Decreased Thalamic Activity Is a Correlate for Disconnectedness during Anesthesia with Propofol, Dexmedetomidine and Sevoflurane But Not S-Ketamine.

Establishing the neural mechanisms responsible for the altered global states of consciousness during anesthesia and dissociating these from other drug-related effects remains a challenge in consciousness research. We investigated differences in brain activity between connectedness and disconnectedness by administering various anesthetics at concentrations designed to render 50% of the subjects unresponsive. One hundred and sixty healthy male subjects were randomized to receive either propofol (1.7 µg/ml; n = 40), dexmedetomidine (1.5 ng/ml; n = 40), sevoflurane (0.9% end-tidal; n = 40), S-ketamine (0.75 µg/ml; n = 20), or saline placebo (n = 20) for 60 min using target-controlled infusions or vaporizer with end-tidal monitoring. Disconnectedness was defined as unresponsiveness to verbal commands probed at 2.5-min intervals and unawareness of external events in a postanesthesia interview. High-resolution positron emission tomography (PET) was used to quantify regional cerebral metabolic rates of glucose (CMRglu) utilization. Contrasting scans where the subjects were classified as connected and responsive versus disconnected and unresponsive revealed that for all anesthetics, except S-ketamine, the level of thalamic activity differed between these states. A conjunction analysis across the propofol, dexmedetomidine and sevoflurane groups confirmed the thalamus as the primary structure where reduced metabolic activity was related to disconnectedness. Widespread cortical metabolic suppression was observed when these subjects, classified as either connected or disconnected, were compared with the placebo group, suggesting that these findings may represent necessary but alone insufficient mechanisms for the change in the state of consciousness.SIGNIFICANCE STATEMENT Experimental anesthesia is commonly used in the search for measures of brain function which could distinguish between global states of consciousness. However, most previous studies have not been designed to separate effects related to consciousness from other effects related to drug exposure. We employed a novel study design to disentangle these effects by exposing subjects to predefined EC50 doses of four commonly used anesthetics or saline placebo. We demonstrate that state-related effects are remarkably limited compared with the widespread cortical effects related to drug exposure. In particular, decreased thalamic activity was associated with disconnectedness with all used anesthetics except for S-ketamine.

Safety, tolerability and immunogenicity of PRV-101, a multivalent vaccine targeting coxsackie B viruses (CVBs) associated with type 1 diabetes: a double-blind randomised placebo-controlled Phase I trial.

AIMS/HYPOTHESIS: Infection with coxsackie B viruses (CVBs) can cause diseases ranging from mild common cold-type symptoms to severe life-threatening conditions. CVB infections are considered to be prime candidates for environmental triggers of type 1 diabetes. This, together with the significant disease burden of acute CVB infections and their association with chronic diseases other than diabetes, has prompted the development of human CVB vaccines. The current study evaluated the safety and immunogenicity of the first human vaccine designed against CVBs associated with type 1 diabetes in a double-blind randomised placebo-controlled Phase I trial. METHODS: The main eligibility criteria for participants were good general health, age between 18 and 45 years, provision of written informed consent and willingness to comply with all trial procedures. Treatment allocation (PRV-101 or placebo) was based on a computer-generated randomisation schedule and people assessing the outcomes were masked to group assignment. In total, 32 participants (17 men, 15 women) aged 18-44 years were randomised to receive a low (n=12) or high (n=12) dose of a multivalent, formalin-inactivated vaccine including CVB serotypes 1-5 (PRV-101), or placebo (n=8), given by intramuscular injections at weeks 0, 4 and 8 at a single study site in Finland. The participants were followed for another 24 weeks. Safety and tolerability were the primary endpoints. Anti-CVB IgG and virus-neutralising titres were analysed using an ELISA and neutralising plaque reduction assays, respectively. RESULTS: Among the 32 participants (low dose, n=12; high dose, n=12; placebo, n=8) no serious adverse events or adverse events leading to study treatment discontinuation were observed. Treatment-emergent adverse events considered to be related to the study drug occurred in 37.5% of the participants in the placebo group and 62.5% in the PRV-101 group (injection site pain, headache, injection site discomfort and injection site pruritus being most common). PRV-101 induced dose-dependent neutralising antibody responses against all five CVB serotypes included in the vaccine in both the high- and low-dose groups. Protective titres ≥8 against all five serotypes were seen in >90% of participants over the entire follow-up period. CONCLUSIONS/INTERPRETATION: The results indicate that the tested multivalent CVB vaccine is well tolerated and immunogenic, supporting its further clinical development. TRIAL REGISTRATION: ClinicalTrials.gov NCT04690426. FUNDING: This trial was funded by Provention Bio, a Sanofi company.

A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease.

