Effects of a newly developed transdermal clonidine delivery system (M-5041T) on EEG sleep-wake cycle in relation to plasma concentration in rabbits.

1. The effects of a transdermal clonidine delivery system (M-5041T) on EEG sleep pattern with relation to plasma concentrations in unrestrained rabbits were investigated and compared with those of intravenous (i.v.) administration of clonidine. 2. Although M-5041T did not affect the EEG recorded from cortex and hippocampus at doses up to 2.5 mg/kg, slow theta waves in hippocampal EEG accompanied by low-voltage slow waves in cortex were induced at a higher dose of 12.5 mg/kg. On i.v. injection (0.25 mg/kg), EEG tracings with bursts of high-voltage slow waves in cortical EEG and slow theta waves in hippocampus were observed. 3. At doses of 0.5 and 2.5 mg/kg, M-5041T did not cause any alterations of the sleep-wake cycle, and plasma concentrations of 1-2 ng/ml were maintained for an 8-hr observation period. However, this delivery system significantly suppressed the incidence of rapid-eye movement sleep (REMS) from 11.9 to 4.7% and enhanced drowsiness (DW) from 9.0 to 21.0% during the 8-hr recording period at 12.5 mg/kg with a plasma concentration of up to 10 ng/ml. Contrary to transdermal administration, i.v. clonidine (0.25 mg/kg) completely blocked light and deep slow wave sleep as well as REMS with a plasma concentration indicated more than 10 ng/ml at 2 hr post administration. Recovery to a normal sleep-wake cycle was eventually established thereafter. The incidence of REMS and DW were significantly decreased from 11.9 to 6.3% and increased from 9.0 to 25.5%, respectively. 4. Concurrent monitoring of clonidine concentrations in cerebrospinal fluid (CSF) indicated that CSF concentrations after patching M-5041T, as well as i.v. clonidine, were almost equal to plasma levels. 5. These results suggest that alteration of the sleep-wake cycle with clonidine occurs depending upon brain concentrations, which increase to a level similar to that in plasma after administration, and that M-5041T at doses of less than 2.5 mg/kg could establish effective hypertensive therapy without obvious effects on the cycle.