Effect of a single 1200 Mg dose of Mucinex® on mucociliary and cough clearance during an acute respiratory tract infection.

BACKGROUND: Observational studies suggest that orally administered guaifenesin (GGE) may thin lower respiratory tract secretions but none have examined its effects on mucociliary and cough clearance (MCC/CC) during a respiratory tract infection (RTI). The current study was a randomized, parallel-group, double-blind, placebo-controlled study in non-smoking adults who suffered from an acute upper RTI. METHODS: We assessed the effects of a single dose of Mucinex(®) 1200 mg (2 × 600 mg extended release tablets) (ER GGE) on 1) MCC/CC by assessing the rate of removal from the lung of inhaled radioactive tracer particles (Tc99m-sulfur colloid), 2) sputum dynamic rheology by stress/strain creep transformation over the linear part of the curve, 3) sessile drop interfacial tension by the deNouy ring technique, and 4) subjective symptom measures. MCC was measured during the morning (period 1) and compared to that in the afternoon 4 h later (period 2) immediately following either drug (n = 19) or placebo (n = 19). For both period 1 and 2 subjects performed 60 voluntary coughs from 60 to 90 min after inhalation of radio-labeled aerosol for a measure of CC. Sputum properties were measured from subjects who expectorated sputum during the cough period post treatment (n = 8-12 for each cohort). RESULTS: We found no effect of ER GGE on MCC or CC compared to placebo. MCC through 60 min for period 1 vs. 2 = 8.3 vs. 11.8% (placebo) and = 9.7 vs. 11.1% (drug) (NS) and CC for period 1 vs. 2 was 9.9 vs. 9.1% (placebo) and 10.8 vs. 5.6% (drug) (NS). There was no significant difference in sputum biophysical properties after administration of drug or placebo. CONCLUSIONS: There was no significant effect of a single dose of ER GGE on MCC/CC or on sputum biophysical properties compared to placebo in this population of adult patients with an acute RTI. ClinicalTrials.gov Identifier: NCT01114581.

Duration of action of hypertonic saline on mucociliary clearance in the normal lung.

Inhalation of hypertonic saline (HS) acutely enhances mucociliary clearance (MC) in both health and disease. In patients with cystic fibrosis (CF), repeated use of HS causes a sustained improvement in MC as well as clinical benefit. The pharmacodynamic duration of activity on MC may be an important determinant of its therapeutic potential in other airways diseases. Before moving toward testing the clinical benefits of HS for non-CF indications, we sought to assess the duration of pharmacodynamic effects of HS in healthy subjects by performing radiotracer clearance studies at baseline, 30-min post-HS administration, and 4-h post-HS administration. Indeed, acceleration of MC was observed when measured 30 min after HS inhalation. This acceleration was most pronounced in the first 30 min after inhaling the radiotracer in the central lung region (mean Ave30Clr = 15.5 vs. 8.6% for 30-min post-HS treatment vs. mean baseline, respectively, P < 0.005), suggesting that acute HS effects were greatest in the larger bronchial airways. In contrast, when MC was measured 4 h after HS administration, all indices of central lung region MC were slower than at baseline: Ave30Clr = 5.9% vs. 8.6% (P = 0.10); Ave90Clr = 12.4% vs. 16.8% (P < 0.05); clearance through 3 h = 29.4 vs. 43.7% (P < 0.002); and clearance through 6 h = 39.4 vs. 50.2% (P < 0.02). This apparent slowing of MC in healthy subjects 4-h post-HS administration may reflect depletion of airway mucus following acute HS administration.

Removal of sedimentation decreases relative deposition of coarse particles in the lung periphery.

