Effects of Short-Term Varenicline Administration on Emotional and Cognitive Processing in Healthy,Non-Smoking Adults: A Randomized,Double-Blind,Study

Varenicline is an effective and increasingly prescribed drug for smoking cessation, but has been associated with depressive symptoms and suicidal behavior. However, it remains unclear whether those changes in mood and behavior are directly related to varenicline use, or caused by smoking cessation itself or reflects depression and suicidality rates in smokers, independent of treatment. To investigate the influence of varenicline on mood and behavior independent of smoking and smoking cessation, we assessed the effects of varenicline on emotional processing (a biomarker of depressogenic effects), emotion-potentiated startle reactivity, impulsivity (linked with suicidal behavior), and cognitive performance in non-smoking subjects. We used a randomized, double-blind design, in which we administered varenicline or placebo to healthy subjects over 7 days (0.5 mg/day first 3 days, then 1 mg/day). Cognitive and emotional processing was assessed by a battery of computerized tasks and recording of emotion-potentiated startle response. A total of 41 subjects were randomized, with 38 subjects included in the analysis. The varenicline group did not differ from placebo in terms of negative biases in emotional processing or mood. However, compared with placebo, the varenicline group scored higher on working and declarative memory. In conclusion, short-term varenicline use did not influence negative biases in emotional processing or impulsivity in non-smoking subjects, thereby not supporting direct depressogenic or suicidal risk behavior-inducing effects. In contrast, varenicline may have cognitive-enhancing effects.     

The Acute Effect of Loperamide on Ileostomy Output: A Randomized,Double‐Blinded,Placebo‐Controlled,Crossover Study

High stoma output is a common problem in patients with ileostomy and can lead to dehydration and electrolyte disturbances. The first drug of choice to reduce stoma output is often loperamide. The aim was to assess the acute effect of loperamide on (a) ileostomy output in g/day, (b) gastrointestinal transit time and (c) patient‐reported effects. A total of 12 patients completed this double‐blinded, randomized, placebo‐controlled, crossover study, consisting of a 3‐day treatment period with loperamide 12 mg/day or placebo followed by the reverse after a washout period of 5–7 days. Patients collected stoma output and noted food and fluid intake over 48 hr and swallowed a capsule with radiopaque markers for the determination of gastrointestinal transit time over 24 hr. At the end of the study, patients were asked to report their treatment sequence. Ileostomy output was significantly reduced during loperamide treatment (p < 0.02) with a median of 16.5% (range ?5% to 46%). Transit time was reduced significantly for the passage of 10% of the markers (p = 0.02), but not for 50% and 100% of the markers. Fifty‐eight per cent (N = 7) of the patients reported the correct treatment sequence (p = 0.41). Loperamide 12 mg/day reduced ileostomy output statistically significantly, but with varying effects among patients and without reaching the clinical significance of 20% set‐up by this study. Dose–response studies should be performed, and standard treatment doses of loperamide should be reassessed. The study was registered at ClinicalTrials.gov – NCT02266849.     

Haemodynamic Influences of Bisoprolol in Hypertensive Middle‐Aged Men: A Double‐Blind,Randomized, Placebo‐Controlled Cross‐Over Study

Treatment with beta‐blockers appears to show inferior reduction in central versus peripheral blood pressure. We aimed to examine simultaneous changes in central and peripheral blood pressure, vascular resistance, cardiac function and arterial stiffness during beta‐blockade. Haemodynamics were investigated after 3 weeks of bisoprolol treatment (5 mg/day) in a double‐blind, randomized, placebo‐controlled cross‐over trial in never‐treated 16 Caucasian males with grade I–II primary hypertension using continuous tonometric pulse wave analysis and whole‐body impedance cardiography. Bisoprolol decreased radial (134/80 versus 144/89 mmHg) and aortic blood pressure (122/80 versus 130/90 mmHg) and heart rate (57 versus 68 beats/min) when compared with placebo (p < 0.05 for all). Ejection duration (336 versus 316 ms) and stroke volume (109 versus 98 ml) were increased (p < 0.01 for all), while cardiac output was not significantly changed (6.2 versus 6.6 l/min). Bisoprolol decreased pulse wave velocity (7.8 versus 8.9 m/s, p < 0.001), but after adjustment for blood pressure, the decrease was not significant (8.16 versus 8.52 m/s, p = 0.464). The treatment reduced pulse pressure amplification from central to peripheral circulation (30 versus 38%, p = 0.002). No differences were observed in systemic vascular resistance, augmentation index, aortic characteristic impedance or total arterial stiffness after bisoprolol versus placebo. Bisoprolol decreased central and peripheral blood pressure and pulse wave velocity in male individuals with grade I to grade II hypertension. The decrease in pulse wave velocity was related to the antihypertensive effect. Reduced pulse pressure amplification indicates that peripheral blood pressure was reduced more efficiently than central blood pressure.     

