Antiobesity and Antioxidative Effect of Fermented Brown Rice Using In Vitro with In Vivo Caenorhabditis elegans Model.

Naturally occurring phytochemicals from plants or grains are crucial in reducing various metabolic disorders. Bioactive phytonutrients are abundant in the Asian dietary staple, brown rice. This research evaluated the impact of lactic acid bacteria (LABs) bioconversion and fermentation on antioxidant and antiobesity activities and ferulic acid content in brown rice. The combination of bioconversion with Pediococcus acidilactici MNL5 among all LABs used showed a synergistic impact with 24 h of solid-state brown rice fermentation. The 24-h MNL5 fermented brown rice (FBR) demonstrated the most potent pancreatic lipase inhibitory activity (85.5 ± 1.25%) compared to raw brown rice (RBR) (54.4 ± 0.86%). The antioxidant potential of MNL5-FBR was also found to be highest in the DPPH assay (124.40 ± 2.40 mg Trolox Equiv./100 g, DW), ABTS assay (130.52 ± 2.32 mg Trolox Equiv./100 g, DW), and FRAP assay (116.16 ± 2.42 mg Trolox Equiv./100 g, DW). Based on higher antioxidant and antiobesity activities, samples were quantified for ferulic acid content using the HPLC-MS/MS approach. Furthermore, C. elegans supplementation with FBR showed enhanced life span and lipid reduction in fluorescence microscope analysis compared to the control. Our results indicate that the expression study using the C. elegans model (N2 and Daf-2 models) fat gene was conducted, showing a lowering of obesity ability in FBR-fed worms. Our study indicates that FBR has improved antioxidant and antiobesity actions, especially in MNL5-FBR, and can be employed to develop functional foods that combat obesity.

Nivolumab Exposure-Response Analyses of Efficacy and Safety in Previously Treated Squamous or Nonsquamous Non-Small Cell Lung Cancer.

Purpose: Nivolumab is a fully human IgG4 monoclonal antiprogrammed death-1 antibody with demonstrated efficacy, including durable responses and prolonged survival, in patients with previously treated, advanced non-small cell lung cancer (NSCLC). Exposure-response (E-R) analyses for efficacy and safety were conducted to inform the benefit-risk assessment of nivolumab in this patient population.Experimental Design: The analyses used clinical trial data from patients with squamous (n = 293) or nonsquamous (n = 354) NSCLC from four clinical trials who received nivolumab doses of 1 to 10 mg/kg every 2 weeks. E-R efficacy analyses were performed by investigating the relationship between time-averaged nivolumab concentration after the first dose (Cavg1) and the probability of overall survival by histology. E-R safety analyses examined relationships between nivolumab Cavg1 and hazards of adverse events leading to discontinuation or death (AEs-DC/D).Results: Nivolumab exposure was not associated with overall survival [the 95% confidence interval (CI) of effect included 1] in patients with squamous (HR, 0.802; 95% CI, 0.555-1.16) or nonsquamous NSCLC (HR, 0.94; 95% CI, 0.683-1.29). Similarly, nivolumab exposure was not associated with AEs-DC/D in the overall population (HR, 0.917; 95% CI, 0.644-1.31). The risk of AEs-DC/D was similar among patients with squamous or nonsquamous histology.Conclusions: Nivolumab monotherapy demonstrated a wide therapeutic margin, as evidenced by relatively flat E-R relationships over the range of exposures produced by doses of 1 to 10 mg/kg every 2 weeks (Q2W), supporting the use of the initially approved dose of 3 mg/kg Q2W in patients with NSCLC. Clin Cancer Res; 23(18); 5394-405. ©2017 AACR.

Evaluation of Immunogenicity of Nivolumab Monotherapy and Its Clinical Relevance in Patients With Metastatic Solid Tumors.