Lung deposition of >0.5-µm particles is strongly influenced by gravitational sedimentation, with deposition being reduced in microgravity (µG) compared with normal gravity (1G). Gravity not only affects total deposition, but may also alter regional deposition. Using gamma scintigraphy, we measured the distribution of regional deposition and retention of radiolabeled particles ((99m)Tc-labeled sulfur colloid, 5-µm diameter) in five healthy volunteers. Particles were inhaled in a controlled fashion (0.5 l/s, 15 breaths/min) during multiple periods of µG aboard the National Aeronautics and Space Administration Microgravity Research Aircraft and in 1G. In both cases, deposition scans were obtained immediately postinhalation and at 1 h 30 min, 4 h, and 22 h postinhalation. Regional deposition was characterized by the central-to-peripheral ratio and by the skew of the distribution of deposited particles on scans acquired directly postinhalation. Relative distribution of deposition between the airways and the alveolar region was derived from data acquired at the various time points. Compared with inhalation in 1G, subjects show an increase in central-to-peripheral ratio (P = 0.043), skew (P = 0.043), and tracheobronchial deposition (P < 0.001) when particles were inhaled in µG. The absence of gravity caused fewer particles to deposit in the lung periphery than in the central region where deposition occurred mainly in the airways in µG. Furthermore, the increased skew observed in µG likely illustrates the presence of localized areas of deposition, i.e., "hot spots", resulting from inertial impaction. In conclusion, gravity has a significant effect on deposition patterns of coarse particles, with most of deposition occurring in the alveolar region in 1G but in the large airways in µG.

Effect of inhaled dust mite allergen on regional particle deposition and mucociliary clearance in allergic asthmatics.

BACKGROUND: Acute exacerbations in allergic asthmatics may lead to impaired ability to clear mucus from the airways, a key factor in asthma morbidity. OBJECTIVE: The purpose of this study was to determine the effect of inhaled house dust mite challenge on the regional deposition of inhaled particles and mucociliary clearance (MCC) in allergic asthmatics. METHODS: We used gamma scintigraphy (inhalation of (99m) Tc -sulphur colloid particles) to measure the regional particle deposition and MCC in allergic asthmatics (n=12) 4 h following an inhaled dust mite allergen challenge (Dermatophagoides farinae extract; PD(max) =fall in forced expiratory volume in 1 s of 10%) for comparison with baseline non-challenge measures. RESULTS: In responders (n=9 PD(max) dose), lung function returned to pre-challenge values by 3 h but was significantly decreased at 6 and 24 h in three of the responders (i.e. late-phase response) and induced sputum eosinophils were increased at 24 h post-challenge (P<0.05). Responders showed enhanced bronchial airway deposition of inhaled particles (P<0.05) and slowed clearance from the central lung zone (P<0.01) at 4 h post-challenge compared with the baseline (no allergen challenge) that was predicted by the PD(max) allergen concentration (r=-0.70, P<0.05). The decline in lung function at 24 h post-challenge correlated with reduced MCC from the central lung zone (r=-0.78, P<0.02) and PD(max) . Non-responders (n=3) showed no change in lung function, regional deposition or MCC post-challenge vs. baseline. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that regional deposition and clearance of inhaled particles may be sensitive for detecting mild airway obstruction associated with early- and late-phase allergen-induced effects on mucus secretions. The study was listed on clinicaltrials.gov (NCT00448851).

In vivo uptake of inhaled particles by airway phagocytes is enhanced in patients with mild asthma compared with normal volunteers.

BACKGROUND: The uptake of inhaled particulate matter by airway phagocytes is an important defence mechanism contributing to the clearance of potentially toxic substances, including aeroallergens, from the lung. Since airway monocytes and macrophages can also function as antigen presenting cells, their ability to engulf materials deposited on the airway surface is of particular interest in patients with allergic asthma. To determine whether airway mononuclear phagocytes of patients with allergic asthma might have enhanced phagocytic activity, the in vivo uptake of inhaled radiolabelled particles was compared in 10 patients with mild allergic asthma and 8 healthy (non-allergic) individuals. METHODS: Phagocyte function was assessed by quantifying the proportion of radioactivity associated with cellular and supernatant fractions of induced sputum 2 h after inhalation of radiolabelled sulfur colloid particles. All subjects were pretreated with albuterol before sputum induction. A standardised breathing pattern was used to target aerosol deposition in the bronchial airways. RESULTS: In vivo particle uptake by airway cells was significantly greater in patients with asthma than in healthy volunteers (57.2% (95% CI 46.5% to 67.9%) vs 22.3% (95% CI 4.9% to 39.6%), p<0.01), as was in vitro phagocytosis of opsonised zymosan-A bioparticles. There was also a significant correlation (r = 0.85, p<0.01) between the percentage of sputum mononuclear phagocytes and the percentage uptake of particles in the patients with asthma but not in the control subjects. CONCLUSIONS: In vivo particle uptake by airway macrophages is enhanced in persons with mild asthma. Enhanced uptake and processing of particulate antigens could contribute to the pathogenesis and progression of allergic airways disease and may contribute to the increased risk of disease exacerbation associated with particulate exposure.

