The GP, the rep and the handouts.
Explore the source record for details and available documents.
Drug Industry↗
Biomedical subjects
W F Seidel
Publications and source records attributed to W F Seidel.
Response-rate suppression in operant paradigm as predictor of soporific potency in rats and identification of three novel sedative-hypnotic neuroactive steroids.
Novel neuroactive steroids were evaluated for their effects on operant responding, rotorod motor performance, and electroencephalogram recording in rats. Co 134444, Co 177843, and Co 127501 were compared with the prototypical gamma-aminobutyric acid(A)-positive allosteric modulators triazolam, zolpidem, pentobarbital, pregnanolone, and CCD 3693. Each of the compounds produced a dose-related decrease in response rates under a variable-interval 2-min schedule of positive reinforcement in an operant paradigm. In addition, all compounds produced a dose-related increase in ataxia and significant increases in nonrapid eye movement sleep in this experiment or have been previously reported to do so. Co 134444, Co 177843, and Co 127501 increased nonrapid eye movement sleep at doses that had no effect on rapid eye movement sleep. All of the compounds were more potent at decreasing operant responding than they were at increasing ataxia. Furthermore, the potency of compounds to produce response-rate suppression in an operant paradigm appeared to be a better predictor of soporific potency than did potency in the rotorod assay. The screening for sedative-hypnotic activity resulted in the identification of the novel orally active neuroactive steroids Co 134444, Co 177843, and Co 127501.
Animals↗
Compensatory sleep responses to wakefulness induced by the dopamine autoreceptor antagonist (-)DS121.
The effect of the dopamine autoreceptor antagonist (-)DS121 on wakefulness, locomotor activity, body temperature and subsequent compensatory sleep responses was examined in the rat. Animals entrained to a light-dark cycle were treated at 5 h after lights-on (CT-5) with 0.5, 1, 5 or 10 mg/kg i.p. (-)DS121 or methylcellulose vehicle. An additional group received 5 mg/kg i.p. (-)DS121 or vehicle 6 h after lights-off (CT-18). At CT-5, (-)DS121 dose-dependently increased wakefulness, locomotor activity and body temperature, and decreased both non-rapid eye movement sleep (NREM) and rapid eye movement sleep (REM) during the first 4 h post-treatment relative to vehicle controls. REM interference lasted up to 3 h longer than NREM. Low doses of (-)DS121 (0.5 and 1 mg/kg) produced relatively little waking that was not followed by significant compensatory sleep responses. In contrast, higher doses (5 and 10 mg/kg) produced compensatory hypersomnolence (robust increases in NREM immediately after the primary waking effect) that was proportional to the duration of drug-induced wakefulness. NREM recovery 24 h post-treatment was the same for the 5 mg/kg (65.4 +/- 9.9 min) and 10 mg/kg (64.8 +/- 9.3 min) doses, but was not proportional to prior wake duration. NREM displaced by drug-induced wakefulness was recovered completely by 24 h post-treatment at the 5 mg/kg dose, but only 63.5% recovered at 10 mg/kg. In contrast, equivalent wakefulness produced by sleep deprivation yielded 100% NREM recovery. At CT-18, (-)DS121 (5 mg/kg) increased wakefulness without disproportionately increasing locomotor activity, and was compensated fully by 24 h post-treatment. These data show that (-)DS121 dose-dependently increases wakefulness, which is followed by hypersomnolence that is proportional to drug-induced wake-promoting efficacy.
Animals↗
CCD-3693: an orally bioavailable analog of the endogenous neuroactive steroid, pregnanolone, demonstrates potent sedative hypnotic actions in the rat.
An endogenous neuroactive steroid, pregnanolone, and an orally available synthetic analog, CCD-3693, were administered to rats at the middle of their circadian activity phase (6 hr after lights off). Electroencephalogram-defined sleep-wake states, locomotor activity and body temperature were concurrently measured 30 hr before and after treatment. Identical procedures were used to test triazolam and zolpidem. Triazolam (0.1-1.6 mg/kg), zolpidem (2.5-10 mg/kg) and the neuroactive steroids (10-30 mg/kg) produced dose-dependent increases in non-rapid eye movement (NREM) sleep. At this dose and time of day (in which the rats were predominantly awake during the 6 hr before treatment) the neuroactive steroids appeared more intrinsically efficacious in promoting NREM sleep than the benzodiazepine ligands. The neurosteroids did not, however, significantly interfere with rapid eye movement sleep and were more selective in reducing (EEG) wakefulness, with relatively less locomotor activity impairment during waking than triazolam and zolpidem. In addition, the benzodiazepine receptor ligands showed distinct "rebound" wakefulness after the NREM sleep-promoting effect subsided, although the neuroactive steroids did not. In addition, in vitro binding studies and in vivo pharmacological data confirmed that CCD-3693 was orally active in standard tests of anxiety, anticonvulsant, loss-of-righting and passive avoidance.
Administration, Oral↗
Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat.
Modafinil, a novel compound for treating excessive sleepiness, potently increases wakefulness in laboratory rodents, cats, monkeys and humans. Although its mechanism of action is unknown, modafinil appears to be unlike classic stimulants. We investigated this generality by testing the selectivity of this compound for wake-promoting effects (e.g., relative to locomotor effects) and homeostatic sleep responses after drug-induced waking relative to the prototypical stimulant methamphetamine (METH). Continuous measures of electroencephalogram (EEG) sleep-wakefulness, locomotor activity (LMA) and body temperature (Tb) were obtained from adult male Wistar rats 3 days before and after treatment with modafinil (30, 100 and 300 mg/kg i.p.), 0.25% methylcellulose (vehicle) or METH (0.5 and 1.0 mg/kg i.p.). Individually housed rats in a 24-h light-dark cycle (LD 12:12) were treated 5 h after lights-on (CT-5). LMA and Tb were monitored via intraperitoneal telemetry. Sleep-wake stages and LMA were recorded every 10 s, Tb every minute. During the first 3 h post-treatment, modafinil and METH significantly and dose-dependently increased EEG wake time (P < .01 for 30 mg/kg modafinil, all other P < .0001) and wake episode duration. Although the cumulative increases in wakefulness were statistically equivalent, METH, but not modafinil, produced subsequent rebound hypersomnolence. At these equipotent wake-promoting doses, modafinil produced the same total amount of REM sleep inhibition but during a longer time than METH. Modafinil also increased LMA amount (counts/h, P < .001) and LMA intensity (counts/min awake, P < .001) less than METH. Both rebound hypersomnolence and increased LMA intensity, which are undesirable features in wake-promoting drugs, were not observed after modafinil treatment, and thus further differentiated modafinil from amphetamine-like stimulants.
Animals↗
Alpha-2 adrenergic modulation of sleep: time-of-day-dependent pharmacodynamic profiles of dexmedetomidine and clonidine in the rat.
Alpha adrenergic agonists such as clonidine are widely used for their antihypertensor effects, but they also cause sedation. The mechanisms underlying soporific effects of such compounds are poorly understood, but appear to involve the alpha-2 adrenergic receptor sub-type. To further investigate the role of this receptor in sleep-wake regulation, rats received injections i.p. either during their peak of activity (circadian time CT-18: 6 hr after lights out) or near the mid-point of their sleep-dominated phase (CT-5: 5 hr after lights on) with either the highly selective alpha-2 agonist dexmedetomidine (dMED) 0.02 to 0.04 mg/kg or the less selective alpha-2 agonist, clonidine 0.04 to 0.08 mg/kg, or vehicle. Clonidine and dMED showed remarkable overall similarities in their soporific profiles. Except for the lower dose of clonidine, both CT-5 and CT-18 treatments increased the percent of time spent in non-REM (NREM) sleep. The increase in NREM was followed by a reduction of NREM sleep that was accompanied by locomotor activity and body temperature above control levels. After CT-5 treatments, this period of reduced NREM sleep was followed by a secondary increase in NREM 7 to 10 hr posttreatment. REM sleep was markedly reduced for 9 to 10 hr after all treatments at both times of day, with elevated REM levels 18 to 30 hr posttreatment. Pre-treatment with the selective alpha-2 antagonist atipamezole (0.5 mg/kg) reversed the effects of CT-18 dMED 0.04 mg/kg except REM sleep suppression, which was only partially reversed. The NREM-inducing potency of dMED 0.02 mg/kg was greater when administered at CT-18 than at CT-5. Taken together with other evidence, these findings suggest that the profound NREM-inducing effects of dMED may be mediated by postsynaptic alpha-2 adrenoceptors. Furthermore, the pharmacodynamic action of alpha-2 adrenergic agonists, like many other sedative hypnotics (e.g., benzodiazepines), produce a hysteresis in sleep-wake regulation characterized by "rebound" waking after drug-induced sleep.
