Bioequivalence and Food Effect of Dapagliflozin/Saxagliptin/Metformin Extended-release Fixed-combination Drug Products Compared With Coadministration of the Individual Components in Healthy Subjects

PurposeFixed-combination drug products (FCDPs) for patients with type 2 diabetes mellitus (T2DM) may show efficacy comparable to their individual components (ICs) while improving adherence to treatment. This study evaluated the bioequivalence and safety of 2 dapagliflozin/saxagliptin/metformin extended-release (XR) FCDPs relative to their ICs: saxagliptin and dapagliflozin/metformin XR.MethodsThis randomized, open-label, single-dose, single-center crossover study was conducted in 84 healthy subjects aged 18–55 years. The primary objective was to evaluate the fed-state bioequivalence of a dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP and a dapagliflozin 10-mg/saxagliptin 5-mg/metformin 1000-mg XR FCDP relative to the ICs. Secondary objectives included the evaluation of the effect of food on the pharmacokinetic (PK) parameters of saxagliptin, dapagliflozin, and metformin in both FCDPs and characterization of the PK parameters of the active metabolite of saxagliptin, 5-hydroxy saxagliptin, in healthy subjects. PK parameters (AUC_0–∞, AUC_0–t, and C_max) were used to assess the bioequivalence of the 2 FCDPs with their ICs. The C_max and AUC_0–t of the study drugs were compared between female and male subjects to assess sex differences in exposure. Safety and tolerability of both FCDPs and ICs were also assessed with adverse events, vital signs (systolic and diastolic blood pressures and pulse rate), 12-lead ECG, physical examinations, and laboratory assessments.FindingsBoth dapagliflozin/saxagliptin/metformin XR FCDPs were bioequivalent to their ICs. For the dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP, the 90% CI for the geometric mean ratio of dapagliflozin C_max was slightly above the 80%–125% bioequivalence limit, which is unlikely to be clinically relevant. Food delayed the absorption of the study drugs in both FCDPs, which is unlikely to have a clinically relevant impact on efficacy. In both cohorts, exposure was higher in female subjects compared with male subjects, potentially due to the lower body weight of the female subjects. The safety profile and tolerability of the FCDPs were similar to those of their ICs, and no deaths or serious adverse events were reported.ImplicationsThese data support the use of the dapagliflozin/saxagliptin/metformin XR FCDP in patients with T2DM. ClinicalTrials.gov identifier: NCT03169959.     

Port Wine “Caviar”: Product Development,Sensorial Analysis,and Marketing Evaluation

The aim of this work was to develop a new product, port wine “caviar,” consisting of products based on red and white port wines used in different concentrations. Sample R+ consisted of red port wine at a concentration of 90%, sample R- was red port at 75%, sample W+ was white port at 90%, and sample W- was white port at 75%, all (m/m). The use of two types of port is related to different colors and the two concentrations related to the intensity. The results from the sensory analysis showed that the red port “caviar” at 90% was the best among the products tested, either in the preference test or in the evaluation of the individual characteristics. Furthermore, the market study revealed that this product can be successfully commercialized, particularly for the gourmet kitchen, which is one the main usages identified by the respondents.     

Toxicological characterization of ZnO nanoparticles in malignant and non‐malignant cells

