Increasing vigilance without incurring the negative consequences of extended wakefulness such as daytime sleepiness and cognitive impairment is a major challenge in treating many sleep disorders. The present work compares two closely related mGluR2/3 antagonists LY3020371 and LY341495 with two well-known wake-promoting compounds caffeine and d-amphetamine. Sleep homeostasis properties were explored in male Wistar rats by manipulating levels of wakefulness via (1) physiological sleep restriction (SR), (2) pharmacological action, or (3) a combination of these. A two-phase nonlinear mixed-effects model combining a quadratic and exponential function at an empirically estimated join point allowed the quantification of wake-promoting properties and any subsequent sleep rebound. A simple response latency task (SRLT) following SR assessed functional capacity of sleep-restricted animals treated with our test compounds. Caffeine and d-amphetamine increased wakefulness with a subsequent full recovery of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep and were unable to fully reverse SR-induced impairments in SRLT. In contrast, LY3020371 increased wakefulness with no subsequent elevation of NREM sleep, delta power, delta energy, or sleep bout length and count, yet REM sleep recovered above baseline levels. Prior sleep pressure obtained using an SR protocol had no impact on the wake-promoting effect of LY3020371 and NREM sleep rebound remained blocked. Furthermore, LY341495 increased functional capacity across SRLT measures following SR. These results establish the critical role of glutamate in sleep homeostasis and support the existence of independent mechanisms for NREM and REM sleep homeostasis.

Background Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We evaluated tofacitinib efficacy and safety in the 52-week maintenance study, OCTAVE Sustain, by baseline Mayo endoscopic subscore (MES) following 8-week induction. Methods The proportion of patients achieving efficacy endpoints at Week 24 or 52 of OCTAVE Sustain was evaluated by baseline MES following 8-week induction. Using logistic regression, the difference in treatment effect (tofacitinib vs. placebo) between baseline MES (0 vs. 1) for each endpoint was assessed. Adverse events were evaluated. Results At Week 52 of OCTAVE Sustain, a numerically higher proportion of tofacitinib-treated patients achieved remission with OCTAVE Sustain baseline MES of 0 versus 1 (61.9% vs. 36.5% for tofacitinib 5 mg twice daily [BID] and 75.0% vs. 54.2% for tofacitinib 10 mg BID). Similar trends were observed for endoscopic remission and endoscopic improvement. Logistic regression analyses showed a larger treatment effect at Week 52 in patients with baseline MES of 0 versus 1 for clinical response (p = 0.0306) in the tofacitinib 5 mg BID group (other endpoints all p > 0.05); differences were not significant for any endpoint in the 10 mg BID group (all p > 0.05). Infection adverse events were less frequent among patients with baseline MES 0 versus 1. Conclusions MES may be important in predicting long-term efficacy outcomes for tofacitinib maintenance treatment. Aiming for endoscopic remission during induction with tofacitinib 10 mg BID may allow successful maintenance with tofacitinib 5 mg BID. Safety was consistent with the known tofacitinib safety profile. Trial registration NCT01458574.

This paper considers the impacts of various patterns of differential or excess mortality on the biological and statistical interpretation of 2-year rodent carcinogenicity studies. It provides suggestions on experimental design that are intended to maximize the value of such studies for carcinogenic risk assessment. Specifically, it recommends dose reduction, possibly to the level of dose cessation, when biologically feasible and considers the merits of termination of the entire study as alternatives to the commonly employed strategy of terminating particular dose groups. It then recommends statistical analysis modifications that are appropriate when these suggestions on experimental design are adopted. One of the recommended modifications is a new statistical test to determine whether a dose group exceeds the maximum tolerated dose (MTD) on the basis of mortality. While the authors provide recommendations for the most commonly occurring exigencies, they acknowledge the need for and strongly support the practice of active engagement of the appropriate regulatory agency, e.g., the FDA, prior to any action.

Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). These post hoc analyses assessed associations between C-reactive protein (CRP), partial Mayo score (PMS), and efficacy outcomes during tofacitinib induction in UC. Methods Patients received tofacitinib 10 mg twice daily (BID) in an 8-week, phase 2 induction study and 2 identical, 8-week, phase 3 induction studies (OCTAVE Induction 1&2); induction nonresponders (IndNR) received an additional 8 weeks of tofacitinib 10 mg BID in an open-label, long-term extension study. Associations between CRP and PMS, and efficacy outcomes (clinical response, clinical remission, endoscopic improvement, and endoscopic remission) were analyzed using univariate and multivariable logistic regression and receiver operating characteristic curves. Results Changes from baseline in the logarithm of CRP ([log]CRP) and PMS at week 4 were associated with clinical response at week 8 (univariate: per unit, odds ratio [OR], 0.55 [95% confidence interval (CI), 0.48-0.62]; and 0.42 [0.37-0.47], respectively). Among IndNR, change from baseline in PMS at week 8 was associated with clinical response at week 16 (univariate: per unit, OR, 0.59; 95% CI, 0.46-0.75). C-reactive protein at week 4 (area under the curve [AUC] > 0.6) and PMS at weeks 2 and 4 (AUC, > 0.7) generally exhibited predictive value for week 8 efficacy outcomes. Conclusions Patients who achieved clinical response at week 8 had larger decreases in CRP and PMS at week 4 than patients who did not. IndNR who achieved clinical response at week 16 with extended tofacitinib induction had a larger decrease in PMS at week 8 vs those who did not. ClinicalTrials.gov:NCT00787202;NCT01465763;NCT01458951;NCT01470612.