A comparison of drug transport in pulmonary absorption models: isolated perfused rat lungs, respiratory epithelial cell lines and primary cell culture

Purpose: To evaluate the ability of human airway epithelial cell layers and a simple rat isolated perfused lung (IPL) model to predict pulmonary drug absorption in rats in vivo. Method: The permeability of seven compounds selected to possess a range of lipophilicity was measured in two airway cell lines (Calu-3 and 16HBE14o-), in normal human bronchial epithelial (NHBE) cells and using a simple isolated perfused lungs (IPL) technique. Data from the cell layers and ex vivo lungs were compared to published absorption rates from rat lungs measured in vivo. Results: A strong relationship was observed between the logarithm of the in vivo absorption half-life and the absorption half-life in the IPL (r = 0.97; excluding formoterol). Good log-linear relationships were also found between the apparent first-order absorption rate in vivo and cell layer permeability with correlation coefficients of 0.92, 0.93, 0.91 in Calu-3, 16HBE14o- and NHBE cells, respectively. Conclusion: The simple IPL technique provided a good prediction of drug absorption from the lungs, making it a useful method for empirical screening of drug absorption in the lungs. Permeability measurements were similar in all the respiratory epithelial cell models evaluated, with Calu-3 having the advantage for routine permeability screening purposes of being readily availability, robust and easy to culture

A Cell-based Computational Modeling Approach for Developing Site-Directed Molecular Probes

Modeling the local absorption and retention patterns of membrane-permeant small molecules in a cellular context could facilitate development of site-directed chemical agents for bioimaging or therapeutic applications. Here, we present an integrative approach to this problem, combining in silico computational models, in vitro cell based assays and in vivo biodistribution studies. To target small molecule probes to the epithelial cells of the upper airways, a multiscale computational model of the lung was first used as a screening tool, in silico. Following virtual screening, cell monolayers differentiated on microfabricated pore arrays and multilayer cultures of primary human bronchial epithelial cells differentiated in an air-liquid interface were used to test the local absorption and intracellular retention patterns of selected probes, in vitro. Lastly, experiments involving visualization of bioimaging probe distribution in the lungs after local and systemic administration were used to test the relevance of computational models and cell-based assays, in vivo. The results of in vivo experiments were consistent with the results of in silico simulations, indicating that mitochondrial accumulation of membrane permeant, hydrophilic cations can be used to maximize local exposure and retention, specifically in the upper airways after intratracheal administration

Cognitive functioning in patients treated with electroconvulsive therapy

Lucie Kalisova, Marketa Kubinova, Jiri Michalec, Jakub Albrecht, Katerina Madlova, Jiri Raboch Department of Psychiatry, First Faculty of Medicine, Charles University, General University Hospital in Prague, Prague, Czech Republic Background: Electroconvulsive therapy (ECT) is an effective treatment method for severe mental illnesses. ECT has gone through significant modernization. Side effects of ECT have largely decreased. Temporary disturbance of cognitive performance can be still present as a side effect of electroconvulsive treatment. Methods: Cognitive functioning in the sample of patients with severe and acute mental illness treated with electroconvulsive therapy (ECT) was assessed. Basic assessment of cognitive functions was applied in the beginning, in the middle, and at the end of ECT course treatment with the Montreal Cognitive Assessment (MoCA). Complex and detailed testing of cognitive functions using the MATRICS Consensus Cognitive Battery (MCCB) was done at two points in time – within the first week of and then 6 weeks after the end of ECT. Results: Participants had cognitive deficits at baseline, which were most likely influenced markedly by the psychopathology of the illness itself. The improvement in cognition came together with the reduction in psychopathology; psychopathology scores were significantly reduced during ECT treatment. Compared to the baseline, all scores for cognitive testing were significantly improved but remained low in comparison with the controls. After 6 weeks, there was further significant improvement. Conclusion: Our results confirm the safety and efficacy of ECT in the treatment of severe mental disorders. Keywords: electroconvulsive therapy, cognition, side effects, MCC

Enteral tube feeding and mortality in hospitalized older patients: A multicenter longitudinal study

Background & aims: The literature regarding enteral nutrition and mortality in older frail people is limited and still conflicting. Moreover, the potential role of comprehensive geriatric assessment is poorly explored. We therefore aimed to investigate whether the Multidimensional Prognostic Index (MPI), an established tool that assesses measures of frailty and predicts mortality, may help physicians in identifying patients in whom ETF (enteral tube feeding) is effective in terms of reduced mortality. Methods: Observational, longitudinal, multicenter study with one year of follow-up. Data regarding ETF were recorded through medical records. A standardized comprehensive geriatric assessment was used to calculate the MPI. Participants were divided in low (MPI-1), moderate (MPI-2) or severe (MPI-3) risk of mortality. Data regarding mortality were recorded through administrative information. Results: 1064 patients were included, with 79 (13 in MPI 1–2 and 66 in MPI-3 class) receiving ETF. In multivariable analysis, patients receiving ETF experienced a higher risk of death (odds ratio, OR = 2.00; 95% confidence intervals, CI: 1.19–3.38). However, after stratifying for their MPI at admission, mortality was higher in MPI-3 class patients (OR = 2.03; 95%CI: 1.09–3.76), but not in MPI 1–2 class patients (OR = 1.51; 95%CI: 0.44–5.25). The use of propensity score confirmed these findings. Conclusions: ETF is associated with a higher risk of death. However, this is limited to more frail patients, suggesting the importance of the MPI in the prognostic evaluation of ETF. © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolis