In healthy young men without sleep disorders, suvorexant promoted sleep with some evidence of residual effects at the highest doses.

The effect of a 15% reduction in maternal nutrition for the first 70 days of gestation on cardiovascular and hypothalamic–pituitary–adrenal (HPA) axis responses to administration of corticotropin releasing hormone (CRH) + arginine vasopressin (AVP) was studied at 128 0.7 days gestation in fetal sheep and postnatally, at 85 4.5 days in young lambs. The effect on the fetal cardiovascular response to acute hypoxaemia was also examined. Under basal conditions, fetal heart rate (FHR) was reduced (P<0.05) and basal femoral artery vascular resistance (FVR) was increased (P<0.05) in fetuses of dietary-restricted (R) ewes compared with controls (C). Fetal mean arterial pressure (MAP) was similar in both groups. Femoral artery vascular resistance was also greater during hypoxaemia in R fetuses compared with C fetuses (P<0.05), suggesting that chemoreflex mechanisms were augmented in the R group. The fetal ACTH response to CRH + AVP was similar in both groups. However, cortisol responses to CRH + AVP were smaller in R fetuses compared with C fetuses (P<0.05). Postnatally, basal MAP (P<0.05), and ACTH (P<0.01) and cortisol (P<0.001) responses were greater in R lambs compared with C lambs. It was concluded that modest maternal undernutrition during pregnancy alters development of the cardiovascular system, producing elevated blood pressure in postnatal life. Development of the HPA axis is also altered, with reduced activity during fetal life, but increased activity postnatally. The data suggest that the HPA axis may play a role in mediating the elevation of MAP in R lambs.

No abstract

Orexin neuropeptides regulate sleep/wake through orexin receptors (OX1R, OX2R); OX2R is the predominant mediator of arousal promotion. The potential for single OX2R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX2R-single antagonist. Preclinically, MK-1064 promotes sleep and increases both rapid eye movement (REM) and non-REM (NREM) sleep in rats at OX2R occupancies higher than the range observed for dual orexin receptor antagonists. Similar to dual antagonists, MK-1064 increases NREM and REM sleep in dogs without inducing cataplexy. Two Phase I studies in healthy human subjects evaluated safety, tolerability, pharmacokinetics and sleep-promoting effects of MK-1064, and demonstrated dose-dependent increases in subjective somnolence (via Karolinska Sleepiness Scale and Visual Analogue Scale measures) and sleep (via polysomnography), including increased REM and NREM sleep. Thus, selective OX2R antagonism is sufficient to promote REM and NREM sleep across species, similarly to that seen with dual orexin receptor antagonism.

Relebactam is a novel class A and C β-lactamase inhibitor that is being developed in combination with imipenem-cilastatin for the treatment of serious infections with Gram-negative bacteria. Here we report on two phase 1 randomized, double-blind, placebo-controlled pharmacokinetics, safety, and tolerability studies of relebactam administered with or without imipenem-cilastatin to healthy participants: (i) a single-dose (25 to 1,150 mg) and multiple-dose (50 to 625 mg every 6 h [q6h] for 7 to 14 days) escalation study with men and (ii) a single-dose (125 mg) study with women and elderly individuals.

ABSTRACT. Infants who have had bronchopulmonary dysplasia (BPD) are at an increased risk of sudden infant death syndrome. Because failure of the cardiorespiratory response to hypoxia is suggested to play a key role in sudden infant death syndrome, we tested the hypothesis that infants who have had BPD have a reduced respiratory chemoreflex response to hypoxia. We examined the reflex respiratory responses to breath-by-breath alternations in fractional inspired oxygen concentration in eight infants who had had BPD (mean gestation = 27 wk, mean postnatal age = 93 d) who were no longer on supplemental oxygen and compared the responses with those of 12 preterm infants who had not required supplemental oxygen or been mechanically ventilated since birth (mean gestation = 30 wk, mean postnatal age = 38 d). For test runs we alternated fractional inspired oxygen concentration through two gas delivery lines between 0.21 and 0.16 on a breath-by-breath basis, and for control runs we alternated the inspirate between the two gas lines with a fractional inspired oxygen concentration of 0.21 in each. Respiration was measured using inductance plethysmography. infants with BPD showed no significant differences between test and control responses for any respiratory variable. In contrast, all respiratory variables in the preterm infants showed test responses significantly greater than control. We speculate that the "blunted" chemoreflex respiratory response seen in infants with BPD may predispose them to subsequent respiratory failure, but we do not know which component of the chemoreflex is impaired. (Pediatr Res 35: 677481,1994)

