Nicole Calder

Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men.

STUDY OBJECTIVES Suvorexant (MK-4305) is an orexin receptor antagonist being developed for the treatment of insomnia. This report describes the effects of nighttime administration of suvorexant on polysomnography (PSG) sleep parameters in healthy young men. DESIGN Randomized, double-blind, placebo-controlled, 4-period crossover PSG study, followed by an additional 5(th) period to assess pharmacokinetics. SETTING Sleep laboratory. PARTICIPANTS Healthy young men between 18 and 45 years of age (22 enrolled, 19 completed). INTERVENTIONS Periods 1-4: suvorexant (10 mg, 50 mg, or 100 mg) or placebo 1 h before nighttime PSG recording. Period 5: suvorexant 10 mg, 50 mg, or 100 mg. MEASUREMENTS AND RESULTS In Periods 1-4, overnight sleep parameters were recorded by PSG and next-morning residual effects were assessed by psychomotor performance tests and subjective assessments. Statistically significant sleep-promoting effects were observed with all doses of suvorexant compared to placebo. Suvorexant 50 mg and 100 mg significantly decreased latency to persistent sleep and wake after sleep onset time, and increased sleep efficiency. Suvorexant 10 mg significantly decreased wake after sleep onset time. There were no statistically significant effects of suvorexant on EEG frequency bands including delta (slow wave) activity based on power spectral analysis. Suvorexant was well tolerated. There was no evidence of next-day residual effects for suvorexant 10 mg. Suvorexant 50 mg statistically significantly reduced subjective alertness, and suvorexant 100 mg significantly increased reaction time and reduced subjective alertness. There were no statistically significant effects of any suvorexant dose on digit symbol substitution test performance. In Period 5, plasma samples of suvorexant were collected for pharmacokinetic evaluation. The median T(max) was 3 hours and apparent terminal t(½) was 9-13 hours. CONCLUSIONS In healthy young men without sleep disorders, suvorexant promoted sleep with some evidence of residual effects at the highest doses.

Effect of Morphine and Pregabalin Compared With Diphenhydramine Hydrochloride and Placebo on Hyperalgesia and Allodynia Induced by Intradermal Capsaicin in Healthy Male Subjects

UNLABELLED Intradermal (ID) capsaicin injection in humans induces spontaneous pain, flare, primary hyperalgesia, secondary hyperalgesia, and allodynia. Secondary hyperalgesia and allodynia are a reflection of central sensitization. The effect of treatment of single doses of (1) pregabalin, 300 mg single oral dose, and (2) morphine, 10 mg IV, on the area of secondary hyperalgesia induced by ID capsaicin injection was studied by using a randomized, double-blinded, placebo-controlled, 4-period, cross-over design in 20 healthy men. Compared with active placebo diphenhydramine (50 mg oral dose), pregabalin and morphine significantly reduced the area of secondary hyperalgesia over 15 to 240 minutes after capsaicin injection (approximately 25%, P = .002 and approximately 33%, P < .001, respectively). A smaller reduction was observed when pregabalin and morphine were compared with true placebo (approximately 13%, P = .081 and approximately 24%, P = .009, respectively). Diphenhydramine, on the other hand, increased the area of secondary hyperalgesia in comparison with true placebo (approximately 16%, P = .061). The relationship between the baseline area of hyperalgesia and assay sensitivity suggests that establishing minimum entry criteria for the baseline area of hyperalgesia requirement increases the sensitivity of the assay. PERSPECTIVE These results suggest that the minimally invasive intradermal capsaicin model, when it is compared with true placebo, can potentially be used for an early assessment of relevant pharmacology of novel analgesic compounds in healthy subjects. This platform may provide a means to rapidly assess new analgesics and enhance dose selection and decision-making during clinical development.

