Novel α7 nicotinic acetylcholine receptor modulators as potential antitussive agents.

A novel series of α7 nicotinic acetylcholine receptor (nAChR) modulators was designed and evaluated for antitussive activity in an in vivo guinea pig model of chemically induced cough. Compound 16 at all tested doses (9.5, 3 and 1 mg/kg) significantly (p < 0.01) reduced the cumulative number of coughs and showed similar results to a positive control (codeine at 30 mg/kg). Among three different administration routes (intraperitoneal, oral and inhalation), compound 16 exerted a significant antitussive effect in guinea pigs at an inhaled dose as low as 0.4 mg/kg (p < 0.05). α7 nAChR modulators may provide a novel, non-narcotic approach to therapy in patients with acute and chronic cough.

Impact of whole-body versus nose-only inhalation exposure systems on systemic, respiratory, and cardiovascular endpoints in a 2-month cigarette smoke exposure study in the ApoE-/- mouse model.

Cigarette smoking is one major modifiable risk factor in the development and progression of chronic obstructive pulmonary disease and cardiovascular disease. To characterize and compare cigarette smoke (CS)-induced disease endpoints after exposure in either whole-body (WB) or nose-only (NO) exposure systems, we exposed apolipoprotein E-deficient mice to filtered air (Sham) or to the same total particulate matter (TPM) concentration of mainstream smoke from 3R4F reference cigarettes in NO or WB exposure chambers (EC) for 2 months. At matching TPM concentrations, we observed similar concentrations of carbon monoxide, acetaldehyde, and acrolein, but higher concentrations of nicotine and formaldehyde in NOEC than in WBEC. In both exposure systems, CS exposure led to the expected adaptive changes in nasal epithelia, altered lung function, lung inflammation, and pronounced changes in the nasal epithelial transcriptome and lung proteome. Exposure in the NOEC caused generally more severe histopathological changes in the nasal epithelia and a higher stress response as indicated by body weight decrease and lower blood lymphocyte counts compared with WB exposed mice. Erythropoiesis, and increases in total plasma triglyceride levels and atherosclerotic plaque area were observed only in CS-exposed mice in the WBEC group but not in the NOEC group. Although the composition of CS in the breathing zone is not completely comparable in the two exposure systems, the CS-induced respiratory disease endpoints were largely confirmed in both systems, with a higher magnitude of severity after NO exposure. CS-accelerated atherosclerosis and other pro-atherosclerotic factors were only significant in WBEC.

A 6-month systems toxicology inhalation study in ApoE-/- mice demonstrates reduced cardiovascular effects of E-vapor aerosols compared with cigarette smoke.

Smoking cigarettes is harmful to the cardiovascular system. Considerable attention has been paid to the reduced harm potential of alternative nicotine-containing inhalable products such as e-cigarettes. We investigated the effects of E-vapor aerosols or cigarette smoke (CS) on atherosclerosis progression, cardiovascular function, and molecular changes in the heart and aorta of female apolipoprotein E-deficient (ApoE-/-) mice. The mice were exposed to aerosols from three different E-vapor formulations: 1) carrier (propylene glycol and vegetable glycerol), 2) base (carrier and nicotine), or 3) test (base and flavor) or to CS from 3R4F reference cigarettes for up to 6 mo. Concentrations of CS and base or test aerosols were matched at 35 µg nicotine/L. Exposure to CS, compared with sham-exposed fresh air controls, accelerated atherosclerotic plaque formation, whereas no such effect was seen for any of the three E-vapor aerosols. Molecular changes indicated disease mechanisms related to oxidative stress and inflammation in general, plus changes in calcium regulation, and altered cytoskeletal organization and microtubule dynamics in the left ventricle. While ejection fraction, fractional shortening, cardiac output, and isovolumic contraction time remained unchanged following E-vapor aerosols exposure, the nicotine-containing base and test aerosols caused an increase in isovolumic relaxation time similar to CS. A nicotine-related increase in pulse wave velocity and arterial stiffness was also observed, but it was significantly lower for base and test aerosols than for CS. These results demonstrate that in comparison with CS, E-vapor aerosols induce substantially lower biological responses associated with smoking-related cardiovascular diseases.NEW & NOTEWORTHY Analysis of key urinary oxidative stress markers and proinflammatory cytokines showed an absence of oxidative stress and inflammation in the animals exposed to E-vapor aerosols. Conversely, animals exposed to conventional cigarette smoke had high urinary levels of these markers. When compared with conventional cigarette smoke, E-vapor aerosols induced smaller atherosclerotic plaque surface area and volume. Systolic and diastolic cardiac function, as well as endothelial function, were further significantly less affected by electronic cigarette aerosols than conventional cigarette smoke. Molecular analysis demonstrated that E-vapor aerosols induce significantly smaller transcriptomic dysregulation in the heart and aorta compared with conventional cigarette smoke.