Sudden intense sensory stimuli elicit a cascade of involuntary responses, including a short-latency skeletal muscular response ('eyeblink startle response') and longer-latency autonomic responses. These responses are enhanced when subjects anticipate an aversive event compared to periods when subjects are resting ('fear potentiation'). It has been reported previously that the anxiolytic diazepam can suppress fear-potentiation of the eyeblink startle response in human volunteers. The present experiment aimed to confirm and extend these observations by examining the effect of another benzodiazepine, lorazepam, on the eyeblink and skin conductance components of the acoustic startle, and on fear-potentiation of these responses. Eighteen male volunteers participated in three weekly sessions in which they received oral treatment with placebo, lorazepam (1 mg) and lorazepam (2 mg), according to a balanced three-period, crossover, double-blind design. Two hours after ingestion of the treatments, electromyographic responses of the orbicularis oculi muscle and skin conductance responses were evoked by sound pulses during alternating periods in which the threat of an electric shock (electrodes attached to the subject's wrist) was present (THREAT) and absent (SAFE). The THREAT condition was associated with significant increase in the amplitude of the electromyographic (EMG) and skin conductance responses; there were also increases in baseline skin conductance, the number and amplitude of 'spontaneous' skin conductance fluctuations and self-rated anxiety. Lorazepam attenuated the effect of THREAT on self-rated anxiety and on the amplitude of the EMG response, but had no significant effect on fear-potentiation of the skin conductance responses. These results extend previous findings of the effect of diazepam on the fear-potentiated eyeblink startle response to lorazepam, and suggest that fear-potentiation of the later autonomic component of the startle response may be less sensitive to benzodiazepines than the fear-potentiated eyeblink response and self-rated anxiety.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Body sway increases in older adults and may lead to an increase in the risk of falling.• The problem of impaired stability in the elderly may be compounded by the use of hypnotics, which have been associated with an increased risk of next-day falls as well as drowsiness.• The potential adverse effects of hypnotic drugs on steadiness may be exacerbated during the night, in the event that an individual needs to get out of bed. WHAT THIS STUDY ADDS• This study examines the effects of gaboxadol (an investigational treatment for insomnia), zolpidem (a current hypnotic included as an active control) and placebo on body sway and attention/information processing ability following bedtime dosing in elderly subjects who were woken during the night for assessments.• Zolpidem and gaboxadol increased body sway at various time points during the night relative to placebo; at 1.5 h post dose, the time of peak concentrations of both drugs, gaboxadol produced less impairment than zolpidem.• Compared with placebo, neither gaboxadol nor zolpidem impaired attention/informationprocessing ability as assessed by critical flicker fusion. AIMSTo evaluate tolerability, pharmacokinetics and night-time effects on body sway and critical flicker fusion (CFF) of gaboxadol following bedtime dosing in healthy elderly subjects. METHODSSubjects (17 women, seven men) aged 65-75 years received gaboxadol 10 mg, zolpidem 5 mg (active control) or placebo at 22.00 h in a three-period, randomized, double-blind crossover study. They were awakened during the night for evaluation of body sway and CFF. Pharmacokinetics of gaboxadol were assessed during a fourth single-blind treatment period. Adverse events were recorded throughout the study.