Microsatellite analysis of induced sputum DNA in patients with lung cancer in heavy smokers and in healthy subjects.

Abnormality in the fragile histidine triade (FHIT), a candidate tumor suppressor gene located in chromosome region 3 (3p14.2), has been frequently found in multiple tumor types, including lung cancer. In this study, the authors assessed the consistency of DNA microsatellite analysis of induced sputum (IS), as compared to that of blood and plasma. They also evaluated the loss of heterozigosity (LOH) and microsatellite instability (MSI) in 3 different loci, D3S1300, D3S1313, and D3S1234, all internal to the FHIT gene, in IS, blood, and plasma from patients with lung cancer, smokers, and healthy subjects. Eighteen patients with lung cancer (3 females, age mean +/- SD: 63 +/- 7 years), 39 smokers (23 females, age mean +/- SD: 57 +/- 6 years and cigarette pack-years mean +/- SD: 34 +/- 12), and 22 healthy nonsmoking subjects (13 females, age mean +/- SD: 63 +/- 5 years) were studied. DNA was extracted from blood, plasma, and IS, by means of a standard method. Analysis of LOH and MSI were performed using a fluorescent polymerase chain reaction (PCR)-based approach, followed by capillary electrophoresis. The ratios between the peak heights (phs), expressed as random fluorescence units, from plasma/blood (p/b) and induced sputum/blood (is/b) in all three loci were considered. The biases (agreement limits) between the mean ph ratio from p/b and is/b of D3S1300, D3S1313, and D3S1234 were respectively 0.07 (- 0.39 to 0.53), 0.016 (- 0.32 to 0.35), - 0.10 (- 0.51 to 0.30) in the patients; - 0.04 (- 0.52 to 0.43), - 0.06 (- 0.31 to 0.18), - 0.08 (- 0.48 to 0.30) in smokers; and - 0.11 (- 0.40 to 0.17), - 0.05 (- 0.53 to 0.43), - 0.09 (- 0.51 to 0.33) in healthy subjects. LOH and MSI in at least one locus were observed in 55% of patients, in 18% of smokers, and in 4.5% of healthy subjects (P < 0.001). These results showed that IS DNA provided data that were consistent with those from blood and plasma. These findings highlight new prospects for early tumor detection by a noninvasive technique based on the analysis of genetic alterations in induced sputum.

Quality control of spirometry: a lesson from the BRONCUS trial.

This report describes the quality control programme used within the Bronchitis Randomized on N-acetylcysteine (NAC) Cost-Utility Study, a trial designed to assess the decline in lung function, exacerbation rate, health status, and cost-effectiveness with NAC or a placebo in 523 patients with chronic obstructive pulmonary disease over a 3-yr period. Spirometry was scored from 0 (worst quality) to 6 (best quality). The mean score of 314 spirometries from 243 patients evaluated during the trial was 5.63+/-0.83. Linear regression analysis of the scores of 47 participating centres plotted against the time at which spirometries were performed yielded an intercept of 5.7+/-0.5 and a slope of -0.0001+/-0.001, which suggests that the initial high quality was maintained over time. Retrospective examination of a further 345 postbronchodilator spirometries from 208 patients with a forced expiratory volume at one second exceeding the mean individual value recorded over the study in excess of 20% revealed a slightly lower quality of the start-of-test manoeuvre compared with the 314 spirometries. In conclusion, these findings would suggest that the quality control programme is likely to have helped achieve and maintain long-term spirometry performance in the Bronchitis Randomized on N-acetylcysteine (NAC) Cost-Utility Study trial. Special care should be paid to the spirometries whose forced expiratory volume in one second values exceed the mean value.

Eotaxin and CCR3 are up-regulated in exacerbations of chronic bronchitis.

