Heart and systemic effects of statin pretreatment in a rat model of abdominal sepsis. Assessment by Tc99m-sestamibi biodistribition

PURPOSE: To evaluate the heart and the Tc-99m-sestamibi biodistribution after statin pretreatment in a rat model of abdominal sepsis. METHODS: Twenty-four Wistar rats were randomly distributed into four groups (n=6 per group): 1) sepsis with simvastatin treatment, 2) sepsis with vehicle, 3) sham control with simvastatin and 4) sham control with vehicle. 24 hours after cecal ligation and puncture rats received 1.0MBq of Tc-99m-sestamibi i.v. 30min after, animals were euthanized for ex-vivo tissue counting and myocardium histological analysis. RESULTS: Myocardial histologic alterations were not detected 24 hours post-sepsis. There was significantly increased cardiac Tc-99m-sestamibi activity in the sepsis group with simvastatin treatment (1.9$\pm$0.3%ID/g, p<0.001) in comparison to the sepsis group+vehicle (1.0$\pm$0.2% ID/g), control sham group+ simvastatin (1.2$\pm$0.3% ID/g) and control sham group (1.3$\pm$0.2% ID/g). Significant Tc-99m-sestamibi activity in liver, kidney and lungs was also detected in the sepsis group treated with simvastatinin comparison to the other groups. CONCLUSIONS: Statin treatment altered the biodistribution of Tc-99m-sestamibi with increased cardiac and solid organ activity in rats with abdominal sepsis, while no impact on controls. Increased myocardial tracer activity may be a result of a possible protection effect due to increased tissue perfusion mediated by statins

Tear proteomic analysis of Sjogren syndrome patients with dry eye syndrome by two-dimensional-nano-liquid chromatography coupled with tandem mass spectrometry

We examined the tear film proteome of patients with Sjögren's syndrome (SS) and dry eye syndrome (group A), patients with dry eye symptoms (group B) and normal volunteers (group C). Tear samples were pooled from 8 subjects from each group and were subjected to two-dimensional-nano-liquid chromatography coupled with tandem mass spectrometry (2D-nano-LC-MS/MS). The tear breakup time for group A was significantly reduced compared with group B and C (P < 0.001). Group A (Schirmer I test, 2.13 +/- 2.38 mm/5 min) had markedly lower tear volume than group B (5.94 +/- 4.75 mm/5 min) and C (14.44 +/- 6.57 mm/5 min) (P < 0.001). Group A had significantly higher normalized tear protein content (1.8291 +/- 0.2241 mu g/mm) than group B (1.0839 +/- 0.1120 mu g/mm) (P = 0.001) and C (0.2028 +/- 0.0177 mu g/mm) (P = 0.001). The 2D-nano-LC-MS/MS analysis identified a total of 435 proteins, including 182 (54.8%),247 (74.4%) and 278 (83.7%) in group A, B, and C, respectively, with 56 (16.7%) proteins including defensin alpha 1, clusterin and lactotransferrin unique to group A. In conclusion, dry eye syndrome in SS patients is associated with an altered proteomic profile with dysregulated expression of proteins involved in a variety of important cellular process including inflammation, immunity, and oxidative stress

Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer's disease

A novel series of feruloyl-donepezil hybrid compounds were designed, synthesized and evaluated as multitarget drug candidates for the treatment of Alzheimer's Disease (AD). In\uc2\ua0vitro results revealed potent acetylcholinesterase (AChE) inhibitory activity for some of these compounds and all of them showed moderate antioxidant properties. Compounds 12a, 12b and 12c were the most potent AChE inhibitors, highlighting 12a with IC50\uc2\ua0=\uc2\ua00.46\uc2\ua0\uce\ubcM. In addition, these three most promising compounds exhibited significant in\uc2\ua0vivo anti-inflammatory activity in the mice paw edema, pleurisy and formalin-induced hyperalgesy models, in\uc2\ua0vitro metal chelator activity for Cu2+and Fe2+, and neuroprotection of human neuronal cells against oxidative damage. Molecular docking studies corroborated the in\uc2\ua0vitro inhibitory mode of interaction of these active compounds on AChE. Based on these data, compound 12a was identified as a novel promising drug prototype candidate for the treatment of AD with innovative structural feature and multitarget effects

Liquid-liquid extraction combined with high performance liquid chromatography-diode array-ultra-violet for simultaneous determination of antineoplastic drugs in plasma

A liquid-liquid extraction (LLE) combined with high-performance liquid chromatography-diode array detection method for simultaneous analysis of four chemically and structurally different antineoplastic drugs (cyclophosphamide, doxorubicin, 5-fluorouracil and ifosfamide) was developed. The assay was performed by isocratic elution, with a C18 column (5 µm, 250 x 4.6 mm) and mobile phase constituted by water pH 4.0- acetonitrile-methanol (68:19:13, v/v/v), which allowed satisfactory separation of the compounds of interest. LLE, with ethyl acetate, was used for sample clean-up with recoveries ranging from 60 to 98%. The linear ranges were from 0.5 to 100 µg mL-1, for doxorubicin and 1 to 100 µg mL-1, for the other compounds. The relative standard deviations ranged from 5.5 to 17.7%. This method is a fast and simple alternative that can be used, simultaneously, for the determination of the four drugs in plasma, with a range enabling quantification of the drugs in pharmacokinetics, bioequivalence and therapeutic drug-monitoring studies.<br>Um método de extração líquido-líquido (ELL) combinado com cromatografia líquida de alta eficiência-detector de arranjo de diodos foi desenvolvido para análise simultânea de quatro fármacos antineoplásicos quimicamente e estruturalmente diferentes (ciclofosfamida, doxorrubicina, fluoruracila e ifosfamida). O estudo foi realizado sob condições isocráticas, com coluna C18 (5µm, 250 x 4.6 mm) e fase móvel constituída por água pH 4.0-acetonitrila-metanol (68:19:13, v/v/v), que permitiu separação satisfatória dos analitos de interesse. A ELL, com acetato de etila, foi utilizada para limpeza da amostra, com recuperação variando de 60 a 98%. As faixas foram lineares de 0,5 a 100 µg mL-1 para doxorrubicina e 1 a 100 µg mL-1 para os outros compostos. O desvio padrão relativo variou de 5,5 a 17,7%. Este método é uma alternativa rápida e simples que pode ser usado, simultaneamente, para a determinação dos quatro fármacos em plasma, com uma faixa que permite quantificá-los em estudos de farmacocinética, bioequivalência e monitorização terapêutica