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Background: Recent cryo-electron microscopic imaging studies have shown that in addition to binding to the classical extracellular benzodiazepine binding site of the α1β3γ2L γ-aminobutyric acid type A (GABAA) receptor, diazepam also binds to etomidate binding sites located in the transmembrane receptor domain. Because such binding is characterized by low modulatory efficacy, the authors hypothesized that diazepam would act in vitro and in vivo as a competitive etomidate antagonist., Methods: The concentration-dependent actions of diazepam on 20 µM etomidate-activated and 6 µM GABA-activated currents were defined (in the absence and presence of flumazenil) in oocyte-expressed α1β3γ2L GABAA receptors using voltage clamp electrophysiology. The ability of diazepam to inhibit receptor labeling of purified α1β3γ2L GABAA receptors by [H]azietomidate was assessed in photoaffinity labeling protection studies. The impact of diazepam (in the absence and presence of flumazenil) on the anesthetic potencies of etomidate and ketamine was compared in a zebrafish model., Results: At nanomolar concentrations, diazepam comparably potentiated etomidate-activated and GABA-activated GABAA receptor peak current amplitudes in a flumazenil-reversible manner. The half-maximal potentiating concentrations were 39 nM (95% CI, 27 to 55 nM) and 26 nM (95% CI, 16 to 41 nM), respectively. However, at micromolar concentrations, diazepam reduced etomidate-activated, but not GABA-activated, GABAA receptor peak current amplitudes in a concentration-dependent manner with a half-maximal inhibitory concentration of 9.6 µM (95% CI, 7.6 to 12 µM). Diazepam (12.5 to 50 µM) also right-shifted the etomidate-concentration response curve for direct activation without reducing the maximal response and inhibited receptor photoaffinity labeling by [H]azietomidate. When administered with flumazenil, 50 µM diazepam shifted the etomidate (but not the ketamine) concentration-response curve for anesthesia rightward, increasing the etomidate EC50 by 18-fold., Conclusions: At micromolar concentrations and in the presence of flumazenil to inhibit allosteric modulation via the classical benzodiazepine binding site of the GABAA receptor, diazepam acts as an in vitro and in vivo competitive etomidate antagonist.

Eight adult tigers ( Panthera tigris) underwent a complete echocardiographic examination following sedation with medetomidine, midazolam, and induction of general anesthesia using ketamine and isoflurane (phase 1). Atipamezole was used to antagonize medetomidine (phase 2) and a second echocardiographic examination was performed. Physiologic tricuspid and pulmonic regurgitations were common findings in the sample population and one tiger was excluded from final analyses due to the finding of a ventricular septal defect. Measurements and mean arterial pressure were assessed for statistically significant differences between the two examination phases as well as gender and weight. There was a statistically significant difference between interventricular septum thickness at end systole, ejection fraction, and mean arterial pressure between anesthetic phases while fractional shortening and left ventricular internal dimension at end-systole approached, but did not reach, statistical significance between phases. Weight was found to be a statistically significant predictor of stroke volume and left ventricular internal dimension at end-diastole. The echocardiographic measurements obtained during this study can be used as guidelines for future examinations in adult tigers. The effects of medetomidine on these measurements and systolic function should be taken into account when performing echocardiograms and monitoring anesthetic events.

OBJECTIVE To evaluate hemodynamic, respiratory, and sedative effects of buccally administered detomidine gel and reversal with atipamezole in dogs. ANIMALS 8 adult purpose-bred dogs. PROCEDURES Arterial and venous catheters were placed. Baseline heart rate, respiratory rate, cardiac output (determined via lithium dilution with pulse contour analysis), oxygen delivery, systemic vascular resistance, arterial blood gas values, and sedation score were obtained. Detomidine gel (2.0 mg/m 2 ) was administered on the buccal mucosa. Cardiopulmonary data and sedation scores were obtained at predetermined times over 180 minutes. Atipamezole (0.1 mg/kg) was administered IM at 150 minutes. Reversal of sedation was timed and scored. Data were analyzed with an ANOVA. RESULTS Compared with baseline values, heart rate was lower at 45 to 150 minutes, cardiac output and oxygen delivery were lower at 30 to 150 minutes, and systemic vascular resistance was increased at 30 to 150 minutes. There were no significant changes in Paco 2 , Pao 2 , or lactate concentration at any time point, compared with baseline values, except for lactate concentration at 180 minutes. All dogs became sedated; maximum sedation was detected 75 minutes after administration of detomidine. Mean ± SD time to recovery after atipamezole administration was 7.55 ± 1.89 minutes; sedation was completely reversed in all dogs. No adverse events were detected. CONCLUSIONS AND CLINICAL RELEVANCE Buccally administered detomidine gel was associated with reliable and reversible sedation in dogs, with hemodynamic effects similar to those induced by other α 2 -adrenoceptor agonists. Buccally administered detomidine gel could be an alternative to injectable sedatives in healthy dogs.

