalcoholic steatohepatitis. METHODS: Fifty Wistar rats were randomized into five groups: G1 (feed with standard diet); G2 (feed with high-fat diet with 58% of energy from fat); G3 (high-fat diet + standardized Panax ginseng extract at 100 mg/kg/day); G4 (high-fat diet + standardized Camellia sinensis extract at 100 mg/kg/day); and G5 (high-fat diet + bezafibrate at 100 mg/kg/day), given by gavage. The animals were sacrificed eight weeks later and blood was collected for glucose, insulin, cholesterol, triglycerides, AST, ALT, alkaline phosphatase and gamma-glutamyl transferase determinations. The score system for nonalcoholic fatty liver disease was used to analyse the liver samples. RESULTS AND CONCLUSIONS: High-fat diet resulted in a significant increase in animal body weight, biochemical changes and enzymatic elevations. Steatosis, inflammation and hepatocellular ballooning scores were significant high in this group. The biochemical and histological variables were statistically similar in the bezafibrate group and control group. Treatment with Panax ginseng extract prevented obesity and histological features of nonalcoholic steatohepatitis (steatosis and inflammation) compared to high-fat diet. Camellia sinensis showed a less effective biochemical response, with small reduction in steatosis and inflammation but lower ballooning scores.
Assuntos
Ácidos Fíbricos/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Panax/química , Fitoterapia/métodos , Chá/química , Animais , Progressão da Doença , Distribuição Aleatória , Ratos WistarRESUMO
BACKGROUND: Tuberculosis (TB) is a respiratory tract disease caused by Mycobacterium tuberculosis infection. M. tuberculosis exploits immune privilege to grow and divide in pleural macrophages. Fibrates are associated with the immune response and control lipid metabolism through glycolysis with ß-oxidation of fatty acids. RESULTS: In this study, we investigated the effect of fibrate pretreatment on the immune response during M. smegmatis infection in U937 cells, a human leukemic monocyte lymphoma cell line. The protein expression of tumor necrosis factor α (TNF-α), an inflammatory marker, and myeloid differentiation primary response gene 88 (MyD88), a toll like receptor adaptor molecule, in the infected group increased at 1 and 6 h after M. smegmatis infection of U937 cells. Acetyl coenzyme A acetyl transferase-1 (ACAT-1), peroxisome proliferator-activated receptor-α (PPAR-α), TNF-α, and MyD88 decreased in U937 cells treated with fibrates at 12 and 24 h after treatment. More than a 24 h pretreatment with fibrate resulted in similar expression levels of ACAT-1 and PPAR-α between infected vehicle control and infected groups which were pretreated with fibrate for 24 h. However, upon exposure to M. smegmatis, the cellular expression of the TNF-α and MyD88 in the infected groups pretreated with fibrate for 24 h decreased significantly compared to that in the infected vehicle group. CONCLUSION: These results suggest that fibrate pretreatment normalized the levels of inflammatory molecules in Mycobacterium smegmatis-infected U937 cells. Further studies are needed to confirm the findings on pathophysiology and immune defense mechanism of U937 by fibrates during M. tuberculosis infection.
Assuntos
Ácidos Fíbricos/farmacologia , Mediadores da Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Infecções por Mycobacterium/metabolismo , Mycobacterium smegmatis , Acetil-CoA C-Acetiltransferase/metabolismo , Western Blotting , Humanos , Macrófagos/metabolismo , Macrófagos/microbiologia , Fator 88 de Diferenciação Mieloide/metabolismo , PPAR alfa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Células U937RESUMO
Objectives Panax ginseng, Camellia sinensis and bezafibrate were compared for their lipid-lowering, antioxidant and anti-inflammatory properties as potential agents to prevent nonalcoholic fatty liver disease and its progression to nonalcoholic steatohepatitis. Methods Fifty Wistar rats were randomized into five groups: G1 (feed with standard diet); G2 (feed with high-fat diet with 58% of energy from fat); G3 (high-fat diet + standardized Panax ginseng extract at 100 mg/kg/day); G4 (high-fat diet + standardized Camellia sinensis extract at 100 mg/kg/day); and G5 (high-fat diet + bezafibrate at 100 mg/kg/day), given by gavage. The animals were sacrificed eight weeks later and blood was collected for glucose, insulin, cholesterol, triglycerides, AST, ALT, alkaline phosphatase and gamma-glutamyl transferase determinations. The score system for nonalcoholic fatty liver disease was used to analyse the liver samples. Results and conclusions High-fat diet resulted in a significant increase in animal body weight, biochemical changes and enzymatic elevations. Steatosis, inflammation and hepatocellular ballooning scores were significant high in this group. The biochemical and histological variables were statistically similar in the bezafibrate group and control group. Treatment with Panax ginseng extract prevented obesity and histological features of nonalcoholic steatohepatitis (steatosis and inflammation) compared to high-fat diet. Camellia sinensis showed a less effective biochemical response, with small reduction in steatosis and inflammation but lower ballooning scores. .
