Mangiferin attenuates cigarette smoke-induced chronic obstructive pulmonary disease in male albino rats.

We analyzed the ability of mangiferin to suppress cigarette smoke-induced chronic obstructive pulmonary disease. Control rats showed a marked decrease in the ratio of the forced expiratory volume at 0.1 s to forced vital capacity. The decreases in the peak expiratory flow and maximal mid-expiratory flow indicated airway remodeling and enlargement. The expression levels of superoxide dismutase (SOD), heme oxygenase-1 (HO-1), γ-glutamylcysteine synthetase, nuclear factor erythroid 2-related factor 2, and activating transcription factor 4 were increased in the control rats. The levels of oxidative stress, malondialdehyde, and reactive oxygen species peaked after 24 weeks, whereas the SOD and HO-1 levels and the total antioxidant capacity were reduced in control rats. Mangiferin restored the levels of reactive oxygen species, malondialdehyde, SOD, HO-1, and T-AOC to near normal. Increased numbers of infiltrating inflammatory cells were observed in control rats but were significantly reduced by mangiferin. In addition, edema and airway inflammation were reduced by mangiferin.

Treatment response according to small airways disease status: The effects of high-strength extrafine pMDI beclomethasone dipropionate/formoterol fumarate in fixed dose combination in moderate uncontrolled asthmatic patients.

BACKGROUND: Inflammation in small airways is particularly clinically active in severe asthma but they still continue to be ignored as considered silent. Recently, the Atlantis study reports small airways involvement in 91% of the asthma population. Therefore in the era of phenotype driven therapy, the aim of this study was to verify if high-strength extrafine ICS/LABA in fixed dose increases clinical efficacy in moderate asthmatic patients with small airways dysfunction and it could be proposed as phenotype driven therapy. METHODS: In this prospective, non-interventional, real-life pilot study we enrolled 37 consecutive patients with moderate asthma who were uncontrolled despite GINA step 3 treatment. All subjects at enrollment were divided in two groups according to the presence of small airways dysfunction:1) small airways phenotype (SAP) group: smokers (≥10 packs/die), ex-smokers (>20 packs/year) with air trapping (FVC <80% - VR >100% - FEF 25-75%<60%); 2) non-small airways phenotype (NSAP) group: non-smokers, without air trapping (FVC ≥80% - VR ≤ 100% - FEF 25-75%≥60%). We later proceeded in both groups with a step up in therapy with high-strength extrafine pMDI beclomethasone dipropionate/formoterol fumarate (BDP/FF) (200/6 µg) in fixed dose to achieve a better control and followed patients for 6 months. RESULTS: Treatment with extrafine BDP/FF(200/6 µg) in SAP group showed a more significant improvement of FEF25-75%, FVC, RV, and a reduction of alveolar inflammatory markers such as FENO350 and alveolar exhaled pH compared with NSAP patients. CONCLUSIONS: Our preliminary results support the use of high-strength extrafine pMDI BDP/FF (200/6 µg) as phenotype driven treatment directed to small airways dysfunction demonstrating an increase of clinical efficacy in moderate asthmatics with SAP.

Short-term effects of a nicotine-free e-cigarette compared to a traditional cigarette in smokers and non-smokers.