The Effect of a Combination of Diclofenac and Methadone Applied as Gel in a Human Experimental Pain Model – A Randomized,Placebo‐controlled Trial

Pain involves responses in which both peripheral and central mechanisms contribute to the generation of pain. Pre‐clinical laboratory data have supported that a topical formulation of combined diclofenac and methadone (Diclometh) may alleviate local pain, and potentially, the side effect profile should be low. We hypothesized that antiallodynic and antihyperalgesic effects of Diclometh could be demonstrated in a human experimental pain model and that Diclometh would be safe to administer. Thus, the aims were as follows: (i) to compare two doses of Diclometh versus placebo; and (ii) to assess the safety profile of Diclometh. The study was a crossover, randomized, double‐blind, placebo‐controlled comparison of two doses of Diclometh gel (0.1% and 0.2%) administered topically in healthy participants. Nerve growth factor (NGF) and capsaicin intradermal injections were used as human pain models. Pressure stimulation, contact heat stimulation, hyperalgesia (pinprick stimulation) and allodynia (brush stimulation) to mechanical stimulation were performed in the area where capsaicin and NGF were injected. Side effects were recorded on a four‐point Likert scale. Twenty‐one men completed the study (mean age 26.14 ± 5.3). Diclometh 0.2% reduced the capsaicin‐induced dynamic mechanical allodynia compared to placebo (primary end‐point, p = 0.03). No other primary or secondary end‐points were found significantly different (all p > 0.05). All side effects were reported as mild with no differences between treatments (p = 0.15). Indication of antiallodynic effect of Diclometh 0.2% was found. Additionally, it was demonstrated that Diclometh was safe to use.     

Female Drinking From Young Adolescence to Middle Age: A Prospective Longitudinal Study

This study aimed at describing female drinking from young adolescence to middle age in a female Swedish community cohort (N = 238). Different aspects of alcohol habits were assessed at the ages of 14, 27, and 43, and the analyses focused on stability and change over this time. The results showed that large variations in alcohol habits over the life course were normally occurring phenomena. Furthermore, advanced drinking habits were neither necessary nor sufficient for developing heavy drinking or alcohol-related symptoms in adult age. The developmental patterns found in this study resembled the developmental patterns earlier described in male cohorts.     

Motivation to Quit Smoking in Substance Abusing Outpatients: Association with Anxiety and Depressive Symptoms

ABSTRACT

Objectives: This cross-sectional study examined the relationship between motivation to quit smoking and symptoms of depression and anxiety among 216 smokers seeking outpatient substance abuse treatment.

Methods: Subjects were administered the Beck Depression Inventory, the Beck Anxiety Inventory, a Likert scale of readiness to quit smoking, the Smoking Stages of Change Algorithm, the Addiction Severity Index and the Fagerstrom Test for Nicotine Dependence.

Results: There was a relationship between anxiety and motivation to quit smoking, with subjects reporting higher anxiety also reporting greater motivation to quit smoking. This relationship held up after controlling for the effects of substance use severity, race, gender, and cigarettes smoked per day. However, there was no relationship between depression and motivation to quit smoking.

Conclusions: This is one of the few studies examining the role of anxiety and depression on motivation to quit smoking among smokers attending a substance abuse treatment program. The findings help to clarify the relationship between mental health symptoms and motivation to quit smoking in a substance abuse treatment setting.     

