The role of opioid transmission in music-induced pleasure.

Studies conducted in rodents indicate a crucial role of the opioid circuit in mediating objective hedonic reactions to primary rewards. However, it remains unclear whether opioid transmission is also essential to experience pleasure with more abstract rewards, such as music. We addressed this question using a double-blind within-subject pharmacological design in which opioid levels were up- and downregulated by administering an opioid agonist (oxycodone) and antagonist (naltrexone), respectively, before healthy participants (n = 21) listened to music. Participants also performed a monetary incentive delay (MID) task to control for the effectiveness of the treatment and the specificity of the effects. Our results revealed that the pharmacological intervention did not modulate subjective reports of pleasure, nor the occurrence of chills. On the contrary, psychophysiological (objective) measures of emotional arousal, such as skin conductance responses (SCRs), were bidirectionally modulated in both the music and MID tasks. This modulation specifically occurred during reward consumption, with greater pleasure-related SCR following oxycodone than naltrexone. These findings indicate that opioid transmission does not modulate subjective evaluations but rather affects objective reward-related psychophysiological responses. These findings raise new caveats about the role of the opioidergic system in the modulation of pleasure for more abstract or cognitive forms of rewarding experiences, such as music.

Lack of Clinical Relevance of Bilastine-Food Interaction in Healthy Volunteers: A Wheal and Flare Study.

INTRODUCTION: The aim of this study was to compare the pharmacodynamic activity of bilastine administered under fasting and fed conditions in healthy volunteers. METHODS: In this randomized, open-label, two-period, crossover study involving 24 healthy subjects, once-daily oral bilastine 20 mg was administered for 4 days under fasting and fed conditions, with a 7-day washout period. Bilastine plasma concentrations were measured for 24 h after the first and fourth doses in each period. Pharmacodynamic activity was assessed by wheal and flare surface inhibition and subjective assessment of itching, after intradermal injection of histamine 5 µg. RESULTS: When administered under fed versus fasting conditions, exposure to bilastine 20 mg decreased (mean maximum plasma concentration and area under the curve from time 0 to 24 h decreased by 34.27% and 32.72% [day 1], respectively, and 33.08% and 28.87% [day 4]). Despite this, the antihistaminic effect of bilastine 20 mg was not altered by food. On day 1, as assessed by wheal and flare surface inhibition, the maximum effect and duration of action of bilastine did not differ to a significant extent between fasting and fed conditions, with only a short 30-min delay in the onset of wheal inhibition. At steady state (day 4), bilastine's pharmacodynamic effects were not significantly affected under fasting or fed conditions. CONCLUSION: The pharmacokinetic interaction of bilastine with food does not imply a significant reduction of its peripheral antihistaminic efficacy. Despite a slight delay in onset of action on the first treatment day, the global clinical efficacy of bilastine is not affected by coadministration with food.

The Kappa Opioid Receptor and the Sleep of Reason: Cortico-Subcortical Imbalance Following Salvinorin-A.

BACKGROUND: The mechanisms through which kappa opioid receptor (KOR) agonists induce psychotomimetic effects are largely unknown, although the modulation of this receptor has attracted attention for its clinical use. In this work, we characterize the neuropharmacological effects of salvinorin-A, a highly selective KOR agonist. METHODS: Changes in multimodal electroencephalography, single-photon emission computed tomography, and subjective effects following the acute administration of salvinorin-A are reported. The study included 2 sub-studies that employed a double-blind, crossover, randomized, placebo-controlled design. RESULTS: The electroencephalography measures showed a marked increase in delta and gamma waves and a decrease in alpha waves while subjects were under the effect of salvinorin-A. Regarding single-photon emission computed tomography measures, significant decreases in regional cerebral blood flow were detected in multiple regions of the frontal, temporal, parietal, and occipital cortices. Significant regional cerebral blood flow increases were observed in some regions of the medial temporal lobe, including the amygdala, the hippocampal gyrus, and the cerebellum. The pattern of subjective effects induced by salvinorin-A was similar to those observed in relation to other psychotomimetic drugs but with an evidently dissociative nature. No dysphoric effects were reported. CONCLUSION: The salvinorin-A-mediated KOR agonism induced dramatic psychotomimetic effects along with a generalized decrease in cerebral blood flow and electric activity within the cerebral cortex.

