Discrepancy Between Fasting Flow-Mediated Dilation and Parameter of Lipids in Blood: A Randomized Exploratory Study of the Effect of Omega-3 Fatty Acid Ethyl Esters on Vascular Endothelial Function in Patients With Hyperlipidemia.

INTRODUCTION: Omega-3 fatty acid ethyl esters (omega-3), an eicosapentaenoic acid and docosahexaenoic acid preparation (Lotriga®, Takeda Pharmaceutical Company Limited), are approved in Japan to treat triglyceridemia. We investigated the effects of omega-3 on vascular endothelial function, measured by flow-mediated dilation (FMD). METHODS: Patients with dyslipidemia receiving 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors were randomized 1:1 to receive omega-3 at 2 g (QD) or 4 g (2 g BID) for 8 weeks. The primary end point was the change from baseline of fasting  %FMD in each treatment group. Secondary end points included the 4-h postprandial  %FMD and 4-h postprandial triglyceride (TG) level. RESULTS: Thirty-seven patients were randomized to receive omega-3 at 2 g (n = 18) or 4 g (n = 19). Mean fasting %FMD did not increase from baseline to week 8 in the 2-g group (- 1.2%) or 4-g group (- 1.3%). Mean 4-h postprandial %FMD did not change from baseline to week 8 in the 2-g group (0.0%), but increased in the 4-g group (1.0%). Mean 4-h postprandial TG level decreased by 34.7 mg/dl from baseline over week 8 in the 2-g group, with a significantly larger decrease in the 4-g group of 75.9 mg/dl (p < 0.001). No new safety concerns were identified. CONCLUSIONS: Fasting %FMD did not improve after 8 weeks of omega-3 treatment at 2 g or 4 g. After 8 weeks, 4-h postprandial TG levels showed improvement at both doses, with a greater reduction in the 4-g group. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02824432.

Omega-3 fatty acid ethyl esters improve low-density lipoprotein subclasses without increasing low-density lipoprotein-cholesterol levels: A phase 4, randomized study.

BACKGROUND AND AIMS: We aimed to investigate blood lipid and lipoprotein profiles in patients with dyslipidemia receiving hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) after 8 weeks of omega-3 fatty acid ethyl esters (Omega-3) treatment, using high-performance liquid chromatography with highly-sensitive gel filtration columns. METHODS: In this phase 4, randomized, open-label study, patients with dyslipidemia receiving statins were randomized 1:1 to Omega-3 treatment (oral Omega-3 2 g twice daily) or Control (no Omega-3). Primary endpoint was change in mean particle size of low-density lipoprotein (LDL) and small dense LDL (cholesterol monitoring) in the specific 20-lipoprotein fraction assay. Secondary endpoints included changes in lipids, apolipoproteins, and lipoprotein concentrations in fasting blood. Changes were compared between treatments using analysis of covariance, adjusted by baseline fasting triglycerides and age. RESULTS: Fifty-three patients were randomized (Omega-3, n = 24; Control, n = 29). The difference in LDL particle size between Omega-3 and Control groups was significant at week 8 (p = 0.0040). Differences in least squares mean change in concentration from baseline to week 8 between Omega-3 and Control groups were significant for total cholesterol (p = 0.0009), LDL-C (p = 0.0442), non-high-density lipoprotein cholesterol (p = 0.0009), and remnant lipoprotein-cholesterol (p = 0.0396). Differences were significant for apolipoproteins AI, AII, B, B-48, B-100, CII, CIII, and CII/III, but not apolipoprotein E. CONCLUSIONS: Significant increases in LDL particle sizes and significant decreases in blood lipid, lipoprotein and apolipoprotein concentrations were observed with Omega-3 compared with Control. Omega-3 may improve blood lipid profile and increase LDL particle size, resulting in an anti-atherogenic profile.

Treatment preference for weekly versus daily DPP-4 inhibitors in patients with type 2 diabetes mellitus: outcomes from the TRINITY trial.