Objetivos Panax ginseng, Camellia sinensis e bezafibrato foram comparados por suas propriedades hipolipemiantes, antioxidantes e anti-inflamatórias, como potenciais agentes capazes de prevenir a doença hepática gordurosa não alcoólica e sua progressão para esteato-hepatite não alcoólica. Métodos Cinqüenta ratos Wistar foram distribuídos aleatoriamente em cinco grupos: G1 (alimentados com dieta padrão); G2 (alimentados com dieta hipercalórica com 58% de energia a partir de gordura); G3 (dieta rica em gordura + extrato padronizado Panax ginseng em 100 mg / kg / dia); G4 (dieta rica em gordura + extrato de Camellia sinensis padronizado a 100 mg / kg / dia); e G5 (dieta rica em gordura + bezafibrato, a 100 mg / kg / dia), administrado via oral. Os animais foram sacrificados após oito semanas e o sangue foi coletado para determinação da glicose, insulina, colesterol, triglicérides, AST, ALT, fosfatase alcalina e gama-glutamil transferase. O sistema NAS de pontuação para doença hepática gordurosa não alcoólica foi utilizado para analisar as amostras de fígado. Resultados e conclusões A dieta hipercalórica resultou em um aumento significativo no peso corporal dos animais, associado a alterações bioquímicas e elevações enzimáticas. Os escores de esteatose, inflamação e balonização hepatocelular foram significativamente mais elevados neste grupo. As variáveis bioquímicas e histológicas foram estatisticamente semelhantes entre os grupos bezafibrato e controle. O uso do extrato do Panax ginseng esteve associado a um menor ganho de peso dos animais, em média, bem como a menores índices nos escores de esteato-hepatite (esteatose e inflamação) em comparação com o grupo apenas alimentado com dieta hipercalórica. No grupo ...
Assuntos
Animais , Ácidos Fíbricos/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Panax/química , Fitoterapia/métodos , Chá/química , Progressão da Doença , Distribuição Aleatória , Ratos WistarRESUMO
BACKGROUND: Rhabdomyolysis is a syndrome characterized by impaired metabolic integrity of myocytes, causing the release of intracellular constituents into the circulation, and can be a serious side effect of drug intake. CASE REPORT: This report describes a unique case of rabdomyolysis secondary in which ciprofibrate, sirolimus, cyclosporine, and pegylated interferon-α in a liver transplant patient was used. A 47-year-old male liver transplant recipient in 2009, who had hepatitis C and incidental hepatocellular carcinoma, underwent immunosuppressive therapy (cyclosporine and sirolimus). The patient is currently in treatment for viral recurrence with pegylated interferon-α and ribavirin; he had a history of hypertriglyceridemia treated with ciprofibrate. He had development of severe and generalized myalgia and fever after the eighth application of pegylated interferon-α and increasing doses of cyclosporine. Laboratorial tests showed acute renal failure and significant increase in creatine kinase. Rhabdomyolysis secondary to interaction of fibrate-cyclosporine-pegylated interferon-α was postulated. CONCLUSIONS: Medical professionals should be aware of possible drug interactions and should monitor patients receiving these drugs.
