Pharmacokinetics of single- and multiple-dose roflumilast: an open-label, three-way crossover study in healthy Chinese volunteers.

PURPOSE: To determine the pharmacokinetic properties of the common tablet of roflumilast administered in single and multiple oral doses in Chinese subjects. SUBJECTS AND METHODS: Both the single- and multiple-dose studies included 12 adults (6 males and 6 females). In this single-center, open-label study, single doses of 0.25, 0.375, and 0.5 mg were administered using a randomized, three-way crossover design, and then, the 0.375 mg dose was continued for 11 days once daily. The pharmacokinetic parameters for roflumilast and roflumilast N-oxide were determined and the safety evaluation included adverse events assessed by monitoring, physical examination, vital sign tests, and clinical laboratory tests. RESULTS: After every single dose, the time to the maximum concentration (C max) of roflumilast (T max) was 0.25-2.0 hours; thereafter, the concentration declined, with a mean half-life (t 1/2) of 19.7-20.9 hours over the range of 0.25-0.50 mg. As for roflumilast N-oxide, the mean t 1/2 was 23.2-26.2 hours. The area under curve from the beginning to 24 hours (AUC0-24 h), the AUC until infinity (AUCinf), and the C max of roflumilast and roflumilast N-oxide increased in a dose-proportional manner. After multiple doses, the accumulation index (Rac) on the 11th day of the steady state was ~1.63 for roflumilast and 3.20 for roflumilast N-oxide. No significant sex differences were observed in the pharmacokinetic parameters of roflumilast and roflumilast N-oxide. In addition, there were no serious adverse events across the trial. CONCLUSION: Roflumilast was safe and well-tolerated in healthy volunteers, and a linear increase in its C max and AUC values was observed at doses ranging from 0.25 to 0.50 mg.

Effects of acute cooling/rewarming on membrane potential and K(+) currents in rat ventricular myocytes / 生理学报

The effects of acute cooling/rewarming on cardiac K(+) currents and membrane potential were investigated. Membrane potential and current were assessed with whole-cell patch-clamp technique in current- and voltage-clamp modes. When the temperature of bath solution was decreased from 25 °C; to 4 °C, the transient outward current (I(to)) was completely abolished, the sustained outward K(+) current (I(ss)) at +60 mV and the inward rectifier K(+) current (I(K1)) at -120 mV were depressed by (48.5±14.1)% and (35.7±18.2)%, respectively, and the membrane potential became more positive. After the temperature of bath solution was raised from 4 °C; to 36 °C;, the membrane potential exhibited a transient hyperpolarization and then was maintained at a stable level. In some myocytes (36 out of 58), activation of the ATP-sensitive K(+) (K(ATP)) channels after rewarming was observed. The rewarming-induced change in the membrane potential was inhibited by the Na(+)/K(+)-ATPase inhibitor ouabain (100 μmol/L), and the rewarming-elicited activation of K(ATP) channels was inhibited by the protein kinase A inhibitor H-89 (100 μmol/L). Moreover, decrease of the temperature from 25 °C; to 4 °C; did not induce any significant change in cell volume when the cell membrane potential was clamped at 0 mV. However, significant cell shrinkage with spots was observed soon after rewarming-induced activation of K(ATP) channels. These data demonstrate that acute cooling/rewarming has a profound influence on the membrane potential and K(+) currents of ventricular myocytes, and suggest that activation of K(ATP) channels may play a role in cardiac cooling/rewarming injury.