Nivolumab is a fully human IgG4 monoclonal antibody targeting the programmed death-1 (PD-1) receptor that blocks interactions between PD-1 and its ligands on tumor cells to prevent T-cell exhaustion in patients with cancer. It has demonstrated efficacy in multiple tumor types, including melanoma, non-small-cell lung cancer, and renal cell carcinoma. This analysis assessed the immunogenicity of nivolumab and its impact on pharmacokinetics, safety, and efficacy in patients with solid tumors enrolled in 6 clinical studies. The incidence and prevalence of antidrug antibodies (ADAs) were determined by validated electrochemiluminescence assays in samples collected during nivolumab treatment and up to 100 days after the last dose. Confirmed positive samples from the 6 studies were also tested for presence of neutralizing antibodies (NAbs). Among 1086 nivolumab-treated patients, 138 patients (12.7%) were ADA positive (relative to baseline), only 3 (0.3%) of whom were persistently positive for ADA, and 9 (0.8%) were NAb positive at 1 time point. The presence of ADAs was not associated with hypersensitivity, infusion reactions, or loss of efficacy and had minimal impact on nivolumab clearance. Additionally, the presence of NAbs was not associated with loss of efficacy. In conclusion, immunogenicity of nivolumab is not clinically meaningful.

A phase I trial to determine the safety, pharmacokinetics, and pharmacodynamics of intercalated BMS-690514 with paclitaxel/carboplatin (PC) in advanced or metastatic solid malignancies.

PURPOSE: A phase I dose escalation study was performed to determine the maximum tolerated dose (MTD) of intercalated dosing of BMS-690514, a reversible oral panHER/VEGF receptor inhibitor, combined with paclitaxel/carboplatin (PC) in advanced solid tumors. Secondary endpoints included safety, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and preliminary efficacy. EXPERIMENTAL DESIGN: Patients received fixed doses of P (200 mg/m(2)) and C (AUC 6 mg/mL min) q21 days with intercalated BMS-690514 (Days 4-19) starting at 100 mg/day and increasing by 50 mg/day using a 3 + 3 dose escalation design until the MTD was reached. Twenty additional patients were enrolled in the expansion cohort at the recommended phase II dose (RP2D). RESULTS: The MTD was reached at 150 mg/day. DLTs included grade 3 thrombosis at 100 mg (1 patient) and grade 3 diarrhea at 150 mg (1 patient) and 200 mg (2 patients). Serious adverse events (AEs) occurring in 20/37 patients included neutropenia (n = 5), diarrhea (n = 4), pulmonary embolism (n = 3), and simultaneous dehydration, acute renal failure, and febrile neutropenia (n = 2). BMS-690514-related AEs included diarrhea (97 %), acneiform rash (60 %), fatigue (43 %), nausea (30 %), and anorexia (30 %). There were no treatment-related deaths. Sequential intermittent administration of PC did not affect the PK of BMS-690514. Of the 32 patients evaluable for efficacy, there were 12 partial responses including five patients with non-small-cell lung cancer and 12 patients with stable disease. CONCLUSIONS: The MTD of intercalated BMS-609514 combined with PC was 150 mg/day. This approach was tolerable with manageable toxicities and antitumor activity in a variety of solid tumor types.

Phase I-IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours.

PURPOSE: BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I-IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514. PATIENTS AND METHODS: In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naïve (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD. RESULTS: In phase I (n=28), the MTD was determined to be 200mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n=62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n=4; 4%) and rash (n=2; 2%). Disease control (≥4months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways. CONCLUSION: This phase I-IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200mg/d, including those with EGFR mutations conferring resistance to erlotinib.

Food increased the bioavailability of BMS-690514, an orally active EGFR/HER2/VEGF receptor kinase inhibitor, in healthy subjects.

We studied the effect of food on pharmacokinetics, safety, and tolerability of BMS-690514. Two open-label, randomized, single-dose, 2-treatment, 2-period crossover studies were performed in healthy subjects. In study 1 (N = 26), a single oral dose of BMS-690514, 200 mg, was administered while fasting or after a high-fat meal, and in study 2 (N = 17), a single oral dose of BMS-690514, 200 mg, was administered while fasting or after a light meal. Compared with fasting, the adjusted geometric mean maximum observed plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC(0-T)), area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC(INF)) of BMS-690514 increased by 55%, 33%, and 34%, respectively, following a high-fat meal (951 kcal, 52% fat) and by 41%, 20%, and 20%, respectively, following a light meal (336 kcal, 75% carbohydrate). BMS-690514 was well tolerated in both studies. Most frequently occurring adverse events were diarrhea and acne in study 1 and rash, dry skin, and diarrhea in study 2. Systemic exposure of highly soluble BMS-690514 was increased when given along with a meal, probably through inhibition of intestinal first-pass metabolism and/or efflux transporters by food. These studies also demonstrated a tolerable safety profile of BMS-690514 in the absence and presence of food.