Effects of inhaled iron oxide particles on alveolar epithelial permeability in normal subjects.

Pulmonary inflammation secondary to oxidant generation catalyzed by transition metals associated with inhaled particles is one factor postulated to underlie the acute health effects of particulate air pollution. We postulated that inhaled iron oxide particles with associated amounts of soluble iron should induce mild pulmonary inflammation and lead to altered alveolar epithelial integrity and altered gas exchange. To test this hypothesis we examined the effects of inhaled iron oxide particles on alveolar epithelial permeability. Sixteen healthy subjects inhaled aerosols of iron oxide particles (1.5 microm mass median aerodynamic diameter) having either high or low water-soluble iron content [3.26 +/- 0.25 (SE) and 0.14 +/- 0.04 microg soluble iron/mg of particles, respectively] for 30 min at an average mass concentration of 12.7 mg/m(3). Alveolar epithelial permeability was assessed by measuring the pulmonary clearance of an inhaled radiolabeled tracer molecule ((99m)Tc-DTPA, diethylene triamine pentaacetic acid) using a gamma camera at 1/2 h and 24 h post particle exposure. Carbon monoxide lung diffusing capacity (DL(CO)) and spirometry were also performed before and after breathing the iron oxide. As a control, on a separate day, the procedures were duplicated except that the subject breathed particle-free air. For those subjects breathing aerosols with high soluble iron, we found no significant difference in DTPA clearance half-times after breathing particles versus particle-free air either at 1/2 h (97.4 +/- 15.4 vs. 116.1 +/- 15.5 min, respectively) or 24 h postinhalation (105.1 +/- 13.8 vs. 106.9 +/- 12.9 min, respectively). Likewise, for those subjects breathing aerosols with low soluble iron content we found no significant difference in DTPA clearance half-times after breathing particles versus particle-free air either at 1/2 h (108.6 +/- 31.9 vs. 95.6 +/- 10.8 min, respectively) or 24 h postinhalation (130.0 +/- 18.0 vs. 105.8 +/- 13.7 min, respectively). We found no significant differences in DL(CO) between particle exposures and air exposures. Minor differences in spirometric measurements were noted but were not statistically significant. We conclude that inhalation of iron oxide particles did not cause an appreciable alteration of alveolar epithelial permeability, lung diffusing capacity, or pulmonary function in healthy subjects under the studied conditions.

Effect of aerosolized uridine 5'-triphosphate on mucociliary clearance in mild chronic bronchitis.

Previous studies show that uridine 5'-triphosphate (UTP), a P2Y(2) receptor agonist, is effective at acutely enhancing mucociliary clearance in healthy, nonsmoking adults. UTP solution for inhalation is being developed by Inspire Pharmaceuticals under the compound number INS316. In a double-blind, randomized, crossover, placebo-controlled study we tested the single-dose effect of UTP in chronic smokers with mild chronic bronchitis (n = 15) by measuring the clearance of (99m)Tc-Fe(2)O(3) particles (4.0 microm mass median aerodynamic diameter [MMAD]) after inhalation of nebulized placebo (0.9% saline) and two doses of UTP (20 and 100 mg in the nebulizer). On each study day, gamma camera scanning was performed over a 2-h period. After an initial deposition scan, subjects inhaled placebo or UTP during the first 20 min of scanning. Analysis of whole lung clearance showed that the retention-time curves for each day were biphasic and that the earliest break point in the average curves occurred at 50 min. Mean particle clearance rate (Clr in %/min) through 50 min for placebo treatment was Clr = 0.65 +/- 0.27 whereas treatment with UTP showed Clr significantly increased to 0.95 +/- 0.48 and 0.93 +/- 0.44 for the 20-mg and 100-mg dose respectively, p < 0.005 for both as compared with placebo. These data show that mucociliary clearance associated with mild chronic bronchitis is acutely improved with minimal doses of aerosolized UTP, presumably because of its stimulation of ciliary beating and hydration of airway secretions.

Regional deposition of coarse particles and ventilation distribution in healthy subjects and patients with cystic fibrosis.

