Inhaled Medicines: Past, Present, and Future.

The purpose of this review is to summarize essential pharmacological, pharmaceutical, and clinical aspects in the field of orally inhaled therapies that may help scientists seeking to develop new products. After general comments on the rationale for inhaled therapies for respiratory disease, the focus is on products approved approximately over the last half a century. The organization of these sections reflects the key pharmacological categories. Products for asthma and chronic obstructive pulmonary disease include ß -2 receptor agonists, muscarinic acetylcholine receptor antagonists, glucocorticosteroids, and cromones as well as their combinations. The antiviral and antibacterial inhaled products to treat respiratory tract infections are then presented. Two "mucoactive" products-dornase α and mannitol, which are both approved for patients with cystic fibrosis-are reviewed. These are followed by sections on inhaled prostacyclins for pulmonary arterial hypertension and the challenging field of aerosol surfactant inhalation delivery, especially for prematurely born infants on ventilation support. The approved products for systemic delivery via the lungs for diseases of the central nervous system and insulin for diabetes are also discussed. New technologies for drug delivery by inhalation are analyzed, with the emphasis on those that would likely yield significant improvements over the technologies in current use or would expand the range of drugs and diseases treatable by this route of administration. SIGNIFICANCE STATEMENT: This review of the key aspects of approved orally inhaled drug products for a variety of respiratory diseases and for systemic administration should be helpful in making judicious decisions about the development of new or improved inhaled drugs. These aspects include the choices of the active ingredients, formulations, delivery systems suitable for the target patient populations, and, to some extent, meaningful safety and efficacy endpoints in clinical trials.

Effects of exercise and airway clearance (positive expiratory pressure) on mucus clearance in cystic fibrosis: a randomised crossover trial.

Exercise improves mucus clearance in people without lung disease and those with chronic bronchitis. No study has investigated exercise alone for mucus clearance in cystic fibrosis (CF). The aim of this study was to compare the effects of treadmill exercise to resting breathing and airway clearance with positive expiratory pressure (PEP) therapy on mucus clearance in adults with CF.This 3-day randomised, controlled, crossover trial included 14 adults with mild to severe CF lung disease (forced expiratory volume in 1 s % predicted 31-113%). Interventions were 20 min of resting breathing (control), treadmill exercise at 60% of the participant's peak oxygen consumption or PEP therapy (including huffing and coughing). Mucus clearance was measured using the radioaerosol technique and gamma camera imaging.Treadmill exercise improved whole lung mucus clearance compared to resting breathing (mean difference 3%, 95% CI 2-4); however, exercise alone was less effective than PEP therapy (mean difference -7%, 95% CI -6- -8). When comparing treadmill exercise to PEP therapy, there were no significant differences in mucus clearance from the intermediate and peripheral lung regions, but significantly less clearance from the central lung region (likely reflecting the huffing and coughing that was only in PEP therapy).It is recommended that huffing and coughing are included to maximise mucus clearance with exercise.

Repurposing excipients as active inhalation agents: The mannitol story.

The story of how we came to use inhaled mannitol to diagnose asthma and to treat cystic fibrosis began when we were looking for a surrogate for exercise as a stimulus to identify asthma. We had proposed that exercise-induced asthma was caused by an increase in osmolarity of the periciliary fluid. We found hypertonic saline to be a surrogate for exercise but an ultrasonic nebuliser was required. We produced a dry powder of sodium chloride but it proved unstable. We developed a spray dried preparation of mannitol and found that bronchial responsiveness to inhaling mannitol identified people with currently active asthma. We reasoned that mannitol had potential to replace the 'osmotic' benefits of exercise and could be used as a treatment to enhance mucociliary clearance in patients with cystic fibrosis. These discoveries were the start of a journey to develop several registered products that are in clinical use globally today.

Effects of treadmill exercise versus Flutter® on respiratory flow and sputum properties in adults with cystic fibrosis: a randomised, controlled, cross-over trial.

