scholarly journals 0198 Psychomotor/Cognitive Effects, Pharmacokinetics and Safety of V117957, a Novel, Highly Potent and Selective Partial Agonist for Nociceptin/Orphanin-FQ Peptide (NOP) Receptors, Administered in Combination with Alcohol in Healthy Subjects

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A78-A78
Author(s):  
M Zhou ◽  
S Harris ◽  
A Cipriano ◽  
R Kapil ◽  
E He ◽  
...  
Keyword(s):  
Cognitive Performance ◽  
Healthy Subjects ◽  
Clinical Laboratory ◽  
Partial Agonist ◽  
Sleep Onset ◽  
Dose Effect ◽  
Body Sway ◽  
Tolerability Profile ◽  
Performance Parameters ◽  
Orphanin Fq

Abstract Introduction V117957 is an investigational nociceptin/orphanin-FQ peptide (NOP) receptor partial agonist designed to treat insomnia by promoting sleep onset and maintenance with minimal residual next-day somnolence or psychomotor impairment. The satisfactory safety/tolerability profile of V117957 has been previously established in ~200 healthy subjects with maximum doses at 30mg following a single oral administration and 10mg once daily for 2 weeks. The present study was conducted to assess the safety/tolerability and pharmacokinetics (PK) of V117957 with co-administered alcohol. Methods A randomized, double-blind, double-dummy, placebo-controlled, balanced six-period crossover design was employed. Single doses (2mg, 6mg) of V117957 and placebo were administered orally to healthy subjects in the morning with and without alcohol (0.7g/kg). Pharmacodynamic (PD) effects of V117957 were assessed, and safety/tolerability and PK interactions were also characterized. The primary PD endpoints (body sway, Digit Vigilance Test, and numeric working memory) were measured through 12 hours postdosing. Results Forty-eight subjects were enrolled and randomized; 46 completed. Compared with placebo, alcohol alone showed an impairment on psychomotor/cognitive performances through 2 hours postdose. V117957 alone showed a dose-dependent impairment. Compared with V117957 alone and alcohol alone, co-administration of alcohol and V117957 showed greater impairment until 8 hours postdose. No subject discontinued due to an adverse event (AE). No clinically meaningful treatment-emergent (TE) changes in clinical laboratory values, vital signs, SpO2 measurements, or 12-lead ECG results were observed. The most common TEAE was somnolence. All plasma and urine PK parameters for V117957 and alcohol were comparable when V117957 or alcohol was administered alone or in combination. Conclusion Single oral doses of V117957, 2mg or 6mg, administered alone or in combination with alcohol in healthy subjects resulted in no notable PK interaction between V117957 and alcohol. A dose-effect relationship in the magnitude and duration of impairment was observed for most psychomotor/cognitive performance parameters. Greater effects of V117957 with alcohol were observed for most psychomotor/cognitive performance parameters up to 8 hours post-dose. Support Funded by Imbrium Therapeutics, a subsidiary of Purdue Pharma L.P.

scholarly journals 0502 Safety, Tolerability, and Efficacy of a Novel, Highly Potent and Selective Partial Agonist for Nociceptin/Orphanin-FQ Peptide (NOP) Receptors in Patients with Insomnia Disorder

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A192-A192
Author(s):  
M Zhou ◽  
S Harris ◽  
R Kapil ◽  
A Cipriano ◽  
E He ◽  
...  
Keyword(s):  
Partial Agonist ◽  
Sleep Onset ◽  
Sleep Efficiency ◽  
Residual Effects ◽  
Sleep Onset Latency ◽  
Dependent Manner ◽  
Orphanin Fq ◽  
Nop Receptors ◽  
Insomnia Disorder ◽  
Dose Dependent