The efficacy of inhaled pharmaceuticals depends, in part, on their site of respiratory deposition. Markedly nonuniform ventilation distribution may occur in persons with obstructive airways diseases and may affect particle deposition. We studied the relationship between regional deposition (RDep) and regional ventilation (RVent) in a group of 12 cystic fibrosis (CF) patients with mild to moderate airway obstruction (63 +/- 8% predicted FEV1) and 11 healthy nonsmoking volunteers (104 +/- 13% predicted FEV1) using planar scintigraphic methods. RDep was assessed from initial deposition and 24-h retention images for monodisperse technetium-99m-labeled iron oxide particles (5-microm MMAD). Regional volumes and RVent were assessed from xenon-133 equilibrium and washout, respectively. Six regions of interest per lung were established by dividing each lung into thirds by height and approximately half by width. The two lower regions of the left lung were not analyzed due to activity in the stomach. Remaining regions were categorized as central (two interior-most regions) and peripheral (eight exterior regions). RDep and RVent were computed for the eight peripheral regions. Tracheobronchial (TB) deposition was estimated for each of the peripheral regions as the difference between initial activity and decay-corrected 24-h retention or parenchymal deposition. RDep was computed as the fraction of material within a region normalized to regional volume. RVent for each region was determined by normalizing the xenon washout rate for that region by the total washout rate for the eight peripheral regions. Significant linear associations were found between RDep and RVent in both the healthy subjects and CF patients. In healthy subjects, RDep in the TB airways was positively associated with RVent (p = 0.03). In CF patients, RDep in the TB airways was negatively associated with RVent (p = 0.04) and RDep in the parenchyma was positively associated with RVent (p < 0.001). The initial pattern of RDep in the lung was not significantly associated with RVent in either group. These data suggest that significant coarse particle deposition may occur in the TB airways of poorly ventilated lung regions in CF patients, whereas, particle deposition in the TB airways of the healthy subjects follows ventilation.

Prolonged airway retention of insoluble particles in cystic fibrosis versus primary ciliary dyskinesia.

Patients with cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) have been shown to have impaired large airway clearance of radiolabelled particles as measured by external gamma camera scanning up to 6 hours post deposition. Recent studies suggest that 24-hour retention of particles may reflect some airway retention in addition to alveolar retention. In a retrospective study, we analyzed the relationship between the deposition pattern and 24-hour retention (Ret24 hr) of technetium 99-radiolabelled iron oxide (99Tc-Fe2O3) particles in 20 patients with CF, 12 patients with PCD, and 17 normal subjects. By gamma camera analysis, initial aerosol deposition was analyzed in terms of central-peripheral (C/P) activity within the lungs. Gamma camera scanning was performed immediately following deposition and again at 24 hours to assess residual retention (Ret24 hr) as a percent of initial deposition. C/P analysis was also performed on the 24-hour scan (C/P24). For all subjects, initial deposition pattern (C/P) was inversely related to lung function (forced expiratory volume in 1 second [FEV1]%pred vs. C/P, r = -.54). Ret24 hr was also inversely related to initial deposition pattern for all subjects (Ret24 hr vs. C/P ratio, r = -.42). Analysis of covariance showed that for a given C/P ratio, CF patients had significantly greater Ret24 hr compared to normal subjects (9.8 +/- 2.8 [SE]%). In addition, the CF patients had similar C/P24 as the normal subjects (1.35 +/- 0.40 [SD] vs. 1.10 +/- 0.39, respectively). These results suggest that small airway clearance is compromised in CF patients compared to normal subjects. On the other hand, PCD patients had C/P24 similar to their initial deposition C/P ratios (2.78 +/- 1.72 vs. 2.45 +/- 0.87, respectively), significantly greater than 1.0, and significantly greater than CF or normal subjects, suggesting that PCD patients have prolonged particle retention associated with their large bronchial airways.

In vivo characterization of the transitional bronchioles by aerosol-derived airway morphometry.

