Airflow pattern complexity and airway obstruction in asthma

The scientific and clinical value of a measure of complexity is potentially enormous because complexity appears to be lost in the presence of illness. The authors examined the effect of elevated airway obstruction on the complexity of the airflow (Q) pattern of asthmatic patients analyzing the airflow approximate entropy (ApEnQ). This study involved 11 healthy controls, 11 asthmatics with normal spirometric exams, and 40 asthmatics with mild (14), moderate (14), and severe (12) airway obstructions. A significant (P < 0.02) reduction in the ApEnQ was observed in the asthmatic patients. This reduction was significantly correlated with spirometric indexes of airway obstruction [FEV(1) (%): R = 0.31, P = 0.013] and the total respiratory impedance (R = -0.39; P < 0.002). These results are in close agreement with pathophysiological fundamentals and suggest that the airflow pattern becomes less complex in asthmatic patients, which may reduce the adaptability of the respiratory system to perform the exercise that is associated with daily life activities. This analysis was able to identify respiratory changes in patients with mild obstruction with an adequate accuracy (83%). Higher accuracies were obtained in patients with moderate and severe obstructions. The analysis of airflow pattern complexity by the ApEnQ was able to provide new information concerning the changes associated with asthma. In addition, this analysis was also able to contribute to the detection of the adverse effects of asthma. Because these measurements are easy to perform, such a technique may represent an alternative and/or a complement to other conventional exams to help the clinical evaluations of asthmatic patients.     

Association between airway hyperreactivity and bronchial macrophage dysfunction in individuals with mild asthma

Little is known about the functional capabilities of bronchial macrophages (BMs) and their relationship to airway disease such as asthma. We hypothesize that BMs from asthmatics may be modulated in their function compared with similar cells from healthy individuals. BMs obtained by induced sputum from mild asthmatics (n = 20) and healthy individuals (n = 20) were analyzed using flow cytometry for CD16, CD64, CD11b, CD14, and human leukocyte antigen-DR expression, phagocytosis of IgG opsonized yeast, and oxidant production. Asthma status was assessed by lung function [percent predicted forced vital capacity and forced expiratory volume in 1 s (FEV(1))], percent sputum eosinophils, and nonspecific airway responsiveness [provocative concentration that produces a 20% fall in FEV(1) (PC(20,FEV1))]. Asthmatics with >5% airway eosinophils (AEo+) had decreased BM CD64 expression and phagocytosis compared with asthmatics with <5% eosinophils (AEo-). Among asthmatics, a significant correlation was found between CD64 expression and BM phagocytosis (R = 0.7, P < 0.009). Phagocytosis was also correlated with PC(20,FEV1) (R = 0.6, P < 0.007), lung function (%predicted FEV(1), R = 0.7, P < 0.002) and percent eosinophils (R = -0.6, P < 0.01). In conclusion, BM from asthmatics are functionally modulated, possibly by Th2 cytokines involved in asthma pathology.     

Small airway morphology and lung function in the transition from normality to chronic airway obstruction.

This study investigated the relationships between pathological changes in small airways (<6 mm perimeter) and lung function in 22 nonasthmatic subjects (20 smokers) undergoing lung resection for peripheral lesions. Preoperative pulmonary function tests revealed airway obstruction [ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) < 70%] in 12 subjects and normal lung function in 10. When all subjects were considered together, total airway wall thickness was significantly correlated with FEV1/FVC (r2 = 0.25), reactivity to methacholine (r2 = 0.26), and slope of linear regression of FVC against FEV1 values recorded during the methacholine challenge (r2 = 0.56). Loss of peribronchiolar alveolar attachments was significantly associated (r2 = 0.25) with a bronchoconstrictor effect of deep inhalation, as assessed from a maximal-to-partial expiratory flow ratio <1, but not with airway responses to methacholine. No significant correlation was found between airway smooth muscle thickness and lung function measurements. In conclusion, this study suggests that thickening of the airway wall is a major mechanism for airway closure, whereas loss of airway-to-lung interdependence may contribute to the bronchoconstrictor effect of deep inhalation in the transition from normal lung function to airway obstruction in nonasthmatic smokers.     

