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.

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.

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.

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.

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.