The arousal effect of hyperbaric oxygen through orexin/hypocretin an upregulation on ketamine/ethanol-induced unconsciousness in male rats.

Approaches that facilitate the recovery from coma would have enormous impacts on patient outcomes and medical economics. Orexin-producing neurons release orexins (also known as hypocretins) energy-dependently to maintain arousal. Hyperbaric oxygen (HBO) could increase ATP levels by preserving mitochondrial function. We investigated, for the first time, the arousal effects of HBO and orexins mechanisms in a rat model of unconsciousness induced by ketamine or ethanol. A total of 120 Sprague-Dawley male rats were used in this study. Unconsciousness was induced either by intraperitoneal injection of ketamine or ethanol. The HBO treatment (100% O2 at 3 ATA) was administered immediately after unconsciousness induction for 1 hr. SB334867, orexin-1 receptor (OX1R) inhibitor, or JNJ10397049, orexin-2 receptor (OX2R) inhibitor was administered 30 min intraperitoneally before unconsciousness induction. Loss of righting reflex test (LORR) and Garcia test were used to evaluate the unconsciousness duration and neurological deficits after recovering from unconsciousness, respectively. Enzyme-linked immunosorbent assay was used to measure brain tissue ATP and orexin A levels. Ketamine or ethanol injection resulted in LORR immediately and neurological deficits 6 hr after unconsciousness induction. HBO treatment significantly reduced the LORR duration, improved Garcia scores and unregulated ATP and orexin A levels in the brain tissue. Administration of OX1R inhibitor or OX2 R inhibitor abolished arousal and neurological benefits of HBO. In conclusion, HBO exerted arousal-promoting effects on unconscious rats induced by ketamine or ethanol. The underlying mechanism was via, at least in part, ATP/orexin A upregulation. HBO may be a practical clinical approach to accelerate unconsciousness recovery in patients.

Limited Efficacy of Caffeine and Recovery Costs During and Following 5 Days of Chronic Sleep Restriction.

Objectives: To investigate the effects of caffeine on psychomotor vigilance and sleepiness during sleep restriction and following subsequent recovery sleep. Methods: Participants were N = 48 healthy good sleepers. All participants underwent five nights of sleep satiation (time-in-bed [TIB]: 10 hours), followed by five nights of sleep restriction (TIB: 5 hours), and three nights of recovery sleep (TIB: 8 hours) in a sleep laboratory. Caffeine (200 mg) or placebo was administered in the form of chewing gum at 08:00 am and 12:00 pm each day during the sleep restriction phase. Participants completed hourly 10-minute psychomotor vigilance tests and a modified Maintenance of Wakefulness Test approximately every 4 hours during the sleep restriction and recovery phases. Results: Caffeine maintained objective alertness compared to placebo across the first 3 days of sleep restriction, but this effect was no longer evident by the fourth day. A similar pattern of results was found for Maintenance of Wakefulness Test sleep latencies, such that those in the caffeine group (compared to placebo) did not show maintenance of wakefulness relative to baseline after the second night of restriction. Compared to placebo, participants in the caffeine condition displayed slower return to baseline in alertness and wakefulness across the recovery sleep period. Finally, the caffeine group showed greater N3 sleep duration during recovery. Conclusions: Caffeine appears to have limited efficacy for maintaining alertness and wakefulness across 5 days of sleep restriction. Perhaps more importantly, there may be recovery costs associated with caffeine use following conditions of prolonged sleep loss.

[Neuromonitoring in anaesthesia]. / Narkosetiefenmessung in der Anästhesie - Neue Möglichkeiten und Ziele der Narkoseüberwachung.

Modern computer-based methods to monitor anesthesia are widespread. They are used in order to avoid awareness, to reduce consumption of anesthetics, to optimize recovery times and to detect prolonged times of deep anesthesia and associated immunsuppression, mortality and morbidity. This review illustrates the evidence with which these goals were achieved until now. Finally, a recommendation for each indication is given. The useage of EEG-monitoring may help to avoid awareness and allows a reduced of consumption of anesthetics. The question if a cumulated time of deep anesthesia is associated with elevated mortality might be of a certain importance in the future.

Steady-state methadone effect on generalized arousal in male and female mice.