BACKGROUND: Eosinophils and T lymphocytes represent constant features in the airways of subjects with exacerbated chronic bronchitis. Eotaxin is the most potent and selective eosinophil chemoattractant which can also attracts lymphocytes. The aim of the study was to evaluate the expression of eotaxin and its receptor, CCR3, in bronchial airways during exacerbation of chronic bronchitis. METHODS: By immunohistochemistry we studied eotaxin and CCR3 expression in the lamina propria of 14 subjects with acute exacerbation of chronic bronchitis. 20 asthmatics, and 8 healthy subjects. We determined the cell types expressing the CCR3 receptor by colocalization experiments. We finally studied the relationship between eotaxin and CCR3 and eosinophils and T lymphocytes. RESULTS: The number of eotaxin+ and CCR3+ cells was significantly higher in exacerbated chronic bronchitis (P<0.003 and P<0.002) and asthma (P<0.002 and P<0.0001) when compared to healthy subjects. CCR3 was mainly expressed by eosinophils and to a lesser extent by CD4+ and CD8+ lymphocytes. In exacerbated chronic bronchitis the number of CCR3+ cells was strongly correlated to the number of eosinophils (P<0.0002. r=0.85) and to the number of CD4+ lymphocytes (P<0.05, r=0.57). CONCLUSION: Our study suggests that eotaxin and CCR3 are up-regulated and could be involved in the eosinophil and CD4+ lymphocyte recruitment into the airways which occur during acute exacerbations of chronic bronchitis.

Air pollution and reversible chronic respiratory diseases.

Air pollution is one of the world's most serious environmental problems. It has been common knowledge for many years now that the lung is one of the main target organs of environmental agents. Over the last ten years, in particular, lung diseases have increased dramatically and the literature on the subject reports high death rates from lung cancer and an increased incidence of bronchial asthma and chronic obstructive pulmonary disease (COPD). These respiratory diseases are also caused by exposure to environmental agents, especially air pollution. Outdoor pollution is related to many compounds and, in assessing the air-borne pollutants and their association with respiratory damage, the role of particulate matter (PM) is of major importance. In addition to outdoor pollution, indoor pollution also exists and consists of environmental substances usually found outside which enter the internal environment, and/or of locally produced substances. Air pollution exposure involves the contact of pollutants with the respiratory tract, such exposure being measured according to two parameters: intensity and duration. Generally speaking, the pathogenic effects of environmental pollution on the organism fall into two categories: acute, or short-term effects, and long-term effects, depending on the time required from exposure to the manifestation of its effect. Short-term effects consist of irritant symptoms affecting the airways with different degrees of severity, while long-term effects, related to chronic exposure, are associated with chronic respiratory diseases, and unremitting symptoms such as coughing, wheezing, etc. Moreover, air irritants can give rise to inflammatory damage of the mucous membrane of the airways, thereby making it more susceptible to various types of allergens. In conclusion, air pollution is an important etiological factor for many chronic respiratory disorders, such as bronchial asthma and COPD. Prevention programs and early treatments are essential in an attempt to block the clinical-functional deterioration caused by these respiratory diseases.

GENEBU Project. Equipment and drugs used for home nebulizer therapy in Italy.

The GENEBU Project is an open, observational survey evaluating home nebulizer practices in Italy. It consecutively included patients who were referred to one of the 27 participating chest clinics from May to December 1999 and who had been using a home nebulizer in the previous six months. The information source was a self-administered questionnaire compiled by the enrolled subjects. We collected 1257 questionnaires. The nebulizer equipment was heterogeneous, with at least 92 different models. Jet nebulizers were 90% of the total; 53% of these had a glass reservoir. Almost 80% of the patients selected the nebulizer themselves without any medical advice. In addition, most patients (> 80%) did not receive information on both the interface system and the optimal fill volume of the nebulizer. Corticosteroid nebulisation was widespread (74%), for both occasional and regular daily use, for both acute and chronic diseases from upper to lower airways. Beta 2-agonist (55%), anticholinergic (37%), mucolytic (32%) drugs were also often nebulised. More than 90% of patients mixed some active drugs. We conclude that the nebulizer equipment for home aerosol therapy was very heterogeneous and, probably, not always utilised at its best in Italy. The mixing of drugs and the widespread use of corticosteroids were peculiarities of home nebulizer therapy in Italy.

[Educational programs and self-management in bronchial asthma]. / Programmi educazionali e self-management nell'asma bronchiale.