Objective: To examine patient preference for treatment with the oral once-weekly dipeptidyl peptidase-4 inhibitor (DPP-4i), trelagliptin, and oral once-daily DPP-4i, alogliptin, administered for 8 weeks each in patients with type 2 diabetes mellitus prescribed a daily DPP-4i.Methods: In this randomized, open-label, two-way crossover study, patients received trelagliptin followed by alogliptin (T-A group) or alogliptin followed by trelagliptin (A-T group), for 8 weeks each (NCT03231709, JapicCTI-173662). Treatment preference was assessed using a standardized questionnaire in the overall population and by baseline characteristics. Other outcomes included patient satisfaction with diabetes treatment (assessed using the Diabetes Treatment Satisfaction Questionnaire [DTSQ]), hemoglobin A1c (HbA1c) levels after 8 weeks of treatment with each agent, and safety.Results: Sixty patients from two clinical sites were randomized 1:1 to T-A and A-T groups (each n = 30); baseline characteristics were similar between groups. After 16 weeks of treatment, 51.7% of patients preferred treatment with alogliptin compared with 30.0% selecting trelagliptin (p = .014); preference for alogliptin was consistently greater than for trelagliptin in the secondary analyses by baseline characteristics. DTSQ score and HbA1c levels were similar between treatments after 8 weeks of therapy. Both treatments demonstrated favorable safety and tolerability profiles.Conclusions: Patients expressed a significantly greater treatment preference for once-daily alogliptin than once-weekly trelagliptin, although patient satisfaction and HbA1c levels were similar across treatments. The decision to administer a once-weekly or once-daily DPP-4i is likely to depend on patient preference, patient-physician discussions, and treatment practices of the prescribing physician.

Randomized Multicenter Evaluation of Quality of Life and Treatment Satisfaction in Type 2 Diabetes Patients Receiving Once-Weekly Trelagliptin Versus a Daily Dipeptidyl Peptidase-4 Inhibitor.

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors are an established treatment in type 2 diabetes mellitus (T2DM). The objective of this study was to investigate differences in quality of life (QOL) and treatment satisfaction among treatment-naïve T2DM patients receiving once-weekly trelagliptin or a daily DPP-4 inhibitor. METHODS: In this multicenter, randomized, open-label, parallel-group, phase IV study conducted in Japan, 218 patients were randomized to trelagliptin 100 mg once weekly or a once- or twice-daily DPP-4 inhibitor for 12 weeks (NCT03014479; JapicCTI-173482). QOL and treatment satisfaction were assessed using the Diabetes Therapy-Related QOL (DTR-QOL) Questionnaire and Diabetes Treatment Satisfaction Questionnaire (DTSQ), respectively. The primary endpoint was change from baseline in DTR-QOL total score at week 12. Secondary endpoints included further analysis of the DTR-QOL and DTSQ components. Other endpoints included glycemic control, treatment adherence, and safety. RESULTS: The between-group difference in the change from baseline to week 12 in DTR-QOL total score was 2.418 (95% confidence interval - 1.546, 6.382; P = 0.2305). Analysis of the DTR-QOL and DTSQ results by subscales and stratification generally showed a numerical improvement with trelagliptin over daily DPP-4 inhibitors. QOL and treatment satisfaction improved with a reduction in frequency of concurrent and study drug dosing. Treatment adherence was > 97% for both groups. The effect of trelagliptin on glycemic control was similar to that seen with daily DPP-4 inhibitors. Trelagliptin and daily DPP-4 inhibitors were well-tolerated and demonstrated similar safety profiles. CONCLUSIONS: Once-weekly trelagliptin 100 mg administered for 12 weeks resulted in a numerically, but not statistically, greater improvement in QOL and treatment satisfaction versus daily DPP-4 inhibitors. The decision to administer once-weekly or daily DPP-4 inhibitor treatment is likely to depend on patient preferences and the treatment policies of physicians. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03014479) and JAPIC (JapicCTI-173482). FUNDING: Takeda Pharmaceutical Company Ltd.

Structural insights into the unique polylactate-degrading mechanism of Thermobifida alba cutinase.