Effects of exercise training on airway closure in asthmatics

We previously reported that responsiveness to methacholine (Mch) in the absence of deep inspiration (DI) decreased in healthy subjects after a short course of exercise training. We assessed whether a similar beneficial effect of exercise on airway responsiveness could occur in asthmatics. Nine patients (male/female: 3/6; mean age ± SD: 24 ± 2 yr) with mild untreated asthma [forced expiratory volume in 1 s (FEV(1)): 100 ± 7.4% pred; FEV(1)/vital capacity (VC): 90 ± 6.5%] underwent a series of single-dose Mch bronchoprovocations in the absence of DI in the course of a 10-wk training rowing program (6 h/wk of submaximal and maximal exercise), at baseline (week 0), and at week 5 and 10. The single-dose Mch was established as the dose able to induce ≥15% reduction in inspiratory vital capacity (IVC) and was administered to each subject at every challenge occasion. Five asthmatics (male/female: 1/4; mean age ± SD: 26 ± 3 yr) with similar baseline lung function (FEV(1): 102 ± 7.0% predicted; FEV(1)/VC: 83 ± 6.0%; P = 0.57 and P = 0.06, respectively) not participating in the exercise training program served as controls. In the trained group, the Mch-induced reduction in IVC from baseline was 22 ± 10% at week 0, 13 ± 11% at week 5 (P = 0.03), and 11 ± 8% at week 10 (P = 0.028). The Mch-induced reduction in FEV(1) did not change with exercise (P = 0.69). The reduction in responsiveness induced by exercise was of the same magnitude of that previously obtained in healthy subjects (50% with respect to pretraining). Conversely, Mch-induced reduction in IVC in controls remained unchanged after 10 wk (%reduction IVC at baseline: 21 ± 20%; after 10 wk: 29 ± 14%; P = 0.28). This study indicates that a short course of physical training is capable of reducing airway responsiveness in mild asthmatics.     

Total lung capacity does not change during methacholine-stimulated airway narrowing

The accurate measurement of changes in flow rates from partial flow-volume curves depends on their measurement at the same lung volume. This lung volume can be standardized from total lung capacity (TLC) if this does not change at the same time. We examined the effect of methacholine-stimulated maximal airway narrowing [change in mean forced expiratory volume in 1 s (delta FEV1) = 26.4%] on TLC, measured by whole-body plethysmography, in 10 normal subjects and of moderate airway narrowing (mean delta FEV1 = 34.9%) in 10 asthmatics. The TLC changed from 5.88 to 6.03 liters in normal subjects (P greater than 0.05) and from 6.92 to 6.95 liters (P greater than 0.5) in asthmatics. The results of this study suggest that TLC does not change significantly after methacholine-stimulated maximal airway narrowing in normal subjects and after moderate narrowing in asthmatics.     

Effect of mild-to-moderate airflow limitation on exercise capacity

To determine the effect of mild-to-moderate airflow limitation on exercise tolerance and end-expiratory lung volume (EELV), we studied 9 control subjects with normal pulmonary function [forced expired volume in 1 s (FEV1) 105% pred; % of forced vital capacity expired in 1 s (FEV1/FVC%) 81] and 12 patients with mild-to-moderate airflow limitation (FEV1 72% pred; FEV1/FVC % 58) during progressive cycle ergometry. Maximal exercise capacity was reduced in patients [69% of pred maximal O2 uptake (VO2max)] compared with controls (104% pred VO2max, P less than 0.01); however, maximal expired minute ventilation-to-maximum voluntary ventilation ratio and maximal heart rate were not significantly different between controls and patients. Overall, there was a close relationship between VO2max and FEV1 (r2 = 0.62). Resting EELV was similar between controls and patients [53% of total lung capacity (TLC)], but at maximal exercise the controls decreased EELV to 45% of TLC (P less than 0.01), whereas the patients increased EELV to 58% of TLC (P less than 0.05). Overall, EELV was significantly correlated to both VO2max (r = -0.71, P less than 0.001) and FEV1 (r = -0.68, P less than 0.001). This relationship suggests a ventilatory influence on exercise capacity; however, the increased EELV and associated pleural pressures could influence cardiovascular function during exercise. We suggest that the increase in EELV should be considered a response reflective of the effect of airflow limitation on the ventilatory response to exercise.     

