Gliptin and GLP-1 analog treatment improves survival and vascular inflammation/dysfunction in animals with lipopolysaccharide-induced endotoxemia.

Dipeptidyl peptidase (DPP)-4 inhibitors are used to treat hyperglycemia by increasing the incretin glucagon-like peptide-1 (GLP-1). Previous studies showed anti-inflammatory and antiatherosclerotic effects of DPP-4 inhibitors. Here, we compared the effects of linagliptin versus sitagliptin and liraglutide on survival and vascular function in animal models of endotoxic shock by prophylactic therapy and treatment after lipopolysaccharide (LPS) injection. Gliptins were administered either orally or subcutaneously: linagliptin (5 mg/kg/day), sitagliptin (50 mg/kg/day) or liraglutide (200 µg/kg/day). Endotoxic shock was induced by LPS injection (mice 17.5-20 mg/kg i.p., rats 10 mg/kg/day). Linagliptin and liraglutide treatment or DPP-4 knockout improved the survival of endotoxemic mice, while sitagliptin was ineffective. Linagliptin, liraglutide and sitagliptin ameliorated LPS-induced hypotension and vascular dysfunction in endotoxemic rats, suppressed inflammatory parameters such as whole blood nitrosyl-iron hemoglobin (leukocyte-inducible nitric oxide synthase activity) or aortic mRNA expression of markers of inflammation as well as whole blood and aortic reactive oxygen species formation. Hemostasis (tail bleeding time, activated partial thromboplastin time) was impaired in endotoxemic rats and recovered under cotreatment with linagliptin and liraglutide. Finally, the beneficial effects of linagliptin on vascular function and inflammatory parameters in endotoxemic mice were impaired in AMP-activated kinase (alpha1) knockout mice. The improved survival of endotoxemic animals and other data shown here may warrant further clinical evaluation of these drugs in patients with septic shock beyond the potential improvement of inflammatory complications in diabetic individuals with special emphasis on the role of AMP-activated kinase (alpha1) in the DPP-4/GLP-1 cascade.

In vitro and in vivo characterization of a new organic nitrate hybrid drug covalently bound to pioglitazone.

BACKGROUND/AIMS: Organic nitrates represent a group of nitrovasodilators that are clinically used for the treatment of ischemic heart disease. The new compound CLC-3000 is an aminoethyl nitrate (AEN) derivative of pioglitazone, a thiazolidinedione antidiabetic agent combining the peroxisome proliferator-activated receptor γ agonist activity of pioglitazone with the NO-donating activity of the nitrate moiety. METHODS: In vitro and in vivo characterization was performed by isometric tension recording, platelet function, bleeding time and detection of oxidative stress. RESULTS: In vitro, CLC-3000 displayed more potent vasodilation than pioglitazone alone or classical nitrates. In vitro, some effects on oxidative stress parameters were observed. Authentic AEN or the AEN-containing linker CLC-1275 displayed antiaggregatory effects. In vivo treatment with CLC-3000 for 7 days did neither induce endothelial dysfunction nor nitrate tolerance nor oxidative stress. Acute or chronic administration of AEN increased the tail vein bleeding time in mice. CONCLUSION: In summary, the results of these studies demonstrate that CLC-3000 contains a vasodilative and antithrombotic activity that is not evident with pioglitazone alone, and that 7 days of exposure in vivo showed no typical signs of nitrate tolerance, endothelial dysfunction or other safety concerns in Wistar rats.

Evaluation of a population health strategy to reduce distracted driving: Examining all "Es" of injury prevention.

BACKGROUND: Cell phone use while driving (CPWD) increases the risk of crashing and is a major contributor to injuries and deaths. The objective of this study was to describe the evaluation of a multifaceted, evidence-based population health strategy for the reduction of distracted driving. METHODS: A multipronged campaign was undertaken from 2014 to 2016 for 16- to 44-year-olds, based on epidemiology, focused on personal stories and consequences, using the "Es" of injury prevention (epidemiology, education, environment, enforcement, and evaluation). Education consisted of distracted driving videos, informational cards, a social media AdTube campaign, and a movie theater trailer, which were evaluated with a questionnaire regarding CPWD attitudes, opinions, and behaviors. Spatial analysis of data within a geographic information system was used to target advertisements. A random sample telephone survey evaluated public awareness of the campaign. Increased CPWD enforcement was undertaken by police services and evaluated by ARIMA time series modeling. RESULTS: The AdTube campaign had a view rate of >10% (41,101 views), slightly higher for females. The top performing age group was 18- to 24-year-olds (49%). Our survey found 61% of respondents used handheld CPWD (14% all of the time) with 80% reporting our movie trailer made them think twice about future CPWD. A stakeholder survey and spatial analysis targeted our advertisements in areas of close proximity to high schools, universities, near intersections with previous motor vehicle collisions, high traffic volumes, and population density. A telephone survey revealed that 41% of the respondents were aware of our campaign, 17% from our print and movie theater ads and 3% from social media. Police enforcement campaign blitzes resulted in 160 tickets for CPWD. Following campaign implementation, there was a statistically significant mean decrease of 462 distracted driving citations annually (p = 0.001). CONCLUSION: A multifaceted, evidence-based population health strategy using the Es of injury prevention with interdisciplinary collaboration is a comprehensive method to be used for the reduction of distracted driving. LEVEL OF EVIDENCE: Therapeutic, level IV.

Our Sunshine place: A collective narrative and reflection on the experiences of a mental health crisis leading to an admission to a psychiatric inpatient unit.

Acute mental health inpatient units are complex environments where tensions between clinical and personal recovery can be amplified. The focus for mental health staff is often centred on providing clinical care, whereas from the patient perspective, the admission can represent a profound existential crisis. There are very few user-led accounts of their experiences of psychiatric inpatient unit. This project was developed in the traditions of Analytic Auto-Ethnography, a research methodology which provides a systematic process to reflect on our own experience while still producing trustworthy findings. Through this process, a collective narrative and critical reflection of a group of over 20 individuals with experiences of either providing or receiving care in an acute psychiatric inpatient unit was developed. The narrative developed shows that for some the hospital admission was a time of healing; for others, the inpatient unit represented an alien and unsafe environment, which accentuated the strangeness of the experiences of mental ill health. Common themes among the group were that of an overarching need to make sense of what happened leading up to the admissions and to come to terms with the potential impact of the illness on identity and future. This journey can be best described as a process of healing and moving towards 'wholeness'. Safety, connection, autonomy and control were identified as factors which either facilitated or hindered the process of successfully integrating the various experiences.