Prenatal Tobacco Exposure and Brain Morphology: A Prospective Study in Young Children

It is well known that smoking during pregnancy can affect offspring health. Prenatal tobacco exposure has been associated with negative behavioral and cognitive outcomes in childhood, adolescence, and young adulthood. These associations between prenatal tobacco exposure and psychopathology in offspring could possibly be explained by the influence of prenatal tobacco exposure on brain development. In this prospective study, we investigated the association between prenatal tobacco exposure, behavioral and emotional functioning and brain morphology in young children. On the basis of age and gender, we matched 113 children prenatally exposed to tobacco with 113 unexposed controls. These children were part of a population-based study in the Netherlands, the Generation R Study, and were followed from pregnancy onward. Behavioral and emotional functioning was assessed at age 6 with the Child Behavior Checklist. We assessed brain morphology using magnetic resonance imaging techniques in children aged 6–8 years. Children exposed to tobacco throughout pregnancy have smaller total brain volumes and smaller cortical gray matter volumes. Continued prenatal tobacco exposure was associated with cortical thinning, primarily in the superior frontal, superior parietal, and precentral cortices. These children also demonstrated increased scores of affective problems. In addition, thickness of the precentral and superior frontal cortices was associated with affective problems. Importantly, brain development in offspring of mothers who quit smoking during pregnancy resembled that of nonexposed controls (no smaller brain volumes and no thinning of the cortex). Our findings suggest an association between continued prenatal tobacco exposure and brain structure and function in school-aged children.     

The Effect of Intraspinal Bupivacaine versus Levobupivacaine on the QTc Intervals during Caesarean Section: A Randomized,Double‐blind,Prospective Study

The aim of this study was to describe whether or not spinal anaesthesia with bupivacaine versus levobupivacaine has any effects on the QTc interval during caesarean section. Sixty healthy pregnant women scheduled for elective caesarean section were randomized to spinal anaesthesia with either bupivacaine (the bupivacaine group) or levobupivacaine (the levobupivacaine group). ECG recordings were performed prior to spinal anaesthesia at baseline (T1), 5 min. after spinal anaesthesia, but before uterine incision (T2), and after skin closure (T3). QT intervals were calculated and corrected with the patients' heart rate according to the Bazett formula. Compared with baseline values, mean maximum QTc intervals at T2 and T3 were significantly longer in the levobupivacaine group, but only at T2 in the bupivacaine group. In addition, compared with the bupivacaine group, the QTc maximum interval at T3 was significantly longer in the levobupivacaine group. At T2, the QTc maximum intervals were longer than baseline in both groups. By the end of the surgery, the prolongation of the QTc interval had disappeared in the bupivacaine group but not in the levobupivacaine group.     

Varenicline for Smoking Cessation in Schizophrenia: Safety and Effectiveness in a 12-Week, Open-Label Trial

OBJECTIVES: Varenicline was approved by the FDA in 2006. In 2009, based largely on case reports, the FDA issued a warning of possible adverse neuropsychiatric effects including depression and suicidal thoughts and behavior for varenicline and bupropion. Prospective trials of varenicline have not reported increased incidence of psychiatric adverse events other than sleep disturbance, but smokers with major mental illness have been excluded from large prospective trials of varenicline to date. We sought to evaluate the effect of a standard open-label 12-week varenicline trial on prospectively assessed safety and smoking outcomes in stable, treated adults with schizophrenia spectrum disorder and nicotine dependence. METHODS: One-hundred-and-twelve stable outpatients who smoked >10 cigarettes/day participated in a 12-week, open-label, smoking cessation trial of varenicline and weekly group cognitive behavioral therapy. Participants took varenicline for 4 weeks before attempting cessation. Trained raters collected safety and smoking outcome data weekly. RESULTS: Participants demonstrated improved psychotic symptoms, depressive symptoms and nicotine withdrawal symptoms from baseline to week 12 or early termination. At the end of 12 weeks open label treatment, the 14- and 28-day continuous abstinence rates were 47.3 and 34%, respectively. Expired CO declined significantly during treatment in those who did not achieve abstinence. CONCLUSIONS: This prospective study suggests that varenicline may be well-tolerated and effective for smoking cessation in combination with group CBT in stable outpatients with schizophrenia, a group with high rates of smoking and smoking-attributable morbidity and mortality.     

