Development of Vorinostat-Loaded Solid Lipid Nanoparticles to Enhance Pharmacokinetics and Efficacy against Multidrug-Resistant Cancer Cells

Purpose

To investigate whether delivery of a histone deacetylase inhibitor, vorinostat (VOR), by using solid lipid nanoparticles (SLNs) enhanced its bioavailability and effects on multidrug-resistant cancer cells.

Methods

VOR-loaded SLNs (VOR-SLNs) were prepared by hot homogenization using an emulsification-sonication technique, and the formulation parameters were optimized. The cytotoxicity of the optimized formulation was evaluated in cancer cell lines (MCF-7, A549, and MDA-MB-231), and pharmacokinetic parameters were examined following oral and intravenous (IV) administration to rats.

Results

VOR-SLNs were spherical, with a narrowly distributed average size of ~100 nm, and were physically stable for 3 months. Drug release showed a typical bi-phasic pattern in vitro, and was independent of pH. VOR-SLNs were more cytotoxic than the free drug in both sensitive (MCF-7 and A549) and resistant (MDA-MB-231) cancer cells. Importantly, SLN formulations showed prominent cytotoxicity in MDA-MB-231 cells at low doses, suggesting an ability to effectively counter the P-glycoprotein-related drug efflux pumps. Pharmacokinetic studies clearly demonstrated that VOR-SLNs markedly improved VOR plasma circulation time and decreased its elimination rate constant. The areas under the VOR concentration-time curve produced by oral and IV administration of VOR-SLNs were significantly greater than those produced by free drug administration. These in vivo results clearly highlighted the remarkable potential of SLNs to augment the bioavailability of VOR.

Conclusions

VOR-SLNs successfully enhanced the oral bioavailability, circulation half-life, and chemotherapeutic potential of VOR.     

Method for detecting the reactivity of chemicals towards peptides as an alternative test method for assessing skin sensitization potential

Cosmetics are normally composed of various ingredients. Some cosmetic ingredients can act as chemical haptens reacting toward proteins or peptides of human skin and they can provoke an immunologic reaction, called as skin sensitization. This haptenation process is very important step of inducing skin sensitization and evaluating the sensitizing potentials of cosmetic ingredients is very important for consumer safety. Therefore, animal alternative methods focusing on monitoring haptenation potential are undergoing vigorous research. To examine the further usefulness of spectrophotometric methods to monitor reactivity of chemicals toward peptides for cosmetic ingredients. Forty chemicals (25 sensitizers and 15 non-sensitizers) were reacted with 2 synthetic peptides, e.g., the cysteine peptides (Ac-RFAACAA-COOH) with free thiol group and the lysine peptides (Ac-RFAAKAA-COOH) with free amine group. Unreacted peptides can be detected after incubating with 5,5′-dithiobis-2-nitrobenzoic acid or fluorescamine™ as detection reagents for free thiol and amine group, respectively. Chemicals were categorized as sensitizers when they induced more than 10% depletion of cysteine peptides or more than 30% depletion of lysine peptides. The sensitivity, specificity, and accuracy were 80.0%, 86.7% and 82.5%, respectively. These results demonstrate that spectrophotometric methods can be an easy, fast, and high-throughput screening tools predicting the skin sensitization potential of chemical including cosmetic ingredient.     

Evaluation of Hydrogenation Kinetics and Life Cycle Assessment on Mg2NiHx–CaO Composites

Magnesium-based alloys are attractive as hydrogen storage materials due to their lightweight and high absorption, but their high operating temperatures and very slow kinetics are obstacles to practical applications. Therefore, the effect of CaO has improved the hydrogenation kinetics and slowed down the degradation. The Mg₂NiH_x–CaO composites were prepared by hydrogen-induced mechanical alloying (HIMA). Hydrogenation kinetics was performed by using an Automatic PCT Measuring System and evaluated in the temperature range of 423, 523, and 623 K. As a result of calculating the hydrogen absorption amounts through the hydrogenation kinetics curve, they were calculated as about 0.52 wt%, 1.21 wt%, and 1.59 wt% (Mg₂NiH_x–10 wt% CaO). In this study, the material environmental aspects of Mg₂NiH_x–CaO composites were investigated through life cycle assessment (LCA). LCA was performed analyzing the environmental impact characteristics of the manufacturing process by using Gabi software and the Eco-Indicator 99’ and Centrum voor Milieuweten schappen (CML 2001) methodology. As a result, the contents of global warming potential (GWP) and fossil fuels were found to have a higher impact than other impact categories.     