BACKGROUND: A few studies have assessed the short-term effects of low-dose nicotine e-cigarettes, while data about nicotine-free e-cigarettes (NF e-cigarettes) are scanty. Concerns have been expressed about the use of NF e-cigarettes, because of the high concentrations of propylene glycol and other compounds in the e-cigarette vapor. METHODS: This laboratory-based study was aimed to compare the effects of ad libitum use of a NF e-cigarette or and a traditional cigarette for 5 min in healthy adult smokers (n = 10) and non-smokers (n = 10). The main outcome measures were pulmonary function tests, fraction of exhaled nitric oxide (FeNO) and fractional concentration of carbon monoxide (FeCO) in exhaled breath. RESULTS: The traditional cigarette induced statistically significant increases in FeCO in both smokers and non-smokers, while no significant changes were observed in FeNO. In non-smokers, the traditional cigarette induced a significant decrease from baseline in FEF75 (81 % ± 35 % vs 70.2 % ± 28.2 %, P = 0.013), while in smokers significant decreases were observed in FEF25 (101.3 % ± 16.4 % vs 93.5 % ± 31.7 %, P = 0.037), FEV1 (102.2 % ± 9.5 % vs 98.3 % ± 10 %, P = 0.037) and PEF (109.5 % ± 14.6 % vs 99.2 % ± 17.5 %, P = 0.009). In contrast, the only statistically significant effects induced by the NF e-cigarette in smokers were reductions in FEV1 (102.2 % ± 9.5 % vs 99.5 ± 7.6 %, P = 0.041) and FEF25 (103.4 % ± 16.4 % vs 94.2 % ± 16.2 %, P = .014). DISCUSSION: The present study demonstrated that the specific brand of NF e-cigarette utilized did not induce any majoracute effects. In contrast, several studies have shown that both traditional cigarettes and nicotine-containing e-cigarettes have acute effects on lung function. Our study expands on previous observations on the effects of NF e-cigarettes, but also for the first time describes the changes induced by smoking one traditional cigarette in a group of never smokers. CONCLUSIONS: The short-term use of the specific brand of NF e-cigarette assessed in this study had no immediate adverse effects on non-smokers and only small effects on FEV1 and FEF25 in smokers. The long-term health effects of NF e-cigarette use are unknown but worthy of further investigations. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02102191.

[Effect of resveratrol on chronic obstructive pulmonary disease in rats and its mechanism].

The purpose of this study is to establish COPD animal model by intra-tracheal instillation of bleomycin (BLM) once and exposure to cigarette smoke for continuous 27 d, and to observe the effects of the inhalation on the model. At the 29th day, blood samples were taken from cervical artery for blood-gas analysis and parameters of lung function were recorded. Bronchoalveolar lavage fluid (BALF) was collected to measure intercellular adhesion molecule-1 (ICAM-1) concentration. The results showed that atomization inhaled resveratrol could alleviate rat COPD lung injury accompanied by amelioration of pathological changes, increase the ratio of forced expiratory volume in 0.3 s (FEV0.3) and forced vital capacity (FVC), and decrease the ICAM-1 level in BALF. The ultimate reduction of inflammatory factors was involved, at least in part, in the mechanism of resveratrol effects.

A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis.

BACKGROUND: Inhaled hypertonic saline acutely increases mucociliary clearance and, in short-term trials, improves lung function in people with cystic fibrosis. We tested the safety and efficacy of inhaled hypertonic saline in a long-term trial. METHODS: In this double-blind, parallel-group trial, 164 patients with stable cystic fibrosis who were at least six years old were randomly assigned to inhale 4 ml of either 7 percent hypertonic saline or 0.9 percent (control) saline twice daily for 48 weeks, with quinine sulfate (0.25 mg per milliliter) added to each solution to mask the taste. A bronchodilator was given before each dose, and other standard therapies were continued during the trial. RESULTS: The primary outcome measure, the rate of change (slope) in lung function (reflected by the forced vital capacity [FVC], forced expiratory volume in one second [FEV1], and forced expiratory flow at 25 to 75 percent of FVC [FEF25-75]) during the 48 weeks of treatment, did not differ significantly between groups (P=0.79). However, the absolute difference in lung function between groups was significant (P=0.03) when averaged across all post-randomization visits in the 48-week treatment period. As compared with the control group, the hypertonic-saline group had significantly higher FVC (by 82 ml; 95 percent confidence interval, 12 to 153) and FEV1 (by 68 ml; 95 percent confidence interval, 3 to 132) values, but similar FEF25-75 values. The hypertonic-saline group also had significantly fewer pulmonary exacerbations (relative reduction, 56 percent; P=0.02) and a significantly higher percentage of patients without exacerbations (76 percent, as compared with 62 percent in the control group; P=0.03). Hypertonic saline was not associated with worsening bacterial infection or inflammation. CONCLUSIONS: Hypertonic saline preceded by a bronchodilator is an inexpensive, safe, and effective additional therapy for patients with cystic fibrosis. (ClinicalTrials.gov number, NCT00271310.)

