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1q21.1 hemizygous microdeletion is a copy number variant leading to eightfold increased risk of schizophrenia. In order to investigate biological alterations induced by this microdeletion, we generated a novel mouse model (Df(h1q21)/+) and characterized it in a broad test battery focusing on schizophrenia-related assays. Df(h1q21)/+ mice displayed increased hyperactivity in response to amphetamine challenge and increased sensitivity to the disruptive effects of amphetamine and phencyclidine hydrochloride (PCP) on prepulse inhibition. Probing of the direct dopamine (DA) pathway using the DA D1 receptor agonist SKF-81297 revealed no differences in induced locomotor activity compared to wild-type mice, but Df(h1q21)/+ mice showed increased sensitivity to the DA D2 receptor agonist quinpirole and the D1/D2 agonist apomorphine. Electrophysiological characterization of DA neuron firing in the ventral tegmental area revealed more spontaneously active DA neurons and increased firing variability in Df(h1q21)/+ mice, and decreased feedback reduction of DA neuron firing in response to amphetamine. In a range of other assays, Df(h1q21)/+ mice showed no difference from wild-type mice: gross brain morphology and basic functions such as reflexes, ASR, thermal pain sensitivity, and motor performance were unaltered. Similarly, anxiety related measures, baseline prepulse inhibition, and seizure threshold were unaltered. In addition to the central nervous system-related phenotypes, Df(h1q21)/+ mice exhibited reduced head-to tail length, which is reminiscent of the short stature reported in humans with 1q21.1 deletion. With aspects of both construct and face validity, the Df(h1q21)/+ model may be used to gain insight into schizophrenia-relevant alterations in dopaminergic transmission., published version, peerReviewed

Introduction The dopamine-type-1 receptor has been implicated in major depressive disorder (MDD) by clinical and preclinical evidence from neuroimaging, post-mortem and behavioral studies. To date, however, selective in vivo assessment of D1-receptors has been limited to the striatum in MDD-samples manifesting anger attacks. We employed the PET radioligand, [11C]NNC-112, to selectively assess D1-receptor binding in extrastriatal and striatal regions in a more generalized sample of MDD-subjects. Methods The [11C]NNC-112 nondisplaceable binding-potential (BPND) was assessed using PET in 18 unmedicated, currently-depressed subjects with MDD and 19 healthy controls, and compared between groups using MRI-based region-of-interest analysis. Results The mean D1-receptor BPND was reduced (14%) in the left middle caudate of the MDD group relative to control group (p

Rationale Whilst the FDA-approved anorectic, lorcaserin and various 5-hydroxytryptamine (5-HT)6 receptor antagonists reduce feeding, a direct assessment of their impact upon feeding behaviour is less clear. We therefore examined the action of lorcaserin and the clinical-stage developmental candidate 5-HT6 receptor antagonist, SB-742457, upon microstructural analysis of licking behaviour. Such analysis provides a rich source of information about the mechanisms controlling food intake. Objectives The objective of the present study was to gain insight into the influence upon feeding behaviour of the 5-HT2C receptor agonist, lorcaserin and the developmental 5-HT6 receptor antagonist, SB-742457. Methods The impact of lorcaserin and SB-742457 upon licking behaviour of non-deprived rats for a glucose solution was assessed using microstructural analysis. Results Lorcaserin (0.1–3.0 mg/kg) displayed a dose-dependent ability to reduce glucose consumption via reduction in the number of bouts of licking. A similar action was evident with SB-742457, but only at the lowest dose tested (3.0 mg/kg). Conclusions The behavioural actions of both lorcaserin and SB-742457 demonstrate they directly promote satiety.

Objective To identify the predictive factors for responders to tolvaptan, a novel vasopressin type 2 receptor antagonist for fluid management after cardiovascular surgery. Methods Between January 2013 and May 2014, 113 patients were treated with tolvaptan for fluid management after cardiovascular surgery. As indicators for the effects of tolvaptan, change in bodyweight during the tolvaptan administration period and correlations with perioperative factors were assessed. Thirty-one patients were administered tolvaptan at the first day after surgery (early tolvaptan group). In this group, urine volume during the 6 h before the initial tolvaptan administration was compared with that at 6 h after administration. Results For all the patients, the change in bodyweight during the tolvaptan administration period significantly correlated with pre-operative serum creatinine (r = 0.19, p = 0.04) and albumin levels before tolvaptan administration (r = −0.29, p = 0.002). In the early tolvaptan group, the ratio of urine volume at 6 h before and 6 h after the initial tolvaptan administration significantly correlated with the pre-operative serum creatinine level (r = 0.43, p = 0.02), the serum albumin level before tolvaptan administration (r = −0.50, p = 0.004), and change in bodyweight (r = 0.38, p = 0.03). Conclusions In patients undergoing cardiovascular surgery, deteriorating renal function, increased bodyweight, and hypoalbuminemia were found to be predictive factors for responders to tolvaptan for postoperative fluid management.