Objective: To evaluate the effect of the peripherally acting α 2 -adrenoceptor antagonist vatinoxan (MK-467) on the sedative properties of medetomidine (MED) when injected intramuscularly (IM) in the same syringe and on reversal of this sedation with atipamezole in sheep., Study Design: Randomized, blinded, crossover experimental trial., Animals: Eight healthy adult female sheep., Methods: Sheep received MED (30 μg kg -1 IM) alone or combined in the same syringe with vatinoxan (300 μg kg -1 IM, MED+VAT) with a 2 week washout period. Atipamezole (150 μg kg -1 IM) was administered 30 minutes later for reversal. Sedation was assessed using two sedation scores, a visual analog score and a descriptive scale before treatments (T0) and at intervals up to 5 hours thereafter. Pulse rate (PR) was counted at T0 and at 30 (T30) and 90 (T90) minutes. Rectal temperature was measured at T0 and T90 postinjection. Plasma samples were analyzed for drug concentrations at T30 and T90., Results: The first signs of sedation were seen significantly earlier after MED+VAT (4.6 ± 1.7 minutes versus 9.4 ± 2.6 minutes after MED) and the sedation scores were significantly higher after MED+VAT than MED. All animals laid with head down 10.0 ± 3.4 minutes after MED+VAT, whereas three MED animals did not become recumbent before atipamezole was administered. The plasma concentrations of dexmedetomidine were significantly higher at T30 (2.47 ± 0.2 ng mL -1 ) and significantly lower at T90 (1.23 ± 0.3 ng mL -1 ) with MED+VAT than with MED (1.19 ± 0.8 and 1.83 ± 0.4 ng mL -1 , respectively). While no significant differences were observed between treatments in PR at T30, PR at T90 was significantly higher with MED+VAT than with MED., Conclusions and Clinical Relevance: When administered IM in the same syringe, vatinoxan hastened and intensified the initial sedative effects of MED and enhanced the sedation reversal by atipamezole., (Copyright © 2018 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Objective: Midazolam sedation during elective endoscopy is widely performed and flumazenil is frequently administered after endoscopy to reverse sedation in clinical practice. This study aimed to investigate the safety and efficacy of flumazenil injections after elective endoscopy under midazolam sedation., Methods: Participants who underwent an upper endoscopy under midazolam sedation were randomly divided into two groups. In group I, flumazenil was administered i.v. 10 min after the patient's transfer to the recovery room, and no antidote was injected in group II. The time of stay in the recovery room and adverse events were reviewed through the nursing records. We asked the patients about their pain and degree of satisfaction according to a visual analogue scale (VAS), their memory of the procedure, mental status and the presence of uncomfortable symptoms on the day of the procedure and the day afterwards., Results: The length of stay in recovery was significantly shorter in group I than in group II. No significant differences were found in the number of patients with pain (VAS ≥1), adverse events and discomfort between the two groups. Additionally, there were no differences in the patients' memory of the procedure, satisfaction with sedation, willingness to repeat the endoscopy and mental status., Conclusions: The time in the recovery room after flumazenil administration was significantly shortened, and the use of the drug did not increase the risk of adverse events or discomfort. The use of flumazenil for reversing midazolam sedation seems to be safe and effective., (© 2018 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: There is increasing interest in the use of intranasal naloxone to reverse adverse opioid effects during management of procedural pain in children and in adults after overdose. There are limited data on the pharmacokinetics of intranasal naloxone so in this study we aimed to detail the pharmacokinetic profile of the commercially marketed injectable solution of naloxone 0.4 mg/ml when administered as an intranasal spray., Methods: Twenty healthy volunteers received naloxone as an intranasal spray at a dose of 10 μg/kg. Venous blood sampling was carried out for 90 min after administration to determine the time profile of the plasma concentrations of using tandem mass spectrometry. Pharmacokinetic parameters were calculated using a one-compartment model., Results: Median time to maximum naloxone concentration (Tmax) was 14.5 (95% CI: 9.0-16.5) min, mean maximum naloxone concentration (Cmax) was 1.09 ± 0.56 ng/ml and mean AUC 0-90 min was 37.1 ± 15.0 ng*min/ml. Elimination half-life estimated from the median concentration data was 28.2 min., Conclusion: Our results show a faster uptake of intranasal naloxone to maximum concentration compared with previous studies although with a marked variation in maximum concentration. The findings are consistent with our clinical experience of the time profile for reversing the effects of sufentanil sedation in children., (© 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Objective: To characterize a propofol-medetomidine-ketamine total intravenous anaesthetic in impala (Aepyceros melampus)., Study Design: Prospective clinical study., Animals: Ten adult female impala., Materials and Methods: Impala were immobilized at 1253 m above sea level with 2.0 mg thiafentanil and 2.2 mg medetomidine via projectile darts. Propofol was given to effect (0.5 mg kg -1 boluses) to allow endotracheal intubation, following which oxygen was supplemented at 2 L minute -1 . Anaesthesia was maintained with a constant-rate infusion of medetomidine and ketamine at 5 μg kg -1 hour -1 and 1.5 mg kg -1 hour -1 , respectively, and propofol to effect (initially 0.2 mg kg -1 minute -1 ) for 120 minutes. The propofol infusion was titrated according to reaction to nociceptive stimuli every 15 minutes. Cardiopulmonary parameters were monitored continuously and arterial blood gas samples were analysed intermittently. After 120 minutes' maintenance, the thiafentanil and medetomidine were antagonized using naltrexone (10:1 thiafentanil) and atipamezole (5:1 medetomidine), respectively., Results: All impala were successfully immobilized. The median dose [interquartile range (IQR)] of propofol required for intubation was 2.7 (1.9-3.3) mg kg -1 . The propofol-medetomidine-ketamine combination abolished voluntary movement and ensured anaesthesia for the 120 minute period. Propofol titration showed a generally downward trend. Median (IQR) heart rate [57 (53-61) beats minute -1 ], respiratory rate [10 (9-12) breaths minute -1 ] and mean arterial blood pressure [101 (98-106) mmHg] were well maintained. Arterial blood gas analysis indicated hypoxaemia, hyper- capnia and acidaemia. Butorphanol (0.12 mg kg -1 ) was an essential rescue drug to counteract thiafentanil-induced respiratory depression. All impala regurgitated frequently during the maintenance period. Recovery was calm and rapid in all animals. Median (IQR) time to standing from antagonist administration was 4.4 (3.2-5.6) minutes., Conclusions and Clinical Relevance: A propofol-medetomidine-ketamine combination could provide adequate anaesthesia for invasive procedures in impala. The propofol infusion should begin at 0.2 mg kg -1 minute -1 and be titrated to clinical effect. Oxygen supplementation and airway protection with a cuffed endotracheal tube are essential., (Copyright © 2016 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

The practice of midazolam conscious sedation is well established in dentistry. The drug flumazenil is a specific benzodiazepine antagonist and is an essential requirement in settings where midazolam is used. A literature review has been carried out, examining the available information regarding flumazenil’s safety, administration, potential complications and the regulatory documentation which governs its use. Flumazenil is a safe drug to use for the reversal of midazolam induced conscious sedation although the evidence surrounding its use is limited.

We investigated the effects of acute diazepam (DZP) administration on thiobarbituric acid-reactive substance (TBARS) levels, protein carbonyl content, and on the activities of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase in the brain of rats. Additionally, we investigated the antioxidant role of chronic pretreatment with simvastatin on the effects provoked by DZP. Simvastatin was administered (1 or 10 mg/kg by oral gavage) for 30 days. On the 30th day of treatment, groups were randomized and DZP was administered (0.5 or 1.0 mg/kg by intraperitoneal injection). Control groups received saline. Results showed that DZP enhanced TBARS levels and protein carbonyl content and altered enzymatic activity in the brain of rats. Simvastatin prevented most of the alterations caused by DZP on the oxidative stress parameters. Data indicate that DZP administration causes an oxidative imbalance in the brain areas studied; however, in the presence of simvastatin, some of these alterations in oxidative stress were prevented., (© 2016 Wiley Periodicals, Inc.)

The American College of Medical Toxicology established the Toxicology Investigators Consortium (ToxIC) Case Registry in 2010. The Registry contains all medical toxicology consultations performed at participating sites. The Registry has continued to grow since its inception, and as of December 31, 2015, contains 43,099 cases. This is the sixth annual report of the ToxIC Registry, summarizing the additional 8115 cases entered in 2015. Cases were identified by a query of the Registry for all cases entered between January 1 and December 31, 2015. Specific data reviewed for analysis included demographics (age, race, gender), source of consultation, reason for consultation, agents and agent classes involved in exposures, signs, symptoms, clinical findings, fatalities, and treatment. By the end of 2015, there were 50 active sites, consisting of 101 separate health-care facilities; 51.2 % of cases involved females. Adults between the ages of 19 and 65 made up the majority (64.2 %) of Registry cases. Caucasian race was the most commonly reported (55.6 %); 9.6 % of cases were identified as Hispanic ethnicity. Inpatient and emergency department referrals were by far the most common referral sources (92.9 %). Intentional pharmaceutical exposures remained the most frequent reason for consultation, making up 52.3 % of cases. Of these intentional pharmaceutical exposures, 69 % represented an attempt at self-harm, and 85.6 % of these were a suicide attempt. Nonopioid analgesics, sedative-hypnotics, and antidepressant agents were the most commonly reported agent classes in 2015. Almost one-third of Registry cases involved a diagnosed toxidrome (32.8 %), with a sedative-hypnotic toxidrome being the most frequently described. Significant vital sign abnormalities were recorded in 25.3 % of cases. There were 98 fatalities reported in the Registry (1.2 %). Adverse drug reactions were reported in 4.3 % of cases. Toxicological treatment was given in 65.3 % of cases, with 33.0 % receiving specific antidotal therapy. Exposure characteristics and trends overall were similar to prior years. While treatment interventions were required in the majority of cases, fatalities were rare., Competing Interests: None. Funding Sources This study received funding from the NIH National Institute of Neurological Disorders and Stroke 3U01NS083452-01 (Bird, SB), NIH National Institute on Drug Abuse 1R56DA38366 (Boyer, EW/ Carlson, RG) and 1R01DA037317-01 (Manini, A), and BTG International Inc.