BACKGROUND: Treadmill exercise and airway clearance with the Flutter® device have previously been shown to improve mucus clearance mechanisms in people with cystic fibrosis (CF) but have not been compared. It is therefore not known if treadmill exercise is an adequate form of airway clearance that could replace established airway clearance techniques, such as the Flutter®. The aim of this study was to evaluate respiratory flow, sputum properties and subjective responses of treadmill exercise and Flutter® therapy, compared to resting breathing (control). METHODS: Twenty-four adults with mild to severe CF lung disease (FEV1 28-86% predicted) completed a three-day randomised, controlled, cross-over study. Interventions consisted of 20 min of resting breathing (control), treadmill exercise at 60% of the participant's peak oxygen consumption and Flutter® therapy. Respiratory flow was measured during the interventions. Sputum properties (solids content and mechanical impedance) and subjective responses (ease of expectoration and sense of chest congestion) were measured before, immediately after the interventions and after 20 min of recovery. RESULTS: Treadmill exercise and Flutter® resulted in similar significant increases in peak expiratory flow, but only Flutter® created an expiratory airflow bias (i.e. peak expiratory flow was at least 10% higher than peak inspiratory flow). Treadmill exercise and Flutter® therapy resulted in similar significant reductions in sputum mechanical impedance, but only treadmill exercise caused a transient increase in sputum hydration. Treadmill exercise improved ease of expectoration and Flutter® therapy improved subjective sense of chest congestion. CONCLUSIONS: A single bout of treadmill exercise and Flutter® therapy were equally effective in augmenting mucus clearance mechanisms in adults with CF. Only longer term studies, however, will determine if exercise alone is an adequate form of airway clearance therapy that could replace other airway clearance techniques. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, Registration number # ACTRN12609000168257 , Retrospectively registered (Date submitted to registry 26/2/2009, First participant enrolled 27/2/2009, Date registered 6/4/2009).

Inspiratory flows and volumes in subjects with cystic fibrosis using a new dry powder inhaler device.

INTRODUCTION: Drug inhalation via a dry-powder inhaler (DPI) is a convenient, time efficient alternative to nebulizers in the treatment of cystic fibrosis (CF). Efficient drug administration via DPIs depends on the device resistance and adequate (≥ 45L/min) inspiratory flows and volumes generated by individuals. Dry-powder mannitol is delivered using a RS01 breath-actuated device developed by Plastiape, for Pharmaxis. The study aim was to determine in vivo if CF patients' inspiratory flows and volumes are adequate to use the RS01 DPI device. MATERIALS AND METHODOLOGY: An open, non-interventional study; enrolled 25 CF subjects, aged ≥ 6 years with FEV1 ≥ 30 to < 90‰ predicted. Inspiratory flows and volumes were measured when subjects inhaled in a controlled manner through the RS01 device in series with a spirometer. RESULTS: The mean inspiratory volume (IV) of CF subjects was 1.83L ± 0.97. Their achieved mean ± SD peak inspiratory flow (PIF) was 75.5 ± 27.2L/min. Twenty-three subjects (92%) achieved PIF of > 45L/min with the inhaler device; eighteen of those subjects (78%) had a baseline FEV1 of > 1L. CONCLUSION: Use of the RS01 DPI device allowed adequate inspiratory flow and volume for dispersion of dry-powder mannitol in CF patients.

Inspiratory Flows and Volumes in Subjects with Non-CF Bronchiectasis Using a New Dry Powder Inhaler Device.

INTRODUCTION: Drug inhalation via a dry-powder inhaler (DPI) is a convenient, time efficient alternative to nebulizers in the treatment of cystic fibrosis (CF) or non-CF bronchiectasis. Efficient drug administration via DPIs depends on the device resistance and adequate (≥45L/min) inspiratory flows and volumes generated by individuals. Drypowder mannitol is delivered using a RS01 breath-actuated device developed by Plastiape, for Pharmaxis. The study aim was to determine in vivo if non-CF bronchiectasis patients' inspiratory flows and volumes are adequate to use the RS01 DPI device. MATERIALS AND METHODOLOGY: An open, non-interventional study; enrolled 17 subjects with non-CF bronchiectasis, 18 to 80 years, with baseline FEV1 ≥1.0L and ≥50‰ predicted. Inspiratory flows and volumes were measured when subjects inhaled in a controlled manner through the RS01 device in series with a spirometer. RESULTS: The mean inspiratory volume (IV) of non-CF bronchiectasis subjects was 2.08 ± 0.5L and achieved a mean PIF of 78.6 ± 11.2L/min with the inhaler device. CONCLUSION: Use of the RS01 DPI device allowed adequate inspiratory flow and volume for dispersion of dry-powder mannitol in non-CF bronchiectasis patients.

The effects of mannitol on the transport of ciprofloxacin across respiratory epithelia.