Serum vascular endothelial growth factor and its receptor level in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a disorder which encompasses not only morphological changes in parenchyma, central and peripheral airways but also in structural and functional changes of pulmonary vessels. The role of angiogenic factors leading to abnormal pulmonary vessel remodeling remains unclear. We have investigated a cytokine vascular endothelial growth factor (VEGF) known to be involved in angiogenesis, and its soluble receptors (sVEGF R1, sVEGF R2) in the serum of 20 patients with mild COPD and 10 patients with very severe COPD, using sensitive enzyme-linked immunoassays. The control group consisted of 10 healthy volunteers. We found that the concentration of VEGF in the serum of patients with mild COPD was significantly higher (665.31 +/- 102.20 pg/mL) in comparison to the control group (318.94 +/- 51.40 pg/mL; p < 0.05), and there was a strong negative correlation with FEV1 (r = -0.859; p < 0.001). Additionally, the level of sVEGF R1 in the serum of patients with very severe COPD was also significantly higher (96.60 +/- 26.85 pg/mL) than in the control (36.01 +/- 3.29 pg/mL; p < 0.05) and a positive correlation between the serum level of sVEGF R1 and FEV1 was found (r = 0.748; p < 0.01). Moreover, we observed an insignificant increase of sVEGF R2 in the serum of patients with mild COPD and those with very severe COPD. These results suggest that VEGF and sVEGF R1 receptor are involved in the development of abnormal pulmonary vascular remodelling in patients with COPD.     

Plasminogen activator inhibitor-1 (PAI-1) and urokinase plasminogen activator (uPA) in sputum of allergic asthma patients

Urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) have been associated with asthma. The aim of this study was to evaluate concentration of uPA and PAI-1 in induced sputum of house dust mite allergic asthmatics (HDM-AAs). The study was performed on 19 HDM-AAs and 8 healthy nonatopic controls (HCs). Concentration of uPA and PAI-1 was evaluated in induced sputum supernatants using ELISA method. In HDM-AAs the median sputum concentration of uPA (128 pg/ml; 95% CI 99 to 183 pg/ml) and PAI-1 (4063 pg/ml; 95%CI 3319 to 4784 pg/ml) were significantly greater than in HCs (17 pg/ml; 95%CI 12 to 32 pg/ml; p<0.001 and 626 pg/ml; 95%CI 357 to 961 pg/ml; p<0.001 for uPA and PAI-1 respectively). The sputum concentration of uPA correlated with sputum total cell count (r=0.781; p=0.0001) and with logarithmically transformed exhaled nitric oxide concentration (eNO) (r=0.486; p=0.035) but not with FEV1 or bronchial reactivity to histamine. On the contrary, the sputum PAI-1 concentration correlated with FEV1 (r=-0,718; p=0.0005) and bronchial reactivity to histamine expressed as log(PC20) (r=-0.824; p<0.0001) but did not correlate with sputum total cell count or eNO. The results of this study support previous observations linking PAI-1 with airway remodeling and uPA with cellular inflammation. Moreover, the observed effect of uPA seems to be independent of its fibrynolytic activity.     

Correlation of exhaled breath temperature with bronchial blood flow in asthma

In asthma elevated rates of exhaled breath temperature changes (Δe°T) and bronchial blood flow (Q_aw) may be due to increased vascularity of the airway mucosa as a result of inflammation.We investigated the relationship of Δe°T with Q_aw and airway inflammation as assessed by exhaled nitric oxide (NO). We also studied the anti-inflammatory and vasoactive effects of inhaled corticosteroid and β₂-agonist.Δe°T was confirmed to be elevated (7.27 ± 0.6 Δ°C/s) in 19 asthmatic subjects (mean age ± SEM, 40 ± 6 yr; 6 male, FEV₁ 74 ± 6 % predicted) compared to 16 normal volunteers (4.23 ± 0.41 Δ°C/s, p < 0.01) (30 ± 2 yr) and was significantly increased after salbutamol inhalation in normal subjects (7.8 ± 0.6 Δ°C/ s, p < 0.05) but not in asthmatic patients. Q_aw, measured using an acetylene dilution method was also elevated in patients with asthma compared to normal subjects (49.47 ± 2.06 and 31.56 ± 1.6 μl/ml/min p < 0.01) and correlated with exhaled NO (r = 0.57, p < 0.05) and Δe°T (r = 0.525, p < 0.05). In asthma patients, Q_aw was reduced 30 minutes after the inhalation of budesonide 400 μg (21.0 ± 2.3 μl/ml/min, p < 0.05) but was not affected by salbutamol.Δe°T correlates with Q_aw and exhaled NO in asthmatic patients and therefore may reflect airway inflammation, as confirmed by the rapid response to steroids.     