We investigated the influence of the peripherally acting α2 -adrenoceptor antagonist MK-467 on the sedative and antinociceptive actions and plasma drug concentrations of medetomidine, an α2 -adrenoceptor agonist that is used in veterinary medicine as a sedative and analgesic agent. Eight healthy beagle dogs received intravenous medetomidine (10 μg/kg) or medetomidine with MK-467 (250 μg/kg) in a randomized crossover design. A standardized nociceptive pressure stimulus was applied to a nail bed of a hindlimb. Times for withdrawal of the limb and for head lift were measured, and sedation was scored. EEG data were collected prior to and after stimulation. Plasma drug concentrations were measured. Co-administration of MK-467 significantly attenuated medetomidine analgesia, as assessed with limb withdrawal, and also shortened the duration of sedation. The apparent plasma clearance of both enantiomers of medetomidine, dexmedetomidine and levomedetomidine, was more than doubled in the presence of MK-467. Antagonism by MK-467 of medetomidine-evoked vasoconstriction is seen as the mechanism behind this pharmacokinetic drug interaction. Thus, MK-467 attenuated the antinociceptive and sedative effects of medetomidine. This can probably be explained by increased clearance and decreased concentrations of dexmedetomidine in plasma after co-administration of MK-467 with racemic medetomidine., (© 2016 John Wiley & Sons Ltd.)

Hispidulin is well-known natural bioactive flavone on behalf of its pharmacological aspects. This review contains data on isolation, synthetic methodology, pharmacokinetics and bioactivities of hispidulin. The article provides a critical assessment of present knowledge about hispidulin with some clear conclusions, perspectives and directions for future research in potential applications.

Introduction: Analyzing hospital naloxone use may assist in identification of areas for quality and safety improvement. Our primary objective is to quantitate the incidence of hospital naloxone use and to assess certain patient populations at risk., Methods: During the years 2008 to 2011, each clinical scenario where naloxone was administered on an in-patient care ward was reviewed. The events were assessed to separate situations where naloxone rescue was effective in reversing opioid-induced intoxication vs. others. Further analysis was conducted to stratify patient populations at greatest risk., Results: Naloxone was administered for well-defined opioid-induced respiratory depression and oversedation 61% of the time, the remainder used for patient deterioration of other etiology. Surgical populations are at risk with an incidence of 3.8/1,000 hospitalized patients, and this is the greatest within 24 hours of surgery. General surgical patients represent the highest surgical patient risk at 5.5/1,000. Medical patients represent lower risk at 2.0/1,000. Patients with patient-controlled analgesia and epidural opioid infusion are high risk at 12.1 and 13.1/1,000 patients, respectively. Many quality and safety interventions were gradually implemented in response to this data and are summarized. These include nursing and provider education, electronic medical record modification, and more stringent patient monitoring practices., Conclusion: Examination of naloxone use can assist in the identification and stratification of patients at risk for opioid-induced respiratory depression and oversedation and can serve as a driver for improvements in hospital patient safety. This information can also guide other institutions interested in similar improvements., (© 2015 World Institute of Pain.)

Background: Moderate sedation has been standard for noninvasive gastrointestinal procedures for decades yet there are limited data on reversal agent use and outcomes associated with need for reversal of sedation., Aim: To determine prevalence and clinical significance of reversal agent use during endoscopies and colonoscopies., Methods: Individuals with adverse events requiring naloxone and/or flumazenil during endoscopy or colonoscopy from 2008 to 2013 were identified. A control group was obtained by random selection of patients matched by procedure type and date. Prevalence of reversal agent use and statistical comparison of patient demographics and risk factors against controls were determined., Results: Prevalence of reversal agent use was 0.03% [95% confidence interval (CI), 0.02-0.04]. Events triggering reversal use were oxygen desaturation (64.4%), respiration changes (24.4%), hypotension (8.9%), and bradycardia (6.7%). Two patients required escalation of care and the majority of patients were stabilized and discharged home. Compared with the control group, the reversal group was older (61±1.8 vs. 55±1.6, P=0.01), mostly female (82% vs. 50%, P<0.01), and had lower body mass index (24±0.8 vs. 27±0.7, P=0.03) but received similar dosages of sedation. When adjusted for age, race, sex, and body mass index, the odds of reversal agent patients having a higher ASA score than controls was 4.7 (95% CI, 1.7-13.1), and the odds of having a higher Mallampati score than controls was 5.0 (95% CI, 2.1-11.7) with P<0.01., Conclusions: Prevalence of reversal agent use during moderate sedation is low and outcomes are generally good. Several clinically relevant risk factors for reversal agent use were found suggesting that certain groups may benefit from closer monitoring.

Background: Ethanol is widely known for its depressant effects; however, the underlying neurobiological mechanisms are not clear. Calcium-activated anion channels (CAACs) contribute to extracellular chloride levels and thus may be involved in regulating inhibitory mechanisms within the central nervous system. Therefore, we hypothesized that CAACs influence ethanol behavioral sensitivity by altering CAAC expression., Methods: We assessed the role of CAACs in ethanol-induced loss of righting reflex (LORR) and locomotor activity using intracerebroventricular infusions of several nonselective CAAC blockers. CAAC expression was determined after ethanol exposure., Results: Ethanol-induced LORR (4.0 g/kg, intraperitoneally [i.p.]) was significantly attenuated by all 4 CAAC blockers. Blocking CAACs did not impact ethanol's low-dose (1.5 g/kg, i.p.) locomotor-impairing effects. Biochemical analysis of CAAC protein expression revealed that cortical Bestrophin1 (Best1) and Tweety1 levels were reduced as early as 30 minutes following a single ethanol injection (3.5 g/kg, intraperitoneally [i.p.]) and remained decreased 24 hours later in P2 fractions. Cortical Best1 levels were also reduced following 1.5 g/kg. However, CAAC expression was unaltered in the striatum following a single ethanol exposure. Ethanol did not affect Tweety2 levels in either brain region., Conclusions: These results suggest that CAACs are a major target of ethanol in vivo, and the regulation of these channels contributes to select behavioral actions of ethanol., (Copyright © 2016 by the Research Society on Alcoholism.)

