A bioavailability/bioequivalence and pharmacokinetic study of two oral doses of torasemide (5 and 10 mg): prolonged-release versus the conventional formulation.

1. The main objective of the present study was to compare the bioavailability/bioequivalence of a new prolonged-release (PR) formulation of torasemide with an immediate-release (IR) formulation. In addition, we assessed the pharmacokinetics of both formulations, as well as the urine pharmacodynamics. 2. Two doses (5 and 10 mg) of PR torasemide were compared with the same doses of IR torasemide in a single-blind, single-dose, two-treatment, two-period, cross-over, sequence-randomized clinical trial in 20 healthy volunteers (two groups; n = 10 in each group). Torasemide plasma concentrations were measured by high-pressure liquid chromatography-electrospray ionization mass spectrometry. Torasemide urine concentrations, the diuretic effect of torasemide, urine electrolytes and urine density were also determined. 3. Plasma bioequivalence parameters, based on logged values, were as follows: (i) in the 5 mg group, the area under the plasma drug concentration-time curve from t = 0 to last measurable drug concentration at time t (AUC(0-t)) tablet ratio was 1.03 (90% confidence interval (CI) 0.91-1.17) and C(max) was 0.82 (90% CI: 0.68-0.98); and (ii) in the 10 mg group, the AUC(0-t) was 1.07 (90% CI 0.99-1.14) and C(max) was 0.68 (90% CI 0.60-0.78). The PR formulation showed a significantly prolonged t(max) compared with the IR formulation. The amount of torasemide recovered in the urine 24 h after administration was higher with the PR formulation for both doses. The natriuretic rate versus torasemide excretion rate for the PR and IR formulations were successfully regressed to a sigmoid E(max) model. Pharmacodynamic urine evaluations were similar with both formulations, although urine volume and urine electrolyte excretion were lower for the PR formulation in the first hour after administration. However, the PR formulation showed higher natriuretic efficiency. No significant adverse events were reported. 4. In conclusion, both formulations of torasemide showed similar systemic exposure (AUC). However, the PR formulation had a lower rate of absorption (lower C(max) and prolonged t(max)). The PR formulation had urinary excretion rates that were associated with a higher natriuretic efficiency and more constant diuresis.

Eberconazole cream: topical and general tolerability, sensitisation potential, and systemic availability.

Eberconazole is a topical imidazole derivative, which has shown high potency against dermatophytes and yeasts (several species of Candida, Malassezia) in vitro and in experimental models. Clinical trials have found that the compound has a high degree of efficacy against dermatophytes and good tolerability. Evaluation of its a) topical and general tolerability, b) eventual development of sensitisation, c) local availability, and d) degree of systemic absorption. Two clinical trials with 28 healthy young volunteers of both sexes were performed. In Study I, placebo or eberconazole cream (2%) were applied at increasing doses: day 1 (0.5 g), days 2-3 (1 g), days 4-5 (2 g), days 6-7 (4 g), days 8-9 (8 g), and days 10-11 (12 g). On day 1, each application area was washed with ethanol-soaked gauzes at different times to assess availability of the active compound. In Study II, eberconazole cream (1%) was applied on day 1 and again at least one week later. After the first application, blood and urine samples were obtained at different times to assess systemic absorption. The only change observed was slight redness in a few volunteers after both active and placebo applications. This remitted spontaneously without intervention and we were able to continue with the administration of repeated increasing-doses. A few participants described side effects; these were all of mild intensity, and occurred in areas where placebo or eberconazole were applied, mainly within the first hour postapplication. The most frequent effect after the first application was coldness, and after repeated increasing-doses there was itching. No signs or symptoms of skin reactivity were observed following reexposure to the product. No clinically relevant changes were observed in vital signs (systolic and diastolic blood pressure, heart rate, body temperature), ECG, or analytical parameters (clinical haematology and biochemistry). The quantity of compound collected through washing gauzes decreased progressively over time. Plasma and urine concentrations of eberconazole were below the quantification limit of the analytical method (5 ng/ml) at all times. Eberconazole cream is a topical antimycotic drug that has good local and general tolerability. It has acceptable topical availability, no detectable systemic drug levels, and does not appear to cause skin sensitivity.