Tolerability, pharmacokinetics and night-time effects on postural sway and critical flicker fusion of gaboxadol and zolpidem in elderly subjects

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/information-processing ability as assessed by critical flicker fusion. AIMS To evaluate tolerability, pharmacokinetics and night-time effects on body sway and critical flicker fusion (CFF) of gaboxadol following bedtime dosing in healthy elderly subjects. METHODS Subjects (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. RESULTS The number of subjects with adverse events was 14 for gaboxadol 10 mg, seven for zolpidem and nine for placebo; most were mild or moderate in intensity. Two women discontinued the study following gaboxadol; one vomited and one experienced a severe vasovagal syncope after venepuncture. Mean gaboxadol t(max) was 2 h, t((1/2)) was 1.7 h, AUC(0-infinity) was 430 ng.h ml(-1) and C(max) was 139 ng ml(-1). At 1.5 h and 4 h post dose, zolpidem increased body sway relative to placebo (P < 0.01). Gaboxadol increased body sway at 4 h (P < 0.001) and 8 h (P < 0.05) relative to placebo. At 1.5 h, the time point closest to peak drug concentrations, zolpidem increased body sway compared with gaboxadol (P < 0.01). Gaboxadol and zolpidem had no effects on CFF vs. placebo. CONCLUSIONS A bedtime dose of gaboxadol 10 mg was generally well tolerated. Changes in body sway at 1.5 h after bedtime dosing were smaller with gaboxadol 10 mg than with zolpidem 5 mg, whereas changes were similar at 4 h for both treatments and returned to near baseline at 8 h.

The nasal mucosal late allergic reaction to grass pollen involves type 2 inflammation (IL-5 and IL-13), the inflammasome (IL-1β), and complement

Non-invasive mucosal sampling (nasosorption and nasal curettage) was used following nasal allergen challenge with grass pollen in subjects with allergic rhinitis, in order to define the molecular basis of the late allergic reaction (LAR). It was found that the nasal LAR to grass pollen involves parallel changes in pathways of type 2 inflammation (IL-4, IL-5 and IL-13), inflammasome-related (IL-1β), and complement and circadian-associated genes. A grass pollen nasal spray was given to subjects with hay fever followed by serial sampling, in which cytokines and chemokines were measured in absorbed nasal mucosal lining fluid, and global gene expression (transcriptomics) assessed in nasal mucosal curettage samples. Twelve of 19 subjects responded with elevations in interleukin (IL)-5, IL-13, IL-1β and MIP-1β/CCL4 protein levels in the late phase. In addition, in these individuals whole-genome expression profiling showed upregulation of type 2 inflammation involving eosinophils and IL-4, IL-5 and IL-13; neutrophil recruitment with IL-1α and IL-1β; the alternative pathway of complement (factor P and C5aR); and prominent effects on circadian-associated transcription regulators. Baseline IL-33 mRNA strongly correlated with these late-phase responses, whereas a single oral dose of prednisone dose-dependently reversed most nasal allergen challenge-induced cytokine and transcript responses. This study shows that the LAR to grass pollen involves a range of inflammatory pathways and suggests potential new biomarkers and therapeutic targets. Furthermore, the marked variation in mucosal inflammatory events between different patients suggests that in the future precision mucosal sampling may enable rational specific therapy.

Assessment of the AccuSwayPLUS System in Measuring the Effect of Lorazepam on Body Sway in Healthy Volunteers

AbstractAim: To assess the AccuSwayPLUS system, which aims to quantify deficiency in human balance, using the measurement of the effect of lorazepam on body sway in healthy volunteers. Methods: A double-blind, randomised, placebo-controlled, two-way crossover study in 12 healthy male and female volunteers. Participants received a single oral dose of lorazepam 2mg and placebo, 1 week apart. Body sway was assessed using the AccuSwayPLUS system, by measuring the length of the path of the centre-of-pressure (COP), and the area of the 95% confidence ellipse enclosing the COP (A95). Body sway was assessed at baseline and at 2, 3, 4, 6, 12, 18 and 24 hours after administration, in two positions: with the participants’ eyes open and feet apart at hip’s width (EOFA), and with their eyes shut and feet together (ESFT). Results: Statistically significant differences in body sway between lorazepam and placebo were detected for up to 18 hours after administration. The largest change in body sway was 2 hours post-dose, in the EOFA position; the mean (95% confidence interval) difference between lorazepam and placebo in fold change of A95 was 7.67 (3.88, 15.17), and in length of COP was 1.61 (1.23, 2.10). Conclusion: The findings confirm that the AccuSwayPLUS system is a useful tool for detecting changes in body sway induced by centrally acting drugs.