BACKGROUND: In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease. METHODS: In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life). RESULTS: Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P = 0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group. CONCLUSIONS: In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.).

Foundations of Human Consciousness: Imaging the Twilight Zone.

What happens in the brain when conscious awareness of the surrounding world fades? We manipulated consciousness in two experiments in a group of healthy males and measured brain activity with positron emission tomography. Measurements were made during wakefulness, escalating and constant levels of two anesthetic agents (experiment 1, n = 39), and during sleep-deprived wakefulness and non-rapid eye movement sleep (experiment 2, n = 37). In experiment 1, the subjects were randomized to receive either propofol or dexmedetomidine until unresponsiveness. In both experiments, forced awakenings were applied to achieve rapid recovery from an unresponsive to a responsive state, followed by immediate and detailed interviews of subjective experiences during the preceding unresponsive condition. Unresponsiveness rarely denoted unconsciousness, as the majority of the subjects had internally generated experiences. Unresponsive anesthetic states and verified sleep stages, where a subsequent report of mental content included no signs of awareness of the surrounding world, indicated a disconnected state. Functional brain imaging comparing responsive and connected versus unresponsive and disconnected states of consciousness during constant anesthetic exposure revealed that activity of the thalamus, cingulate cortices, and angular gyri are fundamental for human consciousness. These brain structures were affected independent from the pharmacologic agent, drug concentration, and direction of change in the state of consciousness. Analogous findings were obtained when consciousness was regulated by physiological sleep. State-specific findings were distinct and separable from the overall effects of the interventions, which included widespread depression of brain activity across cortical areas. These findings identify a central core brain network critical for human consciousness.SIGNIFICANCE STATEMENT Trying to understand the biological basis of human consciousness is currently one of the greatest challenges of neuroscience. While the loss and return of consciousness regulated by anesthetic drugs and physiological sleep are used as model systems in experimental studies on consciousness, previous research results have been confounded by drug effects, by confusing behavioral "unresponsiveness" and internally generated consciousness, and by comparing brain activity levels across states that differ in several other respects than only consciousness. Here, we present carefully designed studies that overcome many previous confounders and for the first time reveal the neural mechanisms underlying human consciousness and its disconnection from behavioral responsiveness, both during anesthesia and during normal sleep, and in the same study subjects.

Effects of remifentanil on pharyngeal swallowing and esophageal motility: no impact of different bolus volumes and partial antagonism by methylnaltrexone.

Remifentanil impairs swallowing, and disturbed accommodation to bolus volume may be one of the underlying causes. It is not fully understood whether remifentanil-induced swallowing dysfunction is mediated by peripheral or central mechanisms. So, this study aimed to investigate if remifentanil-induced swallowing dysfunction is dependent on the bolus volume and whether the effect of remifentanil could be counteracted by methylnaltrexone, a peripherally acting opioid antagonist. Nineteen healthy volunteers were included in this double-blinded, randomized, placebo-controlled, crossover study. Study participants received target-controlled remifentanil infusions and placebo infusions in a randomized order. Methylnaltrexone was administered by intravenous injection of doses of 0.3 mg/kg. Recordings of pressure and impedance data were acquired using a combined manometry and impedance solid-state catheter. Data were analyzed from three series of bolus swallows, baseline, during study medication exposure, and 15 min after methylnaltrexone. Remifentanil induced significant effects on multiple pharyngeal and esophageal function parameters. No significant differences in remifentanil-induced swallowing dysfunction related to different bolus volumes were found. Pharyngeal effects of remifentanil were not significantly counteracted by methylnaltrexone, whereas on the distal esophageal level, effects on distension pressures were counteracted. Changes in pharyngeal and esophageal pressure flow variables were consistent with previous results on remifentanil-induced swallowing dysfunction and uniform across all bolus volumes. The effects of remifentanil on the pharyngeal level and on the proximal esophagus appear to be predominantly centrally mediated, whereas the effects of remifentanil on the distal esophagus may be mediated by both central and peripheral mechanisms.NEW & NOTEWORTHY In this randomized controlled trial, we used the "Swallow Gateway" online platform to analyze the effects of remifentanil on pharyngeal and esophageal swallowing. It is not fully understood whether remifentanil-induced swallowing dysfunction is mediated by peripheral or central mechanisms. By using methylnaltrexone, we demonstrated that effects of remifentanil on pharyngeal swallowing were predominantly centrally mediated, whereas its effects on the distal esophagus may be mediated by both central and peripheral mechanisms.

Kinetic analysis and optimisation of 18F-rhPSMA-7.3 PET imaging of prostate cancer.

