Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) represents a significant cause of global morbidity and mortality, with a substantial economic impact. Recent changes in the Global initiative for chronic Obstructive Lung Disease (GOLD) guidance refined the classification of patients for treatment using a combination of spirometry, assessment of symptoms, and/or frequency of exacerbations. The aim of treatment remains to reduce existing symptoms while decreasing the risk of future adverse health events. Long-acting bronchodilators are the mainstay of therapy due to their proven efficacy. GOLD guidelines recommend combining long-acting bronchodilators with differing mechanisms of action if the control of COPD is insufficient with monotherapy, and recent years have seen growing interest in the additional benefits that combination of long-acting muscarinic antagonists (LAMAs), typified by tiotropium, with long-acting β₂-agonists (LABAs), such as formoterol and salmeterol. Most studies have examined free combinations of currently available LAMAs and LABAs, broadly showing a benefit in terms of lung function and other patient-reported outcomes, although evidence is limited at present. Several once- or twice-daily fixed-dose LAMA/LABA combinations are under development, most involving newly developed monotherapy components. This review outlines the existing data for LAMA/LABA combinations in the treatment of COPD, summarizes the ongoing trials, and considers the evidence required to inform the role of LAMA/LABA combinations in treatment of this disease.     

Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy

Measurements of early tumor responses to therapy have been shown, in some cases, to predict treatment outcome. We show in lymphoma-bearing mice injected intravenously with hyperpolarized [1-(13)C]pyruvate that the lactate dehydrogenase-catalyzed flux of (13)C label between the carboxyl groups of pyruvate and lactate in the tumor can be measured using (13)C magnetic resonance spectroscopy and spectroscopic imaging, and that this flux is inhibited within 24 h of chemotherapy. The reduction in the measured flux after drug treatment and the induction of tumor cell death can be explained by loss of the coenzyme NAD(H) and decreases in concentrations of lactate and enzyme in the tumors. The technique could provide a new way to assess tumor responses to treatment in the clinic.     

Mapping and quantifying hyperpolarized 3He magnetic resonance imaging apparent diffusion coefficient gradients.

We measured hyperpolarized 3He magnetic resonance imaging (MRI) apparent diffusion coefficients (ADC) and quantified ADC gradients in each three-by-three voxel region of interest (ROI). Such local ADC gradients can be represented in vector maps showing the magnitude (|G3x3|) and direction of ADC gradients, providing a qualitative visualization tool and quantitative measurement of airway and air space heterogeneity. Twenty-four subjects (15 male, mean age=67+/-7 yr) with global initiative for chronic obstructive lung disease (GOLD) stage II (n=9, mean age 68+/-6 yr), GOLD stage III chronic obstructive pulmonary disease (COPD; n=7, mean age 67+/-8 yr), and age-matched healthy volunteers (n=8, mean age 67+/-6 yr) were enrolled based on their age and spirometry results. Hyperpolarized 3He MRI was performed on a whole body 3.0 Tesla system. Mean 3He ADC and ADC standard deviation were calculated for the center coronal slice, and the mean magnitude and direction of the ADC gradient vectors were calculated for each three-by-three voxel matrix (|G3x3|). While the 3He ADC standard deviation was not significantly different, mean |G3x3| was significantly different between subjects with stage II (0.14+/-0.03 cm/s) and stage III COPD (0.19+/-0.03 cm/s; P<0.005) and between healthy subjects (0.12+/-0.03 cm/s) and those with stage II COPD (P<0.02). The second order statistic |G3x3| may provide a sensitive measure of ADC heterogeneity for ROI representing 9.4x9.4x30 mm or 2.6 cm3 of lung tissue.     