Mucus clearance and lung function in cystic fibrosis with hypertonic saline.

BACKGROUND: Abnormal homeostasis of the volume of airway surface liquid in patients with cystic fibrosis is thought to produce defects in mucus clearance and airway defense. Through osmotic forces, hypertonic saline may increase the volume of airway surface liquid, restore mucus clearance, and improve lung function. METHODS: A total of 24 patients with cystic fibrosis were randomly assigned to receive treatment with inhaled hypertonic saline (5 ml of 7 percent sodium chloride) four times daily with or without pretreatment with amiloride. Mucus clearance and lung function were measured during 14-day baseline and treatment periods. RESULTS: Long-term inhalation of hypertonic saline without pretreatment with amiloride (i.e., with placebo pretreatment) resulted in a sustained (> or =8 hours) increase in 1-hour rates of mucus clearance, as compared with those with amiloride pretreatment (14.0+/-2.0 vs. 7.0+/-1.5 percent, respectively; P=0.02) and increased 24-hour rates of mucus clearance over baseline. Furthermore, inhalation of hypertonic saline with placebo improved the forced expiratory volume in one second (FEV1) between the baseline period and the treatment period (mean difference, 6.62 percent; 95 percent confidence interval, 1.6 to 11.7; P=0.02), whereas hypertonic saline with amiloride did not improve FEV1 (mean difference, 2.9 percent; 95 percent confidence interval, -2.2 to 8.0; P=0.23). Forced vital capacity (FVC), the forced expiratory flow between 25 and 75 percent of FVC (FEF25-75), and respiratory symptoms also significantly improved in patients treated with hypertonic saline and placebo, whereas the residual volume as a proportion of total lung capacity (RV:TLC) did not change in either group. A comparison of the changes in lung function in the two groups showed no significant difference. In vitro data suggested that sustained hydration of airway surfaces was responsible for the sustained improvement in mucus clearance, whereas inhibition of osmotically driven water transport by amiloride accounted for the observed loss of clinical benefit. CONCLUSIONS: In patients with cystic fibrosis, inhalation of hypertonic saline produced a sustained acceleration of mucus clearance and improved lung function. This treatment may protect the lung from insults that reduce mucus clearance and produce lung disease.

Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: effect on lung function, health status and sputum.

OBJECTIVE: Inhaled mannitol increases mucus clearance in patients with bronchiectasis by an unclear mechanism. The effect of mannitol on lung function, health status and sputum properties was investigated. METHODOLOGY: Nine patients with bronchiectasis inhaled 400 mg of mannitol once daily for 12 days. Health status was assessed using the St George's Respiratory Questionnaire (SGRQ). Sputum was analysed for viscosity, elasticity, spinnability, surface tension, contact angle, solids, mucociliary transportability (MCTR) on a frog palate, and cough transportability (CTR) on a simulated cough machine. RESULTS: Lung function was unchanged with treatment (baseline FEV1 82.0 +/- 16.2%) apart from an improvement in FEF from 85.4 +/- 13% (baseline) to 90.7 +/- 14.4% (P < 0.05; 12th treatment; visit 7). The total SGRQ score (mean +/- SD) of 49.3 +/- 13.8 at baseline, decreased by 12.4 +/- 10.2 (P < 0.01; visit 7) and 10.1 +/- 9.4 units (P < 0.02) 6-10 days after treatment cessation. The baseline subscores for symptoms (72.9 +/- 11.8), activity (44.7 +/- 20.9) and impact (44.4 +/- 14.3) were reduced by 0.8 +/- 9.1 (P > 0.7), 8.4 +/- 16.0 (P > 0.1) and 19.2 +/- 13.7 (P < 0.005) units, respectively (visit 7). Mannitol reduced the baseline (mean +/- SE) surface tension from 94.5 +/- 1.4 to 84.7 +/- 2.1 mN/m (P < 0.0001), contact angle from 51.1 +/- 2.8 to 33.2 +/- 2.4 degrees (P < 0.0001), spinnability from 11.6 +/- 0.4 to 10.0 +/- 0.2 mm (P < 0.005), and solids from 5.7 +/- 0.4 to 4.3 +/- 0.7% (P < 0.02), acutely (visit 7). Viscosity, elasticity and MCTR did not change significantly, while CTR was increased from 25.8 +/- 1.0 to 34.1 +/- 2.7 mm (P < 0.003). CONCLUSION: Mannitol significantly improved the health status over 12 days and this improvement was maintained for 6-10 days after cessation of treatment. In addition, mannitol reduced the tenacity, increased the hydration of mucus acutely and improved cough clearability in patients with bronchiectasis.

