A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer

Lessons Learned

• The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy.
• Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily.
• The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma.

BackgroundThe RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC.MethodsThis was a phase I study with a 3+3 design in patients with treatment‐naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy.ResultsA total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose‐limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment‐related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression‐free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated‐ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated‐ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells.ConclusionTrametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.     

风险管理在护理管理中的应用分析

目的:探讨风险管理在护理管理中的应用效果。方法:选取2012年8月~12月实施风险管理前于我科接受手术治疗患者180例作为对照组;2014年1月~5月于我科接受手术治疗的210例患者作为观察组,对实施护理风险管理前后患者对护理工作者工作质量的评价、护理工作者应急能力等指标进行比较。结果:1护理质量:风险管理应用到护理管理中,患者投诉情况、护理不良事件发生情况以及满意情况均优于应用前(P<0.05)。2工作质量:风险管理应用后,护理工作人员在责任心、沟通能力、服务态度以及操作熟练程度方面评分均显著高于应用前,P<0.05。3风险意识:风险管理应用后,护理工作者对于风险管理、风险因素的认识,风险管理态度以及应急能力均较之于应用前显著提高。结论:风险管理应用于护理管理,可降低护理纠纷,提高患者护理满意度。     

Baicalin-loaded PEGylated lipid nanoparticles: characterization,pharmacokinetics, and protective effects on acute myocardial ischemia in rats

Context: Baicalin has many pharmacological activities, including protective function against myocardial ischemia by antioxidant effects and free radical scavenging activity. However, its rapid elimination half-life in plasma and poor water solubility limits its clinical efficacy.

Objective: Novel baicalin-loaded PEGylated nanostructured lipid carriers (BN-PEG-NLC) were developed to improve bioavailability of BN, to prolong retention time in vivo and to enhance its protective effect.

Methods: In this study, BN-PEG-NLC were prepared by the emulsion-evaporation and low temperature-solidification method using a mixture of glycerol monostearate and polyethylene glycol monostearate as solid lipids, and oleic acid as the liquid lipid. The physicochemical properties of NLC were characterized. The pharmacokinetic and pharmacodynamic behaviors of BN-PEG-NLC or BN-NLC were evaluated in acute MI rats.

Results and discussion: The particle size, zeta potential, and entrapment efficiency for BN-PEG-NLC were observed as 83.9?nm, ?32.1?mV, and 83.5%, respectively. The release profiles of BN from both BN-PEG-NLC and BN-NLC were fitted to the Ritger–Peppas modal, which presented burst release initially and prolonged release afterwards. Pharmacokinetics results indicated that BN-PEG-NLC exhibited a 7.2-fold increase in AUC in comparison to BN solution, while a 3-fold increase in comparison to BN-NLC. Biodistribution results revealed that BN-PEG-NLC exhibited higher heart drug concentration compared with BN-NLC as well as BN solution. In the present study, BN-PEG-NLC significantly ameliorated infarct size.

Conclusion: The results of the present study imply that PEG-NLC could be the biocompatible carriers for heart-targeted drug delivery to improve myocardial ischemia.     

Antimicrobial activity of selected synbiotics targeted for the elderly against pathogenic Escherichia coli strains

The aim of the present study was to evaluate the antimicrobial activity of two synbiotic combinations, Lactobacillus fermentum with short-chain fructooligosaccharides (FOS-LF) and Bifidobacterium longum with isomaltooligosaccharides (IMO-BL), against enterohaemorrhagic Escherichia coli O157:H7 and enteropathogenic E. coli O86. Antimicrobial activity was determined (1) by co-culturing the synbiotics and pathogens in batch cultures, and (2) with the three-stage continuous culture system (gut model), inoculated with faecal slurry from an elderly donor. In the co-culture experiments, IMO-BL was significantly inhibitory to both E. coli strains, while FOS-LF was slightly inhibitory or not inhibitory. Factors other than acid production appeared to play a role in the inhibition. In the gut models, both synbiotics effectively inhibited E. coli O157 in the first vessel, but not in vessels 2 and 3. E. coli O86 was not significantly inhibited.