Modulation of delta activity by hypnotics in middle-aged subjects: studies with a benzodiazepine (flurazepam) and a cyclopyrrolone (zopiclone).

Period crossing analysis was used to study the effects of flurazepam (30 mg) and zopiclone (5, 7.5, and 10 mg) on delta wave activity (0.5-2.0 Hz) during the first 4 h of sleep in middle-aged subjects. The drugs do not affect the visual scoring of slow wave sleep in middle age, but modification of delta activity does occur. Mean amplitude of delta wave activity over the 4-h period was reduced by both drugs, while the total number of delta waves and their mean period increased. The number of high-amplitude delta waves (greater than 60 microV) was decreased by the drugs, and those of low amplitude (10-60 microV) increased. Power in the frequency band 1.2-2.0 Hz was reduced.

Performance overnight in shiftworkers operating a day-night schedule.

Performance was measured during the day (0800-1700 hours) and during the night (1700-0800 hours) of a day-night schedule, and the effect of caffeine (300 mg) was studied during the overnight periods of work. The sleep electroencephalogram was recorded together with oral temperature and urinary electrolyte excretion. Impairment of performance within 9 h after the beginning of the daytime work period was minimal, and was limited to a test of continuous performance, but impairment of performance within 9 h after the beginning of the overnight work period was more pronounced and included lowered vigilance. Impaired performance overnight was related to time on task and circadian rhythmicity, and was alleviated to some extent by the use of caffeine.

Studies on the possible central and peripheral effects in man of a cholinesterase inhibitor (pyridostigmine).

The effect of a reversible cholinesterase inhibitor (pyridostigmine: 30 mg, 8-hourly for 3 days) on psychomotor performance and visual function and on the electrical activity of the brain was studied in healthy man. It was not possible to detect any change during the six individual experimental sessions over the 3 days, but with pooling of the data there was a drug effect. The threshold for detection of a flickering light was increased and less responses were missed on a dynamic visual-acuity task. Visuo-motor coordination was impaired. The observations were consistent with the known activity of the drug and suggest an increase in central arousal and minimal alteration in motor coordination.

Biological studies with continuous-wave radiofrequency (28 MHz) radiation.

Effects of high-frequency (28 MHz) continuous-wave radiation have been studied in the rat and monkey. No histopathological (rat-125 mW cm-2 for 28 days) or hematological (monkey-25 mW cm-2 for 24 days) changes could be attributed to the radiation. In the monkey (125 mW cm-2 for 11 days) there was an increase in urinary calcium concentration which was most likely due to restricted movement. In the rat (220 mW cm-2 for 13 days) there was reduced uptake of iodine by the thyroid, lower levels of plasma thyroid-stimulating hormone, and reduced ratio of protein bound to nonprotein bound iodine. Food consumption was also decreased. The changes are likely to have arisen as a compensatory response to an induced heat load. A nonthermal effect of continuous-wave high-frequency radiation has not been shown in this study. The effects were likely to be associated with either physiological compensation for induced heating or restriction of movement.

Adaptation to irregularity of rest and activity.

The adaptation to a 9-d schedule of irregular rest and activity was studied. Sleep was recorded; patterns of oral temperature, urinary excretion, and performance at a series of tasks were measured. The relationships between circadian rhythmicity, length of time on task, and cumulative sleep loss were examined.

Visual motor co-ordination and dynamic visual acuity.

Data on the effect of an antihistamine (triprolidine 10 mg) on visuo-motor coordination and dynamic visual acuity were used to establish interactions between these skills. Analysis of covariance and principal component analysis were used. The analyses suggested two main effects--an effect on the activity of the neuromuscular system and one which impaired ability to anticipate target movement. Detection of impaired performance by any task may have wider implications to the effectiveness of the individual than that obviously suggested by the skill itself.

Immediate effects on human performance of a 1,5-genzodiazepine (clobazam) compared with the 1,4-benzodiazepines, chlordiazepoxide hydrochloride and diazepam.

