PubMed · 9287863
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Y Needham. 1997. Glaucoma.. https://pubmed.ncbi.nlm.nih.gov/9287863/
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Currently available antidepressants have a delayed onset of action and there is considerable interest in developing new products which exhibit a shorter time to response. Previous authors have suggested using a cure model to characterize the time to response for the combination of the patients who respond and the patients who do not respond. In this paper, we use the cure model and propose a Cramer-von Mises statistic to compare the time to response distributions for patients who respond to therapy. The asymptotic null distribution of the statistic is derived. A bootstap procedure is also proposed for sample sizes typical in antidepressant clinical trials. Results of the simulation study suggest that for common designs and sample sizes used in such trials, the statistic has reasonable size and power properties as long as censoring is moderate.
The acid-base equilibrium constants of the beta-blockers atenolol, oxprenolol, timolol and labetalol were determined by automated potentiometric titrations. The pKa values were obtained in water-rich or water methanol medium (20% MeOH) to obviate the solubility problems associated with the compounds. The initial estimates of pKa values were obtained from Gran's method and then, were refined by the NYTIT and ZETA versions of the LETAGROP computer program. The resultant values were 9.4 (I = 0.1 M KCl, 20% methanol) for atenolol, 9.6 (I = 0.1 M KCl) for oxprenolol, 9.4 (I = 0.1 M KCl, 20% methanol) for timolol and 7.4 and 9.4 (I = 0.1 M KCl) for labetalol. The potentiometric method was found to be accurate and easily applicable. The operational criteria for applying the methodology are indicated.
BACKGROUND: Nebivolol is a beta(1)-selective adrenergic receptor antagonist with proposed nitric oxide (NO)-mediated vasodilating properties in humans. In this study, we explored whether nebivolol indeed induces NO production and, if so, by what mechanism. We hypothesized that not nebivolol itself but rather its metabolites augment NO production. METHODS AND RESULTS: Mouse thoracic aorta segments were bathed in an organ chamber. Administration of nebivolol did not affect NO production. When nebivolol was allowed to metabolize in vivo in mice, addition of plasma of these mice caused a sustained 2-fold increase in NO release. Interestingly, coadministration of a selective beta(2)-adrenergic receptor antagonist (butoxamine) prevented the response. Immunohistochemistry and Western blot analysis demonstrated the presence of beta(2)- but not beta(1)-adrenergic receptors on endothelial cells. In the absence of calcium, metabolized nebivolol failed to increase NO production, suggesting a role for calcium-dependent NO synthase. With digital fluorescence imaging, a rapid and sustained rise in endothelial cytosolic free Ca(2+) concentration was observed after administration of metabolized nebivolol, which also was abrogated by butoxamine pretreatment. CONCLUSIONS: In vivo metabolized nebivolol increases vascular NO production. This phenomenon involves endothelial beta(2)-adrenergic receptor ligation, with a subsequent rise in endothelial free [Ca(2+)](i) and endothelial NO synthase-dependent NO production. This may be an important mechanism underlying the nebivolol-induced, NO-mediated arterial dilation in humans.