Inhalation of antibiotics and mucolytics is the most important combination of inhaled drugs for chronic obstructive lung diseases and has become a standard part of treatment. However, it is yet to be determined whether the administration of a mucolytic has an effect on the transport rate of antibiotics across the airway epithelial cells. Consequently, the aim of this study was to investigate the effects of inhalation dry powder, specifically mannitol, on ciprofloxacin transport using a Calu-3 air-interface cell model. Transport studies of ciprofloxacin HCl were performed using different configurations including single spray-dried ciprofloxacin alone, co-spray-dried ciprofloxacin with mannitol, and deposition of mannitol prior to ciprofloxacin deposition. To understand the mechanism of transport and interactions between the drugs, pH measurements of apical surface liquid (ASL) and further transport studies were performed with ciprofloxacin base, with and without the presence of ion channel/transport inhibitors such as disodium cromoglycate and furosemide. Mannitol was found to delay absorption of ciprofloxacin HCl through the increase in ASL volume and subsequent reduction in pH. Conversely, ciprofloxacin base had a higher transport rate after mannitol deposition. This study clearly demonstrates that the deposition of mannitol prior to ciprofloxacin on the air-interface Calu-3 cell model has an effect on its transport rate. This was also dependent on the salt form of the drug and the timing and sequence of formulations administered.

Effect of inhaled dry powder mannitol on mucus and its clearance.

Insufficient hydration at the airway surface can make mucus adherent and poorly cleared. Cough, the major mechanism of mucus clearance in disease, is ineffective when mucus is adhesive. Inhaled mannitol creates an osmotic drive for water to move into the airway lumen. The consequent increased hydration of the airway surface decreases the adherence of mucus to the epithelium, facilitates the coupling of mucus and cilia thereby increasing mucus clearance. Inhaled mannitol also promotes effective coughing and stimulates mucociliary clearance. The beneficial effect of mannitol on mucus and its clearance has been demonstrated in patients with asthma, bronchiectasis and cystic fibrosis. Inhaled dry powder mannitol (Bronchitol™) is promising to be an effective treatment for the clearance of retained airway secretions.

Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic treatment of non-cystic fibrosis bronchiectasis.

BACKGROUND: Inhaled dry powder mannitol enhanced mucus clearance and improved quality of life over 2 weeks in non-cystic fibrosis bronchiectasis. This study's objective was to investigate the efficacy and safety of dry powder mannitol over 12 weeks. METHODS: Patients with bronchiectasis confirmed by high-resolution CT (HRCT) scan, aged 15 to 80 years, with FEV1≥50% predicted and ≥1 L participated in a randomized, placebo-controlled, double-blind study. Patients with a negative mannitol provocation test were randomized to inhale 320 mg mannitol (n=231) or placebo (n=112) bid for 12 weeks. To further assess safety, the same mannitol dose/frequency was administered to a patient subset in an open-label extension over 52 weeks. Primary end points were changes from baseline at 12 weeks in 24-h sputum weight and St. George's Respiratory Questionnaire (SGRQ) score. RESULTS: There was a significant difference of 4.3 g in terms of change in sputum weight over 12 weeks (95% CI, 1.64-7.00; P=.002) between mannitol and placebo; however, this was largely driven by a decrease in sputum weight in the placebo group. This was associated, in turn, with more antibiotic use in the placebo group (50 of 112 [45%]) than in the inhaled mannitol group (85 of 231 [37%]). There was no statistical difference between the groups (P=.304) in total SGRQ score (mannitol, -3.4 points [95% CI, -4.81 to -1.94] vs placebo, -2.1 points [95% CI, -4.12 to -0.09]). In a subgroup study (n=82), patients receiving mannitol showed less small airway mucus plugging on HRCT scan at 12 weeks compared with patients receiving placebo (P=.048). Compliance rates were high, and mannitol was well tolerated with adverse events similar to those of placebo. CONCLUSION: Because the difference in sputum weights appears to be associated with increased antibiotic use in the placebo group, a larger controlled study is now required to investigate the long-term mannitol effect on pulmonary exacerbations and antibiotic use. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT0027753; URL: www.clinicaltrials.gov.

Effects of exercise on respiratory flow and sputum properties in patients with cystic fibrosis.