Pulmonary function changes and immunomodulation of cytokine expression by zafirlukast after sensitization and allergen challenge in brown Norway rats.

BACKGROUND: The cysteinyl leukotrienes are known important mediators in bronchial asthma. OBJECTIVE: Our purpose was to evaluate the effect of zafirlukast on the late-phase reaction, bronchial hyper-responsiveness (BHR) and T cell-related cytokine mRNA expression in ovalbumin (OA)-sensitized brown Norway rats (BNRs). METHODS: Thirty BNRs were equally divided into three groups. Group I and II animals were sensitized and then provoked with OA. Zafirlukast was given intraperitoneally (i.p.) to group I animals prior to provocation. Group II animals received i.p. normal saline. Group III animals (controls) were not sensitized and breathed aerosolized saline. After OA provocation, the animals were anaesthetized. Pulmonary function tests (PFT) were performed at baseline and after varying doses of acetylcholine. Thereafter, bronchoalveolar lavage (BAL) was performed and the lungs were examined histologically. Total RNA was extracted from lung tissue and reverse transcriptase-polymerase chain reaction (RT-PCR) was performed using primers for IL-2, IL-4, IL-5, IL-6, IL-10, TNF-alpha, IFN-gamma, iNOS and beta-actin. RESULTS: Group II OA-treated BNRs had worse PFT results, more severe bronchoconstriction in response to acetylcholine, and more severe inflammation in lung tissue than the other two groups. Group II had higher IL-2, IL-4, IL-10 and IFN-gamma cytokine levels in BAL fluid and higher IL-2, IL-4, IL-5, IL-6, IL-10, IFN-gamma, TNF-alpha and iNOS mRNA levels when compared with group I. CONCLUSION: Zafirlukast is effective in preventing late-phase bronchoconstriction and BHR, reducing inflammatory response, and decreasing IL-2, IL-4, IL-5, IL-6, IL-10 and IFN-gamma and iNOS mRNA expression.

The short-term repeatability of histamine bronchial testing in young males. The SUS study.