Objective: To assess the sedative and immobilization effect of intranasal administration (INS) of midazolam (MID) without or with INS dexmedetomidine (DXM), and some physiological changes induced by the drugs. The ability of INS atipamezole to reverse the DXM component was also assessed., Study Design: Prospective 'blinded' experimental study., Animals: In total, 15 pigeons., Methods: Pigeons were sedated by INS MID alone at a dose of 5 mg kg(-1) (group MID, n = 6) or in combination with INS DXM at a dose 80 μg kg(-1) (group MID-DXM, n = 6). Measurements were made of heart rate (HR), respiratory rate (fR ) and cloacal temperature (CT). The degree of sedation was assessed at 15 minutes prior to, immediately after, and at intervals until 100 minutes after drug administrations. Following MID-DXM, INS atipamezole (250 μg kg(-1) ) was administered and the same indices measured 5 and 10 minutes later., Results: MID had no effect on HR and fR , and although CT decreased, it remained within physiological range. MID-DXM caused significant falls in HR, fR and CT that persisted until the end of sedation. Atipamezole antagonized sedation and cardiorespiratory side effects of MID-DXM within 10 minutes of application. In addition, for MID compared to MID-DXM, the lowest sedation scores [10 (7-14) and 10.5 (5-14) versus 2 (1-4) and 2 (1-5)] were achieved in the 10th and 20th minute versus the 20th and 30th minute of the sedation, respectively., Conclusions and Clinical Relevance: MID alone, given INS had minimal side effects on vital functions but caused inadequate immobilization of pigeons for restraint in dorsal recumbency. MID-DXM caused an effective degree of immobilization from 20 to 30 minutes after administration, at which time birds tolerated postural changes without resistance. Atipamezole antagonized both side effects and sedation, but complete recovery had not occurred within 10 minutes after its application., (© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)

High doses of phenylephrine and diazepam (1 and 10 mg/kg, respectively) suppressed the development of generalized tonic-clonic pentylenetetrazole-induced convulsions in 86-100% rats, but did not prevent local clonic pentylenetetrazole-induced convulsions. Diazepam in the specified dose produced strong sedation, while phenylephrine had no sedative effect in the open-field test. Combined intragastric administration of phenylephrine in a medium and individually ineffective dose (0.3 mg/kg) and diazepam in a high dose (10 mg/kg) potentiated the anticonvulsant effect of diazepam: it prevented not only tonic-clonic, but also clonic pentylenetetrazole-induced convulsions in 100% rats and 2.6-fold increased anticonvulsant activity of diazepam. The specified combination of diazepam and phenylephrine had no sedative effect. The mechanism of potentiation of the anticonvulsive effect and elimination of the sedative side effect is based on stimulation of gastric mucosa afferents by phenylephrine.

Background and Purpose: N(6)-(3-methoxyl-4-hydroxybenzyl) adenine riboside (B2) is an analog of N(6)-(4-hydroxybenzyl) adenine riboside (NHBA), which was originally isolated from Gastrodia elata Blume. Our laboratory has previously demonstrated that B2 can produce strong sedative and hypnotic effects, but the mechanism remains to be determined. There is evidence that gamma-aminobutyric acid (GABA) acts as an inhibitory neurotransmitter in the brain, plays a major role in sleep regulation, and participates in the sedative and hypnotic effects of B2. Therefore, we studied the interactions between B2 and several GABAergic neurochemical parameters based on the sedative and hypnotic effects of B2., Experimental Approach: The GABA and glutamic acid (Glu) in the mouse brain were derivatized with o-phthalaldehyde (OPA) and measured by high performance liquid chromatography-electrochemical detection (HPLC-ECD). The GAD and GABA-T enzyme activities were determined by measuring GABA and NADH production, respectively. The sleep structure analyses were performed by EEG studies in mice., Key Results: B2 increased the GABA levels and GAD enzyme activity in the mouse hypothalamus and cortex. The EEG results confirmed that B2 significantly shortened the sleep latency and increased the amount of NREM sleep. The GAD enzyme inhibitor semicarbazide (SCZ) blocked the sedative and hypnotic effects of B2., Conclusions and Implications: These findings suggest that the GAD enzyme plays a significant role in the sedative and hypnotic effects of B2. Therefore B2 may be a promising candidate for further clinical studies and the appropriate use of GAD agonist may be a promising approach for sleep disorders., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To study an expediency and efficacy of application of different reverses drugs (naloxone, flumazenil, neostigmine, galantamine, sugammadex) either their separate or combined using., Methods: We studied 119 patients underwent endoluminal endoscopic procedures and surgeries on trachea-bronchial tree and intestines under sedation or general anaesthesia., Results: The article deals with conceptual approaches to the reversal of residual effects of opioids, benzodiazepine sedation and neuromuscular block (the so-called agonist-antagonist technique)., Conclusions: A reversion of neuromuscular block without using of antagonists' combination does not provide complete recovery of psychomotor and cognitive functions for rapid socialization of patients after anaesthesia.

Background: Endoscopy under midazolam sedation requires a 2-h recovery facility., Aim: To study the potential of shortening patients' stay without jeopardizing patients' safety by the use of the benzodiazepine-antagonist flumazenil in the everyday practice and to investigate the feasibility of a study comparing midazolam with recovery with midazolam-flumazenil and immediate discharge., Methods: Consecutive ambulatory patients referred for endoscopy under midazolam sedation with ASA I or II, escorted by a person, were eligible. Flumazenil was given on arrival in the recovery room. Patients were discharged when adequate Aldrete scores and physical mobility were present. The next day, they were contacted by telephone., Results: A total of 1,506 patients participated. They received 5 mg midazolam, while 887 patients also received 50 mcg fentanyl. The median dose of flumazenil was 0.2 mg. Oxygen desaturation (sO2 <92%) occurred in 15% during the procedure without an effect on recovery and discharge times. Patients left the department 65 min after the last midazolam administration. The majority (82.7%) were fully alert during their journey home. At home, 2.7% went to bed, 45.2% took a nap, and 40% undertook activities. Almost every patient (98.8%) liked the shortened recovery time. Three patients had an incident (fainting, fall, and near-fall) without consequences. Based on this low incidence, a non-inferiority comparison of midazolam-flumazenil with midazolam-recovery would require a total of 32,650 patients., Conclusions: Administration of flumazenil resulted in a safe shortening of the recovery period and offers the possibility for substantial savings in time, space, and nurse resources. A non-inferiority comparison will not be practicable.

Both alcohol withdrawal syndrome (AWS) and benzodiazepines can cause delirium. Benzodiazepine-associated delirium can complicate AWS and prolong hospitalization. Benzodiazepine delirium can be diagnosed with flumazenil, a GABA-A receptor antagonist. By reversing the effects of benzodiazepines, flumazenil is theorized to exacerbate symptoms of AWS and precludes its use. For patients being treated for alcohol withdrawal, flumazenil can diagnose and treat benzodiazepine delirium without precipitating serious or life-threatening adverse events. Hospital admission records were retrospectively reviewed for patients with the diagnosis of AWS who received both benzodiazepines and flumazenil from December 2006 to June 2012 at a university-affiliated inpatient toxicology center. The day of last alcohol consumption was estimated from available blood alcohol content or subjective history. Corresponding benzodiazepine, flumazenil, and adjunctive sedative pharmacy records were reviewed, as were demographic, clinical course, and outcome data. Eighty-five patients were identified (average age 50.3 years). Alcohol concentrations were detectable for 42 patients with average 261 mg/dL (10-530 mg/dL). Eighty patients were treated with adjunctive agents for alcohol withdrawal including antipsychotics (n = 57), opioids (n = 27), clonidine (n = 35), and phenobarbital (n = 23). Average time of flumazenil administration was 4.7 days (1-11 days) after abstinence, and average dose was 0.5 mg (0.2-1 mg). At the time of flumazenil administration, delirium was described as hypoactive (n = 21), hyperactive (n = 15), mixed (n = 41), or not specified (n = 8). Response was not documented in 11 cases. Sixty-two (72.9 %) patients had significant objective improvement after receiving flumazenil. Fifty-six patients required more than one dose (average 5.6 doses). There were no major adverse events and minor adverse effects included transiently increased anxiety in two patients: 1 patient who received 0.5 mg on abstinence day 2 and another patient who received 0.2 mg flumazenil on abstinence day 11. This is the largest series diagnosing benzodiazepine delirium after AWS in patients receiving flumazenil. During the treatment of AWS, if delirium is present on day 5, a test dose of flumazenil may be considered to establish benzodiazepine delirium. With the limited data set often accompanying patients with AWS, flumazenil diagnosed benzodiazepine delirium during the treatment of AWS and improved impairments in cognition and behavior without serious or life-threatening adverse events in our patients.

