Regional targeting of inhaled beta2-agonist to the proximal airways is more important than distal alveolar deposition for bronchodilation. Altering intrapulmonary deposition through aerosol particle size can appreciably enhance inhaled drug therapy and may have implications for developing future inhaled treatments.
Rationale Small airways function studies in lung disease have used three promising multiple breath washout (MBW) derived indices: indices of ventilation heterogeneity in the acinar (S acin ) and conductive (S cond ) lung zones, and the lung clearance index (LCI). Since peripheral lung structure is known to change with age, ventilation heterogeneity is expected to be affected too. However, the age dependence of the MBW indices of ventilation heterogeneity in the normal lung is unknown. Objectives The authors systematically investigated S acin , S cond or LCI as a function of age, testing also the robustness of these relationships across two laboratories. Methods MBW tests were performed by never-smokers (50% men) in the age range 25e65 years, with data gathered across two laboratories (n¼120 and n¼60). For comparison with the literature, the phase III slopes from classical single breath washout tests were also acquired in one group (n¼120). Measurements and main results All three MBW indices consistently increased with age, representing a steady worsening of ventilation heterogeneity in the age range 25e65. Age explained 7e16% of the variability in S acin and S cond and 36% of the variability in LCI. There was a small but significant gender difference only for S acin . Classical single breath washout phase III slopes also showed age dependencies, with gender effects depending on the normalisation method used. Conclusions With respect to the clinical response, age is a small but consistent effect that needs to be factored in when using the MBW indices for the detection of small airways abnormality in disease.
Deposition was assessed by a dual headed gamma camera after inhalation of the drug. Results-The total mean (SD) percentage deposition of the drug in the normal subjects was 21-6% (8.9%) with the MDI alone, 20-9% (7-8%) with the AMDI with spacer, and 12-4% (3-5%) with the DPI. For the patients, the mean percentage deposition was 18-2% (7.8%) with the MDI alone, 19-0% (8-9%) with the MADI and spacer, and 11-4% (5-0%) with the DPI. Bronchodilatation achieved by the patients was similar with all three techniques. Mean peripheral lung deposition was significantly greater with a spacer device than when the MDI was used alone in both normal subjects (49.4% (6-1%) v 44-1% (9.9%)) and patients (38-6% (11.1%) v 30-4% (9.4%)).
Two-dimensional (2D or planar) imaging with (99m)Tc radiolabels enables quantification of whole-lung and regional lung depositions for orally inhaled drug products. This article recommends standardized methodology for 2D imaging studies. Simultaneous anterior and posterior imaging with a dual-headed gamma camera is preferred, but imaging with a single-headed gamma camera is also acceptable. Correction of raw data for the effects of gamma ray attenuation is considered essential for accurate quantification, for instance, using transmission scanning with a flood-field source of (99m)Tc or (57)Co. Evidence should be provided of the accuracy of the quantification method, for instance, by determining "mass balance." Lung deposition may be expressed as a percentage of ex-valve or ex-device dose, but should also be given as mass of drug when possible. Assessment of regional lung deposition requires delineation of the lung borders, using X-ray computed tomography, radioactive gas scans ((133)Xe or (81m)Kr), or transmission scans. When quantifying regional lung deposition, the lung should be divided into outer (O) and inner (I) zones. A penetration index should be calculated, as the O/I ratio for aerosol, normalized to that for a radioactive gas or transmission scan. A variety of methods can be used to assess lung deposition and distribution. Methodology and results should be documented in detail, so that data from different centers may be compared. The use of appropriate methodology will provide greater confidence in the results of 2D imaging studies, and should allay concerns that such studies are qualitative or semiquantitative in nature.