1 The immediate effects on human performance of the 1,5-benzodiazepine, clobazam (20 mg), and the 1,4-benzodiazepines, chlordiazepoxide hydrochloride (20 mg) and diazepam (10 mg), were studied by adaptive tracking and measurement of reaction time. Each drug was ingested at 09.00 h and performance was measured at 09 h 30 min (0.5 h), 11 h 30 min (2.5 h), 14 h 30 min (5.5 h) and 18 h 30 min (9.5 h after ingestion). 2 With diazepam decrements in performance on adaptive tracking were observed at 0.5 h and 2.5 h and performance was enhanced at 9.5 h after ingestion. With clobazam performance at individual times did not differ significantly from control, but there was evidence of an improvement in performance during the day. There was no evidence of impaired performance on adaptive tracking after chlordiazepoxide hydrochloride. 3 Reaction time was slowed at 0.5 h and 2.5 h after diazepam and chlordiazepoxide hydrochloride. A decrease in reaction time was observed at 9.5 h after diazepam. No changes in reaction time were observed after clobazam. 4 The subjects as a group differentiated correctly between performance decrements on adaptive tracking after diazepam and the absence of performance decrements after clobazam and chlordiazepoxide hydrochloride. The persistence of the decrement in performance after diazepam was accurately assessed. 5 It is evident that the nature and persistence of impaired performance and the ability to appreciate impaired performance vary considerably between the benzodiazepines, and that the choice of a benzodiazepine should include careful consideration of performance sequelae.

Behavioural sequelae of methaqualone in man and in the monkey (Macaca mulatta).

1 Residual effects in man of methaqualone hydrochloride (400 mg) were studied by adaptive tracking and by reaction time. Performance was measured at 10 h, 13 h, 16 h, 19 h and 34 h after the overnight ingestion of the drug. There was no evidence of impaired performance on adaptive tracking from 10 h to 19 h, but enhanced performance (P = 0.001) was observed 34 h after ingestion. With reaction time an increase (P = 0.01) was observed 10 h and a decrease (P = 0.05) was observed 19 h after ingestion. 2 Effects in the monkey (Macaca mulatta) of methaqualone (20 and 30 mg/kg body weight) were studied by a delayed matching task in which total response time was measured. No consistent effects on matching behaviour or on total response time were observed 2 h after intraperitoneal injection. 3 The studies suggest that methaqualone hydrochloride may be a valuable hypnotic for occasional use by persons involved in skilled activity.

Comparison of the residual effects of two benzodiazepines (nitrazepam and flurazepam hydrochloride) and pentobarbitone sodium on human performance.

1 The residual effects of two benzodiazepines, nitrazepam (10 mg) and flurazepam hydrochloride (30 mg), and pentobarbitone sodium (200 mg) were studied by adaptive tracking and by reaction time. Performance was measured at 10 h, 13 h, 16 h, 19 h and 34 h after ingestion of each drug. Impaired performance on adaptive tracking was observed at 10 h, 13 h, 16 h and 19 h after nitrazepam and pentobarbitone sodium and at 10 h, 13 h and 16 h after flurazepam hydrochloride. Enhanced performance was observed at 34 h after nitrazepam and pentobarbitone sodium. 2 Increased reaction time persisted to 16 h after nitrazepam, flurazepam hydrochloride and pentobarbitone sodium and reaction time was also increased at 34 h after nitrazepam and pentobarbitone sodium. 3 During the morning immediately after ingestion, the subjects as a group were able to differentiate correctly between placebo and drugs, but they were not able to assess accurately the persistence of the residual effects of nitrazepam and pentobarbitone sodium. 4 Flurazepam hydrochloride would appear to be a more promising benzodiazepine than nitrazepam for use as a hypnotic by persons involved in skilled activity. There was a rapid recovery of performance during the afternoon and, unlike pentobarbitone sodium and nitrazepam, subjects retained the ability to recognize impaired skill.

Human performance after a barbiturate (heptabarbitone).

1 The residual effects of heptabarbitone given overnight were studied by an adaptive tracking technique. Decrements in performance were observed at the 10 h interval after 200 mg, at the 10 h and 13 h intervals after 300 mg and at the 10 h, 13 h, 16 h and 19 h intervals after 400 mg of the drug. Decrements in performance at each interval and the persistence of the effects were dose related. 2 Subjective assessments of performance correlated with measured performance, but the subjects, as a group, over-estimated their performance after placebo and heptabarbitone. With heptabarbitone (400 mg) highly significant decrements in performance persisted to the 19 h interval after ingestion, but subjective assessments of performance to the 19 h interval did not differ significantly from subjective assessments of control activity of the day before. 3 Individual blood concentrations of heptabarbitone did not give a significant correlation with individual performance decrements, though the blood concentrations and performance decrements at each dose were related.