Abstract Introduction V117957 is a recently described investigational oral, potent, and selective nociceptin/orphanin-FQ peptide (NOP) receptor partial agonist which was previously evaluated in ~200 healthy subjects. Its satisfactory safety/tolerability profile has been established with the top doses at 30mg following a single oral administration and 10mg once daily for 2 weeks. V117957 demonstrated favorable drug-like properties for insomnia treatment, including oral bioavailability, fast absorption, and rapid elimination. Methods A total of 52 patients with insomnia disorder have been evaluated in two separate randomized, double-blind, crossover, placebo-controlled sleep studies. Insomnia disorder was confirmed by screening polysomnography (PSG). All subjects received orally, for two consecutive nights, either V117957 10mg or placebo in Study #1 or 0.5, 1, 3, 6mg or placebo in Study #2. Efficacy was measured via PSG for the primary endpoint of sleep efficiency (SE) and secondary endpoints of sleep onset (latency to persistent sleep [LPS]) and maintenance (wakefulness after sleep onset [WASO]). Efficacy also was measured by patient diary (subjective sleep latency [sSL], subjective total sleep time [sTST], sWASO). Pharmacodynamics (PD) on next-day residual effects were also measured, including cognitive, psychomotor and mood effects. Results V117957 showed statistically significant greater sleep efficiency and less WASO in a dose-dependent manner (0.5-10 mg) and a statistically significant reduction in LPS at 10mg, as compared to placebo. V117957 at 0.5mg and 1mg exhibited next-day residual effects similar to placebo. At doses of 3mg or higher, V117957 showed dose-dependent next-day residual effects. V117957 was safe and well-tolerated across all doses tested with no serious adverse events, with somnolence being the most frequent treatment-emergent adverse event. No concerning laboratory findings and no clinically significant findings on vital signs and electrocardiograms have been attributed to V117957 in these subjects. Conclusion V117957 was safe and well-tolerated in patients with insomnia disorder. These results demonstrated that NOP receptors represent a novel mechanistic treatment for insomnia disorder and support continued evaluation of V117957. Support Funded by Shionogi and Imbrium Therapeutics, a subsidiary of Purdue Pharma L.P.

scholarly journals 0500 Evaluation of the Human Abuse Potential of Single Oral Doses of V117957, a Novel, Highly Potent and Selective Partial Agonist for Nociceptin/Orphanin-FQ Peptide (NOP) Receptors

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A191-A192
Author(s):  
S Harris ◽  
M Zhou ◽  
A Cipriano ◽  
R Kapil ◽  
M Shet ◽  
...  
Keyword(s):  
Partial Agonist ◽  
Motor Impairment ◽  
Positive Control ◽  
Abuse Potential ◽  
Statistical Criterion ◽  
Tolerability Profile ◽  
Orphanin Fq ◽  
Double Blind ◽  
Cns Depressant ◽  
Drug Liking

Abstract Introduction The satisfactory safety/tolerability profile of V117957, an investigational NOP receptor partial agonist, has been previously established in ~200 healthy subjects with maximum doses at 30mg following a single oral administration and 10mg once daily for 2 weeks. V117957 exhibited linear plasma exposures at doses up to 10mg. In patients with insomnia disorder, V117957 demonstrated dose-dependent improvement in sleep efficiency and sleep maintenance between 0.5mg and 10mg as measured by polysomnography and patient diaries. The current study evaluated the abuse potential and safety of V117957 in healthy, nondependent recreational polydrug users with a history of central nervous system (CNS) depressant use. Methods The abuse potential of V117957 (1mg, 6mg, 10mg), placebo, and triazolam (0.5mg, 1mg) were assessed in a randomized, double-blind, double-dummy, placebo- and positive-controlled crossover study. Triazolam was utilized as a positive control based on its comparable pharmacokinetic and pharmacodynamic characteristics. V117957 doses (1mg, 6mg, 10mg) were selected to represent therapeutic, mid-range supratherapeutic, and maximum-tolerated supratherapeutic doses, respectively. Subjects were qualified based on pharmacodynamic responses following a single oral 0.75mg triazolam dose. Drug liking was measured through 24 hours, including the primary endpoint of maximum “at the moment” Drug-Liking Visual Analog Scale, as recommended by FDA. Secondary endpoints included Divided Attention Test (DAT) and Choice Reaction Time (CRT). Results The positive control (triazolam 0.5mg, 1mg) produced statistically significant greater abuse potential and cognitive/motor impairment versus placebo, which demonstrated study validity. In contrast, V117957 at 1mg was not statistically significantly different from placebo. At the supra-therapeutic doses of 6 and 10mg, V117957 was associated with abuse potential and cognitive/motor impairment greater than placebo, yet similar to those of triazolam 0.5 and 1mg. Conclusion Overall, in this valid study, V117957 1mg and placebo were associated with statistically significant lower potential for abuse and reduced cognitive/motor impairment compared with the two supratherapeutic doses of V117957 (6mg, 10mg), and triazolam (0.5mg, 1mg). V117957 1mg met FDA’s statistical criterion for similarity to placebo. Support Funded by Imbrium Therapeutics, a subsidiary of Purdue Pharma L.P.