Regional measurements of pulmonary edema by using magnetic resonance imaging

Athree-dimensional magnetic resonance imaging (MRI) method to measurepulmonary edema and lung microvascular barrier permeability wasdeveloped and compared with conventional methods in nine mongrel dogs.MRIs were obtained covering the entire lungs. Injury was induced byinjection of oleic acid (0.021-0.048 ml/kg) into a jugularcatheter. Imaging followed for 0.75-2 h. Extravascular lung waterand permeability-related parameters were measured from multiple-indicator dilution curves. Edema was measured as magnetic resonance signal-to-noise ratio (SNR). Postinjury wet-to-dry lung weight ratio was 5.30 ± 0.38 (n = 9). Extravascular lung water increased from 2.03 ± 1.11 to 3.00 ± 1.45 ml/g(n = 9, P < 0.01). Indicatordilution studies yielded parameters characterizing capillary exchangeof urea and butanediol: the product of the square root of equivalentdiffusivity of escape from the capillary and capillary surface area(D^1/2S)and the capillary permeability-surface area product(PS). The ratio ofD^1/2Sfor urea toD^1/2Sfor butanediol increased from 0.583 ± 0.027 to 0.852 ± 0.154 (n = 9, P < 0.05). Whole lung SNR atbaseline, before injury, correlated withD^1/2Sand PS ratios (both P < 0.02). By using rate of SNR change, the mismatch of transcapillaryfiltration flow and lymph clearance was estimated to be0.2-1.8 ml/min. The filtration coefficient was estimated fromthese values. Results indicate that pulmonary edema formation duringoleic acid injury can be imaged regionally and quantified globally, andthe results suggest possible regional quantification by usingthree-dimensional MRI.

     

Proteinases in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide, and we have little specific therapy to offer these patients. One potential strategy to limit loss of lung function in COPD would be to inhibit matrix-degrading proteinases. Several serine proteinases and matrix metalloproteinases are expressed in association with COPD in humans. Application of gene-targeted macrophage elastase and neutrophil elastase to a mouse model of cigarette-smoke-induced emphysema has uncovered roles for these proteinases in airspace enlargement, and has identified many interactions between these proteolytic systems.     

Plasma lipoproteins in chronic obstructive pulmonary disease

Plasma lipoprotein fractions have been assessed in 29 patients with chronic obstructive pulmonary disease (COPD), and compared with non-COPD subjects. Triglycerides were significantly lower in COPD females only, the other parameters being almost identical. Thus, the atherosclerosis index of plasma lipoproteins in COPD did not differ almost at all from that of non-COPD subjects, demonstrating that the low prevalence of angina and/or myocardial infarction in COPD patients is not only a consequence of reduced coronary atherosclerosis.     

Molecular mechanisms in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with progressive airflow obstruction. Tobacco smoking is the main risk factor worldwide. In contrast to asthma, anti-inflammatory therapies are rather ineffective in improving chronic symptoms and reducing inflammation, lung function decline, and airway remodeling. Specific drugs that are directed against the remodeling and chronic inflammation, thereby preventing lung tissue damage and progressive lung function decline, must be developed. Experimental models and expression studies suggest that anti-vascular endothelial growth factor (VEGF) receptor strategies may be of use in patients with emphysema, whereas anti-HER1-directed strategies may be more useful in patients with pulmonary mucus hypersecretion, as seen in chronic bronchitis and asthma. Growth factors and cytokines including VEGF, fibroblast growth factors, transforming growth factor-β, tumor necrosis factor-α, CXCL1, CXCL8, and CCL2, and signal transduction proteins such as mitogen-activated protein kinase p38 and nuclear factor-⦊B, seem to be important pathogenetic molecules in COPD. Specific antagonists for these proteins may be effective for different inflammatory diseases. However, their efficacy for COPD therapy has not yet been demonstrated. Finally, other drugs such as retinoic acids may provide restoration of lung tissue structure. Such approaches, however, must await the first results of growth factor or cytokine antagonist therapy in chronic lung diseases.     

Models of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations.     

Analysis of intrapulmonary O(2) concentration by MR imaging of inhaled hyperpolarized helium-3.

