MK-2206 was well tolerated, with evidence of AKT signaling blockade. Rational combination trials are ongoing to maximize clinical benefit with this therapeutic strategy.
Aprepitant triple therapy was generally well tolerated; CR were greater with aprepitant, although not statistically significant. Pharmacokinetics suggest that the adult dosing regimen is appropriate for adolescents.
The pattern of lung injury induced by the inhalation of ozone (O(3)) depends on the dose delivered to different tissues in the airways. This study examined the distribution of O(3) uptake in a single, symmetrically branched airway bifurcation. Reaction in the epithelial lining fluid was assumed to be so rapid that O(3) concentration was negligible along the entire surface of the bifurcation wall. Three-dimensional numerical solutions of the continuity, Navier-Stokes and convection-diffusion equations were obtained for steady inspiratory and expiratory flows at Reynolds numbers ranging from 100 to 500. The total rate of O(3) uptake was found to increase with increasing flow rate during both inspiration and expiration. Hot spots of O(3) flux appeared at the carina of the bifurcation for virtually all inspiratory and expiratory Reynolds numbers considered in the simulations. At the lowest expiratory Reynolds number, however, the location of the maximum flux was shifted to the outer wall of the daughter branch. For expiratory flow, additional hot spots of flux were found on the parent branch wall just downstream of the branching region. In all cases, O(3) uptake in the single bifurcation was larger than that in a straight tube of equal inlet radius and wall surface area. This study provides insight into the effect of flow conditions on O(3) uptake and dose distribution in individual bifurcations.
A novel phenyl acetamide series of short-acting T-type calcium channel antagonists has been identified and evaluated using in vitro and in vivo assays. Heterocycle substitutions of the 4-position of the phenyl acetamides afforded potent and selective antagonists that exhibited desired short plasma half-lives across preclinical species. Lead compound TTA-A8 emerged as a compound with excellent in vivo efficacy as indicated by its significant modulation of rat sleep architecture in an EEG telemetry model, favorable pharmacokinetic properties, and excellent preclinical safety. TTA-A8 recently progressed into human clinical trials, and in line with our predictions, preliminary studies (n = 12) with a 20 mg oral dose afforded a high C max of 1.82 ± 0.274 μM with an apparent terminal half-life of 3.0 ± 1.1 h.
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