Cutinases are enzymes known to degrade polyester-type plastics. Est119, a plastic-degrading type of cutinase from Thermobifida alba AHK119 (herein called Ta_cut), shows a broad substrate specificity toward polyesters, and can degrade substrates including polylactic acid (PLA). However, the PLA-degrading mechanism of cutinases is still poorly understood. Here, we report the structure complexes of cutinase with ethyl lactate (EL), the constitutional unit. From this complex structure, the electron density maps clearly showed one lactate (LAC) and one EL occupying different positions in the active site cleft. The binding mode of EL is assumed to show a figure prior to reaction and LAC is an after-reaction product. These complex structures demonstrate the role of active site residues in the esterase reaction and substrate recognition. The complex structures were compared with other documented complex structures of cutinases and with the structure of PETase from Ideonella sakaiensis. The amino acid residues involved in substrate interaction are highly conserved among these enzymes. Thus, mapping the precise interactions in the Ta_cut and EL complex will pave the way for understanding the plastic-degrading mechanism of cutinases and suggest ways of creating more potent enzymes by structural protein engineering.

Delayed Administration of BQ788, an ETB Antagonist, after Experimental Traumatic Brain Injury Promotes Recovery of Blood-Brain Barrier Function and a Reduction of Cerebral Edema in Mice.

Traumatic brain injury (TBI) is induced by immediate physical disruption of brain tissue, and causes death and disability. Studies on experimental TBI animal models show that disruption of the blood-brain barrier (BBB) underlies brain edema and neuroinflammation during the delayed phase of TBI. In neurological disorders, endothelin-1 (ET-1) is involved in BBB dysfunction and brain edema. In this study, the effect of ET antagonists on BBB dysfunction and brain edema were examined in a mouse focal TBI model using lateral fluid percussion injury (FPI). ET-1 and ETB receptors were increased at 2-7 days after FPI, which was accompanied by extravasation of Evans blue (EB) and brain edema. Repeated intracerebroventricular administration of BQ788 (15 nmol/day), an ETB antagonist, from 2 days after FPI promoted recovery of EB extravasation and brain edema, while FR 139317, an ETA antagonist, had no effect. Delayed intravenous administration of BQ788 also promoted recovery from FPI-induced EB extravasation and brain edema. While FPI caused decreases in claudin-5, occludin, and zonula occludens-1 proteins, BQ788 reversed FPI-induced reductions of them. Immunohistochemical observation of the cerebrum after FPI showed that ETB receptors are predominantly expressed in glial fibrillary acidic protein (GFAP)-positive astrocytes. BQ788 reduced FPI-induced increases in GFAP-positive astrocytes. GFAP-positive astrocytes produced vascular endothelial growth factor-A (VEGF-A) and matrix metalloproteinase-9 (MMP9). FPI-induced increases in VEGF-A and MMP-9 production were reversed by BQ788. These results suggest that ETB receptor antagonism during the delayed phase of focal TBI promotes recovery of BBB function and reduction of brain edema.

Octopamine and cooperation: octopamine regulates the disappearance of cooperative behaviours between genetically unrelated founding queens in the ant.

We investigated whether octopamine (OA) is associated with the disappearance of cooperation in Polyrhachis moesta ant queens. Queens of P. moesta facultatively found the colony with genetically unrelated queens. The founding queens perform frequent food exchange with these non-related queens and partake in cooperative brood rearing, whereas single colony queens exclude non-related queens via aggressive behaviour. Thus, aggression is a factor that reduces cooperation. Given that aggression is generally associated with brain OA in insects, we hypothesized that OA controls the behavioural change in cooperation in the ant queen, via an increase in aggression. To test this hypothesis, we compared the amounts of OA and related substances in the brain between founding and colony queens, and observed the interaction of founding queens following oral OA administration. The brain OA levels in colony queens were significantly higher than those in founding queens. Oral administration of OA to founding queens caused significantly less trophallaxis and allogrooming behaviour than in the control founding queens, but with no significant increase in aggression. These results suggest that OA promotes the disappearance of cooperation in founding queens of P. moesta. This is the first study to reveal the neuroendocrine mechanism of cooperation in ant queens.