Inhalation of hyperpolarized (3)He allows magnetic resonance imaging (MRI) of ventilated airspaces. (3)He hyperpolarization decays more rapidly when interacting with paramagnetic O(2). We describe a method for in vivo determination of intrapulmonary O(2) concentrations ([O(2)]) based on MRI analysis of the fate of measured amounts of inhaled hyperpolarized (3)He in imaged regions of the lung. Anesthetized pigs underwent controlled normoventilation in a 1.5-T MRI unit. The inspired O(2) fraction was varied to achieve different end-tidal [O(2)] fractions (FET(O(2))). With the use of a specifically designed applicator, (3)He (100 ml, 35-45% polarized) was administered at a predefined time within single tidal volumes. During subsequent inspiratory apnea, serial two-dimensional images of airways and lungs were acquired. At least once in each animal studied, the radio-frequency excitation used for imaging was doubled at constant FET(O(2)). Signal intensity measurements in regions of interest of the animals' lungs (volume range, 54-294 cm(3)), taken at two different radio-frequency excitations, permitted calculation of [O(2)] in these regions of interest. The [O(2)] fractions in the regions of interest correlated closely with FET(O(2)) (R = 0.879; P < 0.0001). O(2)-sensitive (3)He-MRI may allow noninvasive study of regional distribution of ventilation and alveolar PO(2) in the lung.     

Quantifying mixing using magnetic resonance imaging

Mixing is a unit operation that combines two or more components into a homogeneous mixture. This work involves mixing two viscous liquid streams using an in-line static mixer. The mixer is a split-and-recombine design that employs shear and extensional flow to increase the interfacial contact between the components. A prototype split-and-recombine (SAR) mixer was constructed by aligning a series of thin laser-cut Poly (methyl methacrylate) (PMMA) plates held in place in a PVC pipe. Mixing in this device is illustrated in the photograph in Fig. 1. Red dye was added to a portion of the test fluid and used as the minor component being mixed into the major (undyed) component. At the inlet of the mixer, the injected layer of tracer fluid is split into two layers as it flows through the mixing section. On each subsequent mixing section, the number of horizontal layers is duplicated. Ultimately, the single stream of dye is uniformly dispersed throughout the cross section of the device. Using a non-Newtonian test fluid of 0.2% Carbopol and a doped tracer fluid of similar composition, mixing in the unit is visualized using magnetic resonance imaging (MRI). MRI is a very powerful experimental probe of molecular chemical and physical environment as well as sample structure on the length scales from microns to centimeters. This sensitivity has resulted in broad application of these techniques to characterize physical, chemical and/or biological properties of materials ranging from humans to foods to porous media (1, 2). The equipment and conditions used here are suitable for imaging liquids containing substantial amounts of NMR mobile (1)H such as ordinary water and organic liquids including oils. Traditionally MRI has utilized super conducting magnets which are not suitable for industrial environments and not portable within a laboratory (Fig. 2). Recent advances in magnet technology have permitted the construction of large volume industrially compatible magnets suitable for imaging process flows. Here, MRI provides spatially resolved component concentrations at different axial locations during the mixing process. This work documents real-time mixing of highly viscous fluids via distributive mixing with an application to personal care products.     

The genetics of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a significant cause of global morbidity and mortality. Previous studies have shown that COPD aggregates in families, suggesting a genetic predisposition to airflow obstruction. Many candidate genes have been assessed, but the data are often conflicting. We review the genetic factors that predispose smokers to COPD and highlight the future role of genomic scans in identifying novel susceptibility genes.     

Circadian rest-activity rhythm in chronic obstructive pulmonary disease

To characterize circadian rest-activity rhythm in COPD, 26 cases (66.9 ± 8.5y) and 15 controls (63.0 ± 10.7y) were assessed by actimetry. Rhythm fragmentation was measured by intradaily variability (IV), while synchronization to the 24-h light-dark cycle was measured by interdaily stability (IS). The average activity during the least active 5-h period (L5) and the average activity during the most active 10-h period (M10) were used to calculate the relative amplitude mean [RAm = (M10-L5)/(M10+L5)]. COPD patients presented higher IVm (0.242 ± 0.097 vs 0.182 ± 0.063) and L5 (36.849 ± 18.239 vs 19.888 ± 12.268) and lower RAm (0.696 ± 0.134 vs 0.833 ± 0.093) than controls. Future studies on the effects of chronotherapy measures in COPD are warranted.     

