Systemic exposure to anticholinergics used for chronic obstructive pulmonary disease (COPD) may lead to side effects. This study assessed safety, tolerability, and pharmacokinetics of multiple doses of aclidinium bromide, a novel, long-acting antimuscarinic. Sixteen healthy participants received aclidinium bromide 200, 400, or 800 microg or placebo by dry-powder inhaler for 5 days, with > or =7 days washout. Aclidinium bromide and metabolite pharmacokinetics were assessed. Aclidinium bromide plasma levels were below the lower limit of quantification (LLOQ: 0.05 ng/mL) after 200 microg and in most participants after 400 microg. Plasma levels in all participants were below the LLOQ at all doses, including the highest dose, beyond 1 hour postdose. AUC(0-t) and C(max) at steady state were, respectively, 0.08 ng.h/mL and 0.12 ng/mL (aclidinium bromide), 0.40 ng.h/mL and 0.14 ng/mL (alcohol metabolite), and 13.47 ng.h/mL and 2.26 ng/mL (acid metabolite). The t(max) for aclidinium bromide 800 microg was 15 minutes (first kinetic time point). Adverse event frequency was comparable between treatment groups and placebo. The most commonly reported adverse events, probably treatment related, were coughing (n = 2) and dysphagia (n = 1); 94% of adverse events were mild. These data suggest a low systemic bioavailability and favorable safety profile for aclidinium bromide with repeated dosing for COPD.
Peripheral noxious stimuli have been shown to induce prostaglandin (PG) E 2 release at the site of inflammation and in the spinal cord. The antiinflammatory and antinociceptive effects of cyclooxygenaseinhibiting drugs are thought to depend on the inhibition of PG synthesis. R-Flurbiprofen, however, does not inhibit cyclooxygenase activity in vitro but still produces antinociceptive effects. To find out whether Rflurbiprofen acts via inhibition of spinal PG release, concentrations of PGE 2 and flurbiprofen in spinal cord tissue were assessed by microdialysis. The catheter was transversally implanted through the dorsal horns of the spinal cord at level L4. R-and S-flurbiprofen (9 and 27 mg kg Ϫ1 , respectively) were administered intravenously 10 -15 min before subcutaneous injection of formalin into the dorsal surface of one hindpaw. Flurbiprofen was rapidly distributed into the spinal cord with maximal concentrations after 30 -45 min. Baseline PGE 2 dialysate concentrations were 100.6 Ϯ 6.4 pg ml Ϫ1 (mean Ϯ SEM). After formalin injection they rose about threefold with a maximum of 299.4 Ϯ 68.4 pg ml Ϫ1 at 7.5 min. After ϳ1 h PGE 2 levels returned to baseline. Both flurbiprofen enantiomers completely prevented the formalin-induced increase of spinal PGE 2 release and reduced PGE 2 concentrations below basal levels. S-and R-flurbiprofen at 9 mg kg Ϫ1 produced a minimum of 15.8 Ϯ 5.2 and 27.7 Ϯ 14.9 pg ml Ϫ1 , respectively, and 27 mg kg Ϫ1 S-and R-flurbiprofen resulted in 11.7 Ϯ 1.7 and 9.3 Ϯ 4.7 pg ml Ϫ1 , respectively. PGE 2 levels remained at the minimum up to the end of the observation period at 5 h. When 27 mg kg Ϫ1 R-flurbiprofen was injected intravenously without subsequent formalin challenge, baseline immunoreactive PGE 2 concentrations were not affected. S-Flurbiprofen (27 mg kg Ϫ1 ), however, led to a moderate reduction (ϳ40%). The data suggest that antinociception produced by R-flurbiprofen is mediated at least in part by inhibition of stimulated spinal PGE 2 release and support the current view that increased spinal PGE 2 release significantly contributes to nociceptive processing.
The bioavailability of beta-aescin--the main active constituent of horse chestnut seed extract--in a nonretarded test medication in comparison with that in a retarded reference formulation was evaluated in 2 randomized crossover clinical trials involving 18 healthy volunteers each. Serum concentration/time curves derived under steady-state conditions and pharmacokinetic parameters measured during both studies showed no significant difference between absorption rates for the retarded versus nonretarded preparation. In the first study, investigators found a test-to-reference ratio of 1.06 (90% confidence interval [CI] range: 99-113) for the area under the curve (AUC; the primary outcome measure). Absorption rates were diminished during the night compared with daytime rates for both study preparations. In the second study, using AUC and maximum concentration (Cmax) as the primary characteristics, investigators analyzed bioavailability based on the mean of 2 consecutive daytime periods and obtained estimates of 1.07 for AUC (90% CI range: 0.96-1.19) and 1.05 for Cmax (90% CI range: 0.90-1.21). Bioequivalence of the test and reference drug preparations was thus established according to the Note for Guidance on the Investigation of Bioavailability and Bioequivalence. Both treatments were equally well tolerated.
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