Spinosin is a C-glycoside flavonoid isolated from the seeds of Zizyphus jujuba var. spinosa. This study investigated the effect of spinosin on cholinergic blockade-induced memory impairment in mice. Behavioral tests were conducted using the passive avoidance, Y-maze, and Morris water maze tasks to evaluate the memory-ameliorating effect of spinosin. Spinosin (10 or 20mg/kg, p.o.) significantly ameliorated scopolamine-induced cognitive impairment in these behavioral tasks with a prolonged latency time in the passive avoidance task, an increased percentage of spontaneous alternation in the Y-maze task and a lengthened swimming time in target quadrant in the Morris water maze task. In addition, a single administration of spinosin in normal naïve mice also enhanced the latency time in the passive avoidance task. To identify the mechanism of the memory-ameliorating effect of spinosin, receptor antagonism analysis and Western blotting were performed. The ameliorating effect of spinosin on scopolamine-induced memory impairment was significantly antagonized by a sub-effective dose (0.5mg/kg, i.p.) of 8-hydroxy-2-(di-N-propylamino)tetralin, a 5-HT1A receptor agonist. In addition, spinosin significantly increased the expression levels of phosphorylated extracellular signal-regulated kinases and cAMP response element-binding proteins in the hippocampus. Taken together, these results indicate that the memory-ameliorating effect of spinosin may be, in part, due to the serotonergic neurotransmitter system, and that spinosin may be useful for the treatment of cognitive dysfunction in diseases such as Alzheimer's disease., (Copyright © 2014. Published by Elsevier Inc.)

Chloral hydrate is the most commonly used sedative for paediatric diagnostic procedures in China with a success rate of around 80%. Intranasal dexmedetomidine is used for rescue sedation in our centre. This prospective investigation evaluated 213 children aged one month to 10 years who were not adequately sedated following administration of chloral hydrate. Children were randomly assigned to receive rescue intranasal dexmedetomidine at 1 μg.kg(-1) (group 1), 1.5 μg.kg(-1) (group 2) or 2 μg.kg(-1) (group 3). The sedation level was assessed every 10 min using a modified observer's assessment of alertness/sedation scale. Successful rescue sedation in groups 1, 2 and 3 were 56 (83.6%), 66 (89.2%) and 51 (96.2%), respectively. Increasing the rescue dose was associated with an increased success rate with an odds ratio of 4.12 (95% CI 1.13-14.98), p = 0.032. We conclude that intranasal dexmedetomidine is effective for sedation in children who do not respond to chloral hydrate., (© 2014 The Association of Anaesthetists of Great Britain and Ireland.)

Eugenol is utilized together with zinc oxide in odontological clinical for the cementation of temporary prostheses and the temporary restoration of teeth and cavities. This work explored the antinociceptive effects of the eugenol in different models of acute pain in mice and investigated its possible modulation of the inhibitory (opioid) and excitatory (glutamatergic and pro-inflammatory cytokines) pathways of nociceptive signaling. The administration of eugenol (3-300 mg/kg, p.o., 60 min or i.p., 30 min) inhibited 82 ± 10% and 90 ± 6% of the acetic acid-induced nociception, with ID₅₀ values of 51.3 and 50.2 mg/kg, respectively. In the glutamate test, eugenol (0.3-100 mg/kg, i.p.) reduced the response behavior by 62 ± 5% with an ID₅₀ of 5.6 mg/kg. In addition, the antinociceptive effect of eugenol (10 mg/kg, i.p.) in the glutamate test was prevented by the i.p. treatment for mice with naloxone. The pretreatment of mice with eugenol (10 mg/kg, i.p.) was able to inhibit the nociception induced by the intrathecal (i.t.) injection of glutamate (37 ± 9%), kainic (acid kainite) (41 ± 12%), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (55 ± 5%), and substance P (SP) (39 ± 8%). Furthermore, eugenol (10 mg/kg, i.p.) also inhibited biting induced by tumor necrosis factor alpha (TNF-α, 65 ± 8%). These results extend our current knowledge of eugenol and confirm that it promotes significant antinociception against different mouse models of acute pain. The mechanism of action appears to involve the modulation of the opioid system and glutamatergic receptors (i.e., kainate and AMPA), and the inhibition of TNF-α. Thus, eugenol could represent an important compound in the treatment for acute pain., (© 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.)

Objectives: To evaluate the effectiveness of two doses of doxapram in reversing acepromazine sedation in dogs., Methods: Using a crossover design, 10 adult mixed-breed dogs received 0·05 mg/kg acepromazine, intramuscularly (im) followed 30 minutes later by one of the three randomly determined treatments: 0·0625 mL/kg saline, intravenously (iv), 1·25 mg/kg doxapram, iv or 2·5 mg/kg doxapram, iv. Sedation scores were obtained by a single, blinded observer at 0, 15 and 30 minutes after acepromazine administration and at 5, 15 and 30 minutes after the treatment administration., Results: The mean baseline sedation score of all the treatments was not different among treatments. All the dogs had a significant increase in sedation score at 30 minutes after acepromazine administration. Both the low and high doses of doxapram showed a significant decrease in sedation score compared to saline, but there was no significant difference between the two doses. Five dogs in the high dose group panted after treatment injection, and this was significantly more than in the low dose group., Clinical Significance: Doxapram is effective in reducing the sedative effects of acepromazine over a short period of time. A dose of 1·25 mg/kg effectively decreases acepromazine sedation without causing panting., (© 2013 British Small Animal Veterinary Association.)

Background: Flumazenil is generally administered to antagonise the sedative effect of midazolam. However, although flumazenil completely antagonises the sedative effect of midazolam, a few effects remain unantagonised. Hence, it is unclear whether flumazenil restores the attenuation of the arterial-cardiac baroreflex (i.e. arterial-heart rate reflex) induced by midazolam. We investigated the antagonistic effect of flumazenil administered after midazolam on cardiac baroreflex, to reveal whether complete recovery from midazolam-induced sedation by flumazenil administration is accompanied by restoration of midazolam's attenuating effects on the cardiac baroreflex., Method: Twelve healthy male subjects received midazolam followed by flumazenil until complete recovery from midazolam sedation. Before and during midazolam sedation, and after flumazenil administration, cardiac baroreflex function was assessed by sequence analysis and transfer function analysis between spontaneous oscillations in systolic arterial pressure and R-R interval., Results: During midazolam sedation, defined by an Observer's Assessment of Alertness/Sedation scale score of 3, BIS value decreased significantly. Simultaneously, the baroreflex indices of the two analyses decreased significantly compared with baseline, suggesting attenuated cardiac baroreflex function. With complete recovery from midazolam sedation by flumazenil, indicated by an Observer's Assessment of Alertness/Sedation scale score of 5, BIS values returned to the baseline level. Simultaneously, cardiac baroreflex indices also returned to baseline levels., Conclusion: The present results suggest that complete recovery from midazolam sedation by flumazenil is accompanied by restoration of the attenuated cardiac baroreflex function induced by midazolam., (© 2012 The Acta Anaesthesiologica Scandinavica Foundation.)