Rationale Interval timing in the free-operant psychophysical procedure is sensitive to the monoamine-releasing agent d-amphetamine, the D2-like dopamine receptor agonist quinpirole, and the D1-like agonist 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzepine (SKF-81297). The effect of d-amphetamine can be antagonized by selective D1-like and 5-HT2A receptor antagonists. It is not known whether d-amphetamine’s effect requires an intact 5-hydroxytryptamine (5-HT) pathway. Objective The objective of this study was to examine the effects of d-amphetamine, quinpirole, and SKF-81297 on timing in intact rats and rats whose 5-hydroxytryptaminergic (5-HTergic) pathways had been ablated. Materials and methods Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50-s trials in which reinforcement was provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic functions were fitted to the data for derivation of timing indices (T50, time corresponding to %B = 50%; Weber fraction). The effects of d-amphetamine (0.4 mg kg−1 i.p.), quinpirole (0.08 mg kg−1 i.p.), and SKF-81297 (0.4 mg kg−1 s.c.) were compared between intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. Results Quinpirole and SKF-81297 reduced T50 in both groups; d-amphetamine reduced T50 only in the sham-lesioned group. The lesion reduced 5-HT levels by 80%; catecholamine levels were not affected. Conclusions d-Amphetamine’s effect on performance in the free-operant psychophysical procedure requires an intact 5-HTergic system. 5-HT, possibly acting at 5-HT2A receptors, may play a ‘permissive’ role in dopamine release.

Background Patients with hypoalbuminemia often fail to respond to increased doses of loop diuretics. We therefore performed a post hoc analysis to investigate the pharmacological action of tolvaptan and whether it is dependent on the serum albumin level. Methods This analysis was based on four previous clinical trials of tolvaptan in patients with liver cirrhosis who exhibited insufficient response to conventional diuretics. We analyzed the correlation between the change in the initial 24-h cumulative urine volume from baseline and the serum albumin level at baseline, and assessed potential predictive factors of response to tolvaptan. Results The correlation coefficient was 0.029 in the placebo group and −0.112 in the 7.5 mg tolvaptan group of patients with liver cirrhosis. Administration of tolvaptan provoked a stable response regardless of the serum albumin level. Tolvaptan use was identified as a significant predictor of pharmacological action, and was shown to change the initial urine volume by 885 mL (P

INTRODUCTION: The aim of this article is to discuss methods used to analyze health-related quality of life (HRQoL) data from randomized controlled trials (RCTs) for decision analytic models. The analysis presented in this paper was used to provide HRQoL data for the ivabradine health technology assessment (HTA) submission in chronic heart failure. METHODS: We have used a large, longitudinal EuroQol five-dimension questionnaire (EQ-5D) dataset from the Systolic Heart Failure Treatment with the I f Inhibitor Ivabradine Trial (SHIFT) (clinicaltrials.gov: NCT02441218) to illustrate issues and methods. HRQoL weights (utility values) were estimated from a mixed regression model developed using SHIFT EQ-5D data (n = 5313 patients). The regression model was used to predict HRQoL outcomes according to treatment, patient characteristics, and key clinical outcomes for patients with a heart rate ≥75 bpm. RESULTS: Ivabradine was associated with an HRQoL weight gain of 0.01. HRQoL weights differed according to New York Heart Association (NYHA) class (NYHA I-IV, no hospitalization: standard care 0.82-0.46; ivabradine 0.84-0.47). A reduction in HRQoL weight was associated with hospitalizations within 30 days of an HRQoL assessment visit, with this reduction varying by NYHA class [-0.07 (NYHA I) to -0.21 (NYHA IV)]. CONCLUSION: The mixed model explained variation in EQ-5D data according to key clinical outcomes and patient characteristics, providing essential information for long-term predictions of patient HRQoL in the cost-effectiveness model. This model was also used to estimate the loss in HRQoL associated with hospitalizations. In SHIFT many hospitalizations did not occur close to EQ-5D visits; hence, any temporary changes in HRQoL associated with such events would not be captured fully in observed RCT evidence, but could be predicted in our cost-effectiveness analysis using the mixed model. Given the large reduction in hospitalizations associated with ivabradine this was an important feature of the analysis. FUNDING: The Servier Research Group.

Background Tolvaptan has been approved in Japan for the treatment of hepatic edema. An important consideration in providing a clinical benefit to patients with liver cirrhosis is the improvement of ascites-related clinical symptoms. In the present post hoc analysis, we aimed to identify factors that were predictive of the potency of tolvaptan, and to examine the relationship between changes in initial urine volume and improvement in ascites-related clinical symptoms. Methods This post hoc analysis was based on three previous phase 2 and 3 clinical trials of tolvaptan in patients with liver cirrhosis. Predictive factors associated with a change in initial urine volume were identified. A change of ≥500 mL from baseline confirmed the pharmacological action of tolvaptan treatment. The relationship between the change in initial urine volume and improvement in ascites-related clinical symptoms was also examined. Results A total of 152 patients were enrolled in this study. Body weight and BUN were identified as predictive parameters. Among patients with a change in initial urine volume of ≥500 mL, 75 % demonstrated improvement in ascites-related clinical symptoms, while no improvement was seen in those with a change of

