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1 Opioid drugs act on speci®c receptors which are principally classi®ed into m, d and k subtypes. Spiradoline (U-62066E) is a k-selective agent which has been shown to possess potent anti-nociceptive eects but does not show cross tolerance with morphine. 2 We have assessed the neuroendocrine eects of spiradoline in healthy volunteers with two doses (1.6 and 4.0 mg kg 71 , i.m.) of the compound. Six male non-smokers aged 19 ± 27 years were studied by use of a randomized, double-blind three-limb placebo-controlled cross-over design. Blood was taken from an in-dwelling venous cannula basally and at 15 min intervals for 2 h for determination of serum cortisol, prolactin, growth hormone (GH) and catecholamines. 3 Psychological function was assessed by the Stanford Sleepiness Scale (SSS) and the Addiction Research Centre Inventory (ARCI) administered before the medication and at 35 min, 1 h 25 min and 2 h afterwards. Cardiovascular variables were recorded at 10 min intervals. Results were analysed by analysis of variance. 4 Spiradoline showed a signi®cant (P50.05) dose-dependent increase in free water clearance, as predicted for a k-opioid agonist. It also caused a dose-dependent stimulation of prolactin, (increment over baseline for higher dose 214%), GH (433%) and cortisol (215%) release (P50.05). There were no signi®cant drug-related changes in plasma catecholamines, blood pressure, pulse or psychological variables. 5 We have therefore con®rmed that k-opioids increase free-water clearance and may participate in the stimulation of prolactin and GH release. In contrast to m and d-opioid agonists, this novel k-agonist stimulates cortisol release in man.

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Tirilazad mesylate pharmacokinetics were assessed in 12 young and 12 elderly volunteers (six men and six women per age group). Subjects received single 10-minute intravenous infusions of 1.5 mg/kg and 3.0 mg/kg tirilazad mesylate. Plasma tirilazad mesylate concentrations were determined by HPLC. There were no significant dose effects on clearance, but half-life increased with dose because of assay insensitivity at the lower dose. Mean half-lives were 16.3 +/- 15.5 and 21.4 +/- 12.6 hours for young and elderly subjects, respectively, at the 3.0 mg/kg dose. At the same dose, mean tirilazad mesylate systemic clearance was 0.630 +/- 0.254 and 0.428 +/- 0.090 L/hr/kg, respectively. The decreased clearance in elderly volunteers was primarily attributable to a lower clearance in elderly women relative to young women. The small effect of age on tirilazad clearance is likely to have minimum clinical impact. Tirilazad clearance was approximately 40% higher in young women than in young men. The clinical importance of this observation is unknown.