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ABSTRACT: The current study investigated whether candidate cognitive endophenotypes may be used to validate a schizo-obsessive subtype. Using within-subject random effect regression analyses and cross-trait cross-relative analyses, we evaluated the association between obsessive-compulsive symptoms (OCSs) and cognitive performance in 984 patients with nonaffective psychosis (22.5% with OCSs), 973 unaffected siblings (7.7% with OCSs), 851 parents (4.2% with OCSs), and 573 controls (4.5% with OCSs). No significant within-subject associations between OCSs and cognitive functioning were found for patients and siblings. Severity of OCSs was associated with worse set-shifting ability in parents and worse processing speed in controls, but effect sizes were small (0.10 and 0.05 respectively). Cross-trait cross-relative analyses yielded no significant results. Contrary to our expectations, neither within-subject analyses nor cross-relative analyses yielded a clear association between OCSs and cognitive performance. Results do not support a schizo-obsessive subtype associated with cognitive impairment. [ABSTRACT FROM AUTHOR]

Understanding the factors influencing a drug's potential to prolong the QTc interval on an electrocardiogram is essential for the correct evaluation of its safety profile. To explore the effect of dosing time on drug-induced QTc prolongation, a randomized, crossover, clinical trial was conducted in which 12 healthy male subjects received levofloxacin at 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00. Using a pharmacokinetic-pharmacodynamic (PK-PD) modeling approach to account for variations in PKs, heart rate, and daily variation in baseline QT, we find that the concentration-QT relationship shows a 24-hour sinusoidal rhythm. Simulations show that the extent of levofloxacin-induced QT prolongation depends on dosing time, with the largest effect at 14:00 (1.73 (95% prediction interval: 1.56-1.90) ms per mg/L) and the smallest effect at 06:00 (−0.04 (−0.19 to 0.12) ms per mg/L). These results suggest that a 24-hour variation in the concentration-QT relationship could be a potentially confounding factor in the assessment of drug-induced QTc prolongation. [ABSTRACT FROM AUTHOR]

Daily rhythms in physiology may affect the pharmacokinetics of a drug. The aim of this study was to evaluate 24-hour variation in the pharmacokinetics of the CYP3A substrate midazolam. Oral (2 mg) and intravenous (1 mg) midazolam was administered at six timepoints throughout the 24-hour period in 12 healthy volunteers. Oral bioavailability (population mean value [RSE%] of 0.28 (7.1%)) showed 24-hour variation that was best parameterized as a cosine function with an amplitude of 0.04 (17.3%) and a peak at 12:14 in the afternoon. The absorption rate constant was 1.41 (4.7%) times increased after drug administration at 14:00. Clearance (0.38 L/min (4.8%)) showed a minor 24-hour variation with an amplitude of 0.03 (14.8%) L/min and a peak at 18:50. Simulations show that dosing time minimally affects the concentration time profiles after intravenous administration, while concentrations are higher during the day compared to the night after oral dosing, reflecting considerable variation in intestinal processes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Mammalian circadian rhythms are driven by the circadian pacemaker of the suprachiasmatic nucleus (SCN) and are synchronized to the external 24-hour light/dark cycle. After advance time zone transitions (eastbound jet lag), overt circadian rhythms require several days to adjust. The retarded adaptation may protect against acute imbalance of different brain systems. Abrupt circadian rhythm changes may trigger migraine attacks, possibly because migraineurs have an inadequate adaptation mechanism. The novel R192Q knock-in migraine mouse model carries mutated Ca(v)2.1 calcium channels, causing increased presynaptic calcium influx and neurotransmitter release. We investigated whether these mice have an abnormal adjustment to phase advance shifts. METHODS: We examined phase resetting to 6-hour advance shifts of the light/dark cycle with behavioral and electroencephalographic recordings in R192Q and wild-type mice. We recorded excitatory postsynaptic currents in the SCN, and electrical impulse frequency in vitro and in vivo. RESULTS: R192Q mice showed a more than twofold enhanced adjustment of behavioral wheel-running activity and electroencephalographic patterns, as well as enhanced shifts of electrical activity of SCN neurons in vivo. No differences were found for in vitro recordings of the electrical impulse frequency in SCN slices. INTERPRETATION: R192Q migraine mice lack the physiological retardation in circadian adaptation to phase advance shifts. The opposite findings in vivo and in vitro exclude involvement of the retinal input pathway or the phase-shifting capacity of the SCN. Thus, the physiological inhibitory process appears to be mediated by Ca(v)2.1 channel-dependent afferent signaling from extra-SCN brain areas to the SCN. [ABSTRACT FROM AUTHOR]