The syndrome of inappropriate antidiuresis is often undertreated with most patients discharged with persistent hyponatraemia. This study tested the hypothesis that an endocrine input is superior to routine care in correcting hyponatraemia and can improve patient outcomes. This single-centre prospective-controlled intervention study included inpatients admitted at a UK teaching hospital, with serum sodium ≤ 127 mmol/l, due to syndrome of inappropriate antidiuresis over a 6-month period. The prospective intervention group (18 subjects with mean serum sodium 120.7 mmol/l) received prompt endocrine input, while the historical control group (23 patients with mean serum sodium 124.1 mmol/l) received routine care. The time needed for serum sodium increase ≥ 5 mmol/l was the primary endpoint. The intervention group achieved serum sodium rise by ≥5 mmol/l in 3.5 vs. 7.1 days in the control group (P = 0.005). In the intervention group, the mean total serum sodium increase was 12 mmol/l with only 5.8 % of patients discharged with serum sodium

The synthesis of ruthenium(II) and osmium(II) arene complexes with the closely related indolo[3,2-c]quinolines N-(11H-indolo[3,2-c]quinolin-6-yl)-ethane-1,2-diamine (L1) and N′-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (L2) and indolo[3,2-d]benzazepines N-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-ethane-1,2-diamine (L3) and N′-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-N,N-dimethylethane-1,2-diamine (L4) of the general formulas [(η6-p-cymene)MII(L1)Cl]Cl, where M is Ru (4) and Os (6), [(η6-p-cymene)MII(L2)Cl]Cl, where M is Ru (5) and Os (7), [(η6-p-cymene)MII(L3)Cl]Cl, where M is Ru (8) and Os (10), and [(η6-p-cymene)MII(L4)Cl]Cl, where M is Ru (9) and Os (11), is reported. The compounds have been comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, spectroscopy (IR, UV–vis, and NMR), and X-ray crystallography (L1·HCl, 4·H2O, 5, and 9·2.5H2O). Structure–activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells as well as cyclin-dependent kinase (cdk) inhibition and DNA intercalation in cell-free settings have been established. The metal-free indolo[3,2-c]quinolines inhibit cancer cell growth in vitro, with IC50 values in the high nanomolar range, whereas those of the related indolo[3,2-d]benzazepines are in the low micromolar range. In cell-free experiments, these classes of compounds inhibit the activity of cdk2/cyclin E, but the much higher cytotoxicity and stronger cell cycle effects of indoloquinolines L1 and 7 are not paralleled by a substantially higher kinase inhibition compared with indolobenzazepines L4 and 11, arguing for additional targets and molecular effects, such as intercalation into DNA. Electronic supplementary material The online version of this article (doi:10.1007/s00775-010-0653-y) contains supplementary material, which is available to authorized users.

Introduction The efficacy and safety of the once-daily topical ophthalmic solutions, alcaftadine 0.25% and olopatadine 0.2%, in preventing ocular itching associated with allergic conjunctivitis were evaluated. Methods Pooled analysis was conducted of two double-masked, multicenter, active- and placebo-controlled studies using the conjunctival allergen challenge (CAC) model of allergic conjunctivitis. Subjects were randomized 1:1:1 to receive alcaftadine 0.25%, olopatadine 0.2%, or placebo. The primary efficacy measure was subject-evaluated mean ocular itching at 3 min post-CAC and 16 h after treatment instillation. Secondary measures included ocular itching at 5 and 7 min post-CAC. Ocular itch was determined over all time points measured (3, 5, and 7 min) post-CAC and the proportion of subjects with minimal itch (itch score

Rationale Conditioned behavioral responses to discrete drug-associated cues can be modulated by the environmental context in which those cues are experienced, a process that may facilitate relapse in humans. Rodent models of drug self-administration have been adapted to reveal the capacity of contexts to trigger drug seeking, thereby enabling neurobiological investigations of this effect. Objectives We tested the hypothesis that dopamine transmission in the nucleus accumbens, a neural structure that mediates reinforcement, is necessary for context-induced reinstatement of responding for ethanol-associated cues. Methods Rats pressed one lever (active) for oral ethanol (0.1 ml; 10% v/v) in operant conditioning chambers distinguished by specific visual, olfactory, and tactile contextual stimuli. Ethanol delivery was paired with a discrete (4 s) light-noise stimulus. Responses on a second lever (inactive) were not reinforced. Behavior was then extinguished by withholding ethanol but not the discrete stimulus in a different context. Reinstatement, expressed as elevated responding for the discrete stimulus without ethanol delivery, was tested by placing rats into the prior self-administration context after administration of saline or the dopamine D1 receptor antagonist, SCH 23390 (0.006, 0.06, and 0.6 μg/side), into the nucleus accumbens core or shell. Results Compared with extinction responding, active lever pressing in saline-pretreated rats was enhanced by placement into the prior ethanol self-administration context. SCH 23390 dose-dependently reduced reinstatement after infusion into the core or shell. Conclusion These findings suggest a critical role for dopamine acting via D1 receptors in the nucleus accumbens in the reinstatement of responding for ethanol cues triggered by placement into an ethanol-associated context.

