The relationship between inspiratory lung function parameters and airway hyper-responsiveness in subjects with mild to moderate COPD

Background: The aim of this study was to evaluate the effects of increasing doses of inhaled histamine on the forced expiratory volume in one second (FEV 1), inspiratory lung function parameters (ILPs) and dyspnea in subjects with mild to moderate chronic obstructive pulmonary disease (COPD). Methods. Thirty-nine (27 males and 12 females) stable COPD patients (GOLD stages I and II) inhaled a maximum of six sequential doses of histamine according to ERS standards until one of these provocative doses produced a 20% decrease in FEV 1 (PD 20). The effects on the FEV 1, the forced inspiratory volume in one second (FIV 1), inspiratory capacity (IC), forced inspiratory flow at 50% of the vital capacity (FIF50), peak inspiratory flow (PIF) and dyspnea score by a visual analogue scale (VAS) were measured and investigated after each dose step. Results: After each dose of histamine, declines in all of the lung function parameters were detected; the largest decrease was observed in the FEV 1. At the PD 20 endpoint, more FEV 1 responders than ILP responders were found. Among the ILPs, the FIV 1 and IC best predicted which patients would reach the PD 20 endpoint. No significant correlations were found between any of the lung function parameters and the VAS results. Conclusions: In COPD patients, the FEV 1 and ILPs declined after each dose of inhaled histamine. FEV 1 was more sensitive to histamine than the ILPs. Of the ILPs, FIV 1 and IC were the best predictors of reaching the PD 20 endpoint. No statistically significant correlations were found between the lung function parameters and the degree of dyspnea

Transport of the anti-cancer drug doxorubicin across cytoplasmic membranes and membranes composed of phospholipids derived from Escherichia coli occurs via a similar mechanism

AbstractAn assay was developed to measure and directly compare transport of doxorubicin across right-side-out cytoplasmic membrane vesicles (ROV) and across model membranes (LUVET) composed of pure phospholipids, isolated from the corresponding cells. Escherichia coli was used as a model organism, since mutants are available which differ in phospholipid composition. Both in LUVET and ROV only passive diffusion across the bilayer is involved, because effects of drug concentration, pH, divalent cations, the phospholipid composition, and the active transport inhibitor verapamil were comparable. Permeability coefficients were about 2–3-times higher in ROV compared to LUVET. Furthermore, in LUVET an average activation energy of 87 kJ/mol and in ROV of 50 kJ/mol was observed. These differences are suggested to result from differences in membrane order between LUVET and ROV and differences in the temperature dependence of membrane order in LUVET and ROV, respectively. Because no background carrier-facilitated doxorubicin transport seems to be present, ROV are an excellent model system to study the effect of phospholipid composition on drug transport after expression of a multidrug resistance-conferring protein. Furthermore, data of passive diffusion of doxorubicin obtained with LUVET are representative for more complex, biologically relevant membrane systems

Verapamil competes with doxorubicin for binding to anionic phospholipids resulting in increased internal concentrations and rates of passive transport of doxorubicin

AbstractIt is well documented that the Ca2+ channel antagonist verapamil can reverse multidrug resistance in cancer cells by decreasing P-glycoprotein mediated drug efflux. However, less information is available about effects of verapamil on drug-phospholipid interactions and on passive diffusion of drugs across the membrane, which both may play an important role in resensitizing cells to anti-cancer drugs. Therefore we studied the binding of verapamil to model membranes (large unilamellar vesicles) composed of various phospholipids and biological membranes. An increase of the amount of anionic phospholipids resulted in an enhanced binding of verapamil. Competition between verapamil and the anti-cancer drug and P-glycoprotein substrate doxorubicin for binding to anionic phospholipids was observed in model membranes composed of synthetic lipids, or composed of native Escherichia coli phospholipid mixtures, and in cytoplasmic membrane vesicles of this organism. Furthermore, verapamil specifically increased the rate of passive diffusion of doxorubicin across model membranes containing anionic phospholipids. It can be concluded that besides the decrease of P-glycoprotein mediated efflux at least two other effects may account for an increase of the internal (free and DNA-bound) doxorubicin concentration in the presence of verapamil; (i) a decrease of binding to anionic phospholipids in plasma-and intracellular membranes and (ii) an increase of the rate of passive import of doxorubicin across the plasma membrane

Reproduction of fatty acid vesicles

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