Insulin Resistance Impairs Cognitive Performance Even in Healthy Subjects at Risk for Diabetes Mellitus

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1830-P ◽  
Author(s):  
GIAN PIO SORICE ◽  
ILARIA IMPROTA ◽  
TERESA MEZZA ◽  
SARA GRIONI ◽  
GIOVANNA MASONE IACOBUCCI ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
At Risk ◽  
Cognitive Performance ◽  
Healthy Subjects

scholarly journals POS0672 FIRST-IN-HUMAN STUDY OF GS-5718, AN ORAL IRAK-4 INHIBITOR, IN HEALTHY SUBJECTS: PHARMACOKINETICS, SAFETY, TOLERABILITY, AND ASSESSMENT OF EFFECT OF FOOD AND ACID REDUCING AGENTS ON EXPOSURE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 581.1-581
Author(s):  
K. Anderson ◽  
C. H. Hsueh ◽  
O. Gurtovaya ◽  
A. Mathur ◽  
J. Taylor ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Clinical Laboratory ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Dose Range ◽  
Human Study ◽  
Reducing Agents ◽  
Pharmacokinetic Parameters ◽  
Once Daily ◽  
Effect Of Food

Background:GS-5718 is a potent and selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor in clinical development for treatment of inflammatory diseases.Objectives:The aim of this first-in-human study was to evaluate the pharmacokinetics, safety, and tolerability of GS-5718; and the effect of food and acid-reducing agents (ARA) on GS-5718 pharmacokinetics in healthy subjects.Methods:This was a blinded, randomized, placebo-controlled, single and multiple (once daily for 10 days) oral dose study. Healthy male and female subjects were enrolled in ascending dose cohorts and randomized to receive GS-5718 (15, 50 or 150 mg) or placebo. GS-5718 was administered fasted in the single ascending dose cohorts, and under fed conditions (standard meal) in the multiple dose cohorts. The effects of a high-fat meal and omeprazole (a representative ARA) on GS-5718 50 mg dose pharmacokinetics were also evaluated. Serial blood samples were collected and GS-5718 pharmacokinetic parameters were characterized. Safety was assessed by review of adverse events (AEs), clinical laboratory tests, and vital signs.Results:A total of 74 subjects (n = 62 GS-5718; n = 12 placebo) enrolled and completed study drug treatments in this study. GS-5718 was generally well tolerated at all evaluated dose levels; AEs were mild in severity and no dose-limiting toxicities, serious AEs, nor clinically relevant electrocardiogram or vital sign abnormalities were observed in subjects administered GS-5718. GS-5718 exposure was approximately dose proportional across the evaluated multiple ascending dose range. GS-5718 showed low-to-moderate pharmacokinetic variability with median half-life of 25 to 33 hours and 1.6 to 2.4- fold accumulation at steady-state, which was achieved by Day 5-7 of dosing. Food had no clinically meaningful impact on GS-5718 exposure (AUC and Cmax) at the 50 mg dose. Co-administration of omeprazole with GS-5718 reduced GS-5718 exposure (AUC and Cmax) by 23% and 43%, respectively, at the 50 mg dose.Conclusion:GS-5718, administered once daily, was well tolerated following single or multiple dosing up to 150 mg. The pharmacokinetic and safety profile of GS-5718 support the further development in inflammatory diseases with once-daily administrations.Disclosure of Interests:Kacey Anderson Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Chia-Hsiang Hsueh Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Oksana Gurtovaya Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Anubhav Mathur Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, James Taylor Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Adrian Serone Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Ahmed A. Othman Shareholder of: Gilead Sciences, Employee of: Gilead Sciences

scholarly journals Performance of the LARC classifier in clinical laboratories.

