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Mioflazine, a nucleoside transport inhibitor, was given PO to dogs at doses of 0.04-10 mg/kg. Sixteen hour polygraphic sleep recordings were made and analysis and sleep stage classification was done by computer. Mioflazine decreased wakefulness and increased slow wave sleep, but did not affect the latencies of either REM sleep or slow wave sleep. This increased sleep was due to an increase in the number of light and deep slow wave sleep epochs. The effect lasted for about 8 h. The decreased wakefulness and increased slow wave sleep could be antagonized by the adenosine antagonist caffeine (2.5 and 10 mg/kg, PO); however, there was not a pure antagonistic effect. It might be that the enhancement of slow wave sleep is due to an activation of brain adenosine receptors. This is the first report of a drug acting on adenosine that given orally improves sleep. Mioflazine might be the prototype of substances worth considering for the treatment of a variety of sleep disorders.

Wauquier, A., W.A.E. Van den Broeck, C.J.E. Niemegeers, and P.A.J. Janssen: Effects of morphine, fentanyl, sufentanil, and the short-acting morphine-like analgesic alfentanil on the EEG in dogs. Drug Dev. Res. 1:167-179, 1981. Visual and computerized methods were used to analyze the effects of intravenously injected narcotic analgesics on the EEG of dogs implanted with cortical and subcortical electrodes. The drugs were morphine (1.6 mg/kg), fentanyl(O.004 mg/kg), sufentanil (0.0004 mg/kg), and a new potent and very short-acting compound under clinical trial i n anaesthesia, alfentanil (0.04, 0.16 and 0.63 mgikg). All compounds increased the amplitude of the EEG, decreased the frequency of the EEG, and produced spindle-like bursts of biphasic waves. These bursts were more frequent and of a higher amplitude following alfentanil than after the other compounds. A computerized on-line power spectral analysis was applied to three derivations (frontal-occipital cortex, dorsal hippocampus, amygdala). The power of the total band width (0-40 Hz) increased following all narcotic analgesics. The duration of this increase was coincident with the period of loss of righting. Spectral analysis of various frequency bands revealed significant differences between the compounds, specifically with regard to fentanyl and alfentanil as compared to morphine and sufentanil. Sleep-wake patterns of the night following injection of alfentanil were studied. This compound did not produce significant postdrug effects.

The effects of the antihistamines astemizole, ketotifen, and terfenadine, given orally at the dose of 10 mglkg, were investigated on 16-hr sleep-wakefulness patterns in dogs. As determined in the Ascaris allergy test in dogs, this dose had marked antihistaminic activity for at least the total duration of the recording. Using a computerized on-line analysis and automatic sleep classification, a differentiation was made between wakefulness, transition to sleep, slow-wave sleep, and REM (or paradoxical) sleep. Astemizole did not significantly change sleep-wakefulness patterns. Ketotifen significantly increased slow-wave sleep and significantly decreased REM sleep. Terfenadine significantly decreased wakefulness and significantly increased both slow-wave sleep and REM sleep. With both ketotifen and terfenadine, REM latency was prolonged. Two different mechanisms appear to be involved in the REM sleep effects seen with terfenadine: an early REM sleep suppressant effect and a late but large REM sleep-enhancing effect. This study shows central effects of terfenadine that are not completely typical for HI antagonists but which are very pronounced at a dose producing much weaker peripheral antihistamine activity than the same dose of ketotifen and astemizole. Key words: sleep-wakefulness patterns, dogs, antihistamines, astemizole, ketotifen, terfenadineHistamine is present in nonmast cells in brain, and is distinctly distributed in a way reminiscent of the distribution of catecholaminergic neurons [Schwartz, 19771. This feature along with the clinical observation that classical antihistamines or HI-receptor antagonists invariably produce sedation at antihistaminic dose levels suggests the involvement of histatninergic neurons in the mechanisms controlling wakefulness.

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