Bronchial asthma is one of the most common chronic diseases in the world and can affect people of all ages. In the last few years there has been a considerable improvement in the etiopathogenetic knowledge of the disease and extremely effective anti-asthmatic drugs are available. However, asthma-related morbidity and mortality are increased, especially in Western countries. In an attempt to reverse this negative trend, for a number of years national and international guidelines on asthma have been published all over the world. These guidelines have the aim of improving asthma diagnosis and treatment and of conveying a fundamental educational message both to health workers and to patients and their families. From the data in the literature it can be clearly seen that only through the application of valid educational programs is it possible for asthmatics to improve their knowledge of the disease and to understand how they can look after themselves by a careful evaluation of their own symptoms and respiratory function. They should also be aware of the drugs available for the treatment of both acute asthmatic crises and chronic asthma, but especially of the fact that this chronic inflammatory affection can be fully treated. In particular, an educational program organized with groups of maximum 10-12 people attending 2 lessons and with helpful training tools, can increase significantly asthma knowledge, treatment compliance and patient self-management. The aim of this review is to highlight the importance of educational programs and those obscure areas which slow down their large scale application and universal acceptance.

The effect of inflammation on mucociliary clearance in asthma: an overview.

Mucociliary clearance (MCC) is one of the most important nonspecific defense mechanisms of the respiratory tract, and its impairment is a well-documented feature of chronic respiratory diseases, including asthma. In vitro and in vivo data suggest that several inflammatory mediators influence the mucociliary apparatus. Epithelial damage and functional abnormalities have been described in bronchial asthma, along with changes in mucus-secreting cells and the chemical and rheological properties of airway fluid. Although the mechanisms of MCC impairment in asthma are not clearly understood, data in the recent literature suggest that airway inflammation plays a major role. In this article, we review studies on MCC alterations in light of up-to-date findings on pathogenetic mechanisms in asthma.

Heat shock protein 70 upregulation is related to HLA-DR expression in bronchial asthma. Effects of inhaled glucocorticoids.

BACKGROUND AND OBJECTIVE: Antigen processing determines the production of peptides from antigens - including allergens - and their binding to class II major histocompatibility complex molecules, that stimulate T-cell responses. Heat shock protein (hsp) 70 are recognized to have a role in chaperoning antigenic peptides and in facilitating class II peptide assembly. We studied the HLA-DR and hsp70 expression on BAL cells and bronchial biopsies from asthmatics, as well as the effect of low dose fluticasone propionate treatment. METHODS: Twenty-three asthmatics and eight normal subjects were selected. In each subject BAL and bronchial biopsies were performed. Eighteen out of 23 asthmatics, underwent the second bronchoscopy after 6 weeks of low dose inhaled fluticasone propionate treatment (250 microg b.d.) in a placebo-controlled double-blind study. BAL fluid and biopsies were processed to evaluate HLA-DR and hsp70 expression by immunochemistry methods. RESULTS: Hsp70 and HLA-DR upregulation was present on professional and non-professional antigen presenting cells (APCs). In asthmatics, the hsp70 and HLA-DR expression was higher in BAL (hsp70 P<0.001, HLA-DR P<0.001) and bronchial epithelium (hsp70 P<0.001, HLA-DR P<0.001) when compared with controls. We also observed a significant correlation between hsp70 and HLA-DR expression in BAL (P<0.005) and epithelium (P<0.001). Fluticasone propionate treatment down-regulated the hsp70 and HLA-DR expression in BAL (hsp70 P < 0.001, HLA-DR P < 0.05) and bronchial epithelium (hsp70 P < 0.05, HLA-DR P < 0.05). A serial section comparison study showed that CD1a+ cells and macrophages were positive for both hsp70 and HLA-DR in the submucosa. CONCLUSIONS: Our results support the hypothesis that hsp70 over-expression implies a potential role for these proteins in antigen processing and/or presentation resulting in an increased activity of APCs, which is essential for the initiation and modulation of the asthmatic immune response in chronic asthma. Fluticasone propionate induces downregulation of HLA-DR and hsp70 molecules thus regulating inflammation by affecting key mechanisms of the allergic response.

Personality profiles and breathlessness perception in outpatients with different gradings of asthma.