Exercise-induced bronchoconstriction alters airway nitric oxide exchange in a pattern distinct from spirometry

Exhaled nitric oxide (NO) is altered in asthmatic subjects with exercise-induced bronchoconstriction (EIB). However, the physiological interpretation of exhaled NO is limited because of its dependence on exhalation flow and the inability to distinguish completely proximal (large airway) from peripheral (small airway and alveolar) contributions. We estimated flow-independent NO exchange parameters that partition exhaled NO into proximal and peripheral contributions at baseline, postexercise challenge, and postbronchodilator administration in steroid-naive mild-intermittent asthmatic subjects with EIB (24-43 yr old, n = 9) and healthy controls (20-31 yr old, n = 9). The mean +/- SD maximum airway wall flux and airway diffusing capacity were elevated and forced expiratory flow, midexpiratory phase (FEF(25-75)), forced expiratory volume in 1 s (FEV(1)), and FEV(1)/forced vital capacity (FVC) were reduced at baseline in subjects with EIB compared with healthy controls, whereas the steady-state alveolar concentration of NO and FVC were not different. Compared with the response of healthy controls, exercise challenge significantly reduced FEV(1) (-23 +/- 15%), FEF(25-75) (-37 +/- 18%), FVC (-12 +/- 12%), FEV(1)/FVC (-13 +/- 8%), and maximum airway wall flux (-35 +/- 11%) relative to baseline in subjects with EIB, whereas bronchodilator administration only increased FEV(1) (+20 +/- 21%), FEF(25-75) (+56 +/- 41%), and FEV(1)/FVC (+13 +/- 9%). We conclude that mild-intermittent steroid-naive asthmatic subjects with EIB have altered airway NO exchange dynamics at baseline and after exercise challenge but that these changes occur by distinct mechanisms and are not correlated with alterations in spirometry.     

Vasoactive intestinal peptide as a bronchodilator in asthmatic subjects

Vasoactive intestinal peptide (V.I.P.) caused bronchodilatation in 7 asthmatic volunteers when given intravenously at the rate of 6 pmol kg-1 min-1 for 15 minutes during a double blind study. Mean baseline FEV1 was 2.8 (+/- 0.3 S.E.) which was 81% of predicted and increased by 0.21 (range 0.1-0.45) l after 15 minutes infusion (p greater than 0.02). Tachycardia and cutaneous flushing were also observed during the infusion. Subsequent induced bronchoconstriction with a predetermined dose of histamine was ameliorated at 180 seconds following challenge when compared with placebo. Mean fall in FEV1 0.26 compared with 0.741 when pre-infusion FEV1 was taken on baseline. Mean fall in FEV1 0.49 l compared with 0.75 l when the FEV1 immediately preceding challenge was used on baseline (p greater than 0.02). The demonstration that V.I.P. is a bronchodilator in asthmatics and ameliorates histamine induced bronchoconstriction has important implications for the pharmacology of asthma.     