PURPOSE: This phase 1 open-label study evaluated the uptake kinetics of a novel theranostic PET radiopharmaceutical, 18F-rhPSMA-7.3, to optimise its use for imaging of prostate cancer. METHODS: Nine men, three with high-risk localised prostate cancer, three with treatment-naïve hormone-sensitive metastatic disease and three with castration-resistant metastatic disease, underwent dynamic 45-min PET scanning of a target area immediately post-injection of 300 MBq 18F-rhPSMA-7.3, followed by two whole-body PET/CT scans acquired from 60 and 90 min post-injection. Volumes of interest (VoIs) corresponding to prostate cancer lesions and reference tissues were recorded. Standardised uptake values (SUV) and lesion-to-reference ratios were calculated for 3 time frames: 35-45, 60-88 and 90-118 min. Net influx rates (Ki) were calculated using Patlak plots. RESULTS: Altogether, 44 lesions from the target area were identified. Optimal visual lesion detection started 60 min post-injection. The 18F-rhPSMA-7.3 signal from prostate cancer lesions increased over time, while reference tissue signals remained stable or decreased. The mean (SD) SUV (g/mL) at the 3 time frames were 8.4 (5.6), 10.1 (7) and 10.6 (7.5), respectively, for prostate lesions, 11.2 (4.3), 13 (4.8) and 14 (5.2) for lymph node metastases, and 4.6 (2.6), 5.7 (3.1) and 6.4 (3.5) for bone metastases. The mean (SD) lesion-to-reference ratio increases from the earliest to the 2 later time frames were 40% (10) and 59% (9), respectively, for the prostate, 65% (27) and 125% (47) for metastatic lymph nodes and 25% (19) and 32% (30) for bone lesions. Patlak plots from lesion VoIs signified almost irreversible uptake kinetics. Ki, SUV and lesion-to-reference ratio estimates showed good agreement. CONCLUSION: 18F-rhPSMA-7.3 uptake in prostate cancer lesions was high. Lesion-to-background ratios increased over time, with optimal visual detection starting from 60 min post-injection. Thus, 18F-rhPSMA-7.3 emerges as a very promising PET radiopharmaceutical for diagnostic imaging of prostate cancer. TRIAL REGISTRATION: NCT03995888 (24 June 2019).

Effects of Bifidobacterium animalis ssp. lactis 420 on gastrointestinal inflammation induced by a nonsteroidal anti-inflammatory drug: A randomized, placebo-controlled, double-blind clinical trial.

AIMS: Use of nonsteroidal anti-inflammatory drugs (NSAIDs) can cause damage to the gastric and duodenal mucosa. Some probiotics have proven useful in ameliorating the harmful side-effects of NSAIDs. Our aim was to evaluate whether oral administration of Bifidobacterium animalis ssp. lactis 420 (B420) can attenuate the increase of calprotectin excretion into faeces induced by intake of diclofenac sustained-release tablets. METHODS: A double-blind, parallel-group, placebo-controlled and randomized clinical study was performed in 50 healthy male and female volunteers aged 20-40 years, in Finland. Study participation consisted of 4 phases: run-in, intervention with B420 or placebo, B420 or placebo + NSAID treatment, and follow-up. The primary outcome was the concentration of calprotectin in faeces. Secondary outcomes were haemoglobin and microbial DNA in faeces and blood haemoglobin levels. RESULTS: Intake of diclofenac increased the faecal excretion of calprotectin in both groups. The observed increases were 48.19 ± 61.55 µg/g faeces (mean ± standard deviation) in the B420 group and 31.30 ± 39.56 µg/g in the placebo group (difference estimate 16.90; 95% confidence interval: -14.00, 47.77; P = .276). There were no significant differences between the treatment groups in changes of faecal or blood haemoglobin. Faecal B. lactis DNA was much more abundant in the B420 group compared to the placebo group (ANOVA estimate for treatment difference 0.85 × 109 /g faeces; 95% confidence interval: 0.50 × 109 , 1.21 × 109 ; P < .0001). CONCLUSIONS: Short-term administration of the probiotic B420 did not protect the healthy adult study participants from diclofenac-induced gastrointestinal inflammation as determined by analysis of faecal calprotectin levels.

Clinical trial site identification practices and the use of electronic health records in feasibility evaluations: An interview study in the Nordic countries.