We studied the relationship between personality profiles, breathlessness perception and clinical and functional features in 36 outpatient asthmatics (12 females; age range: 18-52 yr). Each patient underwent psychometric evaluation with Minnesota Multiphasic Personality Inventory (MMPI). Breathlessness perception was evaluated by Borg's scale during methacholine (M) challenge, and PS20 (the perception score obtained when FEV1 fell by 20%) was recorded. Baseline FEV1 values ranged from 70.0 to 126%. PC20 M values ranged from 0.05 to 31.7 mg/ml. According to a symptoms score system (0 to 12 points), 12 asthmatics were classified as mild, 12 as moderate, and 12 as moderate/severe. We did not find any specific personality profile in asthmatic patients. Sixteen asthmatics had at least one MMPI subscale score indicative of psychological disturbances. We found a significant trend from mild to moderate and moderate/severe asthmatics (p < 0.015), when the number of asthmatics with subscale scores indicative of psychological disturbances was compared to that of asthmatics with normal scores. Moreover, we found that the asthmatics with scores indicative of hypochondriasis showed a significant trend from mild to moderate and moderate/severe asthma (p < 0.015). Furthermore, in all asthmatic patients, hypochondriasis scores were positively correlated to asthma severity score (p < 0.02). PS20 values ranged from 0.1 to 8.1. Twelve asthmatics were hypoperceivers (PS20 < or = 1) and four were hyperperceivers (PS20 > or = 5). We observed a significant trend from mild to moderate and moderate/severe asthmatics (p < 0.025) when we compared the number of hypoperceivers to that of normoperceivers. In conclusion, we found that in outpatients with different grading of asthma, severity of disease is linked to psychological disturbances and poor perception of breathlessness, additionally, hypochondriasis was related to disease severity in all patients.

Mucoactive drugs in the management of chronic obstructive pulmonary disease.

In chronic obstructive pulmonary disease (COPD), mucus hypersecretion is considered one of the main symptoms. Recently the natural history of COPD has been better defined and chronic mucus hypersecretion is now viewed as linked to the acceleration of forced expiratory volume in one second (FEV1) decline and not merely as an "innocent disorder". In the past, mucoactive drugs were claimed to treat mucus hypersecretion. However, since most mucoactive drugs have not been evaluated in large clinical studies, European Respiratory Society and American Thoracic Society COPD guidelines discourage their use for treatment of COPD patients. Clinical trials have been often disappointing because improvement in lung function has been adopted as the main outcome, despite bronchial obstruction in COPD patients being frequently irreversible or poorly reversible. Thus, goals for treatment in COPD patients should include not only improvement in lung function, but also clinical symptoms and quality of life. Moreover, to rightly allocate these drugs in COPD management and to try to modify the natural history and progression of COPD, mucus hypersecretion might require treatment in the first stage of the disease. In conclusion, mucoactive treatments for chronic obstructive pulmonary disease patients should be re-evaluated in the future in patients selected according to demographic factors such as degree and reversibility of bronchial obstruction due to mucus hypersecretion, patient smoking habits and other socioeconomic parameters which have proved to be relevant to the progression of the disease, according to the latest recommendations for guidelines on clinical trials of mucoactive drugs in chronic bronchitis and chronic obstructive pulmonary disease.

Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: a placebo-controlled study.

In a double-blind, parallel-group study, we examined the effect of short-term treatment with inhaled fluticasone propionate (FP) in a group of 20 nonsmoking asthmatic patients who required only beta2-agonists to control their symptoms. We administered FP (250 microg twice daily) or matched placebo for 6 wk. Methacholine challenge was performed before treatment, after 3 wk, and at the end of treatment. Each patient underwent bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsy before and after treatment. Eight patients in the placebo group and nine patients in the FP group completed the study. Bronchial responsiveness to methacholine decreased significantly only after 6 wk of treatment with FP (p < 0.05). When we compared the FP group with the placebo group, we observed a significant decrease only in the number of cells expressing intracellular adhesion molecule-1 (ICAM-1) and MAC-1 (p < 0.04 and p < 0.03, respectively). Moreover, we saw that the tryptase level in BAL decreased (p < 0.001), whereas the eosinophil cationic protein (ECP) level did not change significantly. Additionally, the number of eosinophils and mast cells in the lamina propria in bronchial biopsies specimens was significantly smaller in the FP group than in the placebo group (p < 0.02 and p < 0.01, respectively). Additionally, in the FP group, we found that basement-membrane thickness was significantly decreased when compared with that of the placebo group (p < 0.05). In conclusion, our results show that short-term treatment with low-dose FP reduces inflammatory cell infiltration into the lamina propria in bronchial biopsy specimens. Moreover, short-term low-dose FP treatment might control the intensity of airway remodeling in mild asthma.