Age differences in cholinergic airway responsiveness in relation with muscarinic receptor subtypes

Children seem more susceptible to increased airway reactivity than adults. Such an age-dependent discrepancy in airway reactivity may involve different airway smooth muscle functions. Therefore, we compared the in vivo and in vitro responsiveness of airway smooth muscles between two age groups of animals. Rats of 6 and 21 weeks old were challenged in vivo with acetylcholine (ACh) infused intravenously and airway resistance (R(aw)) was measured. Tracheal muscle was also isolated and the isometric force developed to ACh or KCl was measured. Furthermore, the level of genes encoding muscarinic receptor subtypes (M(1-3)) and acetylcholinesterase (AChE) expressed in the tracheal muscle was determined by RT-PCR. In results, the basal R(aw) was similar in the two age groups. The R(aw) at each ACh dose was significantly greater in young rats than older rats (p<0.05, n=22-27). Tracheal muscles from young rats were more sensitive to ACh than older rats (p<0.05, n=20-21), while receptor-independent muscle contraction to KCl was greater in older rats (p<0.05, n=10-19). Genes encoding AChE, M(2) and M(3) muscarinic receptors were more highly expressed in the tracheal muscles from young than older rats (p<0.05, n=4-6). In conclusion, airway smooth muscle in young rat is more sensitive to cholinergic stimulation in vivo and in vitro compared to older rats, which may be due to a higher expression of M(2) and M(3) muscarinic receptors in airway smooth muscle.     

Lung volume and spirometric standards for healthy female lifetime nonsmokers

The FRC, RV, VC, TLC, RV/TLC (%), FVC, FEV1.0, FEF25-75%, and FEV1.0/FVC (%) were measured in 161 South Australian females aged 18.4-81.2 yr using a Stead-Wells spirometer and helium analyzer. Multiple regression equations were generated to predict these lung volume and spirometric parameters from the best weighted combination of age, mass, standing height, and various other anthropometric variables (FRC: R = 0.715, SEE = 387 ml; RV: R = 0.684, SEE = 256 ml; VC: R = 0.815, SEE = 383 ml; TLC: R = 0.754, SEE = 468 ml; RV/TLC: R = 0.780, SEE = 4.2%; FVC: R = 0.839, SEE = 375 ml; FEV1.0: R = 0.869, SEE = 326 ml; FEV1.0/FVC: R = 0.644, SEE = 5.7%; FEF25-75%: R = 0.753, SEE = 802 ml/s). The range of normality for the lung volumes was defined as the predicted value plus or minus the 95% confidence interval (two-tailed test), and the lower limit of normality for the spirometric variables was designated as the predicted value minus the 95% confidence interval (one-tailed test). Cross-validation of other equations in the literature indicates that they are of limited use for the sample and instrumentation used in this study.     

Contribution of the OBSCN nonsynonymous variants to aspirin exacerbated respiratory disease susceptibility in Korean population

Airway remodeling and exacerbated airway narrowing in asthma have been attributed to the regulation of intracellular Ca(2+) by sarcoplasmic reticulum (SR) of the airway smooth muscle cells. The protein encoded by obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF (OBSCN) is a crucial factor in determining the SR architecture in Obscn(-/-) mice. This study genotyped a total of 55 common single-nucleotide polymorphisms (SNPs) in 592 Korean asthmatics including 163 aspirin exacerbated respiratory disease (AERD) cases and 429 aspirin-tolerant asthma (ATA) controls. Eight SNPs, including two nonsynonymous polymorphisms rs1188722C>T (Leu2116Phe) and rs1188729G>C (Cys4642Ser), and one haplotype BL2_ht1 showed statistically significant associations with AERD development (p=0.003-0.03). Two variants, rs1188722C>T (Leu2116Phe) and rs369252C>A, also revealed nominal association with FEV1 decline by aspirin provocation in asthmatics (p=0.03-0.04). Intriguingly, rs1188722C>T (Leu2116Phe) is a highly conserved amino acid residue among species, suggesting its functional relevance to AERD. In addition, the A allele of rs369252C>A, which was more prevalent in AERD than in ATA, was predicted as a potential branch point (BP) site for alternative splicing (BP score=4.29). Although further functional evaluation is required, our findings suggest that OBSCN polymorphisms, in particular, highly conserved nonsynonymous Leu2116Phe variant, might contribute to aspirin hypersensitivity in asthmatics.     