INTRODUCTION: Feasibility evaluations are performed to create the best possible starting point for the set-up and execution of a clinical trial, and to identify any obstacles for successful trial conduct. New digital technologies can provide various types of data for use in feasibility evaluations. There is a need to identify and compare such data sources for trial site identification and for evaluating the sites' patient recruitment potential. Especially, information is needed on the use of electronic health records. We investigated how different data sources are used by pharmaceutical companies operating in the Nordic countries for identifying trial sites and for evaluating their potential to recruit trial participants. METHODS: This was a semi-structured qualitative interview study with 21 participants from pharmaceutical companies and contract research organizations operating in Finland, Sweden, Denmark and Norway. Qualitative content analysis was applied. RESULTS: For identifying countries and trial sites on a global level, the trial sponsors mostly used databases on previous trial performance. The use of electronic health record data was very limited. Sites' and investigators' visibility in various databases was seen as fundamental for their countries becoming selected into new clinical trials. For estimating the sites' recruitment projections, most sites were seen to base their patient count estimates solely on their previous experience. Some sites had reviewed their electronic health record data, which was considered to increase the accuracy of their recruitment estimates and these sites' attractivity. Along with dialogs with investigators, the sponsors used various data sources to validate the investigators' estimates. Legislative obstacles were seen to hinder the use of electronic health record queries for estimation of patient counts. CONCLUSION: Visibility in the databases used by trial sponsors is crucial for the countries and sites to be identified. Site selection appears to be based on trust and relationships built from experience, but electronic data provide the support upon which the trust is based. Estimation of the number of potential trial participants is a complex and time-consuming process for both investigators and sponsors. Sponsors seem to favour sites who could support their patient count estimates with electronic health record data as they were quicker in providing the estimates and more reliable than sites with no electronic health record evidence. The patient count evaluation process could be simplified, accelerated and made more reliable with more systematic use of electronic health record evidence in the feasibility evaluation phase. This would increase the accuracy of the patient count estimates and, on its part, contribute to improved recruitment success.

Speech is special: The stress effects of speech, noise, and silence during tasks requiring concentration.

Effects of noise on people depend on sound level but also on other sound properties. A systematic comparison of the stress effects of speech and noise with the same frequency content is missing. This study compared stress reactions under sound conditions speech (sound level 65 dB LAeq ), noise (65 dB), and silence (35 dB), all having similar relative frequency contents. Fifty-nine participants were exposed to one out of three sound conditions on average for 48 minutes while performing tasks requiring concentration. Acute physiological stress was estimated by measuring stress hormone concentrations in plasma (cortisol and noradrenaline), heart rate variability (HRV), and blood pressure. Psychological stress measures were subjective noise annoyance, workload, and fatigue. Compared to silence and noise, working during speech was more annoying, loading, but less tiring, and led to elevated HRV LF/HF ratio with time. Speech also raised cortisol levels compared with silence. Although noise was more annoying, and raised cortisol levels compared with silence, working during speech was more loading and caused more physiological stress than other sound conditions. Special care should be paid to noise control in workplaces requiring concentration because already exposure to moderate sound level sounds caused clear physiological effects on people.

Evidence that the multiflorine-derived substituted quinazolidine 55P0251 augments insulin secretion and lowers blood glucose via antagonism at α2 -adrenoceptors in mice.

AIMS: To investigate the mechanism of action of 55P0251, a novel multiflorine-derived substituted quinazolidine that augments insulin release and lowers blood glucose in rodents, but does not act via mechanisms addressed by any antidiabetic agent in clinical use. MATERIALS AND METHODS: Using male mice, we determined the effects of 55P0251 on glucose tolerance, insulin secretion from isolated islets and blood oxygen saturation, including head-to-head comparison of 55P0251 to its inverted enantiomer 55P0250, as well as to other anti-hyperglycaemic multiflorine derivatives discovered in our programme. RESULTS: 55P0251 was clearly superior to its inverted enantiomer in the glucose tolerance test (area under the curve: 11.3 mg/kg 55P0251, 1.19 ± 0.04 min*mol/L vs 55P0250, 1.80 ± 0.04 min*mol/L; P < .0001). For insulin release in vitro, this superiority became visible only under concomitant adrenergic background stimulation (glucose-stimulated insulin release, fmol*islet-1 *30 min-1 : without α2 -adrenoceptor agonist: 500 µmol/L 55P0251, 390 ± 34, vs 55P0250, 459 ± 40, nonsignificant; with α2 -adrenoceptor agonist: 250 µmol/L 55P0251, 138 ± 9, vs 55P0250, 21 ± 6; P < .0001). Since receptor binding assays suggested antagonism at α2A -adrenoceptors as a potential mechanism of action, we measured oxygen saturation in capillary blood from the tail as a surrogate of vasoconstriction, which supported α2 -antagonistic action in vivo (90 mg/kg 55P0251, 83 ± 3%, vs 55P0250, 57 ± 3%; P < .0001). Lack of association between glucose-lowering activities and α2A -adrenoceptor binding affinity arising from comparison of multiflorine derivatives was attributed to differences in their pharmacokinetic properties. CONCLUSIONS: Our findings suggest that 55P0251 and related multiflorine derivatives are to be categorized as α2 -adrenoceptor antagonists with potential to lower blood glucose by blocking α2A -adrenoceptors on pancreatic ß cells.