BACKGROUND: The physiologic mechanisms by which exercise may clear secretions in subjects with cystic fibrosis (CF) are unknown. The purpose of this study was to compare ventilation, respiratory flow, and sputum properties following treadmill and cycle exercise with resting breathing (referred to as "control"). METHODS: In 14 adult subjects with CF, ventilation and respiratory flow were measured during 20 min of resting breathing, treadmill exercise, and cycle exercise in a 3-day crossover study. Treadmill and cycle exercise were performed at the work rate equivalent to 60% of the subject's peak oxygen uptake. Ease of expectoration and sputum properties (solids content and mechanical impedance) were measured before and immediately after the interventions and after 20-min recovery. RESULTS: Ease of expectoration improved following exercise. Ventilation and respiratory flow were significantly higher during treadmill and cycle exercise compared with control. Sputum solids content did not change following treadmill or cycle exercise. There was a significantly greater decrease in sputum mechanical impedance following treadmill exercise compared with control, but no significant decrease in sputum mechanical impedance following cycle exercise compared with control. CONCLUSIONS: The improvement in ease of expectoration following exercise may have been due to the higher ventilation and respiratory flow. The reductions in sputum mechanical impedance with treadmill exercise may have been due to the trunk oscillations associated with walking. TRIAL REGISTRY: Australian and New Zealand Clinical Trials Registry; No. 12605000422628; URL: www.anzctr.org.au.

Mucociliary and cough clearance as a biomarker for therapeutic development.

A workshop/symposium on "Mucociliary and Cough Clearance (MCC/CC) as a Biomarker for Therapeutic Development" was held on October 21­22, 2008, in Research Triangle Park, NC, to discuss the methods for measurement of MCC/CC and how they may be optimized for assessing new therapies designed to improve clearance of airway secretions from the lungs. The utility of MCC/CC as a biomarker for disease progression and therapeutic intervention is gaining increased recognition as a valuable tool in the clinical research community. A number of investigators currently active in using MCC/CC for diagnostic or therapeutic evaluation presented details of their methodologies. Attendees participating in the workshop discussions included those interested in the physiology of MCC/CC, some of who use in vitro or animal methods for its study, pharmaceutical companies developing muco-active therapies, and many who were interested in establishing the methods in their own clinical laboratory. This review article summarizes the presentations for the in vivo human MCC/CC methods and the discussions both at and subsequent to the workshop between the authors to move forward on a number of questions raised at the workshop.

Beneficial effect of inhaled mannitol and cough in asthmatics with mucociliary dysfunction.

Asthmatics with overproduction of mucus that is viscous and sticky have impaired mucociliary clearance (MCC) leading to mucus plugs, and airway obstruction. Inhaled mannitol improves mucus clearance in other hypersecretory diseases. This study investigated the effect of mannitol and cough in asthmatics with mucociliary dysfunction. Seven stable asthmatics, age 52 ± 20 yr, lifelong non-smokers, without the diagnosis of bronchiectasis, with chronic cough and sputum production, treated with inhaled corticosteroids participated in the study. MCC and cough clearance (CC) was measured on 4 visits: at baseline (no cough or mannitol), with mannitol (240 and 480 mg) and cough control (no mannitol) over total 90 min using a radioaerosol technique and imaging with a gamma camera. Cough clearance was assessed after MCC by asking subjects to cough 100 times over 30 min. Premedication with eformoterol (12 µg) on all visits protected all subjects from bronchoconstriction (fall in FEV(1) > 15%) in response to mannitol. Mean (±SD) clearance over 60 min increased from 5.5 ± 5.6% at baseline and 7.3 ± 6.6% with cough control to 19.5 ± 14.6% and 26.4 ± 11.5% with 240 mg (p < 0.003) and 480 mg (p < 0.0001) of mannitol respectively. Total clearance (MCC + CC) over 90 min increased from 6.9 ± 6.5% (baseline) and 12.6 ± 8.3% without mannitol (cough control) to 34.6 ± 13.5 and 36.6 ± 10.4% with 240 and 480 mg mannitol respectively (p < 0.0001). Clearance over 90 min at baseline was not significantly different to cough control (p > 0.05). Mannitol improved clearance in all lung regions (p < 0.005). In conclusion, mannitol improved both mucociliary and cough clearance in asthmatics with mucociliary dysfunction and ineffective cough clearance. Clinical Trial registered with www.anzctr.org.au; Number ACTRN 12609001066279.aspx.

Inhaled mannitol improves the hydration and surface properties of sputum in patients with cystic fibrosis.