Effects of systemic glucocorticosteroids on peripheral neutrophil functions in asthmatic subjects: an ex vivo study

In 21 asthmatic subjects, several functions of isolated peripheral neutrophils (chemokinesis and chemotaxis toward 10% E. coli; superoxide anion generation after PMA; leukotriene B(4) (LTB(4)) release from whole blood and isolated neutrophtls, before and after different stimuli) were evaluated during an acute exacerbation of asthma, and after 14 - 54 days of treatment with systemic glucocorticosteroids (GCS). During acute exacerbation, superoxide anion generation was higher in asthmatics than in eleven normal subjects (39.2 +/- 14.1 vs. 25.2 +/- 7.3 nmol, p < 0.05); there was a significant correlation between FEV(1) (% of predicted) and neutrophil chemotaxis (r = -0.52, p = 0.04). After treatment, there was no significant change in all neutrophil functions, except for a decrease in neutrophil chemotaxis in subjects who showed an FEV(1) increase > 20% after GCS treatment (from 131 +/- 18 to 117 +/- 21 mum, p = 0.005). Chemokinesis sicantly decreased in all subjects, and the changes significantly correlated with an arbitrary score of the total administered dose of GCS (r = 0.57, p < 0.05). These data suggest that neutrophil activation plays a minor role in asthma, and that treatment with GCS is not able to modify most functions of peripheral neutrophils in asthmatic subjects; chemotaxis seems to be related only to the severity of the asthma and it could reflect the improvement of the disease.     

Effect of parathyroidectomy on bone mineral density in hemodialysis patients with secondary hyperparathyroidism: possible usefulness of preoperative determination of parathyroid hormone level for prediction of bone regain.

PURPOSE: To examine longitudinal changes of bone mineral density (BMD) after parathyroidectomy (PTx) in patients undergoing maintenance hemodialysis (HD) with severe secondary hyperparathyroidism (HPT) to determine which factor contributes most to bone changes. METHODS: Fifteen Japanese HD patients who had been refractory to medical therapy were subject to PTx with autotransplantation. We measured BMD by dual energy X-ray absorptiometry (DXA) at the lumbar spine (L2 - 4 BMD) and the distal 1/3 region of the radius (1/3R BMD) at 1, 3, 6, 12, 24, and 36 months after PTx. RESULTS: Baseline Z-score of BMD was markedly low at 1/3R (- 3.07) and slightly low at L2 - 4 (-0.59) in this group. A significant increase in L2 - 4 BMD was observed as early as one month after PTx, which was sustained afterwards. Annual percent changes in L2 - 4 and 1/3R BMD were + 15.6 % and + 6.4 %, respectively. The annual percent changes in BMD at both sites were positively associated with preoperative intact PTH levels (L2 - 4; r = 0.642, p = 0.010, 1/3R; r = 0.884, p < 0.001) and total alkaline phosphatase (ALP) levels (L2 - 4; r = 0.663, p = 0.007, 1/3R; r = 0.858, p < 0.001). Stepwise multiple regression analysis revealed that serum levels of intact PTH and ALP were the best predictors of both percentage and net changes in radial BMD with high determination coefficients (r 2 > 0.8). CONCLUSION: Successful PTx following appropriate supplementation with vitamin D and calcium provides a marked increase in lumbar BMD and a modest increase in radial BMD in HD patients with secondary HPT. Preoperative levels of PTH and ALP are useful for predicting postoperative changes in bone mass.     

Bronchial hyperreactivity and spirometric impairment in polysensitized patients with allergic rhinitis

BACKGROUND: We previously demonstrated in a group of patients with perennial allergic rhinitis alone impairment of spirometric parameters and high percentage of subjects with bronchial hyperreactivity (BHR). The present study aimed at evaluating a group of polysensitized subjects suffering from allergic rhinitis alone to investigate the presence of spirometric impairment and BHR during the pollen season. METHODS: One hundred rhinitics sensitized both to pollen and perennial allergens were evaluated during the pollen season. Spirometry and methacholine bronchial challenge were performed. RESULTS: Six rhinitics showed impaired values of FEV1 without referred symptoms of asthma. FEF 25-75 values were impaired in 28 rhinitics. Sixty-six patients showed positive methacholine bronchial challenge. FEF 25-75 values were impaired only in BHR positive patients (p < 0.001). A significant difference was observed both for FEV1 (p < 0.05) and FEF 25-75 (p < 0.001) considering BHR severity. CONCLUSIONS: This study evidences that an impairment of spirometric parameters may be observed in polysensitized patients with allergic rhinitis alone during the pollen season. A high percentage of these patients had BHR. A close relationship between upper and lower airways is confirmed.     