The lung dose and deposition patterns of drug delivered by dry powder inhaler are not known. The effects of inhaling 400 pg salbutamol delivered by dry powder inhaler (two 200 ug salbutamol Rotacaps), by pressurised metered dose inhaler, and by Acorn nebuliser were studied in nine subjects with chronic stable asthma. Technetium-99m labelled Teflon particles were mixed with micronised salbutamol in the pressurised metered dose inhaler and in the capsules; technetium-99m labelled human serum albumin was mixed with the salbutamol solution for the nebuliser study. The pressurised metered dose inhaler deposited 11-2% (SEM 0-8%) of the dose within the lungs; this was significantly more than the dose deposited by the dry powder inhaler (9-1% (0 6%)), but did not differ significantly from the dose delivered by the nebuliser (9-9% (0-7%)). Distribution within the peripheral third of the lung was significantly greater with the nebuliser than with the other two systems; FEV, improved to a significantly greater extent after inhalation of 400 pg salbutamol from the pressurised metered dose inhaler (35-6% from baseline) than from the nebuliser (25 8%) or dry powder inhaler (25 2%). Thus after inhalation of similar doses of salbutamol a larger proportion of drug was deposited within the lungs when it was inhaled from a metered dose inhaler than from a dry powder system; the nebuliser achieved the greatest peripheral deposition. The bronchodilator response seems to depend on the amount of drug within the lungs rather than its pattern of distribution.Poor inhaler technique is a common problem among asthmatic patients using pressurised aerosol inhalers."q Most of them can use a dry powder bronchodilator aerosol more effectively.4 For children a dry powder inhaler may also be more effective than a pressurised delivery *system.5 Although dry powder inhalers have been used for the management of asthma for more than a decade, very little is known about the pattern of drug delivery within the body or the amount that is deposited in the lungs.In an assessment in vitro salbutamol delivery from a dry powder inhaler (Rotacap) appeared to be half as efficient as delivery from the pressurised metered dose inhaler6; as a result the dose recommended for patients is twice that of the dose used with the pressurised inhaler. Clinical studies, however, have provided less clearcut conclusions, some showing equipotency for the two forms of delivery67 and others suggesting a better response with the pressurised inhaler system.89 Because of these controversies and the lack of data on deposition patterns of dry powder medication within the respiratory tract, we have compared the deposition pattern of salbutamol administered by dry powder inhaler, from a pressurised metered dose inhaler, and an Acorn nebuliser. Methods SUBJECTSWe studied nine subjects with chronic stable asthma (three men, six women) aged 20-68 years. They had a history of well documented asthma of 10-60 years' duration and showed an improvement in FEV, of more than 15% from ba...
Different approaches used to determine pulmonary regions of interest and quantify aerosol deposition produce different results. Our research highlights a genuine need for a consensus to standardize the methodology to facilitate data comparison between laboratories on aerosol deposition.
Aerosol particle size influences airway drug deposition. Current inhaler devices are inefficient, delivering a heterodisperse distribution of drug particle sizes where, at best, 20% reaches the lungs. Monodisperse aerosols are the appropriate research tools to investigate basic aerosol science concepts within the human airways. We hypothesized that engineering such aerosols of albuterol would identify the ideal bronchodilator particle size, thereby optimizing inhaled therapeutic drug delivery. Eighteen stable mildly to moderately asthmatic patients [mean forced expiratory volume in 1 s (FEV1) 74.3% of predicted] participated in a randomized, double-blind, crossover study design. A spinning-top aerosol generator was used to produce monodisperse albuterol aerosols that were 1.5, 3, and 6 microm in size, and also a placebo, which were inhaled at cumulative doses of 10, 20, 40, and 100 microg. Lung function changes and tolerability effects were determined. The larger particles, 6 and 3 microm, were significantly more potent bronchodilators than the 1.5-microm and placebo aerosols for FEV1 and for the forced expiratory flow between exhalation of 25 and 75% of forced vital capacity. A 20-microg dose of the 6- and 3-microm aerosols produced FEV1 bronchodilation comparable to that produced by 200 microg from a metered-dose inhaler. No adverse effects were observed in heart rate and plasma potassium. The data suggest that in mildly to moderately asthmatic patients there is more than one optimal beta2-agonist bronchodilator particle size and that these are larger particles in the higher part of the respirable range. Aerosols delivered in monodisperse form can enable large reductions of the inhaled dose without loss of clinical efficacy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.