Heart rate is an important contributor in the pathophysiology of both coronary artery disease (CAD) and heart failure (HF). Ivabradine is an anti-anginal and anti-ischaemic agent, which selectively and specifically inhibits the I f current in the sino-atrial node and provides pure heart rate reduction without altering other cardiac parameters, including conduction, and without directly affecting other haemodynamic parameters. It is approved for the treatment of CAD and HF. This article summarises the pharmacological properties, pharmacokinetics, clinical efficacy and tolerability of ivabradine in the treatment of CAD and HF, and presents evidence demonstrating that the pharmacological and clinical properties and clinical efficacy of ivabradine make it an important therapeutic choice for patients with stable CAD or HF. The positive effect of ivabradine on angina pectoris symptoms and its ability to reduce myocardial ischemia make it an important agent in the management of patients with stable CAD or chronic HF. Further studies are underway to add to the already robust evidence of ivabradine for the prevention of cardiovascular events in patients with CAD but without clinical HF. The SIGNIFY (Study assessInG the morbidity-mortality beNefits of the I f inhibitor ivabradine in patients with coronarY artery disease) trial includes patients with stable CAD and an LVEF above 40 %, with no clinical sign of HF, and is investigating the long-term effects (over a period of 48 months) of ivabradine in a large study population. So far, this study has included more than 19,000 patients from 51 countries.

Histamine H3 receptor blockade may enhance lesion remyelination in multiple sclerosis (MS). The efficacy (using a magnetic resonance imaging marker of myelination, magnetisation transfer ratio [MTR]), safety and pharmacokinetics of GSK239512, a potent and brain penetrant H3 receptor antagonist/inverse agonist on lesion remyelination in relapsing-remitting MS (RRMS) were assessed. This was a phase II, randomised, parallel-group, placebo-controlled, double-blind (sponsor-unblinded), international, multicentre study (NCT01772199). Patients aged 18–50 with RRMS, receiving intramuscular interferon-β1a or glatiramer acetate, were randomised 1:1 to once-daily oral GSK239512 or placebo, up-titrated over 4–5 weeks to a maximum tolerable dose up to 80 µg and maintained until Week 48. The co-primary endpoints were mean changes in post-lesion MTR in gadolinium-enhanced (GdE) or Delta-MTR defined lesions from pre-lesion values. Adverse events (AE) and withdrawals were monitored. Of the 131 patients randomised, 114 patients completed the study (GSK239512, n = 51; placebo, n = 63) and 27 (GSK239512) and 28 (placebo) patients contributed lesions to the primary analysis. GSK239512 was associated with positive effect sizes of 0.344 [90% confidence interval (CI) 0.018, 0.671] and 0.243 (90% CI −0.112, 0.598) for adjusted mean changes in the normalised MTR for GdE and Delta-MTR lesions, respectively. The overall incidence of AEs was similar between GSK239512 and placebo during the treatment phase although some AEs including insomnia were more common with GSK239512, particularly during the titration period. A small but positive effect of GSK239512 on remyelination was observed. MTR assessment represents a promising method for detecting lesion remyelination in RRMS. Electronic supplementary material The online version of this article (doi:10.1007/s00415-016-8341-7) contains supplementary material, which is available to authorized users.

Background Nicotine replacement therapy (NRT) and varenicline are both effective in helping smokers quit. There is growing interest in combining the two treatments to improve treatment outcomes, but no experimental data exist on whether this is efficacious. This double-blind randomised controlled trial was designed to evaluate whether adding nicotine patches to varenicline improves withdrawal relief and short-term abstinence rates. Methods 117 participants seeking help to stop smoking were randomly allocated to varenicline plus placebo patch or varenicline plus nicotine patch (15 mg/16 hour). Varenicline use commenced one week prior to the target quit date (TQD), patch use started on the TQD. Ratings of urges to smoke and cigarette withdrawal symptoms were collected weekly over 4 weeks post-TQD. Medication use and smoking status were established at 1, 4 and 12 weeks. Participants lost to follow-up were included as continuing smokers. Results 92% of participants used both medications during the first week after the TQD. The combination treatment generated no increase in nausea or other adverse effects. It had no overall effect on urges to smoke or on other withdrawal symptoms. The combination treatment did not improve biochemically validated abstinence rates at 1 week and 4 weeks post-TQD (69% vs 59%, p=0.28 and 60% vs 59%, p=0.91, in the nicotine patch and placebo patch arm, respectively), or self reported abstinence rates at 12 weeks (36% vs. 29%, p=0.39, NS). Conclusions The efficacy of varenicline was not enhanced by the addition of nicotine patches, although further trials would be useful to exclude the possibility of type II error. Trial Registration Clinicaltrials.gov Registration Number: NCT01184664