Effects of tumors on inhaled pharmacologic drugs

Lung carcinomas are now the most common form of cancer. Clinical data suggest that tumors are found preferentially in upper airways, perhaps specifically at carina within bifurcations. The disease can be treated by aerosolized pharmacologic drugs. To enhance their efficacies site-specific drugs must be deposited selectively. Since inhaled particles are transported by air, flow patterns will naturally affect their trajectories. Therefore, in Part I of a systematic investigation, we focused on tumor-induced effects on airstreams, in Part II (the following article [p. 245]), particle trajectories were determined. To facilitate the targeted delivery of inhaled drugs, we simulated bifurcations with tumors on carinas using a commercial computational fluid dynamics (CFD) software package (FIDAP) with a Cray T90 supercomputer and studied effects of tumor sizes and ventilatory parameters on localized flow patterns. Critical tumor sizes existed; e.g., tumors had dominant effects when r/R > or = 0.8 for bifurcation 3-4 and r/R > or = 0.6 for bifurcation 7-8 (r = tumor radius and R = airway radius). The findings suggest that computer modeling is a means to integrate alterations to airway structures caused by diseases into aerosol therapy protocols.     

The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma

GSK256066 is a selective phosphodiesterase 4 inhibitor that can be given by inhalation, minimising the potential for side effects. We evaluated the effects of GSK256066 on airway responses to allergen challenge in mild asthmatics.

Methods

In a randomised, double blind, cross-over study, 24 steroid naive atopic asthmatics with both early (EAR) and late (LAR) responses to inhaled allergen received inhaled GSK256066 87.5 mcg once per day and placebo for 7 days, followed by allergen challenge. Methacholine reactivity was measured 24 h post-allergen. Plasma pharmacokinetics were measured. The primary endpoint was the effect on LAR.

Results

GSK256066 significantly reduced the LAR, attenuating the fall in minimum and weighted mean FEV1 by 26.2% (p = 0.007) and 34.3% (p = 0.005) respectively compared to placebo. GSK256066 significantly reduced the EAR, inhibiting the fall in minimum and weighted mean FEV1 by 40.9% (p = 0.014) and 57.2% (p = 0.014) respectively compared to placebo. There was no effect on pre-allergen FEV1 or methacholine reactivity post allergen. GSK256066 was well tolerated, with low systemic exposure; plasma levels were not measurable after 4 hours in the majority of subjects.

Conclusions

GSK256066 demonstrated a protective effect on the EAR and LAR. This is the first inhaled PDE4 inhibitor to show therapeutic potential in asthma.

Trial Registration

This study is registered on clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00380354","term_id":"NCT00380354"}}NCT00380354     

Vital capacity and inspiratory capacity as additional parameters to evaluate bronchodilator response in asthmatic patients: a cross sectional study

ABSTRACT: BACKGROUND: Bronchodilator response in patients with asthma is evaluated based on post-bronchodilator increase in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). However, the need for additional parameters, mainly among patients with severe asthma, has already been demonstrated. METHODS: The aim of this study was to evaluate the usefulness of vital capacity (VC) and inspiratory capacity (IC) to evaluate bronchodilator response in asthma patients with persistent airflow obstruction. The 43 asthma patients enrolled in the study were stratified into moderate or severe airflow obstruction groups based on baseline FEV1. All patients performed a 6-minute walk test before and after the bronchodilator (BD). A bipolar visual analogue scale post-BD was performed to assess clinical effect. The correlation between VC and IC and clinical response, determined by visual analogue scale (VAS) and 6-minute walk test (6MWT), was investigated. RESULTS: Patients in the severe group presented: 1) greater bronchodilator response in VC (48% vs 15%, p = 0.02), 2) a significant correlation between VC variation and the reduction in air trapping (Rs = 0.70; p < 0.01), 3) a significant agreement between VC and VAS score (kappa = 0.57; p < 0.01). There was no correlation between IC and the reduction in air trapping or clinical data. CONCLUSIONS: VC may be a useful additional parameter to evaluate bronchodilator response in asthma patients with severe airflow obstruction.