Twenty-eight anesthetic events were carried out on 24 free-ranging Scandinavian gray wolves (Canis lupus) by darting from a helicopter with 5 mg medetomidine and 250 mg ketamine during winter in 2002 and 2003. Mean±SD doses were 0.162±0.008 mg medetomidine/kg and 8.1±0.4 mg ketamine/kg in juveniles (7-10 mo old) and 0.110±0.014 mg medetomidine/kg and 5.7±0.5 mg ketamine/kg in adults (>19 mo old). Mean±SD induction time was shorter (P<0.01) in juveniles (2.3±0.8 min) than in adults (4.1±0.6 min). In 26 cases, the animals were completely immobilized after one dart. Muscle relaxation was good, palpebral reflexes were present, and there were no reactions to handling or minor painful stimuli. Mild to severe hyperthermia was detected in 14/28 anesthetic events. Atipamezole (5 mg per mg medetomidine) was injected intramuscularly for reversal 98±28 and 94±40 min after darting in juveniles and adults, respectively. Mean±SD time from administration of atipamezole to coordinated walking was 38±20 min in juveniles and 41±21 min in adults. Recovery was uneventful in 25 anesthetic events, although vomiting was observed in five animals. One adult that did not respond to atipamezole was given intravenous fluids and was fully recovered 8 hr after darting. Two animals died 7-9 hr after capture, despite intensive care. Both mortalities were attributed to shock and circulatory collapse following stress-induced hyperthermia. Although effective, this combination cannot be recommended for darting free-ranging wolves from helicopter at the doses presented here because of the severe hyperthermia seen in several wolves, two deaths, and prolonged recovery in one individual.

Opioid analgesics are the mainstay of treatment of moderate and severe pain. Remifentanil is an ultrashort acting opioid analgesic used in emergency department (ED)procedural sedation, whereas buprenorphine/naloxone (Suboxone) is an opioid agonist-antagonist combination used in the treatment of addiction-prone individuals. We report here a case of buprenorphine/naloxone inhibition of remifentanil analgesia in a patient undergoing ED procedural sedation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Although there have been many reports on the effects of midazolam on vital function and the recovery profile, little is known about muscle power during sedation. The purpose of this study was to investigate the effects of midazolam on muscle power during moderate sedation., Materials and Methods: The subjects were 20 male volunteers classified as American Society of Anesthesiologists physical status I. Each subject underwent 2 experiments in a randomized crossover manner (midazolam and control groups). After baseline data were obtained, midazolam (0.05 mg/kg) was administered. Thirty minutes after midazolam administration, flumazenil (0.5 mg) was administered to antagonize the sedative effects of midazolam in the midazolam group. Heart rate, noninvasive blood pressure, arterial oxygen saturation, respiratory rate, and the bispectral index value were monitored. The Observer's Assessment of Alertness/Sedation scale and the correct-answer rate of the Stroop color word test were assessed. To evaluate muscle power, grip strength and bite force were measured. After baseline measurement, all variables were measured 2, 5, 10, 20, and 30 minutes after midazolam administration and 5, 10, and 20 minutes after flumazenil administration. For statistical comparisons, repeated measures analysis of variance, the Friedman χ(2) test, and the Student t test for paired samples were used., Results: No significant changes were observed for any variable in the control group. In the midazolam group, the bispectral index value and the Observer's Assessment of Alertness/Sedation scale decreased during midazolam sedation. The correct-answer rate of the Stroop color word test decreased 5 and 10 minutes after midazolam administration. Grip strength decreased during midazolam sedation. Bite force increased immediately after midazolam administration and remained increased even after flumazenil administration., Conclusions: Although the detailed mechanisms are unknown, bite force increases despite the muscle-relaxant action of midazolam during sedation and persists even with flumazenil reversal., (Copyright © 2012 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: To establish a safe, reliable and reversible immobilization protocol for captive juvenile crocodiles., Study Design: Prospective, randomized, clinical study., Animals: Thirty male estuarine crocodiles (body mass 1-12.1 kg) and 10 male Australian freshwater crocodiles (body mass 4.1-12.8 kg)., Methods: An optimized dose of medetomidine (0.5 mg kg(-1)) was administered intramuscularly (IM) into the tail (Group 1; n = 5), pelvic limb (Group 2; n = 5) and thoracic limb (Groups 3 and 4; n = 5 in each group) of estuarine crocodiles weighing 3-12.1 kg. Their heart and respiratory rates and degree of immobilization were monitored every 15 minutes until recovery and daily thereafter for 3 subsequent days. In Group 4 (n = 5), medetomidine was antagonized with an optimized dose of atipamezole (2.5 mg kg(-1)) given IM into the thoracic limb and time to recovery recorded. The effects of increasing doses of medetomidine given IM in the thoracic limb (n = 4) and intravenously (n = 6) were determined in 1-2 kg estuarine crocodiles. Australian freshwater crocodiles (4.1-12.8 kg) were administered medetomidine IM into the thoracic limb in divided doses at 0.5 mg kg(-1) (n = 5) and 0.75 mg kg(-1) (n = 5) and similarly monitored., Results: Immobilization was achieved only in the estuarine crocodiles >3 kg and when medetomidine was administered into the thoracic limb. Immobilization was achieved within 30 minutes and the duration of immobilization lasted approximately 90 minutes. Immobilization in estuarine crocodiles was readily reversed with atipamezole. A dose of 0.75 g kg(-1) was required to immobilize Australian freshwater crocodiles and the onset of immobilization was longer and the duration shorter than seen in the estuarine crocodiles. The heart and respiratory rates of all immobilized animals decreased significantly and arterial blood pressure became undetectable in the animals in which it was measured., Conclusions and Clinical Relevance: Medetomidine administered in the thoracic limb of captive estuarine and Australian freshwater crocodiles, ranging from 3 to 12.8 kg, provides a predictable onset and duration of immobilization sufficient for physical examination, sample collection, short minor procedures and translocation of the animals. Atipamezole administered in the thoracic limb results in complete reversal of the effects of medetomidine in the estuarine crocodile and a rapid return to normal behaviour., (© 2012 The Authors. Veterinary Anaesthesia and Analgesia. © 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.)

The Judas technique is a method used for landscape control of feral donkeys (Equus asinus) in northern Australia. Central to the success of any Judas program is the safe, efficient, and humane attachment of the telemetry device. For feral donkeys, this involves the use of field immobilization. We examine the replacement of the current chemical capture agent, succinylcholine, with contemporary immobilization agents to achieve positive animal welfare outcomes. A combination of medetomidine and ketamine delivered by remote injection from a helicopter was used to capture 14 free-ranging feral donkeys for the fitting of telemetry collars in Western Australia in November 2010. Dose rates of 0.14 mg/kg medetomidine and 4.1 mg/kg ketamine were appropriate to immobilize animals in 9 min (± SD = 3). Mean recovery time (total time in recumbency) was 21 min (± 14). All animals recovered uneventfully after being administered atipamezole, a specific antagonist of medetomidine, intramuscularly at 0.35 mg/kg. Physiologic parameters were recorded during recumbency, with environment-related hyperthermia being the only abnormality recognized. No significant complications were encountered, and this drug combination represents an efficient approach to capturing wild donkeys. This new method allows a rapid, safe, cost-effective approach to the immobilization of feral donkeys for use as Judas animals. This drug combination will replace the relatively inhumane succinylcholine for the field immobilization of feral donkeys.