Methadone is widely used in treatment of short-acting opiate addiction. The on-off effects of opioids have been documented to have profound differences from steady-state opioids. The authors hypothesize that opioids play important roles in either generalized arousal (GA) or aversive state of arousal during opioid withdrawal. Both male and female C57BL6 mice received steady-state methadone (SSM) through osmotic pumps at 10 or 20 mg/kg/day, and GA was measured in voluntary motor activity, sensory responsivity, and contextual fear conditioning. SSM did not have any effect on those GA behaviors in either sex. Females had higher activity and less fear conditioning than males. The effects of SSM on stress-responsive orexin gene expression in the lateral hypothalamus (LH) and medial hypothalamus (MH, including perifornical and dorsomedial areas) were measured after the behavioral tests. Females showed significantly lower basal LH (but not MH) orexin mRNA levels than males. A panel of GA stressors increased LH orexin mRNA levels in females only; these increases were blunted by SSM at 20 mg/kg. In summary, SSM had no effect on GA behaviors. In females, SSM blunted the GA stress-induced LH orexin gene expression.

Abuse liability assessment of atomoxetine in a drug-abusing population.

BACKGROUND: Atomoxetine is a non-amphetamine medication approved to treat ADHD in children, adolescents, and adults. Previous studies demonstrated low abuse potential for atomoxetine in recreational drug users. This study assessed the abuse potential of atomoxetine in stimulant-preferring drug abusers compared to methylphenidate and phentermine as positive controls and desipramine and placebo as negative controls. METHODS: Forty male and female, 32-53 years old stimulant-preferring drug abusers completed this balanced Latin-square designed study. Subjects received acute, double-blind doses of placebo, desipramine (100 and 200 mg), methylphenidate (90 mg), phentermine (60 mg), and atomoxetine (45, 90, and 180 mg). Subjective and physiological effects were collected for 24 h following each drug treatment. RESULTS: Methylphenidate and phentermine were liked significantly more than placebo, atomoxetine, or desipramine. No atomoxetine dose was liked significantly more than placebo and liking scores for atomoxetine were similar to, or significantly lower than, desipramine, as assessed by the Drug Rating Questionnaire-Subject. While atomoxetine 45 and 180 mg did not significantly change any Addiction Research Center Inventory (ARCI) scores, atomoxetine 90 mg significantly increased A and BG stimulant scores of the ARCI and both methylphenidate and phentermine produced greater A and BG increases than any atomoxetine dose and also increased MBG (euphoria) scores relative to placebo. CONCLUSIONS: Atomoxetine has significantly less abuse liability than methylphenidate or phentermine and no greater abuse liability than desipramine.

Individual differences in salivary cortisol and alpha-amylase in mothers and their infants: relation to tobacco smoke exposure.

Tobacco smoke exposure affects the activity of both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Statistics reveal 41 million children in the U.S. are regularly exposed to tobacco smoke, but we know little about the effects of environmental tobacco smoke exposure on HPA and SNS activity in early childhood. This study assayed cotinine (a metabolite of nicotine), cortisol, and alpha-amylase (sAA) in the saliva of mother-infant dyads from 197 low income and ethnically diverse families. The dyads were identified as tobacco smoke exposed (N = 82) or nonexposed (N = 115) based on maternal self-reports of smoking and salivary cotinine levels greater or less than 10 ng/ml. As expected, higher rates of maternal smoking behavior were associated with higher levels of cotinine in mothers' and their infants' saliva. On average, smoking mothers' salivary cotinine levels were 281 times higher compared to their nonsmoking counterparts, and 23 times higher compared to their own infant's salivary cotinine levels. Infants of smoking mothers had salivary cotinine levels that were four times higher than infants with nonsmoking mothers. Mothers who smoked had higher salivary cortisol levels and lower sAA activity compared to nonsmoking mothers. There were no associations between maternal smoking behavior, infant's salivary cotinine levels, or tobacco exposure group, and cortisol or sAA measured in infant's saliva. The findings are discussed in relation to the influence of smoking tobacco on the validity of salivary biomarkers of stress.

Assessment and treatment of nocturnal panic attacks.

Nocturnal panic (NP), waking from sleep in a state of panic, is a common occurrence among patients with panic disorder, with 44-71% reporting at least one such attack. NP is a non-REM event that is distinct from sleep terrors, sleep apnea, nightmares or dream-induced arousals. This review outlines recent advances in the characterization of NP, as well as current approaches to the assessment and treatment of NP. In contrast to earlier work, more recent studies suggest that patients with NP do not differ from patients without NP on sleep architecture, sleep physiology, self-reported sleep quality and severity of panic disorder. However, more precise measurement of physiological precipitants and features is warranted. Assessment of NP focuses on ruling out other explanations for NP, with differential diagnosis based on interviews, sleep polysomnography and ambulatory recording of sleep. Psychological treatment (cognitive-behavioral therapy) targets misappraisals of anxiety sensations, hyperventilatory response, and conditioned reactions to internal, physical cues. Recent evidence supports the efficacy of this approach, however, controlled studies on pharmacological agents in the treatment of NP are lacking. Research is needed to examine the effects of combined cognitive-behavioral therapy and medications, compared to medication alone in the treatment of NP.

