Antimuscarinic compounds are increasingly used to treat the symptoms of overactive bladder; however, their use is often restricted by peripheral adverse effects (AEs). On the other hand, data regarding their influence on the central nervous system (CNS) are limited. This randomized, single-blind, parallel-group quantitative-topographical EEG (qEEG) study of clinical phase I investigates the potential CNS adverse effects of the three antimuscarinic drugs--tolterodine, oxybutynin, and trospium chloride--in comparison to placebo. Overall, 4 x 16 (total 64) young, healthy male volunteers were included in the study. The subjects were given either placebo or the clinically recommended daily doses of the drugs dispensed in three doses on a single day (tolterodine 2 mg bid and once placebo, total 4 mg/d; oxybutynin 5 mg tid, total 15 mg/d; and trospium chloride 15 mg tid, total 45 mg/d). The qEEG was recorded prior to and up to 4 hours after each intake of the trial medication (a total of 10 qEEG sessions) under three different conditions: at rest with eyes open, eyes closed, and under mental demand. The drug tolerability was subjectively evaluated by the volunteer and the investigator. In comparison to placebo (10% confidence interval), tolterodine and trospium chloride did not induce changes of the qEEG power in five of the six frequency bands (i.e., delta, alpha 1, alpha 2, beta 1, and beta 2). Isolated power decreases were only observed in the theta frequency band. In contrast, oxybutynin caused significant power reductions in four frequency bands (theta, alpha 1, alpha 2, and beta 1; p < 0.01). The subjectively evaluated drug tolerability was comparable between all treatment groups, although differences in the AE occurrence existed, with the AE frequency being higher in the oxybutynin group. The results of this study support the findings that oxybutynin as a tertiary amine crosses the blood-brain barrier, causing significant qEEG activity changes and more pronounced central adverse effects. Although tolterodine is also a tertiary amine, it shows limited effects on qEEG activity (i.e., slight theta power reductions), comparable to the effects of trospium chloride, a quarternary amine, which barely crosses the blood-brain barrier. The minimal qEEG changes observed with tolterodine and trospium chloride reflect most probably a rebound message from the peripheral target organs. Prescription of oxybutynin thus implicates a higher risk of CNS side effects.

Trospium chloride and oxybutynin are two antimuscarinergic agents used in the treatment of unstable bladder, urge incontinence, combined stress urge incontinence and detrusor hyperreflexia. The possibility that these two drugs produce changes in central nervous electrical activity was examined in an open, prospective, phase I study involving 12 volunteers. Quantitative evaluation of the multichannel electroencephalogram obtained from young healthy volunteers showed statistically significant decreases in alpha and beta 1 activity after oxybutynin, but not after intravenous or oral administration of trospium chloride. The biological activity of both drugs was ascertained by continuous simultaneous recording of the heart rate. A decrease in heart rate was detected after oral administration of oxybutynin, and an increase was seen after i.v. administration of trospium chloride. The results suggest that trospium chloride is less likely to produce central nervous adverse effects than to oxybutynin.

The effect of caffeine (single oral doses of 200 mg and 400 mg) on the CNS was tested under resting conditions and while performing a concentration performance test in a placebo-controlled pilot study on ten healthy males. The EEG was evaluated quantitatively by spectral analysis with a Computer Aided Topographical ElectroEncephaloMetry system. Comparison of the averaged frequency content revealed a clear difference between the change in the functional state of the brain due to the mental arithmetics, on the one hand, and the caffeine effect, on the other. Both states of altered brain activity were reflected in a particular topographical distribution of the frequency change with respect to a frontal-occipital accentuation. Comparison of the two periods of mental arithmetics in the absence or presence of caffeine showed a tendency to concentration-dependent differences from each other. Administration of 200 mg and 400 mg caffeine in the relaxed state effected the decrease in spectral power in the theta and alpha ranges. The concentration performance test without caffeine effected decreases in power in the alpha range in frontal to parietal cortex and enhanced theta power in frontal and occipital regions and the alpha power in occipital cortex. The caffeine-dependent decrease in theta power and the decrease in delta power seen under relaxation conditions after 400 mg are not observed during the concentration performance test in the presence of caffeine.

No abstract

The aim of this study was to investigate the activation process of the central nervous system during mental demand in a complex psychophysiological situation. A 17-channel quantitative topographical EEG was recorded in 48 healthy volunteers (male and female, aged 49 ± 6 years), using the CATEEM system, during four different psychometric tests (simple reaction time measurement, concentration performance, figure detection and word recall test). The mental load varied with each test, producing a graduated increase in spectral power density in delta and theta frequency range on the EEG in the frontotemporal, parietal and occipital regions of the cortex and a generalized decrease in alpha power. During the rest periods after each test a graduated increase in alpha₁ power was seen as a possible expression of change in vigilance level. With this method we were able to differentiate two effects of psychometric tests on brain activity: the actual mental demand itself and the influence on the vigilance level.