Adrenergic alpha-Agonists↗
Sleep homeostasis in suprachiasmatic nuclei-lesioned rats: effects of sleep deprivation and triazolam administration.
The electroencephalogram (EEG) and electromyogram of rats with lesions in the suprachiasmatic nuclei (SCNx) were recorded during two series of 24-h baseline, 6-h sleep deprivation (SD), and 24-h recovery. At recovery onset, rats were injected i.p. with vehicle (VEH) control solution or 0.4 mg/kg triazolam (TRZ) in a balanced crossover design. Consecutive 10-s epochs were scored for vigilance states and EEG power spectra were computed. Arousal states were uniformly distributed during 24-h baseline (wake 47% of recording time, non-rapid-eye movement sleep (nonREMS) 47%, REMS 7%), and EEG spectra (0-25 Hz) were devoid of significant trends. State-specific EEG power spectra profiles in SCNx rats were similar to those of intact animals reported previously. However, EEG delta power (0.5-3.5 Hz) of nonREMS was markedly lower in SCNx rats. Recovery from 6-h SD was characterised by a short-lasting reduction of REMS, and a long-lasting increase of nonREMS time at the cost of wakefulness. EEG delta power rebounded during the first 8 h in recovery, and fell below baseline level after 12 h in recovery. During 0-2 h TRZ recovery, rats spent more time in nonREMS with higher EEG slow wave activity as compared to the corresponding VEH recovery period. EEG slow wave activity fell below baseline levels 10 h after TRZ injection and termination of SD. We conclude that major features of homeostatic sleep EEG regulation are present in SCNx rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Triazolam fails to induce sleep in suprachiasmatic nucleus-lesioned rats.
Rats with suprachiasmatic nuclei (SCN) lesions did not show increased sleep after triazolam (TRZ) injections at any dose from 0.2 to 1.6 mg/kg, whereas 0.4 mg/kg TRZ given intact rats in the middle of their activity phase significantly increased sleep. Across SCN-lesioned and intact rats, the amount of sleep before and after TRZ 0.4 mg/kg was negatively correlated. SCN-lesioned rats did not have a circadian activity-dominant period and so did not accumulate a biological sleep debt. Their lack of response to TRZ may have resulted from the absence of a sleep debt compared to intact rats injected in the middle of their activity phase. These data support our hypothesis that the homeostatic process controlling sleep gates benzodiazepine hypnotic efficacy.
Animals↗
Triazolam-induced sleep in the rat: influence of prior sleep, circadian time, and light/dark cycles.
Rats entrained to 12-h on /12-h off light schedule and injected with triazolam 0.4 mg/kg at the mid-point of their activity phase (6 h after lights out: circadian time = CT-18) had a stronger hypnotic response than animals free-running in constant dark injected at the equivalent circadian time. In contrast, entrained rats injected 5 h after lights on (CT-5) showed increased wake after injection relative to baseline, largely due to REM sleep inhibition. Hypnotic efficacy was found to be inversely related to prior accumulated sleep. During the 6 h before injection, entrained rats injected at CT-18 slept significantly less than the free-running rats, which in turn slept significantly less than entrained rats injected at CT-5. Taken together, the results suggest that the amount of prior sleep was a more important influence on the response to triazolam than either light/dark per se or circadian phase. Methodologically, automated sleep scoring was found to be an efficient method for examining drug effects, particularly when corroborated by concurrent independent physiological variables and spectral analysis.
Animals↗
Direct measurement of daytime sleepiness after administration of cetirizine and hydroxyzine with a standardized electroencephalographic assessment.
