Comparative pharmacokinetics and bioavailability of brimonidine following ocular and dermal administration of brimonidine tartrate ophthalmic solution and gel in patients with moderate-to-severe facial erythema associated with rosacea.

BACKGROUND: Persistent facial erythema is the most common primary pathological feature of rosacea, the only treatment for which is brimonidine tartrate (BT) gel. OBJECTIVES: To assess the relative bioavailability of topical BT gel in comparison with the ophthalmic BT solution. METHODS: A pharmacokinetic study was conducted to compare intraindividual systemic exposures after dermal application of BT gel (0·07%, 0·18% and 0·5%) under maximal use conditions in patients with moderate-to-severe facial erythema associated with rosacea, and administration of BT ophthalmic solution 0·2%. RESULTS: Patients who received BT ophthalmic solution 0·2% three times a day for 1 day had a mean Cmax of 54 ± 28 pg mL(-1) and a mean 0-24-h area under the curve (AUC0-24 h ) of 568 ± 277 pg h mL(-1) . Topical application of BT gel for 29 days resulted in quantifiable systemic exposure in 22%, 48%, 71% and 79% of patients who received BT gel 0·07% twice daily, 0·18% once daily, 0·18% twice daily and 0·5% once daily, respectively. The mean Cmax values for the BT gels ranged between 13 and 25 pg mL(-1) , and mean AUC0-24 h values ranged between 42 and 290 pg h mL(-1) . Systemic exposure increased with applied dose, with no drug accumulation for the duration of treatment. The systemic exposure observed with the highest dose of BT gel (0·5% once daily) was significantly lower than the systemic levels observed for the ophthalmic solution. 0·2% apply for all the concentrations. CONCLUSIONS: The systemic safety profile of BT gel may be considered better than that of the ophthalmic solution.

A new strategy for faster urinary biomarkers identification by Nano-LC-MALDI-TOF/TOF mass spectrometry.

BACKGROUND: LC-MALDI-TOF/TOF analysis is a potent tool in biomarkers discovery characterized by its high sensitivity and high throughput capacity. However, methods based on MALDI-TOF/TOF for biomarkers discovery still need optimization, in particular to reduce analysis time and to evaluate their reproducibility for peak intensities measurement. The aims of this methodological study were: (i) to optimize and critically evaluate each step of urine biomarker discovery method based on Nano-LC coupled off-line to MALDI-TOF/TOF, taking full advantage of the dual decoupling between Nano-LC, MS and MS/MS to reduce the overall analysis time; (ii) to evaluate the quantitative performance and reproducibility of nano-LC-MALDI analysis in biomarker discovery; and (iii) to evaluate the robustness of biomarkers selection. RESULTS: A pool of urine sample spiked at increasing concentrations with a mixture of standard peptides was used as a specimen for biological samples with or without biomarkers. Extraction and nano-LC-MS variabilities were estimated by analyzing in triplicates and hexaplicates, respectively. The stability of chromatographic fractions immobilised with MALDI matrix on MALDI plates was evaluated by successive MS acquisitions after different storage times at different temperatures.Low coefficient of variation (CV%: 10-22%) and high correlation (R2 > 0.96) values were obtained for the quantification of the spiked peptides, allowing quantification of these peptides in the low fentomole range, correct group discrimination and selection of "specific" markers using principal component analysis. Excellent peptide integrity and stable signal intensity were found when MALDI plates were stored for periods of up to 2 months at +4 degrees C. This allowed storage of MALDI plates between LC separation and MS acquisition (first decoupling), and between MS and MSMS acquisitions while the selection of inter-group discriminative ions is done (second decoupling). Finally the recording of MSMS spectra to obtain structural information was focused only on discriminative ions in order to minimize analysis time. CONCLUSION: Contrary to other classical approaches with direct online coupling of chromatographic separation and on the flight MS and/or MSMS data acquisition for all detected analytes, our dual decoupling strategy allowed us to focus on the most discriminative analytes, giving us more time to acquire more replicates of the same urine samples thus increasing detection sensitivity and mass precision.