We have measured bronchial responsiveness (BR) to histamine on two occasions between 5 and 24 h apart, to determine if conventional and new indices of BR are repeatable. A random sample of 29 healthy male subjects with a mean age of 19 (SD 3.44) years from a larger study repeated a Yan method test of BR, recording both partial and maximal expiratory flow volume (PEFV and MEFV) curves. From the MEFV curves log-dose slopes (LDS) for forced expiratory volume in 1 sec (FEV1), forced expiratory flow between 25% and 75% of forced vital capacity (FVC) (FEF(25-75%)), mean expiratory flow at 30% and 40% of FVC (MEF30, MEF40), and the first moment of the spirogram (alpha1) truncated at 75% and 90% of FVC were calculated, as well as the provocative dose that induces a 20% fall in FEV1 (PD20FEV1). From the PEFV curves LDS for alpha(1)75% and alpha(1)90%, and MEF30 and MEF40 were derived. Apart from MEF30 and alpha(1)90% the second test was significantly lower (P<0.05) than the first when measuring the repeatability of spirometric indices, whereas the LDS of the indices showed no significant change. The repeatability expressed as intra-class correlation coefficient (ICC) was highest for LDS FEV1 (0.87), second highest for LDS MEF40 (0.67) and LDS MEF30 (0.65). The LDS for moment indices were much less repeatable and the lowest ICC was found in all LDS indices derived from PEFV curves. Within-subject variance was not influenced by atopic status, smoking habits or recordable PD20FEV1. As tests for bronchial hyper-responsiveness (BHR) the LDS of FEV1, MEF40 and MEF30 seem to be acceptable for use in population studies.

Conservation of small-airway function by tacrolimus/cyclosporine conversion in the management of bronchiolitis obliterans following lung transplantation.

We studied serial lung function in 11 patients with bronchiolitis obliterans syndrome who were treated with tacrolimus conversion following lung or heart-lung transplantation. Our results show that tacrolimus conversion slows the decline of lung function in bronchiolitis obliterans syndrome. The attenuation continues for at least 1 year following conversion.

Effects of perilla seed oil supplementation on leukotriene generation by leucocytes in patients with asthma associated with lipometabolism.

BACKGROUND: Dietary sources of alpha-linolenic acid, such as perilla seed oil, may have the capacity to inhibit the generation of leukotrienes (LTs) by leucocytes in patients with asthma, as has been reported with the consumption of other long-chain n-3 fatty acids. METHODS: The factors affecting the suppression of leukotriene (LT) C4 generation by leucocytes were examined by comparing the clinical features of patients with asthma who had been given dietary perilla seed oil (n-3 fatty acids). Group A consisted of patients in whom the leucocyte generation of LTC4 was suppressed by dietary perilla seed oil. Group B consisted of those in whom LTC4 generation was not suppressed. RESULTS: LTC4 generation by leucocytes decreased significantly in group A after 2 (p < 0.05) and 4 weeks (p < 0.05); conversely, it increased significantly in group B after 4 weeks (p < 0.05). The two study groups differed significantly in terms of LTC4 generation by leucocytes after 4 weeks of dietary supplementation (p < 0.05). Ventilatory parameters such as peak expiratory flow (PEF), forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV(1)) increased significantly after 4 weeks of dietary supplementation in group A (p < 0.05). Values of PEF, FVC, FEV(1) and maximum expiratory flow at 25% of the forced vital capacity (V(25)) differed significantly between groups A and B prior to dietary supplementation. Serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol and phospholipid were significantly decreased by dietary supplementation in group A after 4 weeks. Serum levels of total cholesterol, triglyceride, high-density lipoprotein cholesterol, LDL cholesterol and phospholipid differed significantly between the two study groups prior to dietary supplementation. Serum levels of triglyceride and LDL cholesterol differed significantly between the two study groups after 4 weeks of dietary supplementation. CONCLUSIONS: Dietary supplementation with perilla seed oil in selected patients with asthma suppresses the generation of LTC4 and is associated with clinical features such as respiratory function and lipometabolism.

Effect of inhaled nitric oxide on pulmonary function in cystic fibrosis.