Alertness is a vital function, and medications that do not impair this vital function are clinically desirable in terms of safety. In a comparative study to measure daytime alertness objectively, 60 men and women in good health were assigned to receive either cetirizine, 5 mg, 10 mg, or 20 mg, hydroxyzine, 25 mg, or placebo in a randomized, double-blind, parallel-group design. Subjects slept in the laboratory for 2 consecutive nights to facilitate adaptation. During the second night, the subjects' sleep patterns were recorded by electroencephalogram (EEG), electrooculogram, and chin electromyogram. After the second night, subjects were awakened at 7:30 AM and given a single dose of the assigned treatment. Multiple Sleep Latency Tests (standardized 20-minute opportunities to fall asleep in bed while EEG and eye movements are recorded) were given every 2 hours. Subjects who received cetirizine did not differ from control subjects given placebo in any measure of daytime alertness. Subjects who received hydroxyzine were significantly more sedated than were control subjects given placebo for about 4 hours after treatment. The data from this study provide evidence that cetirizine does not differ from placebo with respect to alertness. The usefulness of the specific and sensitive standardized electroencephalogram, compared with alternative assessments of daytime alertness, is discussed.
Adult↗
Profile of mood states changes during and after 5 weeks of nightly triazolam administration.
This double-blind, placebo-controlled study investigated rebound anxiety during and after 5 weeks of nightly use of triazolam 0.5 mg, a short half-life, rapidly absorbed benzodiazepine hypnotic. The study subjects were chronic insomniacs with moderate levels of psychopathology and prior use of hypnotics. Anxiety was assessed with the Profile of Mood States (POMS), instead of the anxiety scales more typically used in psychopharmacology: the Hamilton Rating Scale for Anxiety and a visual analogue scale. The POMS test was administered twice a day during the study. The results indicated that triazolam was not associated with increased anxiety the morning or the evening after previous-night drug administration. The results are discussed in view of the methodological issues in assessing anxiety in prior studies.
Adult↗
Risk factors for sleep disordered breathing in heterogeneous geriatric populations.
This cross-sectional, multivariate study investigated associations between sleep disordered breathing (SDB) and putative risk factors in a heterogeneous group of 720 individuals over the age of 50 years studied during all-night in-lab polysomnography. Results indicated that: aged men were more likely to show impaired respiration during sleep than aged women; excessive daytime somnolence and parasomniac symptoms (snoring, gasping during sleep) were associated with SDB but insomnia was not; obesity accounted for more variance in SDB than age per se, implying that the prevalence of SDB in some elderly persons could be related to the deposition of body fat seen as individuals grow older. All four risk factors (age, sex, obesity, and symptomatic status) were statistically significant and independent predictors of impaired respiration in sleep in the elderly.
Age Factors↗
Cetirizine effects on objective measures of daytime sleepiness and performance.
Sixty healthy men and women with no sleep complaints, 21 to 45 years of age (mean age 28), were randomly assigned to one of five parallel groups that received one of the following: cetirizine 5 mg (n = 13), 10 mg (n = 13), or 20 mg (n = 11); hydroxyzine 25 mg (n = 12); or placebo (n = 11). After one adaptation night in the lab, the subjects' sleep patterns were recorded from 2300 to 0730 hours. Subjects were in bed during this period. When they awoke at 0730, a test agent was administered according to double-blind technique. Multiple Sleep Latency Tests (MSLT: 20-minute opportunities to fall asleep in bed while EEG and eye movements are recorded) were given at two-hour intervals throughout the day, and a 30-minute vigilance performance test was given at 1000 and 1600 hours. Subjects receiving cetirizine in doses of 5 to 20 mg did not differ from placebo controls in any objective or subjective measure of daytime alertness. Subjects receiving hydroxyzine were significantly more sedated and showed slower reaction times than the placebo control group for at least four hours after treatment. Self-rated feelings of sleepiness, impairment, and fatigue did not differ significantly between groups. This suggests that hydroxyzine subjects may not have been aware of their sleepiness and slower reaction times.
Adult↗
Dose-related effects of triazolam and flurazepam on a circadian rhythm insomnia.