Pheromonal influences on sociosexual behavior in postmenopausal women.

To determine whether a putative human sex-attractant pheromone increases specific sociosexual behaviors of postmenopausal women, we tested a chemically synthesized formula derived from research with underarm secretions from heterosexually active, fertile women that was recently tested on young women. Participants (n = 44, mean age = 57 years) were postmenopausal women who volunteered for a double-blind placebo-controlled study designed, to test an odorless pheromone, added to your preferred fragrance, to learn if it might increase the romance in your life. During the experimental 6-week period, a significantly greater proportion of participants using the pheromone formula (40.9%) than placebo (13.6%) recorded an increase over their own weekly average baseline frequency of petting, kissing, and affection (p = .02). More pheromone (68.2%) than placebo (40.9%) users experienced an increase in at least one of the four intimate sociosexual behaviors (p = .04). Sexual motivation frequency, as expressed in masturbation, was not increased in pheromone users. These results suggest that the pheromone formulation worn with perfume for a period of 6 weeks has sex-attractant effects for postmenopausal women.

Sensory evaluation of alcohol-related and neutral stimuli: psychophysical assessment of stimulus intensity.

Research on reactivity to alcohol cues yielded conflicting results. While some authors report differences in subjective or physiological responses to drug-related stimuli between addicts and healthy controls, other researchers found no group differences in response patterns. Moreover, a dissociation of self-report and psychophysiological measures of cue reactivity is often observed. To some extent, this might be due to confounding stimulus type (neutral vs. drug-related) and stimulus intensity in cue reactivity research. The purpose of the present study is to match alcoholic and nonalcoholic stimuli according to their empirically assessed intensity. Stimulus intensity is estimated by magnitude estimation. Results clearly indicate that alcohol-related cues differ considerably from water and other neutral stimuli with respect to perceived intensity. Moreover, estimation of stimulus intensity depends on mode of presentation (smell vs. combined smell and taste). Results of previous cue reactivity studies in the alcohol field might have been affected in different degrees by confounding stimulus type and intensity.

Safety assessment of encapsulated morphine delivered epidurally in a sustained-release multivesicular liposome preparation in dogs.

We have shown that the epidural (EPI) delivery of morphine encapsulated in multivesicular liposomes (DepoFoam drug delivery system) produces a sustained clearance of morphine and a prolonged analgesia. We have sought to subsequently determine the likelihood of deleterious effects on local tissue of repetitive epidural injections of this encapsulated morphine preparation (C0401). Beagle dogs were prepared according to protocol approved by the Institutional Animal Care and Use Committee under volatile general anesthesia with chronic lumbar EPI catheters and subcutaneous injection ports. Male and female dogs (three groups) received a total of 4 EPI injections at 8-day intervals of 3 mL of C0401 (10 mg/mL morphine) (N = 6), DepoFoam vehicle (N = 6), or 0.9% sodium chloride (N = 6). Following EPI-C0401, but not saline or DepoFoam vehicle, there were transient (< 72 hr) decreases in food consumption, arousal, hindlimb muscle tone, and body temperature. Heart rate was unaltered, but there were modest decreases in blood pressure and respiratory rate, which persisted for 24-72 hr after C0401. No persistent changes in sensory/motor function, body weight, or stool/urine production were observed. Cerebrospinal fluid, blood chemistry, and urinalysis performed at surgery and on the day of sacrifice (24 hr after the last dose) were within normal ranges. Gross pathology at necropsy was unremarkable. Spinal histopathology findings were judged to be minimal (e.g., modest pericatheter inflammation and fibrosis) and present in all dogs. However, a statistical trend in the rank order of pathology scores was noted (Saline < DepoFoam vehicle < C0401). Repeated EPI injection of C0401 at the maximum dose that could be administered (30 mg) resulted in moderate, transient behavioral and physiological effects after each injection, consistent with morphine administration, and a modest effect on cord histopathology. This level of pathology is reflected in the lack of change observed in cerebrospinal fluid and lack of neurological findings. These results suggest that C0401 is without significant pathological effects at this dose after repeated epidural delivery in dogs.