Pharmacokinetics and Sedative Effects of Intranasal Dexmedetomidine in Ambulatory Pediatric Patients.

BACKGROUND: Our aim was to characterize the pharmacokinetics and sedative effects of intranasally (IN) administered dexmedetomidine used as an adjuvant in pediatric patients scheduled for magnetic resonance imaging (MRI) requiring sedation. METHODS: This was an open-label, single-period study without randomization. Pediatric patients from 5 months to 11 years of age scheduled for MRI and receiving IN dexmedetomidine for premedication as part of their care were included in this clinical trial. Single doses of 2-3 µg·kg of dexmedetomidine were applied IN approximately 1 hour before MRI. Five or 6 venous blood samples were collected over 4 hours for dexmedetomidine concentration analysis. Sedation was monitored with Comfort-B scores, and vital signs were recorded. Pharmacokinetic variables were calculated with noncompartmental methods and compared between 3 age groups (between 1 and 24 months, from 24 months to 6 years, and over 6-11 years). RESULTS: We evaluated 187 consecutive patients for suitability, of which 132 were excluded. Remaining 55 patients were recruited, of which 5 were excluded before the analysis. Data from 50 patients were analyzed. The average (standard deviation [SD]) dose-corrected peak plasma concentration (Cmax) was 0.011 liter (0.0051), and the median (interquartile range [IQR]) time to reach peak concentration (tmax) was 37 minutes (30-45 minutes). There was negative correlation with Cmax versus age (r = -0.58; 95% confidence interval [CI], -0.74 to -0.37; P < .001), but not with tmax (r = -0.14; 95% CI, 0.14-0.39; P = .35). Dose-corrected areas under the concentration-time curve were negatively correlated with age (r = -0.53; 95% CI, 0.70 to -0.29; P < .001). Median (IQR) maximal reduction in Comfort-B sedation scores was 8 (6-9), which was achieved 45 minutes (40-48 minutes) after dosing. Median (IQR) decrease in heart rate was 15% (9%-23%) from the baseline. CONCLUSIONS: Dexmedetomidine is relatively rapidly absorbed after IN administration and provides clinically meaningful but short-lasting sedation in pediatric patients.

Effects of intramuscular vatinoxan (MK-467), co-administered with medetomidine and butorphanol, on cardiopulmonary and anaesthetic effects of intravenous ketamine in dogs.

OBJECTIVE: To investigate the impact of intramuscular (IM) co-administration of the peripheral α2-adrenoceptor agonist vatinoxan (MK-467) with medetomidine and butorphanol prior to intravenous (IV) ketamine on the cardiopulmonary and anaesthetic effects in dogs, followed by atipamezole reversal. STUDY DESIGN: Randomized, masked crossover study. ANIMALS: A total of eight purpose-bred Beagle dogs aged 3 years. METHODS: Each dog was instrumented and administered two treatments 2 weeks apart: medetomidine (20 µg kg-1) and butorphanol (100 µg kg-1) premedication with vatinoxan (500 µg kg-1; treatment MVB) or without vatinoxan (treatment MB) IM 20 minutes before IV ketamine (4 mg kg-1). Atipamezole (100 µg kg-1) was administered IM 60 minutes after ketamine. Heart rate (HR), mean arterial (MAP) and central venous (CVP) pressures and cardiac output (CO) were measured; cardiac (CI) and systemic vascular resistance (SVRI) indices were calculated before and 10 minutes after MVB or MB, and 10, 25, 40, 55, 70 and 100 minutes after ketamine. Data were analysed with repeated measures analysis of covariance models. A p-value <0.05 was considered statistically significant. Sedation, induction, intubation and recovery scores were assessed. RESULTS: At most time points, HR and CI were significantly higher, and SVRI and CVP significantly lower with MVB than with MB. With both treatments, SVRI and MAP decreased after ketamine, whereas HR and CI increased. MAP was significantly lower with MVB than with MB; mild hypotension (57-59 mmHg) was recorded in two dogs with MVB prior to atipamezole administration. Sedation, induction, intubation and recovery scores were not different between treatments, but intolerance to the endotracheal tube was observed earlier with MVB. CONCLUSIONS AND CLINICAL RELEVANCE: Haemodynamic performance was improved by vatinoxan co-administration with medetomidine-butorphanol, before and after ketamine administration. However, vatinoxan was associated with mild hypotension after ketamine with the dose used in this study. Vatinoxan shortened the duration of anaesthesia.

Candida antarctica Lipase A-Based Enantiorecognition of a Highly Strained 4-Dibenzocyclooctynol (DIBO) Used for PET Imaging.

