Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents.

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.

Three-dimensional simulations of reactive gas uptake in single airway bifurcations.

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.

Changes in the carbon dioxide expirogram in response to ozone exposure.

The objectives of this study were to quantify pulmonary responses to ozone (O3) exposure by parameters computed from the carbon dioxide expirogram and to compare these responses to decrements in forced expired spirometry. Anatomical dead space (VD) was determined from the pure dead space and transition regions of the expirogram. Four alternative parameters were computed from the alveolar plateau: slope (S), normalized slope (NS), peripheral cross-sectional area (AP) and well-mixed peripheral volume (VMP). Forty-seven healthy nonsmokers (25 men and 22 women) participated in two research sessions in which they exercised on a cycle ergometer for 1 h while orally inhaling either room air at a minute ventilation of 30.6 +/- 3.6 L or room air mixed with 0.252 +/- 0.029 ppm O3 at a minute ventilation of 29.9 +/- 3.7 L. Carbon dioxide expirograms were measured before exposure, 10 min after exposure and 70 min after exposure. Percent changes (mean +/- SD) in expirogram parameters were significant (P < or = 0.002) at both 10 and 70 min after O3 exposure: VD(-4.2 +/- 5.1, -3.3 +/- 6.9), S(16.4 +/- 17.9, +15.1 +/- 20.2), NS(17.5 +/- 15.4, +15.9 +/- 19.2), AP(-8.1 +/- 7.6, -7.7 +/- 9.8) and VMP(-15.4 +/- 13.0, -13.0 +/- 15.2). Percent decrements of forced expired volume in one second (FEV1) were also significant at both 10 min (-13.3 +/- 13.4) and 70 min (-11.1 +/- 9.2) following O3 exposure. Changes in the expirogram as well as decrements in FEV1 were not significant at either time point after air exposure. Thus, the CO2 expirogram is useful for characterizing the effect of O3 exposure on gas transport, and for supplementing forced expired spirometry that is frequently used to quantify lung mechanics.