BACKGROUND: The airway mucus in patients with cystic fibrosis (CF) is dehydrated and adhesive and accumulates in the airways, resulting in chronic inflammation, infection, and progressive loss of lung function. Inhaled mannitol improves mucus clearance and, when administered over 2 weeks, it improves lung function in CF (Jaques et al. Chest. 2008;133(6):1388-1396). The changes in the physical properties of sputum after a 2-week treatment with mannitol were investigated in the same subjects with CF. METHODS: Sputum was collected before and at the end of the 2-week treatment period from 28 subjects with CF who participated in the double-blind crossover study. Mannitol or placebo 420 mg bid was inhaled over 2 weeks. The solids content, surface tension, contact angle, and viscoelasticity were measured. RESULTS: Two-week treatment with mannitol reduced the solids from 7.3% +/- 3.0% to 5.7% +/- 3.0% (P = .012), surface tension from 83.1 +/- 7.2 to 78.6 +/- 8.0 mN/m (P < .039), and contact angle from 52.4 +/- 7.7 to 47.9 +/- 7.3 degrees. There was no significant change in the viscoelastic properties of sputum (P > .1). Placebo treatment had no significant effect on the sputum properties. The change in solids content correlated with the change in both FEV(1) (r = -0.78, P = .004) and forced expiratory flow in the middle half of the FVC (r = -0.80, P = .003), and the percentage change in surface tension and contact angle correlated with the percentage change in the FEV(1) (r = -0.73, P = .012 and r = -0.63, P = .03, respectively) in these subjects. CONCLUSION: Treatment with inhaled mannitol over 2 weeks improved the hydration and surface properties of sputum in patients with CF. This effect was sustained and correlated with airway function changes. TRIAL REGISTRATION: clinicaltrials.gov; Identifier: NCT00455130.

Effect of mannitol and repetitive coughing on the sputum properties in bronchiectasis.

UNLABELLED: Mucociliary clearance increases with increasing doses of mannitol and clearance is enhanced when mannitol inhalation is followed by repetitive voluntary coughing. The aim of the study was to investigate: 1) the effect of increasing doses of mannitol and repetitive coughing on the sputum physical properties; 2) if the changes in sputum properties can predict the efficacy of mucus clearance measured by radioaerosol technique in bronchiectasis patients. Sputum was collected from 14 patients, age: 63+/-6yr, who participated on the mucociliary and cough clearance studies at baseline, with mannitol (160, 320 and 480mg) and control (Daviskas et al. ERJ 2008; 31:765-772). Sputum was collected: 1) on the screening visit before and after mannitol challenge (635mg); 2) at the start and end of each clearance study after 100 repetitive voluntary coughs except on the control study (no mannitol or repetitive coughing). The sputum solids content, surface tension, contact angle and rheology were measured. Mannitol in association with coughing and coughing alone reduced the solids content, surface tension, contact angle and viscoelastic sputum properties (p<0.0001) and this effect, unlike mucociliary clearance, was not dose dependent. The control produced no effect. Total mucus clearance correlated only with the percentage reduction in surface tension on 480mg mannitol and with the reduction in solids content at baseline. IN CONCLUSION: Inhaled mannitol and voluntary repetitive coughing improved the sputum physical properties in bronchiectasis patients and this effect was not dose dependent. Changes in sputum properties do not predict efficacy of mucociliary and cough clearance.

Inhaled mannitol improves lung function in cystic fibrosis.

BACKGROUND: The airways in patients with cystic fibrosis (CF) are characterized by the accumulation of tenacious, dehydrated mucus that is a precursor for chronic infection, inflammation, and tissue destruction. The clearance of mucus is an integral component of daily therapy. Inhaled mannitol is an osmotic agent that increases the water content of the airway surface liquid, and improves the clearance of mucus with the potential to improve lung function and respiratory health. To this end, this study examined the efficacy and safety of therapy with inhaled mannitol over a 2-week period. METHODS: This was a randomized, double-blind, placebo-controlled, crossover study. Thirty-nine subjects with mild-to-moderate CF lung disease inhaled 420 mg of mannitol or placebo twice daily for 2 weeks. Following a 2-week washout period, subjects were entered in the reciprocal treatment arm. Lung function, respiratory symptoms, quality of life, and safety were assessed. RESULTS: Mannitol treatment increased FEV(1) from baseline by a mean of 7.0% (95% confidence interval [CI], 3.3 to 10.7) compared to placebo 0.3% (95% CI, - 3.4 to 4.0; p < 0.001). The absolute improvement with mannitol therapy was 121 mL (95% CI, 56.3 to 185.7), which was significantly more than that with placebo (0 mL; 95% CI, - 64.7 to 64.7). The forced expiratory flow in the middle half of the FVC increased by 15.5% (95% CI, - 6.5 to 24.6) compared to that with placebo (increase, 0.7%; 95% CI, - 8.3 to 9.7; p < 0.02). The safety profile of mannitol was adequate, and no serious adverse events related to treatment were observed. CONCLUSIONS: Inhaled mannitol treatment over a period of 2 weeks significantly improved lung function in patients with CF. Mannitol therapy was safe and well tolerated. TRIAL REGISTRATION: (ClinicalTrials.gov) Identifier: NCT00455130.