Sodium–glucose cotransporter 2 inhibitors reduce day-to-day glucose variability in patients with type 1 diabetes

Aims/IntroductionSodium–glucose cotransporter 2 inhibitors (SGLT2i) are used worldwide because of their multiple benefits for patients with type 2 diabetes. The purpose of this study was to determine the efficacy and safety of SGLT2i in patients with type 1 diabetes.Materials and MethodsPatients with type 1 diabetes who had been treated with SGLT2i for >12 weeks were included in this retrospective observation study. We recorded the changes in body mass, insulin dose, blood and urine test data, and adverse events. The changes in day‐to‐day glucose variability, as the primary end‐point, was evaluated using the interquartile range (P25/P75) of the ambulatory glucose data obtained using continuous glucose monitoring.ResultsA total of 51 patients (37 women; mean age 52.7 years) were included. Glycated hemoglobin and body mass significantly decreased by 0.4% and 1.6 kg, respectively. The total required insulin dose decreased by 9.4% (42.7 ± 26.6–38.7 ± 24.3 units/day). Continuous glucose monitoring data were obtained from 30 patients. P25/P75 decreased by 17.6 ± 20.7% during SGLT2i treatment (P < 0.001). The percentage of time per day within the target glucose range of 70–180 mg/dL significantly increased (from 42.2 to 55.5%, P < 0.001), without an increase in the percentage of time spent in the hypoglycemic range (<70 mg/dL). Urinary ketone bodies were detected in four patients (7.8%), but none developed ketoacidosis.ConclusionsSGLT2i improved day‐to‐day glucose variability and time in the target glucose range, without increasing frequency of hypoglycemia, in patients with type 1 diabetes, and reduced glycated hemoglobin, body mass and the required insulin dose.     

Clinical impact of forced vital capacity on exercise performance in patients with chronic obstructive pulmonary disease

BackgroundForced vital capacity (FVC) has been suggested to be a good biomarker for decreased exercise performance in patients with chronic obstructive pulmonary disease (COPD). However, as FVC is highly correlated with forced expiratory volume in 1 second (FEV₁), the relationship between FVC and exercise capacity should be assessed within the category of FEV1, i.e., COPD severity. However, this was not considered in previous studies. Thus, limited data are available on the association between reduced FVC and exercise capacity measured by 6-min walk distance (6MWD) based on COPD severity.MethodsWe performed a cross-sectional study using data from the Korean COPD Subgroup Study (KOCOSS) cohort. We evaluated 1,386 patients with moderate (n=895) and severe-to-very severe (n=491) COPD. Reduced FVC was defined as FVC <80% predicted and short 6MWD as <350 m. Multivariable logistic regression was used to evaluate the association between reduced FVC and short 6MWD.ResultsThere were no significant differences in respiratory symptoms and quality of life between the patients with reduced FVC and those with preserved FVC. However, patients with reduced FVC had shorter 6MWD (30.5 cm in moderate and 34.5 cm in severe-to-very severe COPD) and higher BODE index scores than those with preserved FVC. The cubic spline model revealed 6MWD peaked around 93% predicted of FVC in moderate COPD, whereas FVC showed a positive association with 6MWD in severe-to-very severe COPD. Multivariable analyses showed that reduced FVC was significantly associated with short 6MWD in both moderate [adjusted odds ratio (aOR) =1.44, 95% confidence interval (CI): 1.03–2.02] and severe-to-very severe (adjusted OR =1.55, 95% CI: 1.01–2.40) COPD.ConclusionsReduced FVC was significantly associated with shorter 6MWD in moderate-to-very severe COPD patients, suggesting that reduced FVC might be reflective of 6MWD-measured exercise capacity in moderate-to-very severe COPD.     

Surgery is a safe,effective first-line treatment modality for noninvasive prolactinomas

Pituitary - Dopamine agonists (DAs) have long been the recommended first-line treatment for prolactinoma. Given the remarkable developments in surgical techniques, however, surgery is on the rise....