[Anesthesia with remifentanil combined with desflurane or sevoflurane in lumbar intervertebral disk operations]. / Anästhesie mit Remifentanil in Kombination mit Desfluran oder Sevofluran bei lumbalen Bandscheibenoperationen.

Recovery characteristics, haemodynamic profile, analgesic requirement and costs were evaluated and compared in patients undergoing elective lumbar discectomy with remifentanil-based anaesthesia using either desflurane or sevoflurane as the volatile anaesthetic agent. Sixty-two patients (ASA I/II status) were randomly assigned to receive either desflurane and remifentanil or sevoflurane and remifentanil (in oxygen/air) for anaesthesia. After induction with 0.5 microgram/kg/min remifentanil, 4 to 5 mg/kg thiopentone and 0.5 mg/kg atracurium, the patients received 0.25 microgram/kg/min remifentanil and 0.5 +/- 0.05 MAC of one of the volatile anaesthetic agents for further maintenance of anaesthesia. At the end of surgery, early emergence from anaesthesia was recorded by assessing the time to sufficient spontaneous respiration, eye opening and tracheal extubation. The total demand of piritramide in the postoperative period was determined using patient-controlled analgesia (PCA device). Quality of pain therapy was assessed via a verbal ranking scale (VRS). Side-effects such as postoperative nausea, vomiting or shivering were recorded in the postanaesthetic care unit. In both groups, the haemodynamic profile was nearly identical. Mean arterial pressure (-18%) and heart rate (-23%) were significantly reduced throughout anaesthesia in both groups. All recovery parameters were significantly shorter in the desflurane group in comparison with the sevoflurane group (e.g. time to tracheal extubation: 8.5 +/- 3.0 min vs. 11.9 +/- 4.6 min). No significant differences between the groups were observed concerning the amount of piritramide required, side-effects such as nausea and vomiting or the total cost of anaesthesia. In conclusion, both anaesthetic techniques provide adequate haemodynamic stability and postoperative pain control in a surgical procedure with minimal trauma. Incidence and severity of side-effects such as nausea, vomiting or shivering did not differ between the groups and were acceptable under clinical conditions. Costs for desflurane were significantly higher than those for sevoflurane, but total costs were not different between the groups. Concerning recovery profile, desflurane/remifentanil seems to have small advantages over sevoflurane/remifentanil in patients undergoing lumbar vertebral disc resection.

Assessment of minimally responsive patients: clinical difficulties of single-case design.

Improved management of very severely central nervous system (CNS) injured individuals has given rise to an increasing number of patients in a minimally responsive state. There is a growing literature stressing the importance of accurately determining these patients' level of cognitive functioning and its role in appropriate rehabilitation and long term management. The single case design model appears to be the intervention of choice, with its great flexibility and tailored approach to each individual case. The recent literature has focused on the technical aspects of the assessment, offering clear procedural guidelines. Unfortunately, there is a dearth of information about clinical factors such as clinical setting and family involvement, which may interfere with or prevent a planned intervention. The case of MT is presented, who was the subject of a single case intervention 9 months following an extremely severe traumatic brain injury. The planned intervention was to examine the effects of a psychostimulant on MT's level of arousal, in order to improve his participation in the rehabilitation programme. Beyond the results (which were equivocal), the clinical difficulties in conducting single case study designs in rehabilitation are discussed. Ways to minimize these difficulties are proposed.

Electrophysiological assessment (The Multiple Sleep Latency Test) of the biphasic effects of ethanol in humans.

The Multiple Sleep Latency Test (MSLT) was used to assess the effects of ethanol at the peak and descending phases of the breath ethanol curve. Ethanol (0.75 g/kg) was administered (at 0900 hr) to 8 healthy, normal-sleeping men, aged 21 to 45 years old after 8 hr of sleep the previous night. MSLTs were conducted and breath ethanol concentrations (BrECs) were measured at 15, 45, 75, 105, 225, and 345 min after drinking was completed. Subjective measures were administered immediately before each sleep latency test. BrECs over the first 75 min (tests 1 to 3) peaked and differed from all subsequent tests (tests 4 to 6) over which BrECs declined. Sleep latency and subjective measures were averaged over tests 1 to 3 and 4 to 6. There was a significant increase in mean sleep latency relative to placebo for tests 1 to 3 and a significant reduction for tests 4 to 6. The subjective measure of stimulation sedation, the Biphasic Alcohol Effects Scale, showed lessened sedation after ethanol versus placebo on tests 1 to 3, compared with tests 4 to 6. This study confirmed the presence of a biphasic ethanol effect using an electrophysiological method (MSLT), showing increased physiological alertness on the peak phase of the BrEC curve and increased sedation on the descending phase. Relative to the effects observed on the MSLT with other low-dose stimulant drugs, the stimulatory effect of ethanol was mild.