Impact of pre-admission antithrombotic therapy on disease severity and mortality in patients hospitalized for COVID-19.

Anticoagulant therapy is a cornerstone treatment for coronavirus disease 2019 (COVID-19) due to the high rates of thromboembolic complications associated with this disease. We hypothesized that chronic antithrombotic therapy could play a protective role in patients hospitalized for COVID-19. Retrospective, observational study of all patients admitted to our hospital for ≥ 24 h from March 1 to May 31, 2020 with SARS-CoV-2. The objective was to evaluate clinical outcomes and mortality in COVID-19 patients receiving chronic anticoagulation (AC) or antiplatelet therapy (AP) prior to hospital admission. A total of 1612 patients were evaluated. The mean (standard deviation; SD) age was 66.5 (17.1) years. Patients were divided into three groups according to the use of antithrombotic therapy prior to admission (AP, AC, or no-antithrombotic treatment). At admission, 9.6% of the patients were taking anticoagulants and 19.1% antiplatelet therapy. The overall mortality rate was 19.3%. On the multivariate analysis there were no significant differences in mortality between the antithrombotic groups (AC or AP) and the no-antithrombotic group (control group). Patients on AC had lower ICU admission rates than the control group (OR: 0.41, 95% CI, 0.18-0.93). Anticoagulation therapy prior to hospitalization for COVID-19 was associated with lower ICU admission rates. However, there were no significant differences in mortality between the patients receiving chronic antithrombotic therapy and patients not taking antithrombotic medications. These findings suggest that chronic anticoagulation therapy at the time of COVID-19 infection may reduce disease severity and thus the need for ICU admission.

Dopamine modulations of reward-driven music memory consolidation.

Music listening provides one of the most significant abstract rewards for humans because hearing music activates the dopaminergic mesolimbic system. Given the strong link between reward, dopamine, and memory, we aimed here to investigate the hypothesis that dopamine-dependent musical reward can drive memory improvements. Twenty-nine healthy participants of both sexes provided reward ratings of unfamiliar musical excerpts that had to be remembered following a consolidation period under three separate conditions: after the ingestion of a dopaminergic antagonist, a dopaminergic precursor, or a placebo. Linear mixed modeling of the intervention data showed that the effect of reward on memory-i.e., the greater the reward experienced while listening to the musical excerpts, the better the memory recollection performance-was modulated by both dopaminergic signaling and individual differences in reward processing. Greater pleasure was consistently associated with better memory outcomes in participants with high sensitivity to musical reward, but this effect was lost when dopaminergic signaling was disrupted in participants with average or low musical hedonia. Our work highlights the flexibility of the human dopaminergic system, which can enhance memory formation not only through explicit and/or primary reinforcers but also via abstract and aesthetic rewards such as music.

First-in-Human Randomized Trial to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the KDM1A Inhibitor Vafidemstat.

BACKGROUND: Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-in-human trial of vafidemstat in healthy young and older adult volunteers. A total of 110 volunteers participated: 87 were treated with vafidemstat and 23 with placebo. OBJECTIVES: The study aimed to determine the safety and tolerability of vafidemstat, to characterize its pharmacokinetic and pharmacodynamic profiles, to assess its central nervous system (CNS) exposure, and to acquire the necessary data to select the appropriate doses for long-term treatment of patients with CNS disease in phase II trials. METHODS: This single-center, randomized, double-blind, placebo-controlled phase I trial included a single and 5-day repeated dose-escalation and open-label CNS penetration substudy. Primary outcomes were safety and tolerability; secondary outcomes included analysis of the pharmacokinetics and pharmacodynamics, including chemoprobe-based immune analysis of KDM1A target engagement (TE) in peripheral blood mononuclear cells (PBMCs) and platelet monoamine oxidase B (MAOB) inhibition. CNS and cognitive function were also evaluated. RESULTS: No severe adverse events (AEs) were reported in the dose-escalation stage. AEs were reported at all dose levels; none were dose dependent, and no significant differences were observed between active treatment and placebo. Biochemistry, urinalysis, vital signs, electrocardiogram, and hematology did not change significantly with dose escalation, with the exception of a transient reduction of platelet counts in an extra dose level incorporated for that purpose. Vafidemstat exhibits rapid oral absorption, approximate dose-proportional exposures, and moderate systemic accumulation after 5 days of treatment. The cerebrospinal fluid-to-plasma unbound ratio demonstrated CNS penetration. Vafidemstat bound KDM1A in PBMCs in a dose-dependent manner. No MAOB inhibition was detected. Vafidemstat did not affect the CNS or cognitive function. CONCLUSIONS: Vafidemstat displayed good safety and tolerability. This phase I trial confirmed KDM1A TE and CNS penetration and permitted characterization of platelet dynamics and selection of phase IIa doses. TRIAL REGISTRATION: EUDRACT No. 2015-003721-33, filed 30 October 2015.