Background Tobacco smoking remains the leading modifiable health hazard and varenicline is amongst the most popular pharmacological options for smoking cessation. The purpose of this study is to critically evaluate the extent of gastrointestinal adverse effects of varenicline when used at maintenance dose (1 mg twice a day) for smoking cessation. Methods We conducted a meta-analysis of randomised controlled trials published in PUBMED and EMBASE according to the PRISMA guidelines. Selected studies satisfied the following criteria: (i) duration of at least 6 weeks, (ii) titrated dose of varenicline for 7 days then a maintenance dose of 1 mg twice-per-day, (iii) randomized placebo-controlled design, (iv) extractable data on adverse event - nausea, constipation or flatulence. Data was synthesized into pooled odd ratios (OR) basing on random effects model. Quality of studies was also rated as per Cochrane risk-of-bias assessment. Number need to harm (NNH) was calculated for each adverse effect. Results 98 potentially relevant studies were identified, 12 of which met the final inclusion criteria (n = 5114). All 12 studies reported adverse events on nausea, which led to an OR of 4.45 (95% CI = 3.79-5.23, p < 0.001; I2 = 0.06%, CI = 0%-58.34%) and a NNH of 5. Eight studies (n = 3539) contain data on constipation pooled into an OR of 2.45 (95% CI = 1.61-3.72, p < 0.001; I2 = 34.09%, CI = 0%-70.81%) with a NNH of 24. Finally, five studies (n = 2516) reported adverse events of flatulence, which pooled an OR of 1.74 (95% CI = 1.23-2.48, p = 0.002; I2 = 0%, CI = 0%- 79.2%) with a NNH of 35. Conclusions Use of varenicline at maintenance dose of 1 mg twice a day for longer than 6 weeks is associated with adverse gastrointestinal effects. In realistic terms, for every 5 treated subjects, there will be an event of nausea, and for every 24 and 35 treated subjects, we will expect an event of constipation and flatulence respectively. Family physicians should counsel patients of such risks accordingly during their maintenance therapy with varenicline.

Background Liver injury due to prescription and nonprescription medications is an expanding public health concern in the United States, with drug-induced liver injury (DILI) being the single most common reason for regulatory actions instituted by the Food and Drug Administration against certain medications and supplements. Case presentation A 69-year-old Latino man was referred to Hepatology Clinic for urgent evaluation of new onset jaundice, nausea and fatigue associated with a >40-fold increase in his transaminase levels and elevated INR and alkaline phosphatase. The patient had received a new prescription for varenicline to aid with smoking cessation approximately 3 weeks prior to his evaluation in Hepatology Clinic. Within 5 days of starting the varenicline, the patient developed new onset of nausea, vomiting, malaise and deep jaundice. The varenicline was discontinued on day 5 by the patient. Hepatologic evaluation revealed no evidence of acute viral hepatitis, autoimmune, metabolic or alcohol-related liver disorders. The patient’s past medical history was notable, however, for chronic hepatitis C. His liver enzymes and synthetic function completely normalized 9 weeks after discontinuation of the varenicline. Conclusion This report represents the second documented cases of drug-induced liver injury related to varenicline therapy, highlighting the need for clinician awareness regarding potential hepatotoxicity of varenicline, particularly among patients with pre-existing liver disease.

Background Migraine with aura is a complex neurological disorder modeled in animals by cortical spreading depression. It is less usual to find complete animal models for the disease so any opportunity to test a human effect back at the bench is welcome. Findings We report the case of a 24 year old woman who developed new onset episodic migraine with visual aura shortly after treatment initiation with the If ion channel blocker ivabradine for frequency control in hypertrophic cardiomyopathy. We studied whether ivabradine could alter cortical spreading depression in a suitable animal model. Sixteen rats received either ivabradine or saline, and the number of depolarization shifts and blood flow changes induced by cortical spreading depression were measured in both groups. No significant differences between the ivabradine and saline group were detected. Conclusions Ivabradine is an interesting substance since it is known to produce migraine-like phosphenes frequently and the patient we report developed de novo migraine with aura. However, we were unable to demonstrate that the drug influences the susceptibility of the brain to cortical spreading depression with acute administration. The combined data show the relationship of migraine aura to cortical spreading depression may have some nuances yet to be identified.

