Beth L. Laube

What the pulmonary specialist should know about the new inhalation therapies

A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols was facilitated by the European Respiratory Society (ERS) and the International Society for Aerosols in Medicine (ISAM), in order to draw up a consensus statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patient. The focus of the consensus statement is the patient-use aspect of the aerosol delivery devices that are currently available. The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel. Specific recommendations for use of the devices can be found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician: is aware of the devices that are currently available to deliver the prescribed drugs; knows the various techniques that are appropriate for each device; is able to evaluate the patients inhalation technique to be sure they are using the devices properly; and ensures that the inhalation method is appropriate for each patient.

Mouthpiece diameter affects deposition efficiency in cast models of the human oral airways.

We examined the effect of altering mouthpiece diameter to 1.5, 2.0, and 2.7 cm on the deposition efficiency of inertial size particles (2, 4, and 8 microm) in adult human oral-pharyngeal-laryngeal (OPL) airway cast models at various inspiratory flow rates (30, 60, 90, and 120 L/min). Deposition efficiency of 2-microm particles was unaffected by changes in mouthpiece diameter at all flow rates. Deposition of 4-microm particles decreased significantly with the 2.0- and 2.7-cm mouthpieces compared to the 1.5 cm mouthpiece at 60, 90, and 120 L/min (p < 0.01). Deposition of 4-microm particles was significantly reduced with the 2.7-cm mouthpiece compared to the 2.0-cm mouthpiece at 90 and 120 L/min (p < 0.05). Deposition efficiency of 8 microm particles decreased significantly with the 2.0- and 2.7-cm mouthpieces compared to the 1.5-cm mouthpiece at 60 L/min (p < 0.05), and with the 2.7-cm mouthpiece compared to the 1.5-cm mouthpiece at 120 L/min (p < 0.05). These results suggest that the effect of mouthpiece diameter varies with particle size, with 2- and 8-microm particles least affected. However, our findings may have important implications for improving the future design of mouthpieces of devices that deliver particles with 4-microm diameters and require inspiratory flow rates of > or = 60 L/min (i.e., DPIs) for adequate drug delivery.

The effect of aerosol distribution on airway responsiveness to inhaled methacholine in patients with asthma

It has been demonstrated that airway deposition of inhaled aerosols is more heterogeneous in patients with asthma than in normal subjects. Nevertheless, the influence of abnormal airway deposition on responses to bronchoactive aerosols is poorly understood. We altered bronchopulmonary deposition heterogeneity of methacholine aerosol in nine asymptomatic patients with asthma by controlling inspiratory flow at high (approximately 60 L/min) versus low (approximately 12 L/min) rates on 2 study days and determined the effect on the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) (often used as a measure of airway responsiveness). Deposition uniformity was quantified from gamma-camera scans of the lungs in terms of the distribution of a technetium-labeled aerosol that was inhaled rapidly or slowly before the inhalation of methacholine. Increased deposition in an inner (large, central airways) versus an outer (peripheral airways and alveoli) zone of the right lung (inner/outer ratio, greater than 1) and higher values of skew (an index of deposition asymmetry) and kurtosis (an index of deposition range) indicated enhanced heterogeneity of deposition. Mean (+/- SD) inner/outer ratio was significantly higher during rapid inspiration compared to slow inspiration with 2.91 +/- 0.51 and 1.84 +/- 0.30, respectively (p less than 0.01). Mean skew and kurtosis were also significantly higher after rapid inspiration, with 1.12 +/- 0.35 and 3.86 +/- 1.25, respectively, compared to 0.74 +/- 0.36 and 2.64 +/- 0.77 after slow inhalation (p less than 0.01). Geometric mean PD20 methacholine was significantly reduced when the aerosol was inhaled rapidly, with 5.9 cumulative methacholine units compared to 15.7 units after slow inhalation (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma

BACKGROUND Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. OBJECTIVE We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. METHODS Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at approximately 30 L/min or approximately 70 L/min. Percent decreases in FEV1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. RESULTS Mean (+/- SD) allergen-induced decrease in FEV1 was 5.4% +/- 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV1 after faster inhalation of CS with 12.6% +/- 11% (p < 0.05). Mean skew values were also significantly decreased after slow inspiration of CS, and differences in decreases in allergen FEV1 and skew values for the two breathing maneuvers were significantly correlated. CONCLUSION These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.Abstract Background: Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. Objective: We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. Methods: Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at ~30 L/min or ~70 L/min. Percent decreases in FEV 1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. Results: Mean (± SD) allergen-induced decrease in FEV 1 was 5.4% ± 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV 1 after faster inhalation of CS with 12.6% ± 11% ( p 1 and skew values for the two breathing maneuvers were significantly correlated. Conclusion: These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.