Effective airway dimensions (EADs) were determined in vivo by aerosol-derived airway morphometry as a function of volumetric lung depth (VLD) to identify and characterize, noninvasively, the caliber of the transitional bronchiole region of the human lung and to compare the EADs by age, gender, and disease. By logarithmically plotting EAD vs. VLD, two distinct regions of the lung emerged that were identified by characteristic line slopes. The intersection of proximal and distal segments was defined as VLD(trans) and associated EAD(trans). In our normal subjects (n = 20), VLD(trans) [345 +/- 83 (SD) ml] correlated significantly with anatomic dead space (224 +/- 34 ml) and end of phase II of single-breath nitrogen washout (360 +/- 53 ml). The corresponding EAD(trans) was 0.42 +/- 0. 07 mm, in agreement with other ex vivo measurements of the transitional bronchioles. VLD(trans) was smaller (216 +/- 64 ml) and EAD(trans) was larger (0.83 +/- 0.04 mm) in our patients with chronic obstructive pulmonary disease (n = 13). VLD(trans) increased with age for children (age 8-18 yr; P = 0.006, n = 26) and with total lung capacity for age 8-81 yr (P < 0.001, n = 61). This study extends the usefulness of aerosol-derived airway morphometry to in vivo measurements of the transitional bronchioles.

Effect of aerosolized uridine-5'-triphosphate on airway clearance with cough in patients with primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormal ciliary structure and function and impaired mucociliary clearance. Because patients with PCD use cough clearance as an airway defense mechanism, we tested the hypothesis that aerosolized uridine-5'-triphosphate (UTP) would improve clearance during cough by its actions to stimulate Cl- secretion and mucin release by goblet cells. We measured clearance during cough in 12 patients with PCD (ages 14 to 71 yr, FEV1 43% to 89% predicted) in a double blind, randomized, crossover study after aerosolization of a single dose of UTP (5 mg/ml, 3.5 ml) or vehicle (0.12% saline, 3.5 ml). Clearance during cough (whole lung) was quantified during and after a series of controlled coughs by measuring the clearance of [99mTc]Fe2O3 particles via gamma camera scanning over 120 min. Safety parameters were recorded during and after drug delivery. Aerosolized UTP improved whole-lung clearance during cough as compared with vehicle (from 0 to 60 min: 0.40 +/- 0.07%/min [UTP] versus 0.26 +/- 0. 04%/min [vehicle] [mean +/- SEM], p = 0.01), and from 0 to 120 min: 0.38 +/- 0.05%/min [UTP] versus 0.25 +/- 0.04%/ min [vehicle], p = 0. 02). Aerosolized UTP is safe, with no serious adverse effects. Whole-lung clearance during cough in patients with defective ciliary function is enhanced after inhalation of UTP.

Regional deposition and retention of particles in shallow, inhaled boluses: effect of lung volume.

The regional deposition of particles in boluses delivered to shallow lung depths and their subsequent retention in the airways may depend on the lung volume at which the boluses are delivered. To evaluate the effect of end-inspiratory lung volume on aerosol bolus delivery, we had healthy subjects inhale radiolabeled, monodisperse aerosol (99mTc-iron oxide, 3.5-microm mass median aerodynamic diameter) boluses (40 ml) to a volumetric front depth of 70 ml into the lung at lung volumes of 50, 70, and 85% of total lung capacity (TLC) end inhalation. By gamma camera analysis, we found significantly greater deposition in the left (L) vs. right (R) lungs at the 70 and 85% TLC end inhalation; ratio of deposition in L to R lung, normalized to L-to-R ratio of lung volume (mean L/R), was 1.60 +/- 0.45 (SD) and 1. 96 +/- 0.72, respectively (P < 0.001 for comparison to 1.0) for posterior images. However, at 50% TLC, L/R was 1.23 +/- 0.37, not significantly different from 1.0. These data suggest that the L and R lungs may be expanding nonuniformly at higher lung volumes. On the other hand, subsequent retention of deposited particles at 2 and 24 h postdeposition was independent of L/R at the various lung volumes. Thus asymmetric bolus ventilation for these very shallow boluses does not lead to significant increases in peripheral alveolar deposition. These data may prove useful for 1) designing aerosol delivery techniques to target bronchial airways and 2) understanding airway retention of inhaled particles.

Bronchial airway deposition and retention of particles in inhaled boluses: effect of anatomic dead space.