Concentrations of nitric oxide (NO) have been found to be reduced in both the upper and lower airway of patients with cystic fibrosis (CF). As NO modulates bronchomuscular tone, low NO levels may contribute to the obstructive lung disease in these patients. To assess whether increasing inspiratory NO concentrations has any impact on lung function, we have studied 13 CF patients aged 14-38 years in a clinically stable condition and nine healthy controls. NO was applied via a mixing chamber for 5 min with NO concentrations of 100 parts per billion, 1 and 40 parts per million. Spirometry was performed at baseline and after inhalation on each occasion. There were no clinical side-effects at any NO concentration and no changes in oxygen saturation were observed. Lung function remained unchanged in all subjects throughout the study period. Sputum nitrate and nitrite concentrations before and after inhalation of high NO concentrations (40 ppm) in eight CF patients did not show any significant changes, even though a tendency to higher nitrate levels was observed (399 +/- 231 vs. 556 +/- 474 mumol l-1). Therefore, inhaled NO at either the physiological levels present in the upper airway of normal individuals or those used therapeutically to treat pulmonary hypertension has no immediate effect on bronchomuscular tone in patients with cystic fibrosis.

Ozone responsiveness in smokers and nonsmokers.

Short-term exposure to ozone causes decrements in lung function, but predictors of responsiveness remain largely unknown. Ninety healthy volunteers (56 never-smokers, age [mean +/- SD] 25 +/- 4 yr; 34 current smokers, 13 +/- 9 pack-yr, age 28 +/- 1 yr) were exposed to 0.22 ppm ozone for 4 h, with exercise, in an environmental chamber. We measured spirometry and specific airway conductance before, during, and immediately after exposure, and assessed symptoms by questionnaire. Smokers experienced a smaller increase in respiratory symptoms following exposure to ozone than did nonsmokers. Decrements in FEV1 were significantly less than for smokers than for nonsmokers (p = 0.0013). Ozone responsiveness (> 15% fall in FEV1) occurred in 16 of 56 never-smokers (28.6%) and 4 of 34 smokers (11.8%). Multiple logistic regression analysis found pack-yr of smoking to be associated with decreased ozone responsiveness (odds ratio [OR] 0.87, p = 0.017). Age, gender, and methacholine responsiveness were not predictive of responder status. Fourteen smokers and 25 nonsmokers were subsequently exposed once to air and twice to ozone; smokers as well as nonsmokers were consistent in their subsequent responsiveness (or lack of responsiveness) to ozone. Healthy smokers have smaller decrements in lung function and fewer symptoms in response to ozone exposure than do nonsmokers.

Effects of cigarette smoking on lung function in adolescent boys and girls.

BACKGROUND: Little is known about the sex-specific effects of cigarette smoking on the level and growth of lung function in adolescence, when 71 percent of people in the United States who smoke tried their first cigarette. METHODS: We studied the effects of cigarette smoking on the level and rate of growth of pulmonary function in a cohort of 5158 boys and 4902 girls 10 to 18 years of age, examined annually between 1974 and 1989 in six cities in the United States. RESULTS: We found a dose-response relation between smoking and lower levels of both the ratio of forced expiratory volume in one second to forced vital capacity (FEB1/FVC) and the forced expiratory flow between 25 and 75 percent of FVC (FEF25-75). Each pack per day of smoking was associated with a 3.2 percent reduction in FEF25-75 for girls (P=0.01) and a 3.5 percent reduction in FEF25-75 for boys (P=0.007). Whereas the FVC level was elevated in smokers, the rate of growth of FVC and FEV1 was reduced. Among adolescents of the same sex, smoking five or more cigarettes a day, as compared with never smoking, was associated with 1.09 percent slower growth of FEV1 per year in girls (95 percent confidence interval 0.70 to 1.47) and 0.20 percent slower growth in boys (95 percent confidence interval, -0.16 to 0.56), and with 1.25 percent slower growth of FEF25-75 per year in girls (95 percent confidence interval 0.38 to 2.13) and 0.93 percent slower growth in boys (95 percent confidence interval, 0.21 to 1.65). Whereas girls who did not smoke reached a plateau of lung function at 17 to 18 years of age, girls of the same age who smoked had a decline of FEV1 and FEF25-75. CONCLUSION: Cigarette smoking is associated with evidence of mild airway obstruction and slowed growth of lung function in adolescents. Adolescent girls may be more vulnerable than boys to the effects of smoking on the growth of lung function.