The enantiomers of aromatic 4-dibenzocyclooctynol (DIBO), used for radiolabeling and subsequent conjugation of biomolecules to form radioligands for positron emission tomography (PET), were separated by kinetic resolution using lipase A from Candida antarctica (CAL-A). In optimized conditions, (R)-DIBO [(R)-1, ee 95%] and its acetylated (S)-ester [(S)-2, ee 96%] were isolated. In silico docking results explained the ability of CAL-A to differentiate the enantiomers of DIBO and to accommodate various acyl donors. Anhydrous MgCl2 was used for binding water from the reaction medium and, thus, for obtaining higher conversion by preventing hydrolysis of the product (S)-2 into the starting material. Since the presence of hydrated MgCl26H2O also allowed high conversion or effect on enantioselectivity, Mg2+ ion was suspected to interact with the enzyme. Binding site predictions indicated at least two sites of interest; one in the lid domain at the bottom of the acyl binding pocket and another at the interface of the hydrolase and flap domains, just above the active site.

Upper Airway Collapsibility during Dexmedetomidine and Propofol Sedation in Healthy Volunteers: A Nonblinded Randomized Crossover Study.

BACKGROUND: Dexmedetomidine is a sedative promoted as having minimal impact on ventilatory drive or upper airway muscle activity. However, a trial recently demonstrated impaired ventilatory drive and induction of apneas in sedated volunteers. The present study measured upper airway collapsibility during dexmedetomidine sedation and related it to propofol. METHODS: Twelve volunteers (seven female) entered this nonblinded, randomized crossover study. Upper airway collapsibility (pharyngeal critical pressure) was measured during low and moderate infusion rates of propofol or dexmedetomidine. A bolus dose was followed by low (0.5 µg · kg · h or 42 µg · kg · min) and moderate (1.5 µg · kg · h or 83 µg · kg · min) rates of infusion of dexmedetomidine and propofol, respectively. RESULTS: Complete data sets were obtained from nine volunteers (median age [range], 46 [23 to 66] yr; body mass index, 25.4 [20.3 to 32.4] kg/m). The Bispectral Index score at time of pharyngeal critical pressure measurements was 74 ± 10 and 65 ± 13 (mean difference, 9; 95% CI, 3 to 16; P = 0.011) during low infusion rates versus 57 ± 16 and 39 ± 12 (mean difference, 18; 95% CI, 8 to 28; P = 0.003) during moderate infusion rates of dexmedetomidine and propofol, respectively. A difference in pharyngeal critical pressure during sedation with dexmedetomidine or propofol could not be shown at either the low or moderate infusion rate. Median (interquartile range) pharyngeal critical pressure was -2.0 (less than -15 to 2.3) and 0.9 (less than -15 to 1.5) cm H2O (mean difference, 0.9; 95% CI, -4.7 to 3.1) during low infusion rates (P = 0. 595) versus 0.3 (-9.2 to 1.4) and -0.6 (-7.7 to 1.3) cm H2O (mean difference, 0.0; 95% CI, -2.1 to 2.1; P = 0.980) during moderate infusion of dexmedetomidine and propofol, respectively. A strong linear relationship between pharyngeal critical pressure during dexmedetomidine and propofol sedation was evident at low (r = 0.82; P = 0.007) and moderate (r = 0.90; P < 0.001) infusion rates. CONCLUSIONS: These observations suggest that dexmedetomidine sedation does not inherently protect against upper airway obstruction.

Pharmacodynamic and pharmacokinetic profile of SM-1, a triple-drug combination to increase total sleep time.

OBJECTIVE: The primary objective was to characterize the pharmacokinetics and pharmacodynamics of SM-1 after administration of a single oral dose to healthy volunteers in a placebo-controlled double-blind trial of daytime sedation. Secondary objectives were to determine the onset, duration, and offset of the sedative effects using subjective and objective measures of sedation. Safety and tolerability of SM-1 were also investigated. METHODS: Males and females 18-45 years of age received SM-1, a combination drug product comprised of diphenhydramine, zolpidem (delayed release), and lorazepam (delayed release). The pharmacokinetic profile of each drug was determined from blood samples. Sedative effects were assessed by visual analog scale, digit symbol substitution test, memory test, and quantitative electroencephalography. RESULTS: Similar number and severity of adverse events were observed following administration of SM-1 and placebo. Onset of sedation, as determined by subjective, performance, and electroencephalography measures, occurred 0.5-1 hr postdose, lasting about 7-7.5 hr. Plasma concentration curves for the two delayed-release components were altered compared with published data for unmodified drugs. Exposure values obtained with the combination product were in good agreement with published values of the drugs given individually. CONCLUSIONS: SM-1 was well tolerated and has pharmacologic activity starting within an hour of ingestion, lasting approximately 7-8 hr. Sedative activity was seen with subjective, psychomotor, and electroencephalography assays.