Effectiveness and safety of intravenous tocilizumab to treat COVID-19-associated hyperinflammatory syndrome: Covizumab-6 observational cohort.

Although the starting event in COVID-19 is a viral infection some patients present with an over-exuberant inflammatory response, leading to acute lung injury (ALI) and adult respiratory distress syndrome (ARDS). Since IL-6 plays a critical role in the inflammatory response, we assessed the efficacy and safety of tocilizumab (TCZ) in this single-centre, observational study in all Covid-19 in-patient with a proven SARS-CoV-2 rapidly progressing infection to prevent ALI and ARDS. 104 patients with COVID-19 treated with TCZ had a lower mortality rate (5·8%) compared with the regional mortality rate (11%), hospitalized patient's mortality (10%), and slightly lower than hospitalized patients treated with our standard of care alone (6%). We found that TCZ rapidly decreased acute phase reactants, ferritin and liver release of proteins. D-Dimer decreased slowly. We did not observe specific safety concerns. Early administration of IL6-R antagonists in COVID-19 patients with impending hyperinflammatory response, may be safe and effective treatment to prevent, ICU admission and further complications.

Alterations in EEG connectivity in healthy young adults provide an indicator of sleep depth.

Current sleep analyses have used electroencephalography (EEG) to establish sleep intensity through linear and nonlinear measures. Slow wave activity (SWA) and entropy are the most commonly used markers of sleep depth. The purpose of this study is to evaluate changes in brain EEG connectivity during sleep in healthy subjects and compare them with SWA and entropy. Four different connectivity metrics: coherence (MSC), synchronization likelihood (SL), cross mutual information function (CMIF), and phase locking value (PLV), were computed focusing on their correlation with sleep depth. These measures provide different information and perspectives about functional connectivity. All connectivity measures revealed to have functional changes between the different sleep stages. The averaged CMIF seemed to be a more robust connectivity metric to measure sleep depth (correlations of 0.78 and 0.84 with SWA and entropy, respectively), translating greater linear and nonlinear interdependences between brain regions especially during slow wave sleep. Potential changes of brain connectivity were also assessed throughout the night. Connectivity measures indicated a reduction of functional connectivity in N2 as sleep progresses. The validation of connectivity indexes is necessary because they can reveal the interaction between different brain regions in physiological and pathological conditions and help understand the different functions of deep sleep in humans.

Dopamine modulates the reward experiences elicited by music.

Understanding how the brain translates a structured sequence of sounds, such as music, into a pleasant and rewarding experience is a fascinating question which may be crucial to better understand the processing of abstract rewards in humans. Previous neuroimaging findings point to a challenging role of the dopaminergic system in music-evoked pleasure. However, there is a lack of direct evidence showing that dopamine function is causally related to the pleasure we experience from music. We addressed this problem through a double blind within-subject pharmacological design in which we directly manipulated dopaminergic synaptic availability while healthy participants (n = 27) were engaged in music listening. We orally administrated to each participant a dopamine precursor (levodopa), a dopamine antagonist (risperidone), and a placebo (lactose) in three different sessions. We demonstrate that levodopa and risperidone led to opposite effects in measures of musical pleasure and motivation: while the dopamine precursor levodopa, compared with placebo, increased the hedonic experience and music-related motivational responses, risperidone led to a reduction of both. This study shows a causal role of dopamine in musical pleasure and indicates that dopaminergic transmission might play different or additive roles than the ones postulated in affective processing so far, particularly in abstract cognitive activities.