The effects of albuterol on the lung function of hospitalized patients with cystic fibrosis.

Twenty-four hospitalized patients with cystic fibrosis were enrolled into a 2-d, double-blind, placebo-controlled, randomized crossover trial comparing albuterol inhalation aerosol with a saline placebo. Aerosols were administered with the first three of four chest physiotherapy sessions given 4 h apart. Spirometry was measured before and 45 min after 7:00 A.M. and 3:00 P.M. therapy and before therapy at 7:00 P.M. and 7:00 A.M. the next morning. The mean percent change in FVC, FEV1, and FEF25-75% at 7:00 A.M. was 10.7, 14.8, and 19.6% with albuterol versus 2.4, 1.0, and -0.8% with placebo (p = 0.0012, < 0.0001, and = 0.003, respectively). A greater than 8% change in FEV1 separated changes with albuterol versus placebo with 96% specificity and occurred in 75% of all patients with albuterol; 71% at 7:00 A.M. versus 24% at 3:00 P.M. The reduction in response at 3:00 P.M. (p < 0.01) was presumably due to prolonged effects of morning therapy ( > 4 h). Individual changes in spirometry were significantly more positive and homogeneous with albuterol versus placebo at both 7:00 A.M. and 3:00 P.M. The mean percent change for the FVC, FEV1, and FEF25-75 across the day (7:00 A.M. pretherapy to 7:00 P.M. pretherapy) was 8.1, 10.1, and 9.7% with albuterol versus 3.9, 3.5 and 2.6% with placebo (p = 0.029, 0.036, and 0.232, respectively). The more positive and homogeneous changes in spirometry with albuterol, along with greater changes in these measures across the day when compared with placebo, suggest that albuterol improves pulmonary function in a majority of hospitalized patients with cystic fibrosis.

Acute safety and effects on mucociliary clearance of aerosolized uridine 5'-triphosphate +/- amiloride in normal human adults.

Impaired mucociliary clearance contributes to the pathophysiology of several airways diseases including cystic fibrosis, asthma, and chronic bronchitis. Extracellular triphosphate nucleotides (adenosine 5'-triphosphate [ATP], uridine 5'-triphosphate [UTP]) activate several components of the mucociliary escalator, suggesting they may have potential as therapeutic agents for airways diseases. We conducted initial (Phase I) studies of acute safety and efficacy of aerosolized UTP alone and in combination with aerosolized amiloride, the sodium channel blocker, in normal human volunteers. Safety was assessed by measurement of pulmonary function. Neither UTP alone nor in combination with amiloride caused any clinically significant adverse effects on airway mechanics, (subdivisions of) lung volumes, or gas exchange. Acute efficacy of UTP and amiloride alone and in combination, was assessed by measuring changes in the clearance of inhaled radiolabeled particles. A 2.5-fold increase in mucociliary clearance was seen in response to UTP alone and in combination with amiloride. We conclude that aerosolized UTP +/- amiloride clearly enhances mucociliary clearance without acute adverse effects in normal adults, and may have therapeutic potential to enhance airways clearance in diseases characterized by retained airways secretions.

Formaldehyde exposure, acute pulmonary response, and exposure control options in a gross anatomy laboratory.

Formaldehyde exposure, acute pulmonary response, and exposure control options were evaluated in a group of 34 workers in a gross anatomy laboratory. Time-weighted average (TWA) exposure to formaldehyde ranged from 0.07-2.94 parts per million (ppm) during dissecting operations. More than 94% were exposed to formaldehyde in excess of the ceiling value of 0.3 ppm recommended by the American Conference of Governmental Industrial Hygienists (ACGIH). The eight-hour TWA exposure of 31.7% of the subjects exceeded the action level of 0.5 ppm set by the Occupational Safety and Health Administration (OSHA). Reported symptoms included irritation of eye (88%), nose (74%), throat (29%), and airways (21%). Forced vital capacity (FVC) and forced expiratory volume in 3 seconds (FEV3) decreased, and FEV1/FVC increased during the exposure. The changes of FEV3 were statistically different from those of the controls. The results strongly support the necessity for designing and testing special local exhaust-ventilated worktables with necessary flexibility for dissecting operations.