Effect of particle size of dry powder mannitol on the lung deposition in healthy volunteers.

There is a lack of in vivo studies focusing on the effect of particle size of dry powder aerosols on lung deposition and distribution. We investigated the dose and distribution of radiolabelled powder aerosols of mannitol in the lungs using single photon emission tomography (SPECT). Three different sized radiolabelled powders were produced by co-spray drying mannitol with 99mTc-DTPA. The primary particle size distribution of the powders measured by laser diffraction showed a volume median diameter of 2, 3 and 4 microm with span 2.3, 2.0 and 2.1, respectively, which corresponded to an aerodynamic diameter of 2.7, 3.6, 5.4 microm and geometric standard deviation of 2.6, 2.4 and 2.7 when the powders were dispersed using an Aeroliser dry powder inhaler. Three capsules each containing approximately 20mg (i.e. a total of 60 mg containing 60-90 MBq) of each of the radiolabelled powders were inhaled by eight healthy volunteers using the Aeroliser inhaler. Images of aerosol deposition in the lungs were acquired using fast, multi-bed position SPECT. The lung dose markedly decreased with increasing aerosol particle size (mean+/-S.E.M.: 44.8+/-2.4, 38.9+/-0.9, 20.6+/-1.6% for 2.7, 3.6, 5.4 microm, respectively, p<0.0001). The sites of deposition of the 2.7 and 3.6 microm aerosols were similar (penetration index, PI=0.63+/-0.05, 0.60+/-0.03, respectively, p>0.3), but different to the 5.4 microm aerosols (PI=0.52+/-0.04, p<0.02). The lung dose followed the in vitro powder dispersion performance, with the % lung dose being related to fine particle fraction by a slope of 0.8 for a regression with intercepts forced through the origin. The SPECT results provide direct evidence that the lung deposition of dry powder aerosols depends on the particle size. The lung dose of the 2.7 and 3.6 microm aerosols using the Aeroliser was double compared to that of the 5.4 microm aerosols and the deposition of the smaller particles was more peripheral.

Inhaled mannitol changes the sputum properties in asthmatics with mucus hypersecretion.

BACKGROUND AND OBJECTIVES: Most asthmatics with mucus hypersecretion have difficulty in clearing their secretions so that mucus plugs and airway obstruction are commonly present. Inhaled mannitol facilitates clearance of mucus. This study investigated the changes in the physical properties of sputum in response to mannitol in asthmatics with chronic cough and sputum production. METHOD: Sputum was collected from 12 asthmatics (26-73 year), lifelong non-smokers, at baseline, after eformoterol (24 mug) and after mannitol on each of four visits. Inhaled mannitol doses were: 635 mg (Visit 1), 240 mg (Visit 2), 360 mg (Visit 3) and 360 mg in the presence of montelukast (Visit 4). Eformoterol was inhaled before mannitol on each visit to prevent bronchoconstiction. Sputum measurements included viscosity, elasticity, surface tension, contact angle-glass and percentage solids. RESULTS: There were no significant differences between the sputum properties at baseline and after eformoterol. Mannitol (360 mg) reduced the baseline (mean +/- SEM) elasticity from 29.9 +/- 4.5 to 15.1 +/- 1.4 Pa (P < 0.0001), viscosity from 18.4 +/- 3.2 to 8.1 +/- 1.2 Pa (P < 0.0001) at 1 rad/ s, surface tension from 92.1 +/- 2.2 to 81.9 +/- 2.5 mN/m (P < 0.0001), contact angle-glass from 57.5 +/- 3.2 to 49.6 +/- 2.0 degrees (P < 0.0001), and percentage solids from 6.9 +/- 0.7 to 5.7 +/- 0.4% (P < 0.0001). All doses of mannitol reduced the sputum properties similarly and no property was further reduced by montelukast (P > 0.4). CONCLUSION: Inhaled mannitol reduced the viscoelasticity, surface tension, contact angle and the solids content of sputum in asthmatics with chronic cough and sputum production, consistent with the osmotic effect of mannitol causing water efflux in the airway lumen.