Prevalence of Sleep Disorders in Adults With Down Syndrome: A Comparative Study of Self-Reported, Actigraphic, and Polysomnographic Findings.

STUDY OBJECTIVES: Sleep problems are often undetected in adults with Down syndrome (DS). Our objective was to determine the prevalence of sleep disorders in adults with DS through self-reported and objective sleep measures. METHODS: We performed a community-based cross-sectional study of 54 adults with DS not referred for sleep disorders. Two polysomnography (PSG) sleep studies were performed. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI); daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS) and the risk for the sleep apnea syndrome (OSA) was identified using the Berlin Questionnaire (BQ). Participants' sleep/wake pattern was assessed from sleep diaries and by wrist actigraphy. PSQI, ESS, and PSG measures were compared with 35 sex-, age-, and body mass index-matched patients in the control groups. RESULTS: In PSG measures, adults with DS showed lower sleep efficiency (69 ± 17.7 versus 81.6 ± 11; P < .001), less rapid eye movement sleep (9.4 ± 5.8 versus 19.4 ± 5.1; P < .001), a higher prevalence of OSA (78% versus 14%; P < .001), and a higher apnea-hypopnea index (23.5 ± 24.5 versus 3.8 ± 10.5; P < .001) than patients in the control group. In the DS group, the questionnaires (mean PSQI 3.7 ± 2.9; mean ESS 6.3 ± 4.5 and mean BQ 1 ± 0) did not reflect the sleep disturbances detected on the PSG. Actigraphy data recorded daytime sleep that was not self-reported (118.2 ± 104.2 minutes). CONCLUSIONS: Adults with DS show severe sleep disruption and a high prevalence of OSA, undetected by self-reported sleep measures. Actigraphy, PSG, and validated simplified devices for screening OSA should be routinely recommended for this population because treatment of sleep disorders can contribute to healthy aging.

Moderate Beer Intake and Cardiovascular Health in Overweight Individuals.

Consistent epidemiological evidence indicates that low-to-moderate alcohol consumption is inversely associated with cardiovascular event presentation, while high levels of alcohol intake are associated to increased cardiovascular risk. Little is known on the effects of moderate beer intake in the metabolic syndrome. The aim of this study is to investigate the effects of moderate and regular daily intake of beer with meals in overweight (body mass index (BMI) of 28⁻29.9 kg/m²) or obese class 1 (BMI of 30⁻35 kg/m²) individuals without other cardiovascular risk factors (dyslipidemia, type 2-diabetes, hypertension) focusing on the effects related to changes in weight, in lipoproteins and vascular endothelial function. We have performed an open, prospective two-arms longitudinal crossover study to investigate the effects associated with regular consumption (four week) of alcohol-free-beer (0 g alcohol/day) or traditional-beer (30 g alcohol/day in men and 15 g alcohol/day in women) on anthropometrical and biochemical parameters, liver and kidney function biomarkers, and vascular endothelial function. After four-week intervention with traditional and/or alcohol-free beer, BMI did not show any significant change and values for liver and kidney functions were within the normal levels. Moderate traditional beer intake did not affect lipid levels-however it significantly increased the antioxidant capacity of high density lipoprotein (HDL). In addition, apoB-depleted serum (after the four-week intervention period) showed a higher potential to promote cholesterol efflux from macrophages. Beer consumption did not induce vascular endothelial dysfunction or stiffness. In summary, our results based on a 12-week prospective study provide evidence that moderate intake of beer (traditional and alcohol-free) does not exert vascular detrimental effects nor increases body weight in obese healthy individuals. In contrast, moderate intake of beer increases the anti-oxidative properties of HDL and facilitates cholesterol efflux, which may prevent lipid deposition in the vessel wall.

Intrinsically regulated learning is modulated by synaptic dopamine signaling.