Lung epithelial permeability and bronchial responsiveness in subjects with stable asthma.

Lung epithelial permeability of asthmatic patients has been reported to be similar or lower than that of healthy subjects and to be correlated or not to bronchial hyperresponsiveness. To clarify these discrepancies, we evaluated 99mTc-DTPA pulmonary clearance in a group of carefully selected asthmatic patients with mild, stable asthma (n = 13; seven women; mean age +/- SD = 27.69 +/- 6.63 years), and compared them with a group of healthy, nonsmoking subjects (n = 8; six women; mean age +/- SD = 24.38 +/- 5.15 years). Selection criteria for asthmatics were as follows: baseline FEV1 > or = 80% of predicted values, no bronchial infections, and/or no asthma attacks during 4 weeks prior to study and peak expiratory flow rate variability lower than 20%, over a period of 3 weeks. Patients controlled symptoms with beta 2-adrenergic drugs only, regularly or on demand. Mean baseline FEV1 (+/-SD) as percent of predicted was 102.38 +/- 13.97 and 112.88 +/- 18.36, respectively (p < 0.05). In the asthmatic group, bronchial responsiveness to methacholine (PC20 M FEV1) ranged between 0.55 and 28.5 mg/mL. Mean value (+/-SD) of DTPA clearance from lungs to blood (evaluated on the first 10 min out of 30 min of the curves) in the asthmatic group was not different from that of control group (68.31 +/- 21.46 and 69.5 +/- 15.73). In the asthmatic patients, there was no correlation between PC20 M values and DTPA T1/2 min of the whole lung, nor between PC20 M and inner and outer lung clearance zones. Moreover, both in asthmatics and healthy subjects, DTPA clearance of outer (alveolar) zones was significantly faster than that of inner (bronchial) zones (57.69 +/- 19.94 vs 102.08 +/- 38.19, p < 0.001, and 59.75 +/- 12.49 vs 103.5 +/- 31.86, p < 0.003, respectively). Our data show that DTPA clearance in patients with stable asthma is similar to that found in healthy subjects; it is not correlated to degree of bronchial responsiveness and occurs more rapidly in the outer zones than in the inner zones, both in asthmatic patients and in healthy subjects. Thus, to date, DTPA clearance index is not a valid tool for identifying and/or monitoring asthmatic patients.

Airways remodeling is a distinctive feature of asthma and is related to severity of disease.

PURPOSE: Airways remodeling, evaluated as the subepithelial layer thickness, was compared in asthmatic patients with that of healthy subjects, and was related to clinical grading of disease, presence of atopy, and length of asthmatic history. SUBJECTS AND METHODS: Thirty-four patients with stable asthma (mean age+/-SD: 26.5+/-9.2 years; 10 female) treated with only inhaled beta2-agonists and eight healthy volunteers (mean age+/-SD: 24.6+/-2.5 years; four female) were recruited for the study. Twenty-seven of 34 asthmatics had atopy. Eleven patients had newly diagnosed conditions (duration of disease < or = 1 year), nine patients had long asthmatic history (> 1 year and < or = 10 years), and 14 had prolonged asthmatic history (> 10 years). Bronchial responsiveness to methacholine (M) was expressed as provocative concentration of M causing a 20% fall in FEV1 (PC20) (mg/mL). Degree of asthma severity was assessed using a 0- to 12-point score based on symptoms, bronchodilator use, and daily peak expiratory flow variability over a 3-week period. Bronchoscopy and bronchial biopsy were performed successfully for all subjects; the subepithelial layer thickness, in biopsy samples, was measured from the base of bronchial epithelium to the outer limit of reticular lamina. RESULTS: In asthmatics, baseline FEV1 values (percent of predicted) ranged from 75.7 to 137.0%, and PC20 M ranged from 0.15 to 14.4 mg/mL. According to the asthma severity score, 14 asthmatics were classified as having mild disease, 14 as having moderate disease, and six as having severe disease. The mean values of subepithelial layer thickness were 12.4+/-3.3 microm (range, 6.8 to 22.1 microm) in asthmatics, and 4.4+/-0.5 microm (range, 3.8 to 5.2 microm) in healthy subjects (p<0.001). Subepithelial layer thickness of those with severe asthma differed significantly from that of patients with moderate and mild asthma (16.7+/-3.1 microm vs 12.1+/-2.7 microm and 10.8+/-2.4 microm, p<0.01 and p<0.003, respectively). Moreover, in asthmatics, degree of thickening was positively correlated to asthma severity score (Spearman rank correlation coefficient [rs]=0.581; p<0.001), and negatively correlated with baseline FEV1 (rs=-0.553; p<0.001) and PC20 M (rs=-0.510; p<0.01). No difference was found between degree of thickening observed in atopic asthmatics, compared with that of nonatopic asthmatics, or between degree of thickening in patients with different lengths of asthmatic history. Lastly, multiple regression analysis revealed that asthma severity score was the significant predictive factor for thickness of subepithelial layer. CONCLUSIONS: We confirmed that airways remodeling is a very distinctive and characteristic pathologic finding of asthma. We also demonstrated that it is related to the clinical and functional severity of asthma, but not to atopy or length of asthmatic history.