The fractional deposition of particles in boluses delivered to shallow lung depths and their subsequent retention in the airways may depend on the relative volume and size of an individual's airways. To evaluate the effect of variable anatomic dead space (ADS) on aerosol bolus delivery we had healthy subjects inhale radiolabeled, monodisperse aerosol (99mTc-iron oxide, 3.5 micron mean mondispersed aerosol diameter) boluses (40 ml) to a volumetric front depth of 70 ml into the lung at a lung volume of 70% total lung capacity end inhalation. By using filter techniques, aerosol photometry, and gamma camera analysis, we estimated the fraction of the inhaled boluses deposited in intrathoracic airways (IDF). ADS by single-breath N2 washout was also measured from 70% total lung capacity. Results showed that among all subjects IDF was variable (range = 0.04-0.43, coefficient of variation = 0.54) and increased with decreasing ADS (r = -0.76, P = 0.001, n = 16). We found significantly greater deposition in the left (L) vs. right (R) lungs; mean L/R (ratio of deposition in L lung to R lung, normalized to ratio of L-to-R lung volume) was 1.58 +/- 0.42 (SD; P < 0.001 for comparison with 1.0). Retention of deposited particles at 2 h was independent of ADS or IDF. There was significant retention of particles at 24 h postdeposition (0.27 +/- 0.05) and slow clearance of these particles continued through 48 h postdeposition. Finally, analysis of central-to-peripheral ratios of initial deposition and 24-h-retention gamma-camera images suggest significant retention of insoluble particles in large bronchial airways at 24 h postdeposition (i.e., 24 h central-to-peripheral ratio = 1.40 +/- 0. 44 and 1.82 +/- 0.54 in the R and L lung, respectively; P < 0.02 for comparison with 1.0). These data may prove useful for 1) designing aerosol delivery techniques to target bronchial airways and 2) understanding airway retention of inhaled particles.

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.

Effect of uridine 5'-triphosphate plus amiloride on mucociliary clearance in adult cystic fibrosis.

Cystic fibrosis (CF) is characterized by abnormal airway epithelial electrolyte transport leading to viscous airway secretions that are difficult to clear. By enhancing Cl- secretion onto and blocking Na+ absorption from the airway surface, treatment with aerosolized uridine 5'-triphosphate (UTP) plus amiloride may improve the rheology of airway secretions and enhance mucociliary clearance in patients with CF. After performing safety studies of aerosolized UTP/amiloride in adult patients with CF, we investigated the effects of inhaled vehicle and UTP/amiloride on mucociliary clearance of [99mTc] iron oxide particles from the airways of adult patients with CF (n = 14). We found no clinically significant adverse effects from inhalation of therapeutic doses of UTP/amiloride. Mean baseline peripheral clearance rates during the first 40 min of clearance measurements were significantly less in patients with CF than in normal subjects (mean +/- SE: 0.30 +/- 0.05 versus 0.54 +/- 0.07%/min, respectively; p = 0.01). Aerosolized UTP and amiloride in combination improved mucociliary clearance from the peripheral airways of the CF lungs to near normal values (0.51 +/- 0.09%/min; p = 0.04) during this period. These data support the concept for the use of UTP in combination with amiloride as therapy to improve clearance of secretions from the lungs of patients with CF.

Variability of fine particle deposition in healthy adults: effect of age and gender.

Recent epidemiologic studies suggest increased mortality among the elderly in association with particulate air pollution. We investigated the variability in fractional deposition (DF) of inhaled particles (2 microns mass median aerodynamic diameter [MMAD]) in 62 subjects with normal lung function, aged 18 to 80 yr. Each subject inhaled 2-microns monodisperse carnauba wax particles while following a breathing pattern previously determined by respiratory inductance plethysmography in that subject (i.e., particles inhaled) was determined by laser aerosol photometry and pneumotachometry at the mouth. DF (mean DF = 0.29 +/- 0.06 (ages 18 to 40 yr), 0.29 +/- 0.07 (ages 41 to 60 yr), and 0.26 +/- 0.06 (age over 60 yr) was independent of age. There was a tendency toward greater DF in female than in male subjects; DF = 0.30 +/- 0.07 (females) and 0.27 +/- 0.06 (males) (p = 0.06); however, because the males had 45% higher minute ventilations than the females, the deposition rate (Drate), or particles depositing per unit of time, was 30% greater in males than in females (p = 0.004). Multiple regression analysis showed that among all subjects, the variability in DF was best predicted by variability in the breathing period (T) associated with the pattern used to breathe the particles, and by the subject's specific airway resistance (sRAW). These results may prove useful in determining age- and gender-relative risks that may be associated with the inhalation of pollutant particles in ambient air.