The increasing usage of zinc oxide nanoparticles (ZnO‐NPs) in industrial applications as well as in consumer products raises concern regarding their potential adverse effects to a greater extend. Numerous studies have demonstrated toxic properties of NPs, however there is still a lack of knowledge concerning the underlying mechanisms. This study was designed to systematically investigate cytotoxicity, apoptosis, cell cycle alterations, and genotoxicity induced by ZnO‐NP. Moreover, it was an aim of the investigations to specify the diverse effects of nanoparticle exposure in malignant in comparison with non‐malignant cells. Therefore, human head and neck squamous cell carcinoma‐derived FaDu cells were incubated with 4–20 µg/ml of ZnO‐NPs for 1–48 hr and tested for cell viability, cell cycle alterations, apoptosis and caspase‐3 gene expression as a sensitive marker of molecular apoptotic processes with regard to time‐ and dose‐dependent effects. Human mesenchymal bone marrow stem cells were used as non‐malignant representatives to examine oxidative stress‐related genotoxicity. Results showed a significant reduction in cell viability as well as dose‐ and time‐dependent increase of apoptotic cells following nanoparticle treatment. Likewise, caspase‐3 gene expression enhanced already before first apoptotic cells were detectable. It could be observed that doses that were cytotoxic in tumor cells did not reduce viability in stem cells. However, the same concentrations already induced significant DNA damage. The findings of the study suggest to keep a more critical eye on the use of nanoparticles as anti‐cancer agents. Yet, additional in vivo studies are needed to assess safety concerns for consumers and patients. Environ. Mol. Mutagen. 59:247–259, 2018. © 2017 Wiley Periodicals, Inc.     

Association between underweight and overweight/obesity with oral health among independently living Brazilian elderly

ObjectivePoor oral status, represented by partial/complete tooth loss, may lead to changes in food choice, which may ultimately lead to underweight, overweight, or obesity. The aim of this study is to evaluate whether poor oral status is associated with underweight or overweight/obesity, regardless of physical activity.MethodsThis cross-sectional study is part of a major project, The Frailty in Brazilian Elderly Study, carried out in Campinas, Brazil (2008–2009). The sample was composed of 900 independent-living older adults. Complete data were available for 875 individuals including sociodemographic, self-reported amount of medications used and eating difficulty questionnaire, smoking habit, depressive symptoms, physical activity, oral examination, and anthropometric assessments according to the WHO criteria. Body mass index was used as an outcome. Multinomial logistic regression was adjusted for confounding variables.ResultsThe mean age of the sample was 72.7 y (±5.81) and the prevalence of edentulism was 47.7%. Edentate individuals not wearing dentures were more likely to be underweight [odds ratio (OR) = 3.94, 95% confidence interval (CI) 1.14–13.64] and overweight/obese (OR = 2.88, 95%CI 1.12–7.40). Males (OR = 0.56, 95%CI 0.36–0.85) and those not using medications (OR = 0.41 95%CI 0.24–0.70) were less likely to be overweight/obese. Individuals who smoke (OR = 2.62, 95%CI 1.26–5.44) were more likely to be underweight. Older individuals with family income between 3.1 and 5 minimum wage (OR = 1.69, 95%CI 1.00–2.87) were more likely to be overweight/obese.ConclusionTo our knowledge, this is one of the first studies associating poor oral health, represented by edentulism not rehabilitated with dentures, with unfavorable body mass, regardless of the two major confounders, physical activity and depression symptoms.     

Assessment of Oxidative, Inflammatory, and Fibrinolytic Biomarkers and DNA Strand Breakage in Hypercholesterolemia

The aim of this study was to assess the levels of oxidative, inflammatory, and fibrinolytic biomarkers as well as DNA strand breakage in hypercholesterolemic subjects. Fasting glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, uric acid, total protein, albumin, apolipoprotein (Apo) A, Apo B, advanced oxidation protein products (AOPP), increased ischemia-modified albumin (IMA), ―SH, NOx, IL-6, and D-dimer levels were assessed, and DNA strand breakage was evaluated using comet assay in 38 patients with hypercholesterolemia and 20 healthy controls. Total cholesterol, triglycerides, LDL cholesterol, Apo A, Apo B, AOPP, IMA, IL-6, and D-dimer concentrations were significantly higher in subjects with hypercholesterolemia. However, NOx and plasma ―SH group concentrations were lower in hypercholesterolemic subjects, while no significant differences were observed with respect to DNA strand breakage between the two groups. Hypercholesterolemia is related to oxidative stress and inflammation. Accordingly, AOPP concentration was higher in subjects with hypercholesterolemia, and we speculate that AOPP can reflect the enhancement of protein oxidation and inflammation.