Short-term treatment with a low dose of inhaled fluticasone propionate decreases the number of CD1a+ dendritic cells in asthmatic airways.

The activation of T-lymphocytes through the recognition of specific allergens is a crucial event in the development of allergic inflammation. Dendritic cells (DC) are potent accessory cells that play an important role in initiating bronchial immune responses by activation of T-lymphocytes. We investigated the distribution of CD1a+ DC in the bronchial biopsies from asthmatic patients, and evaluated the effects of a short course of low dose inhaled fluticasone propionate treatment. Twenty-three mild to moderate stable asthmatic patients and eight normal subjects were included in the study. Bronchoscopy with bronchial biopsies were performed in each subject. Eighteen of the 23 asthmatics underwent a second bronchoscopy after 6 weeks of low dose inhaled fluticasone propionate treatment (250 mcg bd) in a placebo-controlled double-blind study. Biopsies were embedded into glycolmethacrylate resin and analysed by immunohistochemistry methods using specific monoclonal antibodies against CD1a, which is a widely recognized marker for DC. In asthmatics, CD1a+ DC number was significantly higher in bronchial epithelium (P < 0.001) and in lamina propria (P < 0.001) when compared with normal controls. In addition, we observed that a short course of low dose inhaled fluticasone propionate treatment decreased the number of CD1a+ DC in both the bronchial epithelium (P < 0.05) and lamina propria (P < 0.01). The increased number of CD1a+ DC support the hypothesis that DC play an important role in the modulation of the immune response in chronic asthma. Short-term low dose fluticasone propionate treatment induces down-regulation of the CD1a+ DC number.

Bronchial responsiveness to distilled water and methacholine and its relationship to inflammation and remodeling of the airways in asthma.

Although bronchial hyperresponsiveness in asthma is associated with inflammation within the airways, it is not known whether the degree and type of inflammation influence the response to different stimuli and whether pathologic changes of airway structure influence the bronchoconstrictive responses. Therefore, number of inflammatory cells in the epithelium and the lamina propria and the basement membrane thickness were estimated from bronchial biopsies taken in 27 asthmatic subjects (range percent predicted FEV1: 75.6 to 132.1, range of daily PEF variability: 1.9% to 20%) and related to the degree of bronchial responsiveness to ultrasonically nebulized distilled water (UNDW) and methacholine (M). PD20UNDW (provocative dose) was measurable in 15 of 27 patients and ranged between 1.01 and 20.4 ml. PC20M (provocative concentration) ranged between 0.15 and 31.7 mg/ml. In the 15 responders to UNDW, total inflammatory cells (p<0.04) and eosinophils (p<0.015) within the epithelium were higher than in 12 nonresponders to UNDW (PD20 > 34.8 ml). There was no correlation between PD20UNDW and any cell counts whereas negative correlations were found between PC20M and both total inflammatory cells (rs = -0.57; p<0.005) and eosinophils (rs = -0.63; p< 0.0015) within the epithelium. The degree of thickening of subepithelial layer ranged between 7 and 16 micrometers+ (n=26). Thickness correlates both with total inflammatory cells (rs = 0.49; p<0.025) and eosinophils (rs = 0.61; p< 0.003) within the epithelium. Moreover, it was correlated with baseline FEV1 (rs = -0.57; p<0.003) and daily peak expiratory flow (PEF) variability (rs = 0.51; p<0.01). A weak but significant correlation was also found between subepithelial layer thickness and PC20M (rs = -0.42; p<0.04). The results of this study demonstrate that eosinophilic inflammation of bronchial epithelium plays a role in determining UNDW and M responsiveness in asthma. Moreover, they suggest that remodeling of the airways such as thickening of subepithelial layer correlates with indices of asthma severity and could contribute to the degree of M but not to UNDW responsiveness.