We recently provided evidence that an intrinsic reward-related signal-triggered by successful learning in absence of any external feedback-modulated the entrance of new information into long-term memory via the activation of the dopaminergic midbrain, hippocampus, and ventral striatum (the SN/VTA-Hippocampal loop; Ripollés et al., 2016). Here, we used a double-blind, within-subject randomized pharmacological intervention to test whether this learning process is indeed dopamine-dependent. A group of healthy individuals completed three behavioral sessions of a language-learning task after the intake of different pharmacological treatments: a dopaminergic precursor, a dopamine receptor antagonist or a placebo. Results show that the pharmacological intervention modulated behavioral measures of both learning and pleasantness, inducing memory benefits after 24 hr only for those participants with a high sensitivity to reward. These results provide causal evidence for a dopamine-dependent mechanism instrumental in intrinsically regulated learning and further suggest that subject-specific reward sensitivity drastically alters learning success.

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers.

Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150­200 µg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC0t and Cmax) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC0t and Cmax for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC0t or Cmax) was not associated with BMI or weight in our study. These findings contribute to further understand the pharmacokinetic characteristics of ivermectin, highlighting its safety across different dosing regimens. They also correlate with known pharmacokinetic parameters showing stable levels of AUC and Cmax across a wide range of body weights, which justifies the strategy of fix dosing from a pharmacokinetic perspective. TRIAL REGISTRATION: ClinicalTrials.gov NCT03173742.

Phytosterols and Omega 3 Supplementation Exert Novel Regulatory Effects on Metabolic and Inflammatory Pathways: A Proteomic Study.

Cardiovascular disease (CVD) remains one of the major causes of death and disability worldwide. In addition to drug treatment, nutritional interventions or supplementations are becoming a health strategy for CVD prevention. Phytosterols (PhyS) are natural components that have been shown to reduce cholesterol levels; while poly-unsaturated fatty acids (PUFA), mainly omega-3 (ω3) fatty acids, have shown to reduce triglyceride levels. Here we aimed to investigate whether the proteins in the main lipoproteins (low density lipoproteins (LDL) and high density lipoproteins (HDL)) as well as proteins in the lipid free plasma fraction (LPDP) were regulated by the intake of PhyS-milk or ω3-milk, in overweight healthy volunteers by a proteomic based systems biology approach. The study was a longitudinal crossover trial, including thirty-two healthy volunteers with body mass index (BMI) 25-35 kg/m² (Clinical Trial: ISRCTN78753338). Basal samples before any intervention and after 4 weeks of intake of PhyS or ω3-milk were analyzed. Proteomic profiling by two dimensional electrophoresis (2-DE) followed by mass spectrometry-(MALDI/TOF), ELISA, Western blot, conventional biochemical analysis, and in-silico bioinformatics were performed. The intake of PhyS-milk did not induce changes in the lipid associated plasma protein fraction, whereas ω3-milk significantly increased apolipoprotein (Apo)- E LDL content (p = 0.043) and induced a coordinated increase in several HDL-associated proteins, Apo A-I, lecitin cholesterol acyltransferase (LCAT), paraoxonase-1 (PON-1), Apo D, and Apo L1 (p < 0.05 for all). Interestingly, PhyS-milk intake induced a reduction in inflammatory molecules not seen after ω3-milk intake. Serum amyloid P component (SAP) was reduced in the LPDP protein fraction (p = 0.001) of subjects taking PhyS-milk and C-C motif chemokine 2 (CCL2)expression detected by reverse transcription polymerase chain reaction (RT-PCR) analysis in white blood cells was significantly reduced (p = 0.013). No changes were observed in the lipid-free plasma proteome with ω3-milk. Our study provides novel results and highlights that the PhyS-milk induces attenuation of the pro-inflammatory pathways, whereas ω3-milk induces improvement in lipid metabolic pathways.

Monitoring sleep depth: analysis of bispectral index (BIS) based on polysomnographic recordings and sleep deprivation.