A longitudinal examination of the frequency and correlates of self-reported neurobehavioural disability following stroke.

PURPOSE: To determine the frequency, impact, and factors associated with self-reported neurobehavioural disability (NBD) in individuals with stroke. A secondary aim was to examine the course of self-reported NBD over time and associations with outcomes. METHODS: Eighty-seven participants admitted for inpatient rehabilitation post-stroke completed the St Andrew's-Swansea Neurobehavioural Outcome Scale. Demographic and stroke details and measures of functional disability, cognitive impairment, mood, and self-rated impact of NBD symptoms were completed. Twenty-seven participants and 19 close-others were reassessed three to six months following discharge. RESULTS: Overall reporting of neurobehavioural problems was infrequent. The domains of interpersonal and cognitive difficulties were the most commonly identified but were still only reported occasionally. However, even mild NBD was significantly correlated with negative impact. Greater self-reported NBD was significantly correlated with greater functional dependence, anxiety, and depression during inpatient rehabilitation. Self-reports of NBD remained stable over time and, at follow-up, was significantly correlated with depressive symptoms both in participants with stroke and close-others. CONCLUSIONS: In survivors of stroke, self-report of NBD is associated with poor outcomes in function, anxiety, and depression. These findings highlight the importance of routine and comprehensive assessment and intervention to manage NBD following stroke.IMPLICATIONS FOR REHABILITATIONDespite relatively infrequent self-reporting, presence of NBD remained stable across a six month follow-up period following rehabilitation which highlights the potential persistent nature of these difficulties.Even mild levels of self-reported NBD were associated with emotional distress in both stroke survivors and their significant others indicating a need for relevant interventions to support long-term outcomes.Routine screening for the presence of NBD is recommended to facilitate early detection and intervention to optimise post-stroke recovery.

Treating subclinical and clinical symptoms of insomnia with a mindfulness-based smartphone application: A pilot study.

BACKGROUND/OBJECTIVES: Emerging research suggests that face-to-face group mindfulness-based therapies are an effective intervention for insomnia. This pilot study examined the effectiveness of a mindfulness-based smartphone application for improving objectively-measured sleep, self-reported sleep, insomnia severity, pre-sleep arousal and daytime mood. METHOD: A community sample of 23 adults with subclinical to moderately severe symptoms of insomnia were randomized to either a mindfulness or progressive muscle relaxation (PMR) smartphone application for 40 or 60 days. Objective sleep outcomes assessed using actigraphy, and self-report measures of total wake time, cognitive and somatic pre-sleep arousal, and daytime positive and negative affect were assessed for 14 nights at baseline and post-intervention. Insomnia severity was recorded at baseline and post-intervention. RESULTS: A greater reduction in sleep onset latency was observed in the mindfulness group over time, relative to the PMR group. The mindfulness group also reported medium effect size improvements for sleep efficiency. No significant interaction effects were found for self-reported sleep measures, however, main effects of time were found for both groups for total wake time, insomnia severity, cognitive pre-sleep arousal, and daytime positive and negative affect. CONCLUSIONS: These preliminary findings suggest that both mindfulness and PMR smartphone applications have the potential to improve symptoms of insomnia. In particular, this mindfulness-based smartphone application may improve sleep onset latency and reduce the duration of night-awakenings. Further research exploring digital therapeutics as a self-help option for those with insomnia is needed.