[Folate and homocysteine levels during pregnancy affect DNA methylation in human placenta].

OBJECTIVES: DNA methylation is one of the best characterized epigenetic mechanisms that play a regulatory role in genome programming and imprinting during embryogenesis. In this present study, we investigated the association between DNA methylation in the human placenta and the maternal folate and homocysteine concentrations on the Methylenetetrahydrofolatereductase (MTHFR) genetic polymorphism during pregnancy. METHODS: We investigated 107 pregnant women who visited Ewha Woman's University Hospital for prenatal care during their 24-28 weeks-period of gestation. During the second trimester, we measured the serum homocysteine and folate concentrations. The MTHFR 677 genetic polymorphism was determine by performing PCR-RFLP assay. The expression of DNA methylation in the human placentas was estimated by using immunohistochemistry method. RESULTS: Serum folate was negatively correlated with the serum homocysteine concentration for all the MTHFR genotypes. We found positive correlation between the folate concentrations and the DNA methylation in the human placenta (p<0.05). An increasing concentration of homocysteine was associated with reduced DNA methylation in the human placenta. The coefficient value was -2.03 (-3.77, -0.29) on the regression model (p<0.05). CONCLUSION: These findings suggest that the maternal folate and homocysteine levels along with the MTHFR 677 genetic polymorphism during pregnancy affect the DNA methylation in the human placenta.

Evaluation of continuous summary physical performance scores (CSPPS) in an elderly cohort.

BACKGROUND AND AIMS: Physical performance is an important predictor of quality of life among the elderly. A valid and sensitive measure of physical performance is needed in order to evaluate possible interventions. The aim of this study was to examine the validity and reliability of the Continuous Summary Physical Performance Score (CSPPS) and its relationship to the Quartile Summary Physical Performance Score (QSPPS). METHODS: This cross-sectional study of an elderly cohort from 5 centers in the US and Europe included men and women (> age 65) reporting at least two domains of disability. Subjects completed assessments of mobility and ability to perform activities of daily living (ADLs), the physical component of the SF-36, and a self-rating of physical performance. Timed physical performance tests were used to calculate the CSPPS and QSPPS. RESULTS: 216 subjects took part (mean age = 81 years). The distribution of CSPPS scores was similar for men and women, with a mean of 59.2 (SD 17.8), median of 64.3, and range from 1.3 to 91. Subjects with older age, higher degree of disability, and lower self-rated physical performance had lower CSPPS scores. The CSPPS had good test-retest reliability (r = 0.92), and CSPPS and QSPPS are highly correlated (r = 0.94, p < 0.001). However, the QSPPS appears to lack the linearity, and the ranges of the CSPPS for each score of the QSPPS overlap substantially. CONCLUSIONS: In a cohort with moderate to severe disability, the CSPPS appears to be a valid, reproducible measure that can discriminate smaller yet clinically meaningful differences in physical function, as compared with the QSPPS.

Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial.