Crossing a Border for a Low-Cost,High-Risk Environment: Smoking Status and Excessive Drinking among Young Adults in Tijuana

This study examines the drinking and smoking behavior of 2,311 college-age adults traveling from San Diego, California, to Tijuana, Mexico (December 2006 to December 2008). We describe this Border sample's drinking history and smoking status and estimate multivariate models of evening drinking participation and, conditional on drinking, blood alcohol concentration. Noting limitations, we present implications for identifying young adults at high risk for alcohol and tobacco use, particularly females, and lay the foundation for further research examining young adults’ alcohol and tobacco use in reduced price scenarios.     

A Prospective Study of Quit Attempts from Alcohol Problems in a Community Sample: Modeling the Processes of Change

A prospective natural history study was conducted of problem drinkers who were thinking about quitting or reducing their alcohol consumption. Two primary constructs, cognitive appraisals and life events, were measured in a mailed-out baseline survey. A two month follow-up survey identified those who had made reductions in drinking. Regression analyses revealed some support for a cognitive appraisal explanation of change. Respondents who identified more anticipated costs of change were less likely to reduce their drinking. Plans for phase two of this research project - a one year follow-up to identify sustained change attempts - are discussed.     

Adverse Drug Reactions Causing Hospital Admissions in Childhood: A Prospective,Observational, Single‐Centre Study

Adverse drug reactions (ADRs) are common problems in both paediatric and adult medicine. The aim of this study was to prospectively identify the ADRs causing hospital admission of children and identification of the risk factors and involved drugs. The study was performed at the University Hospital in Olomouc, Czech Republic. All patients aged 19 years or under admitted to hospital were included in the study, and all admissions for ADRs were prospectively screened for a period of 9 months. Suspected ADRs were subsequently evaluated in detail, and causality assessment was undertaken to determine whether each suspected reaction was possible, probable or definite. The assessment of ADR causality was performed using the Naranjo algorithm, the Liverpool ADR Causality Assessment Tool and the Edwards and Aronson causality assessment method. During the study period, 2903 admissions were identified; of these, there were 143 admissions of patients with an oncological disease. Sixty‐four admissions (2.2%) were caused by an ADR. Anticancer chemotherapy accounted for 35% of the cases, followed by antibiotics (18%), immunosuppressants and vaccines (9% each). The use of different scoring systems does not lead to the differences in the numbers of ADR‐diagnosed patient but may result in differences in the determination of the level of certainty. ADRs cause a substantial proportion of children's hospital admissions. The majority of the ADR‐diagnosed patient affected the hematopoietic and gastrointestinal systems; the drugs most frequently involved were cytotoxic agents and antibiotics. The most important risk factors identified were female sex and oncological disease.     

Pharmacokinetic Interaction between Faldaprevir and Cyclosporine or Tacrolimus in Healthy Volunteers: A Prospective,Open‐Label,Fixed‐Sequence,Crossover Study

Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus. In this single‐centre, open‐label, fixed‐sequence, crossover study of 32 healthy adult male and female volunteers, subjects received either a single dose of cyclosporine (CsA) 50 mg (N = 16) or tacrolimus (TAC) 0.5 mg (N = 16), followed by a washout of at least 14 days. Each subject then received a loading dose of FDV 240 mg followed by 120 mg FDV once daily for 6 days. FDV 120 mg was then co‐administered with an additional single dose of CsA (50 mg) or TAC (0.5 mg), followed by an additional 6 days of FDV 120 mg once daily. Intensive blood sampling was performed to assess the PK interaction potential. Assessment of relative BA indicated that exposure to CsA co‐administered with FDV was similar to CsA alone. However, the AUC_τ,ss and C_max,ss of FDV were increased by 23% and 41%, respectively, when FDV was co‐administered with CsA. Exposure to TAC was slightly increased (AUC_0‐∞ increased by 27%, no change in C_max) when TAC was co‐administered with FDV. In contrast, exposure to FDV co‐administered with TAC was similar to FDV alone. No unexpected safety findings arose from the trial. The limitations of the study (use of single, low dose of TAC and CsA, and only healthy volunteers in the trial) are discussed.     

Reported Maternal Styles and Substance Use: A Cross-Sectional Study Among Educated Albanian Young Adults

The study explored a predictive model of substance use including perceived maternal parenting style, age and gender. Participants were 347 Albanian young adults (144 males and 203 females) aged 18 to 28 years. They completed the Parental Authority Questionnaire and the Adolescent Alcohol and Drug Involvement Scale. Gender, perceived authoritative maternal style, and age predicted a proportion of substance use involvement. Gender and perceived authoritative maternal style also predicted the proportion of young people at risk for substance use or abuse. Implications of the findings and limitations of the study are discussed.     