Glutathione cycle in stable chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidant/antioxidant imbalance. Glutathione is the most abundant cellular low‐molecular weight thiol and the glutathione redox cycle is the fundamental component of the cellular antioxidant defence system. Concentration of total glutathione and catalytic activities of glutathione peroxidase and glutathione reductase were determined in peripheral blood of patients (n = 109) and healthy subjects (n = 51). Concentration of total glutathione in patients was not changed in comparison to healthy controls. However, we found statistically significant difference between patients with moderate and severe disease stages. Glutathione reductase activity was increased, while glutathione proxidase activity was decreased in the patients with COPD, when compared to healthy controls. We found no significant difference in glutathione peroxidase and glutathione reductase activities between stages. Patients who smoked had lower concentration of total glutathione compared with former smokers and never‐smoking patients. Lung function parameters were inversely associated with glutathione level. Evidence is presented for differential modulation of glutathione peroxidase and glutathione reductase activities in peripheral blood of patients with stable COPD. We suppose that in addition to glutathione biosynthesis, glutathione reductase‐dependent regulation of the glutathione redox state is vital for protection against oxidative stress. Copyright © 2010 John Wiley & Sons, Ltd.     

Skeletal muscle dysfunction in chronic obstructive pulmonary disease

It has become increasingly recognized that skeletal muscle dysfunction is common in patients with chronic obstructive pulmonary disease (COPD). Muscle strength and endurance are decreased, whereas muscle fatigability is increased. There is a reduced proportion of type I fibers and an increase in type II fibers. Muscle atrophy occurs with a reduction in fiber cross-sectional area. Oxidative enzyme activity is decreased, and measurement of muscle bioenergetics during exercise reveals a reduced aerobic capacity. Deconditioning is probably very important mechanistically. Other mechanisms that may be of varying importance in individual patients include chronic hypercapnia and/or hypoxia, nutritional depletion, steroid usage, and oxidative stress. Potential therapies include exercise training, oxygen supplementation, nutritional repletion, and administration of anabolic hormones.     

Genotoxic effects of 3 T magnetic resonance imaging in cultured human lymphocytes

The clinical and preclinical use of high-field intensity (HF, 3 T and above) magnetic resonance imaging (MRI) scanners have significantly increased in the past few years. However, potential health risks are implied in the MRI and especially HF MRI environment due to high-static magnetic fields, fast gradient magnetic fields, and strong radiofrequency electromagnetic fields. In this study, the genotoxic potential of 3 T clinical MRI scans in cultured human lymphocytes in vitro was investigated by analyzing chromosome aberrations (CA), micronuclei (MN), and single-cell gel electrophoresis. Human lymphocytes were exposed to electromagnetic fields generated during MRI scanning (clinical routine brain examination protocols: three-channel head coil) for 22, 45, 67, and 89 min. We observed a significant increase in the frequency of single-strand DNA breaks following exposure to a 3 T MRI. In addition, the frequency of both CAs and MN in exposed cells increased in a time-dependent manner. The frequencies of MN in lymphocytes exposed to complex electromagnetic fields for 0, 22, 45, 67, and 89 min were 9.67, 11.67, 14.67, 18.00, and 20.33 per 1000 cells, respectively. Similarly, the frequencies of CAs in lymphocytes exposed for 0, 45, 67, and 89 min were 1.33, 2.33, 3.67, and 4.67 per 200 cells, respectively. These results suggest that exposure to 3 T MRI induces genotoxic effects in human lymphocytes.