PURPOSE: To assess the efficacy and safety of adding rosiglitazone to an established regimen of glyburide/metformin in patients with type 2 diabetes who had not achieved adequate glycemic control (glycosylated hemoglobin [HbA1C] levels >7.0% and < or =10.0%). METHODS: Following an open-label, lead-in phase to optimize the dosing of glyburide/metformin tablets, 365 patients randomly received additive therapy comprising rosiglitazone (4 mg once daily) or placebo for 24 weeks. Based on glycemic response, rosiglitazone dose was maintained or increased to 4 mg twice daily. Glyburide/metformin dose was maintained or reduced by 2.5/500 mg for symptomatic hypoglycemia. The primary endpoint was the change in HbA1C level from baseline to week 24. The proportions of patients achieving HbA1C levels <7% and a fasting plasma glucose level <126 mg/dL were also assessed. RESULTS: After 24 weeks, therapy with glyburide/metformin plus rosiglitazone resulted in a greater reduction in HbA1C levels (-1.0%, P<0.001) compared with combination therapy that included placebo, and in a larger proportion of patients (42% vs. 14%) who attained levels <7%. The difference in fasting plasma glucose levels between groups was -48 mg/dL (P<0.001), favoring glyburide/metformin plus rosiglitazone. The adverse event profile in the rosiglitazone-treated group included mild-to-moderate edema (8%), hypoglycemia (22%), and weight gain of 3 kg. No patient experienced hypoglycemia requiring third-party assistance. CONCLUSION: In patients with inadequate glycemic control despite established glyburide/metformin therapy, the addition of rosiglitazone improves glycemic control, allowing more patients to achieve an HbA1C level <7% and perhaps delaying the need for insulin treatment.

Efficacy of glyburide/metformin tablets compared with initial monotherapy in type 2 diabetes.

Many patients with type 2 diabetes fail to achieve or maintain the American Diabetes Association's recommended treatment goal of glycosylated hemoglobin levels. This multicenter, double-blind trial enrolled patients with type 2 diabetes who had inadequate glycemic control [glycosylated hemoglobin A(1C) (A1C), >7% and <12%) with diet and exercise alone to compare the benefits of initial therapy with glyburide/metformin tablets vs. metformin or glyburide monotherapy. Patients (n = 486) were randomized to receive glyburide/metformin tablets (1.25/250 mg), metformin (500 mg), or glyburide (2.5 mg). Changes in A1C, fasting plasma glucose, fructosamine, serum lipids, body weight, and 2-h postprandial glucose after a standardized meal were assessed after 16 wk of treatment. Glyburide/metformin tablets caused a superior mean reduction in A1C from baseline (-2.27%) vs. metformin (-1.53%) and glyburide (-1.90%) monotherapy (P = 0.0003). Glyburide/metformin also significantly reduced fasting plasma glucose and 2-h postprandial glucose values compared with either monotherapy. The final mean doses of glyburide/metformin (3.7/735 mg) were lower than those of metformin (1796 mg) and glyburide (7.6 mg). First-line treatment with glyburide/metformin tablets provided superior glycemic control over component monotherapy, allowing more patients to achieve American Diabetes Association treatment goals with lower component doses in drug-naive patients with type 2 diabetes.

Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial.

OBJECTIVE: Metformin is the most commonly prescribed oral antidiabetic agent in the U.S. for adults with type 2 diabetes. The incidence of type 2 diabetes in children has increased dramatically over the past 10 years, and yet, metformin has never been formally studied in children with type 2 diabetes. RESEARCH DESIGN AND METHODS: This study evaluated the safety and efficacy of metformin at doses up to 1,000 mg twice daily in 82 subjects aged 10-16 years for up to 16 weeks in a randomized double-blind placebo-controlled trial from September 1998 to November 1999. Subjects with type 2 diabetes were enrolled if they had a fasting plasma glucose (FPG) levels > or =7.0 and < or =13.3 mmol/l (> or =126 and < or =240 mg/dl), HbA(1c) > or =7.0%, stimulated C-peptide > or =0.5 nmol/l (> or =1.5 ng/ml), and a BMI > 50th percentile for age. RESULTS: Metformin significantly improved glycemic control. At the last double-blind visit, the adjusted mean change from baseline in FPG was -2.4 mmol/l (-42.9 mg/dl) for metformin compared with +1.2 mmol/l (+21.4 mg/dl) for placebo (P < 0.001). Mean HbA(1c) values, adjusted for baseline levels, were also significantly lower for metformin compared with placebo (7.5 vs. 8.6%, respectively; P < 0.001). Improvement in FPG was seen in both sexes and in all race subgroups. Metformin did not have a negative impact on body weight or lipid profile. Adverse events were similar to those reported in adults treated with metformin. CONCLUSION: Metformin was shown to be safe and effective for treatment of type 2 diabetes in pediatric patients.