Background Smoking remains the leading preventable cause of premature deaths. Several pharmacological interventions now exist to aid smokers in cessation. These include Nicotine Replacement Therapy [NRT], bupropion, and varenicline. We aimed to assess their relative efficacy in smoking cessation by conducting a systematic review and meta-analysis. Methods We searched 10 electronic medical databases (inception to Sept. 2006) and bibliographies of published reviews. We selected randomized controlled trials [RCTs] evaluating interventions for smoking cessation at 1 year, through chemical confirmation. Our primary endpoint was smoking cessation at 1 year. Secondary endpoints included short-term smoking cessation (~3 months) and adverse events. We conducted random-effects meta-analysis and meta-regression. We compared treatment effects across interventions using head-to-head trials and when these did not exist, we calculated indirect comparisons. Results We identified 70 trials of NRT versus control at 1 year, Odds Ratio [OR] 1.71, 95% Confidence Interval [CI], 1.55–1.88, P =< 0.0001). This was consistent when examining all placebo-controlled trials (49 RCTs, OR 1.78, 95% CI, 1.60–1.99), NRT gum (OR 1.60, 95% CI, 1.37–1.86) or patch (OR 1.63, 95% CI, 1.41–1.89). NRT also reduced smoking at 3 months (OR 1.98, 95% CI, 1.77–2.21). Bupropion trials were superior to controls at 1 year (12 RCTs, OR1.56, 95% CI, 1.10–2.21, P = 0.01) and at 3 months (OR 2.13, 95% CI, 1.72–2.64). Two RCTs evaluated the superiority of bupropion versus NRT at 1 year (OR 1.14, 95% CI, 0.20–6.42). Varenicline was superior to placebo at 1 year (4 RCTs, OR 2.96, 95% CI, 2.12–4.12, P =< 0.0001) and also at approximately 3 months (OR 3.75, 95% CI, 2.65–5.30). Three RCTs evaluated the effectiveness of varenicline versus bupropion at 1 year (OR 1.58, 95% CI, 1.22–2.05) and at approximately 3 months (OR 1.61, 95% CI, 1.16–2.21). Using indirect comparisons, varenicline was superior to NRT when compared to placebo controls (OR 1.66, 95% CI 1.17–2.36, P = 0.004) or to all controls at 1 year (OR 1.73, 95% CI 1.22–2.45, P = 0.001). This was also the case for 3-month data. Adverse events were not systematically different across studies. Conclusion NRT, bupropion and varenicline all provide therapeutic effects in assisting with smoking cessation. Direct and indirect comparisons identify a hierarchy of effectiveness.

Background Nemaline myopathy (NM) is a rare congenital myopathy characterized by muscle weakness, hypotonia and the presence in muscle fibers of inclusions known as nemaline bodies and a wide spectrum of clinical phenotypes, ranging from severe forms with neonatal onset to asymptomatic forms. The adult-onset form is heterogeneous in terms of clinical presentation and disease progression. Cardiac involvement occurs in the minority of cases and little is known about medical management in this subgroup of NM patients. We report a rare case of heart failure (HF) in a patient with adult-onset NM in whom ivabradine proved to be able to dramatically improve the clinical picture. Case presentation We report a case of a 37-year-old man with adult-onset NM, presenting with weakness and hypotonia of the proximal limb muscles and shoulder girdle, severely limiting daily activities. He developed progressive HF over a period of 6 months while attending a rehabilitation program, with reduced left ventricular ejection fraction (LVEF = 20%), manifested by dyspnea and signs of systemic congestion. The patient was started HF therapy with enalapril, carvedilol, spironolactone and loop diuretics. Target HF doses of these drugs (including carvedilol) were not reached because of symptomatic hypotension causing a high resting heart rate (HR) ≥70 beats per minute (bpm). Further deterioration of the clinical picture occurred with several life-threatening arrhythmic episodes requiring external defibrillation. An implantable cardioverter defibrillator (ICD) was then implanted. Persistent high resting HR was successfully treated with ivabradine with HR lowering from 90 bpm to 55 bpm at 1 month follow up, LVEF rising to 50% at 3 month follow up and to 54% at 2,5 year follow up. To date no more hospitalizations for heart failure occurred. A single hospitalization due to aspiration pneumonia required insertion of a tracheostomy tube to protect airways from further aspiration. At present, the patient is attending a regular rehabilitation program with net improvement in neuromotor control and less limitations in daily activities. Conclusions HF is a rare feature of NM, but it can negatively influence prognosis. Conventional HF therapy and/or heart transplant are the only reasonable strategy in these patients. Ivabradine is a useful, effective and safe drug for therapy in NM patients with HF and should be considered when resting HR remains high despite beta-blockers’ full titration or beta-blockers’ underdosing due to intolerance or side effects.

BACKGROUND: Tolvaptan is a selective vasopressin receptor antagonist (V2R) that increases free water excretion. We wanted to test the hypotheses that tolvaptan changes both renal handling of water and sodium and systemic hemodynamics during basal conditions and during nitric oxide (NO)-inhibition with L-NG-monomethyl-arginine (L-NMMA).METHODS: Nineteen healthy subjects were enrolled in a randomized, placebo-controlled, double-blind, crossover study of two examination days. Tolvaptan 15 mg or placebo was given in the morning. L-NMMA was given as a bolus followed by continuous infusion during 60 minutes. We measured urine output(UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma vasopressin (p-AVP), central and brachial blood pressure(cBP, bBP).RESULTS: During baseline conditions, tolvaptan caused a significant increase in UO, CH2O and p-AVP, and FENa was unchanged. During L-NMMA infusion, UO and CH2O decreased more pronounced after tolvaptan than after placebo (-54 vs.-42% and -34 vs.-9% respectively). U-AQP2 decreased during both treatments, whereas u-ENaCγ decreased after placebo and increased after tolvaptan. CBP and bBP were unchanged.CONCLUSION: During baseline conditions, tolvaptan increased renal water excretion. During NO-inhibition, the more pronounced reduction in renal water excretion after tolvaptan indicates that NO promotes water excretion in the principal cells, at least partly, via an AVP-dependent mechanism. The lack of decrease in u-AQP2 by tolvaptan could be explained by a counteracting effect of increased plasma vasopressin. The antagonizing effect of NO-inhibition on u-ENaC suggests that NO interferes with the transport via ENaC by an AVP-dependent mechanism.