The assessment and management of sleep are increasingly recommended in the clinical practice. Polysomnography (PSG) is considered the gold standard test to monitor sleep objectively, but some practical and technical constraints exist due to environmental and patient considerations. Bispectral index (BIS) monitoring is commonly used in clinical practice for guiding anesthetic administration and provides an index based on relationships between EEG components. Due to similarities in EEG synchronization between anesthesia and sleep, several studies have assessed BIS as a sleep monitor with contradictory results. The aim of this study was to evaluate objectively both the feasibility and reliability of BIS for sleep monitoring through a robust methodology, which included full PSG recordings at a baseline situation and after 40 h of sleep deprivation. Results confirmed that the BIS index was highly correlated with the hypnogram (0.89 ± 0.02), showing a progressive decrease as sleep deepened, and an increase during REM sleep (awake: 91.77 ± 8.42; stage N1: 83.95 ± 11.05; stage N2: 71.71 ± 11.99; stage N3: 42.41 ± 9.14; REM: 80.11 ± 8.73). Mean and median BIS values were lower in the post-deprivation night than in the baseline night, showing statistical differences for the slow wave sleep (baseline: 42.41 ± 9.14 vs. post-deprivation: 39.49 ± 10.27; p = 0.02). BIS scores were able to discriminate properly between deep (N3) and light (N1, N2) sleep. BIS values during REM overlapped those of other sleep stages, although EMG activity provided by the BIS monitor could help to identify REM sleep if needed. In conclusion, BIS monitors could provide a useful measure of sleep depth in especially particular situations such as intensive care units, and they could be used as an alternative for sleep monitoring in order to reduce PSG-derived costs and to increase capacity in ambulatory care.

Comparative efficacy of bilastine, desloratadine and rupatadine in the suppression of wheal and flare response induced by intradermal histamine in healthy volunteers.

OBJECTIVE: To compare the peripheral antihistaminic activity of bilastine, rupatadine and desloratadine in inhibiting the histamine-induced wheal and flare (W&F) response. RESEARCH DESIGN AND METHODS: Twenty-four healthy volunteers aged 18-40 years participated in this crossover, randomized, double-blind, placebo-controlled clinical study. Subjects received single doses of bilastine 20 mg, desloratadine 5 mg, rupatadine 10 mg and placebo. W&F responses induced by intradermal injection of histamine 5 µg were evaluated before treatment (basal value) and at 0.5, 1, 2, 4, 6, 9, 12 and 24 hours after treatment. Fifteen minutes after histamine injection, W&F surface areas (cm2) were quantified using the Visitrak System. Itching sensation was evaluated using a 100 mm visual analog scale. EudraCT number: 2015-000790-13. MAIN OUTCOME MEASURES: The primary outcome measure was the percentage reduction in W&F areas after each active treatment compared with corresponding basal values. RESULTS: Bilastine induced the greatest inhibition in wheal area and was significantly superior to desloratadine and rupatadine from 1 to 12 hours (both p < .001). Rupatadine and desloratadine were better than placebo without differences between them. Maximum wheal inhibition occurred at 6 hours (bilastine 83%, desloratadine 38%, rupatadine 37%). Onset of action was 1 hour for bilastine and 4 hours for desloratadine and rupatadine. Bilastine was significantly superior to desloratadine and rupatadine for flare inhibition from 1-24 hours (both p < .001) with an onset of action at 30 minutes. Bilastine was significantly better than desloratadine (2-12 hours; at least p < .05) and rupatadine (2-9 hours; at least p < .01) for reducing itching sensation. Neither desloratadine nor rupatadine significantly reduced itching compared to placebo. All active treatments were well tolerated. CONCLUSIONS: Bilastine 20 mg induced significantly greater inhibition of the W&F response compared with desloratadine 5 mg and rupatadine 10 mg throughout the 24 hour study period, and had the fastest onset of action. Only bilastine significantly reduced itching sensation versus placebo.

Neurophysiological evidence of impaired self-monitoring in schizotypal personality disorder and its reversal by dopaminergic antagonism.