Multivariate time of peak effects assessment for use in selecting time of testing in acute neurotoxicity studies.

One of the aims of conducting observational assessments shortly following administration of a test compound is to provide information regarding the profile of acute neurotoxic effects. By limiting the time of peak effects (TOPE) determination to a time range-finding study using only gait and arousal as the end-points for determining time of peak effects, as was proposed in the IPCS/WHO Collaborative Study on Neurobehavioral Screening Methods protocol, it is possible that the time of testing selected for the acute study proper may underestimate other neurotoxic effects which show a different time course. We explored the feasibility of including measures of autonomic activity as well as clonic/tonic movements in the TOPE determination in two experiments using chlorpyrifos and carbaryl as test compounds. A scoring system based on the original operational definitions provided in the IPCS/WHO protocol was devised. Results indicated that there were considerable differences in the time course for autonomic effects and convulsive behavior in comparison to effects on gait and arousal. It is concluded that the use of a multivariate approach for TOPE determination may provide a more comprehensive empirical basis for selecting a testing time for studies designed to profile acute neurotoxic effects.

P300 assessment of opiate and cocaine users: effects of detoxification and buprenorphine treatment.

We assessed cognitive function following heroin and cocaine detoxification and investigated whether buprenorphine treatment improves the disruptive effects of detoxification. Three groups of male volunteers meeting DSM-III-R criteria for concurrent opiate and cocaine dependence were tested using an auditory oddball paradigm before and after detoxification, and again on the 15th day of either buprenorphine or placebo treatment. There were no significant differences in P300 amplitude, latency, or topographic distribution between drug-dependent subjects and controls on admission day. Following detoxification there was a significant decrease in P300 amplitude in the drug-dependent group at a time when self-reported signs of withdrawal were minimal. Buprenorphine treatment significantly reversed the P300 amplitude decrement following detoxification, whereas placebo-treated subjects continued to show depressed P300 amplitudes. These data demonstrate that buprenorphine treatment is effective in eliminating detoxification-induced impairments in one measure of cognitive ability.

[Quantitative assessment of catecholamine secretion as a rational principle of anesthesia management in pheochromocytoma surgery]. / Quantitative Erfassung der Katecholaminsekretion als rationale Grundlage des Anästhesiemanagements bei Phäochromozytomexstirpation.

AIM OF THE STUDY: Fifteen patients with phaeochromocytoma who underwent surgery were studied consecutively. METHODS: They received either (10) a balanced anaesthesia technique with isoflurane and fentanyl or (5) a combination of propofol and alfentanil for total intravenous anaesthesia. EEG processing was performed in order to guarantee adequate anaesthetic depth. Antihypertensive therapy was performed with sodium nitropusside. Continuous blood sampling was performed with a roller pump and an autosampler system in order to get high resolution measured of plasma catecholamines. Their concentration was measured by HPLC with electrochemical detection. RESULTS: There were 100fold differences in the maximal catecholamine concentrations during phaeochromocytoma resection between patients. In some cases adrenaline and noradrenaline levels exceeded normal values by a factor of 1000 to 1500. Secretion rates were calculated on a pharmacokinetic basis an revealed secretion rates of 0.3 to 97.3 micrograms/min for adrenalin and 6.7 und 402.8 micrograms/min for noradrenaline. If systolic blood pressures were greater than 160 mmHg sodium nitroprusside was given by infusion with a rate of 300 +/- 315 micrograms/min. Over a period of 69.2 +/- 39.8 min during resection of the tumor the total dose was 7017 +/- 12433 micrograms. CONCLUSIONS: There were positive correlations between plasma catecholamine concentrations, systolic blood pressure values, and infusion rates of sodium nitroprusside. The comparison of the two anaesthetic techniques resulted in a significant reduction of antihypertensive therapy and more stable haemodynamics in patients with total intravenous anaesthesia. However, the beneficial effect of this anaesthesia regimen has to be proven on a larger basis of patients in a randomized manner.