Comparative bioavailability of two escitalopram formulations in healthy human volunteers.

OBJECTIVE: To assess the bioequivalence of two escitalopram formulations (Test formulation: escitalopram (10 mg tablet) manufactured by Apsen Farmacêutica S.A.) Reference formulation: escitalopram (Lexapro; 10 mg tablet) from Lundbeck Brasil Ltda) in healthy volunteers of both sexes. METHODS: The study was conducted using an open, randomized, two-period crossover design with at least a 21-day washout interval. Plasma samples were obtained over a 168 h period. Plasma escitalopram concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM). The following pharmacokinetic parameters were obtained from the escitalopram plasma concentration vs. time curves: AUC(last), AUC(inf) and C(max). RESULTS: The limit of quantification for escitalopram was 0.2 ng x ml(-1). The geometric mean with corresponding 90% confidence interval (CI) for Test/Reference percent ratios were 97.35% (90% CI = 90.28-104.96%) for C(max), 99.60% (90% CI = 92.93-106.74%) for AUC(last) and 99.92% (90% CI = 93.34-106.97%) for AUC(inf). CONCLUSION: Since the 90% CI for AUClast, AUCinf and Cmax ratios were within the 80-125% interval proposed by the US FDA, it was concluded that escitalopram formulation manufactured by Apsen Farmacêutica S.A. is bioequivalent to the Lexapro formulation in regard to both the rate and the extent of absorption.

Long-term nitric oxide deficiency causes muscarinic supersensitivity and reduces beta(3)-adrenoceptor-mediated relaxation, causing rat detrusor overactivity.

BACKGROUND AND PURPOSE: Overactive bladder is a complex and widely prevalent condition, but little is known about its physiopathology. We have carried out morphological, biochemical and functional assays to investigate the effects of long-term nitric oxide (NO) deficiency on muscarinic receptor and beta-adrenoceptor modulation leading to overactivity of rat detrusor muscle. EXPERIMENTAL APPROACH: Male Wistar rats received N(omega)-nitro-L-arginine methyl ester (L-NAME) in drinking water for 7-30 days. Functional responses to muscarinic and beta-adrenoceptor agonists were measured in detrusor smooth muscle (DSM) strips in Krebs-Henseleit solution. Measurements of [(3)H]inositol phosphate, NO synthase (NOS) activity, [(3)H]quinuclidinyl benzilate ([(3)H]QNB) binding and bladder morphology were also performed. KEY RESULTS: Long-term L-NAME treatment significantly increased carbachol-induced DSM contractile responses after 15 and 30 days; relaxing responses to the beta(3)-adrenoceptor agonist BRL 37-344 were significantly reduced at 30 days. Constitutive NOS activity in bladder was reduced by 86% after 7 days and maintained up to 30 days of L-NAME treatment. Carbachol increased sixfold the [(3)H]inositol phosphate in bladder tissue from rats treated with L-NAME. [(3)H]QNB was bound with an apparent K(D) twofold higher in bladder membranes after L-NAME treatment compared with that in control. No morphological alterations in DSM were found. CONCLUSIONS AND IMPLICATIONS: Long-term NO deficiency increased rat DSM contractile responses to a muscarinic agonist, accompanied by significantly enhanced K(D) values for muscarinic receptors and [(3)H]inositol phosphate accumulation in bladder. This supersensitivity for muscarinic agonists along with reductions of beta(3)-adrenoceptor-mediated relaxations indicated that overactive DSM resulted from chronic NO deficiency.