Respiratory pathophysiologic responses: The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma

BACKGROUND Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. OBJECTIVE We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. METHODS Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at approximately 30 L/min or approximately 70 L/min. Percent decreases in FEV1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. RESULTS Mean (+/- SD) allergen-induced decrease in FEV1 was 5.4% +/- 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV1 after faster inhalation of CS with 12.6% +/- 11% (p < 0.05). Mean skew values were also significantly decreased after slow inspiration of CS, and differences in decreases in allergen FEV1 and skew values for the two breathing maneuvers were significantly correlated. CONCLUSION These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.Abstract Background: Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. Objective: We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. Methods: Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at ~30 L/min or ~70 L/min. Percent decreases in FEV 1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. Results: Mean (± SD) allergen-induced decrease in FEV 1 was 5.4% ± 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV 1 after faster inhalation of CS with 12.6% ± 11% ( p 1 and skew values for the two breathing maneuvers were significantly correlated. Conclusion: These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.

Multisite Comparison of Mucociliary and Cough Clearance Measures Using Standardized Methods

BACKGROUND A standardized protocol for measuring mucociliary (MCC) and cough clearance (CC) was developed and tested at the University of North Carolina at Chapel Hill, NC (UNC), Johns Hopkins University (JHU), and the University of Pittsburgh (Pitt). METHODS A total of 50 healthy nonsmoking adults with normal lung function were studied at the three sites: 30 [21 males/9 females (21M/9F)] at UNC, 10 (6M/4F) at JHU, and 10 (4M/6F) at Pitt. Subjects inhaled an aerosol of (99m)technetium sulfur colloid in 0.9% saline (mass median aerodynamic diameter=5.4 μm) under controlled breathing conditions (500 mL/sec, 30 breaths/min) by following a metronome and flow signal from a commercial dosimeter. Following inhalation, subjects sat in front of a gamma camera as sequential lung images were acquired for 60 min. Subjects then coughed 60 times, and images were acquired after each set of 20 coughs, i.e., at 70, 80, and 90 min. Subjects returned to the laboratory approximately 24 hr later for a final image of residual lung activity. Initial aerosol distribution was measured as a central/peripheral (C/P) ratio of activity. MCC/CC was expressed as the area under the retention versus time curve over 90 min (AUC90). RESULTS A multivariate analysis of clearance versus time with site and C/P as covariates showed no significant site-specific differences. Interestingly, MCC/CC was greater in females (n=19) versus males (n=31), with AUC90=0.84 ± 0.11 and 0.90±0.07, respectively (p=0.03), for the combined data set from all sites (not significant for any given site). There were no gender differences for either C/P ratio or 24-hr clearance. CONCLUSIONS This standardized protocol may prove beneficial in multicenter trials for testing new therapies that are designed to improve MCC/CC.

ERS technical standard on bronchial challenge testing: General considerations and performance of methacholine challenge tests

This international task force report updates general considerations for bronchial challenge testing and the performance of the methacholine challenge test. There are notable changes from prior recommendations in order to accommodate newer delivery devices. Rather than basing the test result upon a methacholine concentration (provocative concentration (PC20) causing a 20% fall in forced expiratory volume in 1 s (FEV1)), the new recommendations base the result upon the delivered dose of methacholine causing a 20% fall in FEV1 (provocative dose (PD20)). This end-point allows comparable results from different devices or protocols, thus any suitable nebuliser or dosimeter may be used, so long as the delivery characteristics are known. Inhalation may be by tidal breathing using a breath-actuated or continuous nebuliser for 1 min (or more), or by a dosimeter with a suitable breath count. Tests requiring maximal inhalations to total lung capacity are not recommended because the bronchoprotective effect of a deep breath reduces the sensitivity of the test. The new ERS recommendation for methacholine challenge tests will be the provocative dose rather than concentration http://ow.ly/FBe5309yXn2

