Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine最新文献

This paper presents the results of experiments using an in vitro model and an ex vivo animal model (Rana catesbeiana) to study magnetic particle retention in the conducting airways, specifically the trachea and bronchi. The purpose of these experiments was to determine the significant factors for retention of magnetic particles deposited from an aerosol at the airway surface using a magnetic field. The results indicate that the apparent viscosity of the mucus layer at low shear rates is the most significant obstacle to particle retention. The results also show that particle size and aggregation play major roles in particle retention. The mucus transport rate, unlike the effect of fluid velocity in intravenous applications, did not appear to be a determining factor for particle retention. It was also found that a suitably designed magnetic system, aside from having a high intensity, needs to exert a strong radial field to promote particle aggregation. The findings suggest that one possible approach to magnetic particle retention could be delivery of a mucolytic agent along with the drug particles. This study provides the fundamentals needed for development of a targeted magnetic drug delivery system for inhaled therapeutic aerosol particles.

Imaging has traditionally been separated into two distinct disciplines: functional imaging and structural imaging. Functional imaging encompasses applications such as nuclear medicine (single photon emission computed tomography [SPECT] and positron emission tomography [PET]), autoradiography, magnetic resonance spectroscopy (MRS) and magneto-encephalography (MEG), while structural, or anatomical, imaging includes planar radiography, x-ray computed tomography (CT), and magnetic resonance imaging (MRI). However, today, the distinctions between these are blurring due to advances in software fusion and the development of multi-modality (SPECT/CT, PET/CT) scanners. New techniques such as MRI using hyperpolarized gases (3H and 129Xe) and xenon K-edge synchrotron x-ray subtraction imaging are also being developed to provide the researcher with a variety of ways to probe the airways, and the distribution of pharmaceuticals and subsequent uptake and bio-distribution. This paper reviews advances in imaging to present a contemporary view of the tools available.

Development of dry powder aerosol delivery system involves powder production, formulation, dispersion, delivery, and deposition of the powder aerosol in the airways. Insufficiency of conventional powder production by crystallization and milling has led to development of alternative techniques. Over the last decade, performance of powder formulations has been improved significantly through the use of engineered drug particles and excipient systems which are (i) of low aerodynamic diameters (being porous or of low particle density), and/or (ii) less cohesive and adhesive (via corrugated surfaces, low bulk density, reduced surface energy and particle interaction, hydrophobic additives, and fine carrier particles). Early insights into particle forces and surface energy that help explain the improvement have been provided by analytical techniques such as the atomic force microscopy (AFM) and inverse gas chromatography (IGC). Relative humidity is critical to the performance of dry powder inhaler (DPI) products via capillary force and electrostatic interaction. Electrostatic charge of different particle size fractions of an aerosol can now be measured using a modified electrical low-pressure impactor (ELPI). Compared with powders, much less work has been done on the inhaler devices at the fundamental level. Most recently, computational fluid dynamics has been applied to understand how the inhaler design (such as mouthpiece, grid structure, air inlet) affects powder dispersion. The USP throat is known to under-represent the oropharyngeal deposition of DPI aerosols. Studies using magnetic resonance imaging (MRI) model casts have been undertaken to explain the inter- and intra- subject variation in oropharyngeal deposition. Most of the lung deposition studies performed on commercial products did not allow a thorough understanding of the determinants affecting in vivo lung deposition. A more systematic approach would be necessary to build a useful database on the dependence of lung deposition on the breathing parameters, inhaler design, and powder formulation properties.

Recognition of the importance of breathing pattern in aerosol delivery and deposition has led to the design of devices that allow targeting of deposition to airways and alveoli. Systems incorporating patient feedback provide control of factors affecting deposition, and the control of dose to the lung can now be expected. New devices combined with a medical realization of therapeutic need are beginning to affect the range of drugs now available to the caregiver or in development for the immediate future. The interface between the patient and the device represents a new area of practical research. Facemasks have been shown to be important in terms of drug delivery with different behavior in metered dose inhaler (MDI)/valved holding chambers compared to nebulizers. Recently completed clinical trials have demonstrated the usefulness of therapy targeted to the lungs in reducing systemic toxicity with enhanced efficacy. A prime example is aerosolized cyclosporine, used to prevent rejection in lung transplantation. This agent has recently been shown to reduce mortality in transplant recipients and will lead to a new drug application in the United States. For larger patient populations, the pursuit of therapies to reduce the incidence of ventilator-associated pneumonia (VAP) can affect the outcome of illness in the intubated patient in the Intensive Care Unit (ICU). Patients with idiopathic pulmonary fibrosis (IPF) may benefit from high doses of aerosolized interferon gamma. Patient and caregiver safety are additional factors that will affect future approaches to therapy.

In a small child, normally only a small amount of inhaled aerosol particles reaches the lungs because the majority deposits in the upper airways. In this study, the upper airways of a 9- month-old child, based on computed tomography (CT) data, are modeled to serve as input for a computational fluid dynamics package (CFX). Verification of the validity of aerosol deposition calculations by this package is accomplished by evaluating two test cases, which also can be solved analytically. The numerically found sedimentation fraction in a horizontally placed straight pipe shows deviations from the exact solution for small particle sizes (less than 3 micron) due to small velocities generated by the use of an unstructured mesh. Although these velocities are small compared to the mainstream velocity, they are comparable with the terminal settling velocity of such a particle. Also the test case for inertial impaction in a bend pipe demonstrated the same problem. With this in mind, the aerosol deposition of 3.7-micron particles in the upper airway model of the child (SAINT-model) was calculated. Results were compared with experimentally found results in the literature. For small tidal volumes and flow rates, the computational results matched the experimentally measured results. However, large deviations were found for higher flow rates and small particle sizes. Most probably the incompletely modeled entrance at the nose and inertial effects due to turbulence might be responsible.