Anti-Anginal and Metabolic Effects of Carvedilol and Atenolol in Patients with Stable Angina Pectoris: A Prospective,Randomized, Parallel,Open-Label Study

Background

While recent guidelines have suggested the potential for beta-blockers as first-line agents in chronic stable angina, few data regarding comparative anti-anginal and metabolic effects between beta-blockers with and without vasodilating properties have been reported, particularly in patients with angina pectoris.

Objective

Our objective was to compare the anti-anginal and metabolic effects of carvedilol and atenolol in patients with stable angina pectoris.

Methods

A total of 89 patients (mean age 54.9 ± 9.3 years; male 53.9 %) with stable angina pectoris were randomly assigned to carvedilol (n = 43) or atenolol (n = 46). The subjects undertook an exercise treadmill test and completed the Seattle Angina Questionnaire (SAQ); metabolic parameters were measured at baseline and 6 months after treatment.

Results

The baseline characteristics of both groups were well balanced. Both carvedilol and atenolol significantly reduced heart rate from baseline (76 ± 11 to 66 ± 9 beat/min, p < 0.001; 74 ± 9 to 64 ± 9 beat/min, p < 0.001, respectively) with no significant changes in systolic and diastolic blood pressure. Improvement of time to ST-segment depression during the treadmill exercise and the SAQ scores for angina stability and frequency after 6 months of treatment were similar between groups. There was no significant change from baseline in the level of fasting glucose, insulin, or glycated hemoglobin in either group. However, total cholesterol and low-density lipoprotein cholesterol levels significantly reduced to a greater extent with carvedilol than with atenolol (?23 vs. ?10 and –38 vs. –24 %, respectively, p < 0.05 for both), although the rate of statin use was comparable. No changes were seen in high-density lipoprotein cholesterol and triglyceride levels after 6 months of treatment in both groups compared with baseline.

Conclusions

Both carvedilol and atenolol had a similar anti-anginal effect. Compared with atenolol, carvedilol might have more beneficial effects on lipid metabolism in patients with stable angina pectoris [ClinicalTrials.gov identifier: NCT02547597].

     

Efficacy and Safety of FospropofolFD Compared to Propofol When Given During the Induction of General Anaesthesia: A Phase II,Multi‐centre,Randomized, Parallel‐Group,Active‐Controlled,Double‐Blind,Double‐Dummy Study

The present phase II study aimed to compare the efficacy and safety of fospropofol disodium for injection (Fospropofol_FD) and propofol when given during the induction of general anaesthesia in patients scheduled for elective surgery. Fospropofol_FD is a water‐soluble prodrug of propofol. Approved by the Ethical Committee, 240 participants aged 18–65 years were equally randomly allocated to receive an intravenous bolus of Fospropofol_FD 20 mg/kg or propofol 2 mg/kg without any anaesthetic pre‐treatment. The primary efficacy end‐point was the sedation success rate within 5 min. after administering investigational drugs (the sedation success is defined as obtaining Modified Observer's Assessment of Alertness/Sedation scale score of 1). All the participants completed the induction and intubation within 25 min. after administration. The sedation success rates within 5 min. after administration of Fospropofol_FD 20 mg/kg and propofol 2 mg/kg were 94.50% versus 100% in the intention‐to‐treat population and 95.10% versus 100% in the per‐protocol population, respectively. The non‐inferiority test obtained a p‐value less than 0.025, and the lower limits of the one‐sided 97.5% confidence interval were more than ?0.09. This meant that Fospropofol_FD 20 mg/kg was considered non‐inferior to propofol 2 mg/kg for the primary efficacy end‐point. Compared with propofol 2 mg/kg, Fospropofol_FD 20 mg/kg had a slower sedation efficacy. No serious adverse events were observed in the two groups. The sedation success rate within 5 min. after administration of Fospropofol_FD 20 mg/kg was non‐inferior to propofol 2 mg/kg, and Fospropofol_FD 20 mg/kg can be used for the induction of general anaesthesia safely.