SPECT Imaging for Radioaerosol Deposition and Clearance Studies.

Planar gamma camera scintigraphy is well established for measuring the deposition and clearance of radioaerosols. Single photon emission computed tomography (SPECT) provides threedimensional (3D) reconstructions of the radioactivity distribution, thus avoiding the compression of 3D data into two-dimensional (2D) images and potentially offering superior assessment of aerosol deposition patterns. However, SPECT has traditionally been associated with long imaging times, making it unsuitable for measuring deposition and clearance of radioaerosols with fast clearance. Multi-detector SPECT systems can collect complete SPECT studies in <1 min, allowing both initial deposition and clearance over time to be assessed by dynamic SPECT. Simultaneous transmission measurement with an external source provides attenuation correction for absolute activity quantification as well as aiding in the definition of the lung volume of interest. A dynamic SPECT imaging protocol has been developed to allow fast imaging from the oropharynx to the abdomen using gamma cameras with limited axial field of views. This allows activity quantification not only in the lungs, but also in areas outside the thorax. However, fast dynamic SPECT imaging is technically and computationally more demanding and provides less scope for reducing the radioactivity administered to the subjects. It has been shown that dynamic SPECT, compared to planar imaging, is more sensitive in detecting changes in deposition as measured by the Penetration Index (PI). Thus, SPECT can better differentiate between large and small airways, which is important for lung regional analysis.

Hyperosmolar agents and clearance of mucus in the diseased airway.

Clearance of mucus is an important function of the airways to maintain hygiene. In disease, persistent inflammation leads to excessive production of mucus, with high viscoelasticity and adhesivity, which is not easily transported by cilia or cough interactions. Accumulated mucus in the airways can lead to airway obstruction, bacterial colonisation, and recurrent infections, resulting in poor quality of life and increased morbidity and mortality. Hyperosmolar agents have the potential to alter the physical properties of mucus and facilitate its clearance by increasing the water in the airway lumen and by reducing the entanglements of the mucin network. Clinical studies using radioaerosols, and imaging with a gamma camera, have demonstrated that hypertonic saline (HS; 3-14.4%) and mannitol (300-400 mg) increase clearance of mucus acutely in patients with mild asthma, bronchiectasis, and cystic fibrosis (CF). Further, in sputum studies, a reduction in the viscoelastic properties, surface tension and spinnability and an increase in the hydration of mucus have been measured in response to HS, mannitol, and other sugars. Inhalation of mannitol (400 mg) twice daily over 2 weeks improved the quality of life significantly in patients with bronchiectasis. Inhalation of 7% HS, four times daily, over 2 weeks improved significantly the baseline mucus clearance rate and lung function in CF patients. In addition, inhalation of 7% HS twice daily over 12 months showed similar results to the short-term studies without a change in the bacterial load in CF patients. Further studies of the long-term clinical effect of hyperosmolar agents are needed.

Lung deposition of mannitol powder aerosol in healthy subjects.

Mannitol as a dry powder aerosol is used for bronchoprovocation testing and to enhance mucus clearance in people with excessive airway secretions. The dose and distribution of the deposited aerosol in the lung was investigated using fast single photon emission tomography (SPECT) imaging. Mannitol powder (3 microm particle size) was produced by spray drying and radiolabeled with (99m)Tc-DTPA. Approximately 60 mg of radiolabeled mannitol (containing 52-68 MBq of (99m)Tc-DTPA) was administered to 10 healthy subjects using the Inhalator dry powder inhaler (DPI), and SPECT images (1 min each) were collected. Thirteen percent to 31% of the dose of mannitol loaded in the inhaler deposited in the lungs and the deposited dose correlated positively with the peak inhalation air flow. The regional aerosol lung distribution, as expressed by the penetration index (i.e., ratio of peripheral to central deposition in the lung) varied from 0.31 to 0.88, which however showed no dependency on any flow parameters. The variation in response to the same dose of mannitol within the asthmatic population may in part be explained by these findings.