BACKGROUND: Varenicline is probably the most effective smoking cessation pharmacotherapy, but is less widely used than nicotine replacement therapy. We therefore set out to identify the characteristics of numerically important groups of patients who typically do, or do not, receive varenicline in the UK. METHODS: We used association rule mining to analyse data on prescribing of smoking cessation pharmacotherapy in relation to age, sex, comorbidity and other variables from 477,620 people aged 16 years and over, registered as patients throughout 2011 with one of 559 UK general practices in The Health Improvement Network (THIN) database, and recorded to be current smokers. RESULTS: 46,685 participants (9.8% of all current smokers) were prescribed any smoking cessation treatment during 2011, and 19,316 of these (4% of current smokers, 41% of those who received any therapy) were prescribed varenicline. Prescription of varenicline was most common among heavy smokers aged 31–60, and in those with a diagnosis of COPD. Varenicline was rarely used among smokers who were otherwise in good health, or were aged over 60, were lighter smokers, or had psychotic disorders or dementia. CONCLUSIONS: Varenicline is being underused in healthy smokers, or in older smokers, and in those with psychotic disorders or dementia. Since varenicline is probably the most effective available single cessation therapy, this study identifies under-treatment of substantial public health significance.

Background No study has investigated the admission echocardiographic characteristics of acute heart failure (AHF) patients who are resistant to conventional diuretics and require tolvaptan. Methods We retrospectively analyzed the echocardiographic characteristics of AHF patients who were resistant to conventional diuretics and took tolvaptan (tolvaptan group: 26 patients), and compared them to those who were sensitive to conventional diuretics (conventional group: 180 patients). Results The tolvaptan group had a higher left atrial volume index (96.0 ± 85.0 mL/m2 vs. 45.8 ± 25.9 mL/m2, p

Background Elevated intracranial pressure from cerebral edema is the major cause of early mortality in acute stroke. Current treatment strategies to limit cerebral edema are not particularly effective. Some novel anti-edema measures have shown promising early findings in experimental stroke models. Vasopressin antagonism in stroke is one such target which has shown some encouraging preliminary results. The aim of this report is to highlight the potential use of vasopressin antagonism to limit cerebral edema in patients after acute stroke. Case presentation A 57-year-old Caucasian man with new onset diplopia was diagnosed with vertebral artery aneurysm extending into the basilar circulation. He underwent successful elective vertebral artery angioplasty and coiling of the aneurysm. In the immediate post-operative period there was a decline in his neurological status and brain imaging revealed new midbrain and thalamic hemorrhage with surrounding significant brain edema. Treatment with conventional anti-edema therapy was initiated with no significant clinical response after which conivaptan; a mixed vasopressin antagonist was started. Clinical and radiological evaluation following drug administration showed rapid clinical improvement without identification of significant adverse effects. Conclusions The authors have successfully demonstrated the safety and efficacy of using mixed vasopressin antagonist in treatment of stroke related brain edema, thereby showing its promise as an alternative anti-edema agent. Preliminary findings from this study suggest mixed vasopressin antagonism may have significant utility in the management of cerebral edema arising from cerebrovascular accident. Larger prospective studies are warranted to explore the role of conivaptan in the treatment of brain edema and neuroprotection.

Background Combined use of angiotensin-converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs may induce acute kidney injury in humans, especially when combined with diuretics. The objective of this investigation was to evaluate the effects of benazepril, robenacoxib and their combination in healthy cats. In each of two studies (study 1 followed by study 2), 32 healthy cats were randomised to one of four groups (n = 4 male and 4 female cats per group) in a parallel-group design. The groups received orally once daily for 7 days either placebo (control group), benazepril, robenacoxib or benazepril plus robenacoxib. In study 2, all groups received in addition 0.5 mg/kg furosemide twice daily by subcutaneous injection for 7 days. Results Benazepril, robenacoxib and their combination were well tolerated as evidenced from lack of clinical signs and no negative effects on body weight, feed consumption and clinical chemistry, haematology and urinalysis variables. The primary endpoint of the study was the glomerular filtration rate (GFR), which was estimated from the plasma clearance of iohexol. In the absence of furosemide, GFR was significantly higher in cats receiving the combination of benazepril plus robenacoxib compared to the other three groups, and was also significantly higher in females receiving only benazepril compared to the control. Administration of furosemide induced diuresis, reduced GFR and activated the renin-aldosterone-angiotensin system, evidenced from increased plasma renin activity and plasma aldosterone concentrations. Compared to the control group in cats treated with furosemide, GFR was increased by benazepril (females only) but decreased by robenacoxib (males only). Benazepril, robenacoxib and their combination significantly inhibited the increase in plasma aldosterone induced by furosemide. Conclusions The combination of benazepril and robenacoxib was well tolerated and either increased or had a neutral effect on GFR in healthy cats without or with concomitant furosemide. The combination of benazepril and robenacoxib reduced plasma aldosterone concentrations increased by furosemide. It is recommended to test the efficacy and safety of the combined use of benazepril and robenacoxib in cats with clinical disease, notably proteinuric chronic kidney disease.