Assuntos
Ciclosporina/efeitos adversos , Ácidos Fíbricos/efeitos adversos , Interferon-alfa/efeitos adversos , Transplante de Fígado , Rabdomiólise/induzido quimicamente , Sirolimo/efeitos adversos , Antivirais/uso terapêutico , Interações Medicamentosas , Quimioterapia Combinada , Hepatite C/tratamento farmacológico , Humanos , Imunossupressores , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêuticoRESUMO
Cholesteryl ester transfer protein (CETP) is a plasma protein that reduces high density lipoprotein (HDL)-cholesterol (chol) levels and may increase atherosclerosis risk. n-3 and n-6 polyunsaturated fatty acids (PUFAs) are natural ligands, and fibrates are synthetic ligands for peroxisome proliferator activated receptor-alpha (PPARα), a transcription factor that modulates lipid metabolism. In this study, we investigated the effects of PUFA oils and fibrates on CETP expression. Hypertriglyceridemic CETP transgenic mice were treated with gemfibrozil, fenofibrate, bezafibrate or vehicle (control), and normolipidemic CETP transgenic mice were treated with fenofibrate or with fish oil (FO; n-3 PUFA rich), corn oil (CO, n-6 PUFA rich) or saline. Compared with the control treatment, only fenofibrate significantly diminished triglyceridemia (50%), whereas all fibrates decreased the HDL-chol level. Elevation of the CETP liver mRNA levels and plasma activity was observed in the fenofibrate (53%) and gemfibrozil (75%) groups. Compared with saline, FO reduced the plasma levels of nonesterified fatty acid (26%), total chol (15%) and HDL-chol (20%). Neither of the oil treatments affected the plasma triglyceride levels. Compared with saline, FO increased the plasma adiponectin level and reduced plasma leptin levels, whereas CO increased the leptin levels. FO, but not CO, significantly increased the plasma CETP mass (90%) and activity (23%) as well as increased the liver level of CETP mRNA (28%). In conclusion, fibrates and FO, but not CO, up-regulated CETP expression at both the mRNA and protein levels. We propose that these effects are mediated by the activation of PPARα, which acts on a putative PPAR response element in the CETP gene.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/agonistas , Ácidos Fíbricos/uso terapêutico , Óleos de Peixe/uso terapêutico , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Animais , Bezafibrato/uso terapêutico , Proteínas de Transferência de Ésteres de Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Terapia Combinada , Óleo de Milho/uso terapêutico , Cruzamentos Genéticos , Suplementos Nutricionais , Feminino , Fenofibrato/uso terapêutico , Genfibrozila/uso terapêutico , Hipertrigliceridemia/sangue , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/prevenção & controle , Fígado/metabolismo , Masculino , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Distribuição AleatóriaRESUMO
This study describes the adaptation of a revised Brazilian version of the Patient Competency Rating Scale (PCRS-R-BR), which focuses on executive, mnemonic, and attention functions. Evidence of content-based and external validity is also reported. The cross-cultural adaptation was conducted in five phases: 1) translations and back translations; 2) item analysis by authors; 3) classification by experts; 4) revisions and reformulations by authors; 5) pilot study with a sample of patients with mild and moderate/severe traumatic brain injury (TBI). Data were analyzed descriptively, and the PCRS-R-BR scores of groups with mild vs. moderate/severe TBI were compared using the Mann-Whitney test. Patients and their relatives were divided into groups and compared using repeated-measures analysis. The results of the PCRS-R-BR questionnaire for relatives and discrepancy scores of patients with moderate/severe TBI revealed significantly more impairment than that found in the group of patients with mild TBI. There were significant differences between item and total scores of both groups of patients and relatives. Results indicated a high level of item content agreement between experts. This study found initial evidence of PCRS-R-BR content-based and external validity when the questionnaire was applied to patients with mild and moderate/severe TBI and their relatives.
O presente artigo teve como objetivo apresentar a adaptação transcultural e evidências de validade externa e de conteúdo da versão brasileira revisada da Patient Competency Rating Scale (PCRS-R-BR), com foco nas funções executivas, mnemônicas e atencionais. A adaptação transcultural incluiu cinco fases: 1) tradução e retrotradução; 2) análise de itens por autores; 3) análise de especialistas; 4) revisões e reformulações dos autores; 5) estudo piloto em pacientes com traumatismo cranioencefálico (TCE) leve e moderado/grave. Os dados foram analisados descritivamente e os pacientes com TCE leve e moderado/grave foram comparados nos escores da PCRS-R-BR pelo teste Mann-Whitney. Os pacientes e familiares foram comparados por grupo através da análise de medidas repetidas. Os pacientes com TCE moderado/grave tiveram maior prejuízo que os pacientes com TCE leve no formulário da PCRS-R-BR dos familiares e no escore de discrepância entre pacientes e familiares. Os resultados indicam bons e altos níveis de concordância entre especialistas frente aos componentes avaliados pelos itens. Esse estudo apresentou evidências iniciais de validade de conteúdo da PCRS-R-BR para pacientes com TCE leve e moderado/severo e seus familiares.