Premedication with intranasal dexmedetomidine decreases barbiturate requirement in pediatric patients sedated for magnetic resonance imaging: a retrospective study.

BACKGROUND: Barbiturates are commonly used in ambulatory sedation of pediatric patients. However, use of barbiturates involve risks of respiratory complications. Dexmedetomidine, a highly selective α2-adrenoceptor agonist, is increasingly used for pediatric sedation. Premedication with intranasal (IN) dexmedetomidine offers a non-invasive and efficient possibility to sedate pediatric patients undergoing magnetic resonance imaging (MRI). Our hypothesis was that dexmedetomidine would reduce barbiturate requirements in procedural sedation. METHODS: We included 200 consecutive pediatric patients undergoing MRI, and analyzed their hospital records retrospectively. Half of the patients received 3 µg/kg of IN dexmedetomidine (DEX group) 45-60 min before MRI while the rest received only thiopental (THIO group) for procedural sedation. Sedation was maintained with further intravenous thiopental dosing as needed. Thiopental consumption, heart rate (HR) and peripheral oxygen saturation were recorded. RESULTS: The cumulative thiopental requirement during MRI was (median and interquartile range [IQR]) 4.4 (2.7-6.0) mg/kg/h in the DEX group and 12.4 (9.8-14.8) mg/kg/h in the THIO group (difference 7.9 mg/kg/h, 95% CI 6.8-8.8, P <  0.001). Lowest measured peripheral oxygen saturation remained slightly higher in the DEX group compared to the THIO group (median nadirs and IQR: 97 (95-97) % and 96 (94-97) %, P <  0.001). Supplemental oxygen was delivered to 33% of the patients in the THIO group compared to 2% in the DEX group (P <  0.001). The lowest measured HR (mean and SD) was lower (78 (16) bpm) in the DEX group compared to the THIO group (92 (12) bpm) (P <  0.001). CONCLUSION: Premedication with IN dexmedetomidine (3 µg/kg) was associated with markedly reduced thiopental dosage needed for efficient procedural sedation for pediatric MRI.

Increased Energy Expenditure, Lipolysis and Hyperinsulinemia Confer Resistance to Central Obesity and Type 2 Diabetes in Mice Lacking Alpha2α-Adrenoceptors.

The alpha2A-adrenoceptors (α2A-ARs) are Gi-coupled receptors, which prejunctionally inhibit the release of norepinephrine (NE) and epinephrine (Epi), and postjunctionally inhibit insulin secretion and lipolysis. We have earlier shown that α2A-/- mice display sympathetic hyperactivity, hyperinsulinemia and improved glucose tolerance. Here we employed α2A-/- mice and placed the mice on a high-fat diet (HFD) to test the hypothesis that lack of α2A-ARs protects from diet-induced obesity and type 2 diabetes (T2D). In addition, a high-caloric diet was combined with running wheel exercise to test the interaction of diet and exercise. HFD was obesogenic in both genotypes, but α2A-/- mice accumulated less visceral fat than the wild-type controls, were protected from T2D, and their insulin secretion was unaltered by the diet. Lack of α2A-ARs is associated with an increased sympatho-adrenal tone, which resulted in increased energy expenditure and fat oxidation rate potentiated by HFD. Fittingly, α2A-/- mice displayed enhanced lipolytic responses to Epi, and increased faecal lipids suggesting altered fat mobilization and absorption. Subcutaneous white fat appeared to be thermogenically more active (measured as Ucp1 mRNA expression) in α2A-/- mice, and brown fat showed an increased response to NE. Exercise was effective in reducing total body adiposity and increasing lean mass in both genotypes, but there was a significant diet-genotype interaction, as even modestly increased physical activity combined with lack of α2A-AR signalling promoted weight loss more efficiently than exercise with normal α2A-AR function. These results suggest that blockade of α2A-ARs may be exploited to reduce visceral fat and to improve insulin secretion.

Sedative Plasma Concentrations and Delirium Risk in Critical Illness.