Drug deposition is an important factor that contributes to safety and efficacy outcomes of inhaled steroid therapy. Ciclesonide is a nonhalogenated, inhaled corticosteroid under investigation for the treatment of asthma. Therefore, this study was performed to assess lung deposition of ciclesonide. Technetium-99m (99mTc)-labeled ciclesonide (where the 99mTc-label is physically dissolved in the ciclesonide-hydrofluoroalkane [HFA] solution aerosol) inhaled by healthy volunteers was analyzed by two-dimensional (2-D) and three-dimensional (3-D) imaging to determine lung deposition. Six healthy volunteers inhaled one puff of 40 microg (exactuator, equivalent to 50 microg ex-valve) ciclesonide for 2-D imaging, and two healthy volunteers inhaled 10 puffs of 40 microg ciclesonide for 2-D and 3-D imaging. The ciclesonide aerosol was administered via metered-dose inhaler (MDI) containing HFA-134a as propellant. The ex-actuator mean (+/- standard deviation) deposition of ciclesonide in the lungs was higher (52% +/- 11%) than in the mouth/pharynx (38% +/- 14%). Two-dimensional and 3-D imaging showed that ciclesonide reached all regions of the lung. Mean percent deposition in peripheral regions (47% and 34%) was higher than in lower central regions (17% and 30%), as revealed by 3-D and 2-D imaging, respectively. Inhalation of up to 400 microg of ciclesonide produced no drug-related side effects. In conclusion, ciclesonide administered via metered-dose inhaler using HFA-134a as a propellant provided high lung deposition (>50%), greater distribution throughout peripheral regions of the lungs, and relatively low oropharyngeal deposition.

The aim of the study was to elaborate recommendations for inhalation during mechanical ventilation that could optimize delivery. Delivery of aerosols in vitro from nebulizers during mechanical ventilation is dependent on the dimensions of the ventilator circuit, the nebulizer type, and the ventilator settings. A review of the literature shows that some ventilator settings have a larger influence on the amount of aerosol delivered than others. It has been shown in an in vitro model that the factors influencing delivered aerosol are the ventilator flow rate, the diameter of the endotracheal tube, and the time spent in inspiration (all p < 0.05). Two different nebulizer types were used in the study: an ultrasonic nebulizer (SUN 345) and a high-frequency vibrating mesh nebulizer (Aeroneb Pro). No difference in the amount delivered was seen with different nebulizer types (p = 0.215). For optimizing the amount delivered, the largest possible flow, endotracheal tube, and time spent in inspiration should be used.

Asthma, a chronic inflammatory condition of airways, responds to therapy with anti-inflammatory medications, for example, inhaled (ICS) and/or systemic (SS) corticosteroids. It is associated with impaired clearance of airway secretions. We studied effects of ICS and SS on mucociliary clearance (MC) in outpatient asthma through an in vivo, randomized, placebo-controlled single blind study with patients acting as their own control. Using a gamma camera and radiolabeled aerosol, we measured MC at baseline, after 4 days of nebulized treatment and after 5 days of oral prednisone. MC was expressed as percent of retained activity over time. Spirometry was performed before each MC study. Treatment with nebulized budesonide did not affect MC or forced expiratory volume at 1 sec (FEV1). Treatment with SS was associated with a significant improvement in MC at 24 h (baseline, 41 +/- 6; post-SS, 36 +/- 5; p = 0.04). Post hoc analysis revealed that MC changed only in those patients with significant changes in deposition (specific Central-to-Peripheral ratio C/P--baseline, 1.57 +/- 0.16; post-SS, 1.73 +/- 0.21; n = 6; p = 0.05), suggesting that the changes in MC were not directly related to therapy. In outpatient asthma, MC is unaffected by 4-5 days of anti-inflammatory therapy in spite of significant changes in FEV1.

Genetic therapeutics show great promise toward the treatment of illnesses associated with the lungs; however, current methods of delivery such as jet and ultrasonic nebulization decrease the activity and effectiveness of these treatments. Extremely low transfection rates exhibited by non-complexed plasmid DNA in these nebulizers have been primarily attributed to poor translocation and loss of molecular integrity as a consequence of shear-induced degradation. Current research focusing on methods to increase transfection rates via the pulmonary delivery route has largely concentrated on the incorporation of carbon dioxide in the air stream to increase breath depth as well as the addition of cationic agents that condense DNA into compact, ordered complexes. The purpose of this study was to examine the impact of several classic as well as the latest atomization devices on the structure of non-complexed DNA. Various sizes of plasmid and cosmid DNA were processed through an electrostatic spray, ultrasonic nebulizer, vibrating mesh nebulizer, and jet nebulizer. Results varied dramatically based upon atomization device as well as DNA size. This may explain the inefficiency experienced by genetic therapeutics during pulmonary delivery. More importantly, this suggests that the selection of an atomization device should consider DNA size in order to achieve optimal gene delivery to the lungs.