Utility of inhaled pentamidine prophylaxis in lung transplant recipients.

The incidence of Pneumocystis carinii pneumonia (PCP) has been shown to be high posttransplantation in the absence of prophylaxis. For this reason, lung transplant recipients routinely receive prophylaxis. We report on our results using aerosolized pentamidine prophylaxis in nine patients post-lung transplantation (eight single lung transplants, one double). The patients received monthly treatments of 300 mg of aerosolized pentamidine for a mean of 10.6 months (range, 4 to 21 months). Patients were routinely monitored with serial pulmonary function studies and bronchoscopy as clinically indicated. Two of the patients experienced bronchospasm in response to the therapy. None of the patients experienced any episodes of PCP during the period of inhaled pentamidine prophylaxis. Inhaled pentamidine is a safe and effective form of PCP prophylaxis and may be used instead of sulfamethoxazole-trimethoprim in patients who have a sulfa allergy or other untoward sulfa side effects.

Unspecific bronchial reactivity to carbachol in healthy subjects--effect of age and smoking habits.

Chronic inflammatory processes of the airways induced by long-time cigarette consumption are a crucial factor in the pathogenesis of chronic obstructive pulmonary disease. In contrast, the role of cigarette smoking in the pathogenesis of bronchial hyperreactivity (BHR) is still unclear. The aim of this study was to assess the effect of chronic cigarette consumption on pulmonary function tests and BHR in healthy subjects. 63 healthy smokers and 63 lifetime nonsmokers matched for sex, age, height and weight were evaluated. Pulmonary function was determined by body plethysmography and spirometry. Bronchial provocation was performed by inhalation of increasing doses of carbachol (up to 25 g/l) in isotonic NaCl solution. Pulmonary function tests were within normal limits in all subjects. Nevertheless, midexpiratory flow at 25% of forced vital capacity was significantly smaller, and functional residual capacity was significantly greater in middle-aged smokers (age: 40-60 years) compared to middle-aged nonsmokers (p < 0.05, both comparisons). In young smokers and nonsmokers (age: 20-30 years) pulmonary function tests were not different (p > 0.28, all comparisons). Importantly, the carbachol concentration that provoked a 50% rise in specific airway resistance (PD50sRaw) was similar in smokers and nonsmokers of both age groups (p > 0.05, both comparisons) and did not correlate with the age of the subjects (p > 0.2). No correlations between baseline values of pulmonary function tests and PD50sRaw were observed (p > 0.34, all comparisons). The observations confirm that the distribution profile of BHR is unimodal and apparently not affected by age and smoking habits.

Intrathecal morphine during thoracotomy, Part II: Effect on postoperative meperidine requirements and pulmonary function tests.

The ability of intrathecal morphine (ITM) to reduce post-thoracotomy pain and meperidine requirements was investigated. Thirty adult patients scheduled for thoracic surgery were studied. Following induction with thiamylal sodium and succinylcholine, anesthesia was maintained with 100 micrograms of fentanyl, vecuronium, and enflurane. Prior to skin incision, 16 patients received intrathecal morphine, 12 micrograms/kg, injected at the L3-4 or L4-5 level. The other 14 patients were controls. Postoperatively, patients were evaluated for pain scores and the total doses of meperidine required over 24 hours. The patients in the ITM group required significantly less meperidine compared to the control group (59 +/- 68 v 167 +/- 97 mg, respectively) and had lower pain scores (1.4 +/- 1.1 v 2.4 +/- 0.9 mg, respectively). There were no serious side effects attributable to ITM. It is concluded that ITM is an effective adjunctive treatment for control of post-thoracotomy pain.