BACKGROUND: The relationship between plasma concentration of sedatives and delirium is unknown. OBJECTIVE: We hypothesized that higher plasma concentrations of lorazepam are associated with increased delirium risk, whereas higher plasma concentrations of dexmedetomidine are associated with reduced delirium risk. METHODS: This prospective cohort study was embedded in a double-blind randomized clinical trial, where ventilated patients received infusions of lorazepam and dexmedetomidine. Plasma concentrations of these drugs and delirium assessments were measured at least daily. A multivariable logistic regression model accounting for repeated measures was used to analyze associations between same-day plasma concentrations of lorazepam and dexmedetomidine (exposures) and the likelihood of next-day delirium (outcome), adjusting for same-day mental status (delirium, coma, or normal) and same-day fentanyl doses. RESULTS: This critically ill cohort (n = 103) had a median age of 60 years (IQR: 48-66) with APACHE II score of 28 (interquartile range [IQR] = 24-32), where randomization resulted in assignment to lorazepam (n = 51) or dexmedetomidine (n = 52). After adjusting for same-day fentanyl dose and mental status, higher plasma concentrations of lorazepam were associated with increased probability of next-day delirium (comparing 500 vs 0 ng/mL; odds ratio [OR] = 13.2; 95% CI = 1.4-120.1; P = 0.02). Plasma concentrations of dexmedetomidine were not associated with next-day delirium (comparing 1 vs 0 ng/mL; OR = 1.1; 95% CI = 0.9-1.3; P = 0.45). CONCLUSIONS: In critically ill patients, higher lorazepam plasma concentrations were associated with delirium, whereas dexmedetomidine plasma concentrations were not. This implies that the reduced delirium risk seen in patients sedated with dexmedetomidine may be a result of avoidance of benzodiazepines, rather than a dose-dependent protective effect of dexmedetomidine.

Peripheral α2-adrenoceptor antagonism affects the absorption of intramuscularly coadministered drugs.

OBJECTIVE: We determined the possible effects of a peripherally acting α2-adrenoceptor antagonist, MK-467, on the absorption of intramuscularly (IM) coadministered medetomidine, butorphanol and midazolam. STUDY DESIGN: Randomized, experimental, blinded crossover study. ANIMALS: Six healthy Beagle dogs. METHODS: Two IM treatments were administered: 1) medetomidine hydrochloride (20 µg kg-1) + butorphanol (100 µg kg-1) + midazolam (200 µg kg-1; MBM) and 2) MBM + MK-467 hydrochloride (500 µg kg-1; MBM-MK), mixed in a syringe. Heart rate was recorded at regular intervals. Sedation was assessed with visual analog scales (0-100 mm). Drug concentrations in plasma were analyzed with liquid chromatography-tandem mass spectrometry, with chiral separation of dex- and levomedetomidine. Maximum drug concentrations in plasma (Cmax) and time to Cmax (Tmax) were determined. Paired t-tests, with Bonferroni correction when appropriate, were used for comparisons between the treatments. RESULTS: Data from five dogs were analyzed. Heart rate was significantly higher from 20 to 90 minutes after MBM-MK. The Tmax values for midazolam and levomedetomidine (mean ± standard deviation) were approximately halved with coadministration of MK-467, from 23 ± 9 to 11 ± 6 minutes (p = 0.049) for midazolam and from 32 ± 15 to 18 ± 6 minutes for levomedetomidine (p = 0.036), respectively. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 accelerated the absorption of IM coadministered drugs. This is clinically relevant as it may hasten the onset of peak sedative effects.

Differential Internalization Rates and Postendocytic Sorting of the Norepinephrine and Dopamine Transporters Are Controlled by Structural Elements in the N Termini.

The norepinephrine transporter (NET) mediates reuptake of synaptically released norepinephrine in central and peripheral noradrenergic neurons. The molecular processes governing availability of NET in the plasma membrane are poorly understood. Here we use the fluorescent cocaine analogue JHC 1-64, as well as several other approaches, to investigate the trafficking itinerary of NET in live noradrenergic neurons. Confocal imaging revealed extensive constitutive internalization of JHC 1-64-labeled NET in the neuronal somata, proximal extensions and presynaptic boutons. Phorbol 12-myristate 13-acetate increased intracellular accumulation of JHC 1-64-labeled NET and caused a parallel reduction in uptake capacity. Internalized NET strongly colocalized with the "long loop" recycling marker Rab11, whereas less overlap was seen with the "short loop" recycling marker Rab4 and the late endosomal marker Rab7. Moreover, mitigating Rab11 function by overexpression of dominant negative Rab11 impaired NET function. Sorting of NET to the Rab11 recycling compartment was further supported by confocal imaging and reversible biotinylation experiments in transfected differentiated CATH.a cells. In contrast to NET, the dopamine transporter displayed markedly less constitutive internalization and limited sorting to the Rab11 recycling compartment in the differentiated CATH.a cells. Exchange of domains between the two homologous transporters revealed that this difference was determined by non-conserved structural elements in the intracellular N terminus. We conclude that NET displays a distinct trafficking itinerary characterized by continuous shuffling between the plasma membrane and the Rab11 recycling compartment and that the functional integrity of the Rab11 compartment is critical for maintaining proper presynaptic NET function.