Background: 5-HT(1A)-R-agonist repinotan was shown to counteract a morphine-induced ventilatory depression but had pronociceptive effects at small doses (0.2 μg/kg). It remained to be clarified (1) whether a moderate dose of repinotan, sufficient to stimulate spontaneous breathing, impairs antinociception if plasma concentration decreases over time, and if (2) moderate doses prevent ventilatory depression if given before the opioid., Methods: A dose-response curve of the repinotan effects on spontaneous minute ventilation during continuous remifentanil infusion in anesthetized rats was established to identify moderate doses: (1) tail-flick reflex latencies to assess nociception were recorded until 60 min after cessation of a continuous remifentanil infusion with or without a concomitant moderate repinotan dose (10 μg/kg), and (2) remifentanil boluses (2.5 μg/kg) were given after repinotan (10 and 20 μg/kg)., Results: (1) Remifentanil-induced antinociception lasted only 5 min after infusion was stopped (tail-flick reflex latencies; median [interquartile range], 97 [54-100]% of maximum possible effect; P = 0.034), but was extended by repinotan (10 μg/kg) to 30 min (tail-flick reflex latencies, 100 [75-100]% of maximum possible effect; P = 0.031). Repinotan (10 μg/kg) alone did not have any significant antinociceptive effect. (2) The ventilatory depression by remifentanil boluses (2.5 μg/kg; minute ventilation, -65 [-81 to -56]%; P = 0.031, n = 5) was blunted by repinotan (20 μg/kg; minute ventilation, -24 [-53 to 13]%; P = 0.313, compared with the pretreatment level)., Conclusions: Repinotan prevented remifentanil-induced ventilatory depression in spontaneously breathing, anesthetized rats. Although repinotan did not depress nociception itself, it prolonged the profound antinociception after discontinuation of remifentanil infusion.

Combinations of medetomidine and ketamine were evaluated in free-ranging, wild Norwegian reindeer (Rangifer tarandus tarandus) as part of a reintroduction program in southwestern Norway in November 1995 and November 1996. The drugs were administered by dart from a helicopter. The mean (SD) effective immobilizing doses for 29 adults (8 males, 21 females) were 0.21 (0.04) mg medetomidine/kg and 1.0 (0.2) mg ketamine/ kg based on estimated body mass. There was no significant difference in mean induction times between males and females. However, animals with optimal hits (shoulder or thigh muscles; n=16) had a significantly shorter (P<0.05) mean induction time than did animals with suboptimal hits (abdomen or flank; n=13), 5.6 (2.2) min and 11.1 (4.7) min, respectively. Inductions were calm, and immobilized animals were maintained in sternal recumbency. Clinical side effects included hypoxemia and hyperthermia in most animals. For reversal, all animals received 5 mg atipamezole per mg medetomidine, half intravenously and half intramuscularly, and the mean (SD) time to standing was 3.7 (3.6) min.

Background: Naloxone, as a low-priced and available drug, may be useful in improvement of signs and symptoms of benzodiazepines intoxication. The aim of this study was assessment of its effect on benzodiazepines poisoning., Methods: In this clinical-trial study, patients with typical signs and symptoms of benzodiazepines poisoning, who were referred to a poisoning center in Tehran in 2008, were selected. After recording of patients' characteristics, supportive treatment was initiated and patients were randomly assigned to the case group with intravenous (IV) injection of two 0.4 mg naloxone ampules or to the control group. Their signs and symptoms were evaluated again 0.5 hour later. Each of diazepam, clonazepam and alperazolam drug group had 30 patients and lorazepam drug group had 26 patients, half of which patients in each drug group received naloxone., Results: Most of the participants were female and the mean age was 28 years. There were no significant differences between case and control groups in age, sex, time of drug consumption, tablet counts, signs and symptoms and level of consciousness at the admission time in each drug types. After naloxone injection in case groups, all signs and symptoms significantly improved in all drug types in comparison to control groups except nystagmus. In addition, level of consciousness significantly improved in case groups in all drug types except lorazepam., Conclusion: Findings of the study showed that naloxone is effective in management of benzodiazepines poisoning. However, future clinical trials with greater sample size are recommended.

Key developments in GABA pharmacology over the last 30 years are reviewed with special reference to the advances pioneered by Erminio Costa. His passion for innovative science, and his quest for novel therapies for psychiatric disorders are particularly apparent in his fundamental contributions to the field of GABA research, with a focus on anxiety disorders and schizophrenia. He was a cofounder of the GABAergic mechanism of action of benzodiazepines. He envisaged partial agonists as novel anxiolytics. He identified DBI (diazepam binding inhibitor) as endogenous agonist of neurosteroidogenesis with multiple CNS effects and he pointed to the developmental origin of GABAergic dysfunctions in schizophrenia through his discovery of a reelin deficit, all this in collaboration with Sandro Guidotti. Today, the GABA pharmacology comprises selective hypnotics, non-sedative anxiolytics, memory enhancers and powerful analgesics. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

This study is to examine the sedative, hypnotic and anticonvulsive effects of an adenosine analogue, WS090501. The spontaneous locomotor activity was recorded by open field equipment, and the EEG of rats was recorded by polyphysiograph. Pentylenetetrazol (PTZ)-induced seizure model was used. The spontaneous locomotor activity was decreased by WS090501 at various doses (0.06, 0.13, and 0.25 mg x kg(-1)), and the decreasing rate was 28.4%, 47.1% and 61.2% respectively. Furthermore, the effect of WS090501 on spontaneous locomotor activity of mice can be antagonized by DPCPX, a selective adenosine A1R antagonist, but cannot be antagonized by SCH58261, a selective adenosine A2AR antagonist. The NREM sleep was significantly increased by WS090501 (0.05 and 0.2 mg x kg(-1)), and the increasing rate was 27.6% and 102.8%, respectively, at 6th hour after administration. The REM sleep decreased significantly at the higher dose. PTZ induced serious convulsion in mice. The latency of convulsion was prolonged, and the number of seizure and mortality decreased after administration of WS090501. These results show that WS090501 has potent sedative, hypnotic and anticonvulsive effects, which may be mediated through adenosine A1R.

