Pharmacodynamic and pharmacokinetic profile of SM-1, a triple-drug combination to increase total sleep time.

OBJECTIVE: The primary objective was to characterize the pharmacokinetics and pharmacodynamics of SM-1 after administration of a single oral dose to healthy volunteers in a placebo-controlled double-blind trial of daytime sedation. Secondary objectives were to determine the onset, duration, and offset of the sedative effects using subjective and objective measures of sedation. Safety and tolerability of SM-1 were also investigated. METHODS: Males and females 18-45 years of age received SM-1, a combination drug product comprised of diphenhydramine, zolpidem (delayed release), and lorazepam (delayed release). The pharmacokinetic profile of each drug was determined from blood samples. Sedative effects were assessed by visual analog scale, digit symbol substitution test, memory test, and quantitative electroencephalography. RESULTS: Similar number and severity of adverse events were observed following administration of SM-1 and placebo. Onset of sedation, as determined by subjective, performance, and electroencephalography measures, occurred 0.5-1 hr postdose, lasting about 7-7.5 hr. Plasma concentration curves for the two delayed-release components were altered compared with published data for unmodified drugs. Exposure values obtained with the combination product were in good agreement with published values of the drugs given individually. CONCLUSIONS: SM-1 was well tolerated and has pharmacologic activity starting within an hour of ingestion, lasting approximately 7-8 hr. Sedative activity was seen with subjective, psychomotor, and electroencephalography assays.

Auditory event related potentials as tools to reveal cognitive late effects in childhood cancer patients.

OBJECTIVE: The purpose of this study was to analyze event related potentials mismatch negativity (MMN) and P3a in childhood cancer patients at the time of diagnosis (Study 1) and after treatment (Study 2) to evaluate their clinical usefulness in screening potential treatment-related neurotoxicity. METHODS: The MMN and P3a to phonetic stimuli were examined in 27 childhood cancer patients with age- and sex-matched controls. Neuropsychological tests were also studied. RESULTS: The MMN peak amplitude was attenuated in the patient group at Study 1. Between the studies, poorer enhancement of the MMN peak amplitude correlated with deterioration in the Verbal intelligence quotient (IQ) in leukaemia patients. In addition, prolongation of the MMN peak latency correlated significantly with deterioration in the Full Scale and Performance IQ in the patient group. Deterioration in the Arithmetic subtest and Performance IQ correlated negatively with the age at diagnosis. CONCLUSIONS: The MMN changes between the studies associated with deterioration in the neuropsychological tests indicating that the method could be clinically useful. The performance of the younger patients was more likely to deteriorate during the treatment. SIGNIFICANCE: Changes in the MMN response during cancer treatment seem to be of clinical importance as indicates of the cognitive outcome of childhood cancer patients.

The effects of sleep debt and monotonous work on sleepiness and performance during a 12-h dayshift.

The study examined the effects of the amount of preceding sleep and work pace on sleepiness and cognitive performance during a 12-h dayshift. Twelve process operators (aged 28-56 years) completed a study with four single 12-h dayshifts and preceding night sleep in the laboratory. A simulated distillation process served as a work task. The 12-h shifts differed from each other in terms of the amount of preceding night sleep (23:00-06:30 hours or 2:30-6:30 hours) and work pace (slow or fast). All shifts contained four work simulation sessions of 1.5 h, and each of them included a 15-min alarm session. Cognitive performance was also measured with a 10-choice reaction time test and a mental subtraction test. Objective sleepiness was measured with a continuous electroencephalography/electro-oculography (EEG/EOG) recording during the work periods and with a sleep latency test. Subjective sleepiness at work was measured with the Karolinska Sleepiness Scale. Sleep debt increased the proportion of EEG/EOG-defined and subjective sleepiness at work, but did not impair work or test performance. The fatiguing effect of monotonous work as indicated by EEG/EOG-defined sleepiness was comparable with the effect of sleep debt. The alarm epochs in the middle of monotonous work temporarily decreased EEG/EOG-defined sleepiness. Sleep debt or monotonous work did not have a significant effect on the results of the sleep latency test. None of the sleepiness or performance measures indicated the impairment of a subject's functional capacity at the end of the 12-h shift. Our results suggest that monotonous work is at least as harmful as moderate sleep debt for alertness at work. The results support the view that the last hours of a single 12-h dayshift with frequent pauses are not associated with an increase in sleepiness or performance errors.