Prolonged bronchodilating effect of formoterol versus procaterol in bronchial asthma.

The tolerability and the duration of effect of 12 micrograms of formoterol and 25 micrograms of procaterol administered via metered-dose aerosol to 12 stable asthmatic patients were evaluated in a double-blind, placebo controlled trial. FEV1, pulse rate, and blood pressure were measured at baseline and every two hours after dosing for 12 hours. The bronchodilation peak was observed after two hours for both drugs. Formoterol induced a significant bronchodilating effect for 12 hours compared with both baseline and placebo values. With procaterol, significant bronchodilation occurred for six hours compared with baseline values and four hours compared with placebo. No significant changes were observed in pulse rate and blood pressure with either drug. Four subjects complained of muscle tremor after procaterol administration. We conclude that in subjects with stable asthma, inhaled formoterol at a dose of 12 micrograms maintains significant bronchodilation for 12 hours after dosing and is very well tolerated. Further studies are required to evaluate effectiveness and tolerability of high dose formoterol treatment in acute severe asthma therapy.

Activity of erdosteine on mucociliary transport in patients affected by chronic bronchitis.

The influence of erdosteine (a mucomodulator endowed with mucolytic and antioxidant properties) on human mucociliary transport (MCT) was investigated in a double-blind placebo controlled study. Sixteen former smokers affected by chronic bronchitis, preselected for their mucociliary responsiveness to an inhaled beta 2-agonist, were divided into two groups (matched by number, sex, age and FEV1%) and orally treated with placebo or erdosteine (300 mg t.i.d.) for 8 days. Their MCT was assessed by the bronchofiberscopy technique just before starting the treatment and at the end of the treatment. The pretreatment mucus transport velocity in these patients was significantly decreased with respect to healthy subjects. The erdosteine treatment induced a significant improvement of MCT while placebo was inactive (mean % variation +/- SE against their baseline values being +60.4 +/- 18.4 and -3.0 +/- 5.9, respectively). This peculiar activity of erdosteine on mucus transport may be of clinical usefulness in chronic bronchitic patients and it can be added to beta 2-agonist to restore the decreased MCT.

Variability and reproducibility in the measurement of tracheobronchial clearance in healthy subjects and patients with different obstructive lung diseases.

The purpose of this study was to establish the inter- and intra-subject/patient variability of tracheobronchial clearance, measured for 6 h, using a radioaerosol technique. Inter-subject variability was evaluated in five groups: 33 healthy non-smokers (NS); 19 asymptomatic smokers (S); 40 asthmatics (A); 27 chronic bronchitics (CB) and 12 bronchiectatics (B). Intra-subject variability was evaluated in 16 A and 27 CB who were studied twice. The inter-subject/patient coefficient of variation (CoV) of tracheobronchial clearance was 13% for NS and 28-39% for the remaining four groups. The intra-patient CoV was about half of the inter-patient CoV. Inter-subject CoV (for A and CB) appeared to be independent of initial tracheobronchial deposition of radioaerosol and frequency of cough. We were also able to estimate the approximate number of patients required for a crossover study in order to avoid statistical, type II errors when investigating the effect of a drug or of a therapeutic intervention on tracheobronchial clearance.

Effects of betamethasone on theophylline disposition in man. Are saliva values predictive of serum theophylline levels?

The pharmacokinetic interaction between betamethasone (5 mg/day for 5 days) and theophylline (3.35 mg/kg orally before and after betamethasone treatment) was studied in 13 female patients evaluating saliva and serum theophylline concentrations by means of an enzyme multiplied immunoassay technique. Betamethasone treatment did not significantly change saliva and serum theophylline levels. As regards the potential usefulness of saliva theophylline levels in predicting the concomitant serum concentrations of the bronchodilator, in spite of the significant correlation found in our study (r = 0.758; P less than 0.001), we think that, using individual saliva values, there is a poor predictive value for serum theophylline concentrations.