Measuring alveolar dimensions at total lung capacity by aerosol-derived airway morphometry.

A technique based on particle sedimentation, aerosol-derived airway morphometry (ADAM), was modified to investigate the morphometry of human lung airspaces at full inflation in 54 subjects with normal lung function, ages 18 to 69 years. The technique compares the recovered concentrations of monodisperse aerosol particles after gravitational settling during breath holds to determine effective airspace diameters (EADs) as a function of volumetric lung depth. The method is simple and non-invasive, requiring only several inhalations of aerosol to total lung capacity, breath holds at end inhalation and exhalation to residual volume (RV). The method is sensitive enough to detect differences in the smallest observed airspaces (EADmin) due to normal aging of healthy lungs when older subjects are compared to younger subjects. The average EADmin was larger (p = 0.009) for the oldest adults (293 +/- 54 um, s.d., 50-70 years, n = 13) at the deepest volumetric lung depth (near 40% of TLC into the lung) when compared to the youngest adults (250 +/- 38 um, s.d., 18-40 years, n = 22). The two groups had similar EADs at a depth of 5% of TLC. No gender difference in EADmin was found when comparing all males and females. No correlation was found between EADs and TLC implying number of alveolar airspaces rather than airspace size determines lung volume. The effects of changing the aerosol inhalation volume to TLC ratio was also investigated. Compared to the dichotomous Weibel morphometric model, the average EADs of 22 18-40 year old subjects were found to be equivalent near 1% TLC and 40% TLC, but were larger in size than the model between those extremes with a maximum difference occurring at approximately 3% TLC. This method appears to be extremely sensitive to in vivo changes in airspace dimensions and may prove useful in determining changes in these dimensions associated with normal lung development and early disease states.

Effect of enhanced supramaximal flows on cough clearance.

Efficiency of cough for clearing mucus from the lungs is believed to be a function of peak airflow velocities in the airways. Initial transient supramaximal flows are characteristic of cough, and these peak flow rates can be enhanced by placing a triggered shutter at the mouth, serving the role of the epiglottis. Using radiolabeled monodispersed aerosols (99mTc-iron oxide) and gamma camera analysis, we measured over a 2-h period the efficacy of 60 voluntary vs. shutter coughs for clearing mucus from the airways of patients (n = 15) with chronic airway obstruction (mean ratio of forced expired volume in 1 s to forced vital capacity = 0.55). In a subset of patients (n = 9), we also measured the efficacy of forced expirations, or huffs, without glottis closure. Peak flow rate was greater for shutter than voluntary coughs [9.4 +/- 2.0 (SD) vs. 4.1 +/- 1.9 l/s; P < 0.001]. Retention at 60 min (as a fraction of initial deposition) was significantly different for the 3 study days (control, 0.83 +/- 0.17; voluntary cough, 0.69 +/- 0.18; shutter cough, 0.75 +/- 0.19; P = 0.01), but only control vs. voluntary cough values were significantly different from each other (P = 0.01). In contrast, retention at 120 min was significantly different for the 3 days, but both voluntary and shutter coughs were significantly different from control (P = 0.01 and P = 0.02, respectively) (control, 0.73 +/- 0.16; voluntary cough, 0.61 +/- 0.20; shutter cough, 0.65 +/- 0.20). Patients studied with buffs showed a clearance rate faster than control and similar to that associated with voluntary cough.(ABSTRACT TRUNCATED AT 250 WORDS)

Mg2+-ATP induces filament growth from retinal rod outer segments with disrupted plasma membranes.

Mg2+-ATP produces a large decrease in near-IR light scattering when added to suspensions of rod outer segments (ROS) when the plasma membranes have been disrupted by a gentle dialysis procedure. When this process is studied by light microscopy with video-enhanced image contrast, the Mg2+-ATP-dependent signal is seen to be associated with the formation of filaments which extend only from those ROS lacking plasma membranes. Both the IR light scattering signal and filament growth are inhibited by vanadate and DCCD but not by colchicine, colcemid or cytochalasins.