1976 ◽  
Vol 24 (1) ◽  
pp. 202-210 ◽  
Author(s):  
D A Cotter ◽  
B H Sage
Keyword(s):  
False Positive ◽  
Clinical Laboratory ◽  
False Negative ◽  
Performance Parameters ◽  
Clinical Laboratories ◽  
Normal Ranges ◽  
Abnormal Cells

As part of the installation procedure of the LARC leukocyte differential classifier in a clinical laboratory, a 100-slide protocol is carried out to establish the performance of the classifier in the laboratory. The detailed make-up of this protocol and its relationship to key performance parameters for the leukocyte differential are described in detail. Data from the first ten of these protocols are presented which establish the (a) normal ranges, (b) reproducibility, (c) accuracy, (d) false-positive/false-negative rates for the detection of left shifts and (e) false-positive/false-negative rates for the detection of bloods with abnormal cells.

scholarly journals Effect of Eye-Object Distance on Body Sway during Galvanic Vestibular Stimulation

2018 ◽  
Vol 8 (11) ◽  
pp. 191 ◽  
Author(s):  
Osamu Aoki ◽  
Yoshitaka Otani ◽  
Shinichiro Morishita
Keyword(s):  
Healthy Subjects ◽  
Center Of Pressure ◽  
Force Plate ◽  
Distance Effect ◽  
Vestibular Stimulation ◽  
Galvanic Vestibular Stimulation ◽  
Body Sway ◽  
Mean Square ◽  
Visual Condition ◽  
Object Distance

Gazing at objects at a near distance (small eye-object distance) can reduce body sway. However, whether body sway is regulated by movement in the mediolateral or anteroposterior direction remains unclear. Galvanic vestibular stimulation (GVS) can induce body tilting in the mediolateral or anteroposterior direction. This study examined the directionality of the eye-object distance effect, using body-tilting GVS manipulations. Ten healthy subjects (aged 21.1 ± 0.3 years) stood on a force plate covered with a piece of foamed rubber and either closed their eyes or gazed at a marker located 0.5 m, 1.0 m, or 1.5 m in front of them. The GVS polarities were set to evoke rightward, forward, and backward body tilts. To compare the effects of eye-object distance in the mediolateral and anteroposterior directions, the root mean square (RMS) of the center of pressure (COP) without GVS was subtracted from the COP RMS during GVS. For swaying in the mediolateral direction, significant visual condition-related differences were found during rightward and forward GVS (p < 0.05). Thus, reductions in mediolateral body sway are more evident for smaller eye-object distances during rightward GVS. It would be appropriate to use body-tilting GVS to detect the directionality of the eye-object distance effect.

scholarly journals Differences in Balance Function Between Cancer Survivors and Healthy Subjects: A Pilot Study

2018 ◽  
Vol 17 (4) ◽  
pp. 1144-1149 ◽  
Author(s):  
Shinichiro Morishita ◽  
Yuta Mitobe ◽  
Atsuhiro Tsubaki ◽  
Osamu Aoki ◽  
Jack B. Fu ◽  
...  
Keyword(s):  
Muscle Strength ◽  
Cancer Survivors ◽  
Healthy Subjects ◽  
Center Of Pressure ◽  
Healthy Adults ◽  
Body Sway ◽  
Balance Function ◽  
Adult Cancer Survivors ◽  
Eyes Open ◽  
The Mean

Older adults who have survived cancer experience significantly more falls compared with healthy adults. Adult cancer survivors may also have a lower balance function than healthy adults. We examined muscle strength and balance function among 19 cancer survivors and 14 healthy subjects. The mean age of the cancer survivors was 51.5 ± 11.2 years; 6 men and 13 women. Cancer diagnoses included breast cancer, retroperitoneal sarcoma, acute leukemia, lung cancer, colorectal cancer, thyroid cancer, Ewing’s sarcoma, and tongue cancer. The mean age of healthy subjects was 47.4 ± 14 years; 3 men, 11 women. Muscle strength was assessed using hand grip and knee extensor strength tests. Balance function was evaluated using the Timed Up and Go (TUG) test, and body sway was tested using a force platform. No significant differences were found with respect to right and left grip strength or right and left knee extension strength between the 2 groups. A significantly higher TUG time was observed in cancer survivors than in healthy subjects ( P < .05). With eyes open, the area of the center of pressure was significantly larger in cancer survivors than in healthy subjects ( P < .05). Similarly, the length per area was significantly lower both with eyes open and closed for cancer survivors than for healthy subjects ( P < .05). TUG was significantly correlated with muscle strength in both groups ( P < .05). However, no body sway parameters were related to muscle strength in either group. Cancer survivors had lower balance function that might not have been related to muscle strength. Cancer survivors should be evaluated for balance function as there is a potential for impairment. The findings of this study will be relevant for planning the prevention of falls for cancer survivors.

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