BACKGROUND: Schizotypal personality disorder (SPD) is a schizophrenia-spectrum disorder characterized by odd or bizarre behavior, strange speech, magical thinking, unusual perceptual experiences, and social anhedonia. Schizophrenia proper has been associated with anomalies in dopaminergic neurotransmission and deficits in neurophysiological markers of self-monitoring, such as low amplitude in cognitive event-related brain potentials (ERPs) like the error-related negativity (ERN), and the error positivity (Pe). These components occur after performance errors, rely on adequate fronto-striatal function, and are sensitive to dopaminergic modulation. Here we postulated that analogous to observations in schizophrenia, SPD individuals would show deficits in self-monitoring, as measured by the ERN and the Pe. We also assessed the capacity of dopaminergic antagonists to reverse these postulated deficits. METHODS: We recorded the electroencephalogram (EEG) from 9 SPD individuals and 12 healthy controls in two separate experimental sessions while they performed the Eriksen Flanker Task, a classical task recruiting behavioral monitoring. Participants received a placebo or 1 mg risperidone according to a double-blind randomized design. RESULTS: After placebo, SPD individuals showed slower reaction times to hits, longer correction times following errors and reduced ERN and Pe amplitudes. While risperidone impaired performance and decreased ERN and Pe in the control group, it led to behavioral improvements and ERN amplitude increases in the SPD individuals. CONCLUSIONS: These results indicate that SPD individuals show deficits in self-monitoring analogous to those in schizophrenia. These deficits can be evidenced by neurophysiological measures, suggest a dopaminergic imbalance, and can be reverted by dopaminergic antagonists.

Impact of Chiral Bioanalytical Methods on the Bioequivalence of Ibuprofen Products Containing Ibuprofen Lysinate and Ibuprofen Base.

The purpose was to assess the impact of the use of a chiral bioanalytical method on the conclusions of a bioequivalence study that compared two ibuprofen suspensions with different rates of absorption. A comparison of the conclusion of bioequivalence between a chiral method and an achiral approach was made. Plasma concentrations of R-ibuprofen and S-ibuprofen were determined using a chiral bioanalytical method; bioequivalence was tested for R-ibuprofen and for S-ibuprofen separately and for the sum of both enantiomers as an approach for an achiral bioanalytical method. The 90% confidence interval (90% CI) that would have been obtained with an achiral bioanalytical method (90% CI: Cmax: 117.69-134.46; AUC0 (t) : 104.75-114.45) would have precluded the conclusion of bioequivalence. This conclusion cannot be generalized to the active enantiomer (90% CI: Cmax : 103.36-118.38; AUC0 (t) : 96.52-103.12), for which bioequivalence can be concluded, and/or the distomer (90% CI: Cmax : 132.97-151.33; AUC0 (t) : 115.91-135.77) for which a larger difference was observed. Chiral bioanalytical methods should be required when 1) the enantiomers exhibit different pharmacodynamics and 2) the exposure (AUC or Cmax ) ratio of enantiomers is modified by a difference in the rate of absorption. Furthermore, the bioequivalence conclusion should be based on all enantiomers, since the distomer(s) might not be completely inert, in contrast to what is required in the current regulatory guidelines. In those cases where it is unknown if the ratio between enantiomers is modified by changing the rate of absorption, chiral bioanalytical methods should be employed unless enantiomers exhibit the same pharmacodynamics. Chirality 28:429-433, 2016. © 2016 Wiley Periodicals, Inc.

Acute Sleep Deprivation Induces a Local Brain Transfer Information Increase in the Frontal Cortex in a Widespread Decrease Context.

Sleep deprivation (SD) has adverse effects on mental and physical health, affecting the cognitive abilities and emotional states. Specifically, cognitive functions and alertness are known to decrease after SD. The aim of this work was to identify the directional information transfer after SD on scalp EEG signals using transfer entropy (TE). Using a robust methodology based on EEG recordings of 18 volunteers deprived from sleep for 36 h, TE and spectral analysis were performed to characterize EEG data acquired every 2 h. Correlation between connectivity measures and subjective somnolence was assessed. In general, TE showed medium- and long-range significant decreases originated at the occipital areas and directed towards different regions, which could be interpreted as the transfer of predictive information from parieto-occipital activity to the rest of the head. Simultaneously, short-range increases were obtained for the frontal areas, following a consistent and robust time course with significant maps after 20 h of sleep deprivation. Changes during sleep deprivation in brain network were measured effectively by TE, which showed increased local connectivity and diminished global integration. TE is an objective measure that could be used as a potential measure of sleep pressure and somnolence with the additional property of directed relationships.