Background Tolvaptan, a vasopressin V2 receptor blocker, has a diuretic effect for patients with heart failure. However, there were a few data concerning the effects of tolvaptan in patients with chronic kidney disease (CKD). Methods We retrospectively analyzed 21 patients with chronic heart failure and CKD. Tolvaptan was co-administered with other diuretics in-use, every day. We compared clinical parameters before and after the treatments with tolvaptan. Furthermore, we examined the correlations between baseline data and the change of body weight. Results Tolvaptan decreased the body weight and increased the urine volume (p = 0.001). The urine osmolality significantly decreased throughout the study period. Urinary Na/Cr ratio and FENa changed significantly after 4 h, and more remarkable after 8 h (p = 0.003, both). Serum creatinine increased slightly after 1 week of treatment (p = 0.012). The alteration of body weight within the study period correlated negatively with the baseline urine osmolality (r = −0.479, p = 0.038), the baseline urine volume (r = −0.48, p = 0.028), and the baseline inferior vena cava diameter (IVCD) (r = −0.622, p = 0.017). Hyponatremia was improved to the normal value, and the augmentations of the sodium concentration were negatively associated with the basal sodium levels (p = 0.01, r = −0.546). Conclusions Tolvaptan is effective in increasing diuresis and improved hyponatremia, even in patients with CKD. The baseline urine osmolality, urine volume, and IVCD may be useful predictors for diuretic effects of tolvaptan.

Background Smoking-related cues can trigger drug-seeking behaviors, and computer-based interventions that reduce cognitive biases towards such cues may be efficacious and cost-effective cessation aids. In order to optimize such interventions, there needs to be better understanding of the mechanisms underlying the effects of cognitive bias modification (CBM). Here we present a protocol for an investigation of the neural effects of CBM and varenicline in non-quitting daily smokers. Methods/Design We will recruit 72 daily smokers who report smoking at least 10 manufactured cigarettes or 15 roll-ups per day and who smoke within one hour of waking. Participants will attend two sessions approximately one week apart. At the first session participants will be screened for eligibility and randomized to receive either varenicline or a placebo over a seven-day period. On the final drug-taking day (day seven) participants will attend a second session and be further randomized to one of three CBM conditions (training towards smoking cues, training away from smoking cues, or control training). Participants will then undergo a functional magnetic resonance imaging scan during which they will view smoking-related pictorial cues. Primary outcome measures are changes in cognitive bias as measured by the visual dot-probe task, and neural responses to smoking-related cues. Secondary outcome measures will be cognitive bias as measured by a transfer task (modified Stroop test of smoking-related cognitive bias) and subjective mood and cigarette craving. Discussion This study will add to the relatively small literature examining the effects of CBM in addictions. It will address novel questions regarding the neural effects of CBM. It will also investigate whether varenicline treatment alters neural response to smoking-related cues. These findings will inform future research that can develop behavioral treatments that target relapse prevention. Trial registration Registered with Current Controlled Trials: ISRCTN65690030. Registered on 30 January 2014

Background Tobacco cessation medication adherence is one of the few factors shown to improve smoking cessation rates among methadone-maintained smokers, but interventions to improve adherence to smoking cessation medications have not yet been tested among methadone treatment patients. Methadone clinic-based, directly observed therapy (DOT) programs for HIV and tuberculosis improve adherence and clinical outcomes, but have not been evaluated for smoking cessation. We describe a randomized controlled trial to evaluate whether a methadone clinic-based, directly observed varenicline therapy program increases adherence and tobacco abstinence among opioid-dependent drug users receiving methadone treatment. Methods/Design We plan to enroll 100 methadone-maintained smokers and randomize them to directly observed varenicline dispensed with daily methadone doses or treatment as usual (self-administered varenicline) for 12 weeks. Our outcome measures are: 1) pill count adherence and 2) carbon monoxide-verified tobacco abstinence. We will assess differences in adherence and abstinence between the two treatment arms using repeated measures models. Discussion This trial will allow for rigorous evaluation of the efficacy of methadone clinic-based, directly observed varenicline for improving adherence and smoking cessation outcomes. This detailed description of trial methodology can serve as a template for the development of future DOT programs and can guide protocols for studies among opioid-dependent smokers receiving methadone treatment. Trial Registration clinicaltrials.gov NCT01378858