Exposure to Gamma-aminobutyric-acid (GABA)(A)-receptor agonists and N-Methyl-D-Aspartate (NMDA)-antagonists has been demonstrated to induce neurodegeneration in newborn rats. Exogenous erythropoietin (EPO) protects against NMDA antagonist-mediated neuronal death. In this study we evaluated whether EPO is also effective in limiting neurodegeneration of the GABA(A)-mimetic agent propofol in newborn rats. 6 day old rats were randomized to one of four groups and treated with intraperitoneal applications of 3 x 30 mg/kg propofol at 0, 90 and 180 min, propofol in combination with 5000 IU/kg rEPO, propofol in combination with 20,000 IU/kg rEPO or sham injections of PAD II solution as controls. After 24h, brains of the animals were histopathologically examined and a summation score of degenerated cells was calculated for every brain. Propofol increased neuronal degeneration scores from 16,090+/-4336 to 28,860+/-6569 (p<0.01). This effect was completely abolished by low-dose rEPO (14,270+/-4542, p<0.001 versus propofol only; p>0.05 versus controls). In contrast, high-dose rEPO was not protective (23 930+/-8896, p>0.05 versus propofol only). Propofol may cause neuronal death in newborn rat brains, which is prevented by low-dose rEPO but not high-dose rEPO., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Previous studies in our laboratory showed that cannabinoid CB1 receptor knockout mice (CB1-/-) presented increased anxiety-like behaviours that did not respond to the anxiolytic actions of benzodiazepines. These results suggest that the pharmacological effects of benzodiazepines may involve the participation of cannabinoid CB1 receptors. Therefore, the purpose of this study was to examine the effects of alprazolam and the cannabinoid CB1 receptor antagonist AM251 on behavioural assays (light-dark box test, neurological severity score and step-down inhibitory avoidance test) and on the functional activity of the CB1 receptor (WIN-55,212-stimulated [(35)S] guanosine triphosphate (GTP) gamma binding autoradiography).The administration of alprazolam (40 microg/kg, intraperitoneal (i.p.)) decreased anxiety-like behaviours in the light-dark box test and significantly reduced WIN-55,212-stimulated [(35)S]GTPgamma binding autoradiography in the amygdala and in the CA1 field of the hippocampus, but was without effects on CA2, CA3 and the dentate gyrus (DG) of the hippocampus. The administration of AM251 (3 mg/kg, i.p.) blocked the anxiolytic action of alprazolam (40 microg/kg, i.p.), significantly reduced the sedative (ataxia, neurological severity score in the 0.5 cm bar) and the amnesic actions (short time term memory (1 h after electric shock)) of alprazolam (0.5 mg/kg, i.p.).Taken together, these findings revealed that cannabinoid CB1 receptor plays a pivotal role in the pharmacological actions of benzodiazepines. Furthermore, these results suggest that blockade of cannabinoid CB1 receptors may be useful in the treatment of patients with problems related to the consumption of benzodiazepines. Further clinical trials are needed to test this hypothesis.

Sedation for gastrointestinal endoscopies is obtained by opioids, benzodiazepines, propofol, ketamine and/or droperidol. The pharmacokinetic profile of some sedatives/anesthetics renders them advantageous over others. Opioids, mainly pethidine and fentanyl, are the most popular. Though newer opioids provide a faster recovery, fentanyl is safe and advantageous due to its lower cost. Remifentanil, due to its pharmacokinetic profile (elimination half-life: 9 min), is advantageous for ambulatory patients, though it is not known whether the high cost compensates the benefits. Midazolam is the benzodiazepine of choice as it has a shorter duration of action and a better pharmacokinetic profile than diazepam. Propofol, an intravenous anesthetic, has become very popular for gastrointestinal endoscopies in sedative doses. The opioid and benzodiazepine antagonists, naloxone and flumazenil, are indicated only in particular circumstances, like deep sedation with threatening respiratory depression. Ketamine and droperidol are not popular agents for sedation in the modern endoscopic practice., (Copyright 2010 S. Karger AG, Basel.)

Twenty adult, free-ranging, female Svalbard reindeer (Rangifer tarandus platyrhynchus) were immobilized with medetomidine-ketamine from 30 September through 9 October 1999 at Svalbard, Norway (78 degrees 55'N, 11 degrees 56'E). The animals were approached on foot, and the drugs were administered into the heavy muscles of the shoulder or the thigh by dart syringe injection from 15-25 m. The mean (SD) induction time in 10 animals immobilized with 0.113 (0.009) mg/kg of medetomidine and 2.26 (0.19) mg/kg of ketamine (group 2) was significantly shorter (P < 0.05) than in 10 animals immobilized with 0.215 (0.043) mg/kg of medetomidine and 1.08 (0.21) mg/kg of ketamine (group 1): 6.5 (3.2) versus 14.3 (10.6) min, respectively. Inductions were calm, major clinical side effects were not detected, and there were no significant differences between groups regarding rectal temperature, pulse rate, respiratory rate, or relative arterial oxygen saturation. The 5 mg of atipamezole/1 mg of medetomidine were given half intramuscularly and half subcutaneously for reversal, and the animals were standing within 9.5 (4.5, group 1) and 13.0 (6.4, group 2) min, respectively, after administration of the antagonist.

Background: Incremental sublingual (SL) dosing of triazolam has emerged as a popular sedation technique. Nevertheless, few studies have evaluated the technique's safety or efficacy. Given its popularity, an easily administered rescue strategy is needed., Methods: The authors conducted a randomized controlled clinical trial to investigate how intraoral submucosal flumazenil (0.2 milligram) attenuates central nervous system depression produced by incremental SL dosing of triazolam (three doses of 0.25 mg across 90 minutes) in 14 adults. The authors assessed outcomes by using the Observer's Assessment of Alertness/Sedation (OAA/S) scale, bispectral index (BIS) and physiological monitoring., Results: The OAA/S and BIS scores increased after the flumazenil injection at the 30-minute observation point, but they were not sustained. Six hours after the initial dose of triazolam had been administered (four hours after the flumazenil or placebo challenge), all patients could be discharged from the dental clinic., Conclusions: Deep sedation from incremental SL dosing of triazolam is incompletely reversed by a single intraoral injection of flumazenil. The reversal did not persist. The authors discharged the patients from the dental clinic at 360 minutes., Clinical Implications: A single intraoral injection of flumazenil (0.2 mg) cannot immediately reverse oversedation with triazolam. A higher dose might be effective. Reversal for the purpose of discharging the patient early is neither appropriate nor safe.

The authors report on a case of successful reversal of sedation with flumazenil, a benzodiazepine antagonist, in a child following a moderate traumatic brain injury and demonstrate the utility of flumazenil to reverse benzodiazepine effects in traumatically injured children.

Thyrotropin-releasing hormone (TRH) and its analogs have a number of neurobiological functions and therapeutic uses in disorders of the central nervous system. In this study, the newly synthesized TRH analogs were evaluated for central nervous system activity in pentobarbital-induced sleeping in mice. The most potent TRH analog (L-pGlu-(2-propyl)-L-His-L-ProNH(2) coded as NP-647) was evaluated for its antiepileptic potential in various seizure models in mice in comparison with TRH. Intravenous pretreatment with NP-647 (10 and 20 micromol/kg body wt) significantly delayed the onset and reduced the frequency of convulsions in the pentylenetetrazole model, but not in the maximum electroshock seizure model. Also, it was found to be protective against picrotoxin- and kainic acid-induced seizures. However, NP-647 did not significantly affect theophylline-induced seizures. Further study of the effect of NP-647 on locomotor activity and a functional observational battery revealed that it did not significantly exhibit any undesirable effects as compared with vehicle and TRH. NP-647 did not significantly affect cerebral blood flow, whereas the native peptide TRH markedly increased cerebral blood flow. Furthermore, NP-647 exerted antiepileptic activity without significantly altering plasma thyroid-stimulating hormone levels and mean arterial blood pressure. This suggests that NP-647 is more selective for central nervous system activity and devoid of hormonal and cerebrovascular system effects. In contrast, TRH exhibited cardiac and endocrine effects as marked by significant elevation in mean arterial blood pressure and plasma thyroid-stimulating hormone levels. This study demonstrates that NP-647 has potential antiepileptic activity devoid of undesirable effects and, thus, can be exploited for the prevention and treatment of epilepsy.