Early pulmonary response to allergen is attenuated during acute emotional stress in females with asthma

Some asthma patients and physicians who treat asthma have reported that stress worsens their disease. It has also recently been shown that chronic stressful life events increase airway inflammation 6–24 h after inhalation of antigen in patients with allergic asthma. However, there is no data regarding the effect of an acute stressor on the airway constriction that occurs within minutes of antigen inhalation (early pulmonary response) in this same population. The aim of this study was to examine this effect in eight females with allergic asthma. Each subject was challenged with increasing concentrations of inhaled allergen on a control visit (no stress) and on a stress visit, when they were asked to verbally recount an emotionally stressful situation between each concentration. Systolic (SP) and diastolic (DP) blood pressure, cardiac frequency (fc) and forced expiratory volume in one second (FEV1) were measured on both visits. SP, DP and fc were statistically increased on the stress visit as compared to control. Per cent decrease in FEV1 at the same last dose of allergen was significantly less on the stress visit (11.2±7.0%) compared to control (15.0±8.7%). These findings suggest that the early pulmonary response to inhaled allergen is attenuated while verbally reexperiencing an acute emotional stressor in females with allergic asthma.

The expanding role of aerosols in systemic drug delivery, gene therapy and vaccination: an update

Until the late 1990s, aerosol therapy consisted of beta2-adrenergic agonists, anti-cholinergics, steroidal and non-steroidal agents, mucolytics and antibiotics that were used to treat patients with asthma, COPD and cystic fibrosis. Since then, inhalation therapy has matured to include drugs that: (1) are designed to treat diseases outside the lung and whose target is the systemic circulation (systemic drug delivery); (2) deliver nucleic acids that lead to permanent expression of a gene construct, or protein coding sequence, in a population of cells (gene therapy); and (3) provide needle-free immunization against disease (aerosolized vaccination). During the evolution of these advanced applications, it was also necessary to develop new devices that provided increased dosing efficiency and less loss during delivery. This review will present an update on the success of each of these new applications and their devices. The early promise of aerosolized systemic drug delivery and its outlook for future success will be highlighted. In addition, the challenges to aerosolized gene therapy and the need for appropriate gene vectors will be discussed. Finally, progress in the development of aerosolized vaccination will be presented. The continued expansion of the role of aerosol therapy in the future will depend on: (1) improving the bioavailability of systemically delivered drugs; (2) developing gene therapy vectors that can efficiently penetrate the mucus barrier and cell membrane, navigate the cell cytoplasm and efficiently transfer DNA material to the cell nucleus; (3) improving delivery of gene vectors and vaccines to infants; and (4) developing formulations that are safe for acute and chronic administrations.

Standardization of techniques for using single-photon emission computed tomography (SPECT) for aerosol deposition assessment of orally inhaled products.

Single-photon emission computed tomography (SPECT) can be used to measure the three-dimensional (3D) distribution of inhaled aerosol deposition in the lungs. This is of value in evaluating and optimizing drug delivery by inhalation. 3D imaging has the advantage over planar scintigraphy of giving better data on the distribution of deposition within the lung. There are a variety of different methods of acquisition and analysis of the data, which makes interpretation of results difficult to compare between centers. This article describes a standardized protocol that aims to overcome this problem. Although not being completely prescriptive, it presents the key recommendations that are necessary to ensure consistency. In addition to radiolabel validation, these are (i) having some form of accountability of the activity measurements as quality control, (ii) producing quantitative images by performing attenuation and preferably scatter correction, (iii) defining volumes of interest and calculating parameters in the manner described, and (iv) describing in any report the details of technique used. When carefully used, SPECT imaging is able to produce high-quality quantitative data of the 3D distribution of drug deposition within the lungs. By establishing a standardized protocol, results of 3D imaging of the deposition of orally inhaled aerosols using SPECT should be more comparable, which should enhance collaborations between centers and insure that this form of imaging becomes acceptable to the regulatory authorities.