Forty-eight normal subjects had sleep recordings and multiple sleep latency tests (an EEG measure of sleepiness) before and after a 12-hour shift of sleep-wake schedule. After 2 baseline days, subjects postponed sleep until 12:00 noon, then for three 24-hour periods were in bed from 12:00 noon until 8:00 PM. Treatment in parallel groups were administered before shifted sleeps. Sleep disturbance was greatest in the last quarter of shifted nights (6.5 to 8.5 hours after medication). Subjects taking placebo showed significant sleep loss on shifted nights and increased sleepiness the next day. Triazolam, 0.5 mg, reversed the sleep loss and consequent daytime sleepiness associated with the shifted sleep schedule. Triazolam, 0.25 mg, was not significantly better than placebo. In a dose-related manner, flurazepam mitigated the insomnia, but carryover effects left both dose groups more sleepy than were the placebo control subjects. Whether these laboratory results are applicable to clinically occurring forms of transient insomnia remains to be seen.
Adult↗
Sleep and wakefulness in aircrew before and after transoceanic flights.
Aircrew were studied before and after flying one of two routes: San Francisco (SFO) to London (LHR) or SFO to Tokyo (NRT). After an adaptation night, sleep and daytime sleepiness were objectively measured in SFO and during the first layover (L/O) of the target trip. Baseline sleep was slightly shorter than normally reported for similar age subjects and, for several reasons, is not an ideal basis for subsequent comparison. Nevertheless, L/O sleep periods tended to provide either less total sleep or less efficient sleep. Crewmembers' estimates of their sleep duration correlated well with objective measures, but their estimates of daytime sleepiness correlated poorly with objectively measured sleepiness. During baseline there was a significant midday sleep tendency as measured by the Multiple Sleep Latency Test. This tendency occurred at almost the same time (GMT) on the second L/O day in LHR. Since sleepiness has a persistent rhythm which is maximal twice per day, it is suggested that L/O sleep periods be taken at these times of maximal sleepiness and that peak workload should coincide with the subsequent periods of maximal alertness. Although the overall quality of sleep diminished only slightly on this L/O, it is possible that if this relatively small loss accumulated over successive L/Os, the effects on daytime sleepiness could be measurable.
Aerospace Medicine↗
Effects of alprazolam and diazepam on the daytime sleepiness of non-anxious subjects.
Eighteen non-anxious volunteers underwent sleep recordings and daytime tests of sleepiness, performance, and mood while receiving, either alprazolam 0.5 mg b.i.d. or diazepam 5 mg b.i.d. for 7 consecutive days. Recordings and tests were done before treatment and on the 1st and 7th days of treatment. Nocturnal sleep changes were similar for both groups; there were no statistically significant changes in mood. However, levels of daytime sleepiness differed. Alprazolam subjects showed more daytime sedation than diazepam subjects on treatment day 1, but showed a significant decrease in Day 1-7 daytime sedation. Although diazepam subjects were less sedated at the onset, they showed no tolerance to this effect; thus by treatment day 7, the two groups did not differ in levels of daytime sleepiness. Results suggested that tolerance to alprazolam's sedative effects (which develops during the 1st week of treatment) may be separable from tolerance to its antianxiety effects (which develops after at least 4 weeks). As daytime sedation is common and potentially dangerous with most anxiolytics, selective tolerance to this side effect is highly desirable.
Adult↗
Buspirone: an anxiolytic without sedative effect.
Twelve volunteers with a complaint of chronic insomnia participated in a placebo-controlled, double-blind, crossover study of the effects of buspirone t.i.d. on sleep pattern and daytime function. The drug was tested alone and in combination with flurazepam or triazolam. Buspirone alone did not impair objective measures of daytime wakefulness or performance. Impaired alertness was seen the day after bedtime administration of flurazepam but not after triazolam; buspirone did not alter these effects. Buspirone did not affect the Multiple Sleep Latency Test, a sensitive measure of changes in daytime alertness.
Adult↗
Treatment of a 12-hour shift of sleep schedule with benzodiazepines.
Normal sleepers underwent sleep recordings and daytime tests of sleep tendency, performance, and mood while being shifted 180 degrees in their sleep-wake schedule. After two baseline 24-hour periods, subjects postponed sleep until noon. For the next three 24-hour periods, they were in bed from 1200 to 2000 and received triazolam, flurazepam, or placebo at bedtime in parallel groups. Placebo subjects showed significant sleep loss after the shift. Active medication reversed this sleep loss. Despite good sleep, flurazepam subjects appeared most impaired of the three groups on objective assessments of waking function; triazolam subjects were least impaired.
Adult↗