Gerald C. Smaldone

Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans

The majority of patients who develop bronchiolitis obliterans, after lung transplantation, die within 2–3u2005yrs after onset since treatment with conventional immunosuppression is typically ineffective. A case/control study was conducted in lung transplant recipients with biopsy-documented bronchiolitis obliterans to determine whether aerosol cyclosporin use contributed to increased survival. The cases comprised 39 transplant recipients who received open-label aerosol cyclosporin treatment in addition to conventional immunosuppression. The controls were transplant recipients treated with conventional immunosuppression alone. There were 51 controls from the University of Pittsburgh Medical Center and 100 from a large multicentric database (Novartis Lung Transplant Database). Forced expiratory volume in one second expressed as a percentage of the predicted value was an independent predictor of survival in all patients with bronchiolitis obliterans. Cox proportional-hazards analysis revealed a survival advantage for aerosol cyclosporin cases compared to the Pittsburgh control group. A survival advantage was also seen when comparing study cases to multicentric controls. Aerosol cyclosporin, given with conventional immunosuppression to lung transplant recipients with bronchiolitis obliterans, provides a survival advantage over conventional therapy alone.

Consensus statement: aerosols and delivery devices.

MYRNA B. DOLOVICH, P.Eng., NEIL R. MacINTYRE, F.A.A.R.C, PAULA J. ANDERSON, M.D., CARLOS A. CAMARGO, JR., M.D., Dr.P.H, NANCY CHEW, M.S., R.A.C., CYNTHIA H. COLE, M.D., M.P.H., RAJIV DHAND, M.D., JAMES B. FINK, M.S., R.R.T., F.A.A.R.C., NICHOLAS J. GROSS, M.D., Ph.D., DEAN R. HESS, Ph.D., R.R.T., F.A.A.R.C, ANTHONY J. HICKEY, Ph.D., CHONG S. KIM, Ph.D., TED B. MARTONEN, Ph.D., DAVID J. PIERSON, M.D., F.A.A.R.C, BRUCE K. RUBIN, M.D., and GERALD C. SMALDONE, M.D., Ph.D.

Aerosolized Protein Delivery in Asthma: Gamma Camera Analysis of Regional Deposition and Perfusion

Bioavailability of an aerosolized anti-inflammatory protein, soluble interleukin-4 receptor (IL-4R), was measured in patients with asthma using two different aerosol delivery systems, a prototype aerosol delivery system (AERx tethered model, Aradigm, Hayward, CA) and PARI LC STAR nebulizer (Pari, Richmond, VA). Regional distribution of the drug in the respiratory tract obtained by planar imaging using gamma camera scintigraphy was utilized to explain the differences in bioavailability. The drug, an experimental protein being developed for asthma, was mixed with radiolabel 99mTechnetium diethylene triaminepentaacetic acid (99mTc-DTPA). Aerosols were characterized in vitro using cascade impaction (mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD]); the AERx MMAD 2.0 microm (GSD 1.35), the PARI 3.5 microm (GSD 2.5). Four patients with asthma requiring maintenance aerosolized steroids were studied. First, regional volume was determined utilizing equilibrium 133Xe scanning. Then, after a brief period of instruction, patients inhaled four breaths of protein using AERx (0.45 mg in total) followed 1 week later by inhalation via PARI (3.0 mg nebulized until dry). Each deposition image was followed by a measurement of regional perfusion using injected 99mTc albumin macroaggregates. Deposition of 99mTc-DTPA in the subjects was determined by mass balance. Regional analysis was performed using computerized regions of interest. The regional distribution of deposited drug was normalized for regional volume and perfusion. Following each single inhalation, serial blood samples were drawn over a 7-day period to determine area under the curve (AUC) of protein concentration in the blood. Median AUC(AERx)/AUC(PARI) was 7.66/1, based on the amount of drug placed in each device, indicating that AERx was 7.66 times more efficient than PARI. When normalized for total lung deposition (AUC per mg deposited) the ratio decreased to 2.44, indicating that efficiencies of the drug delivery system and deposition were major factors. When normalized for sC/P and (pU/L)xe ratios (central to peripheral and upper to lower ratios are parameters of regional distribution of deposited particles and regional per- fusion [p]), AUC(AER)x/AUC(PARI) further decreased to 1.35, demonstrating that peripheral sites of deposition with the AERx affected the final blood concentration of the drug. We conclude that inhaled bioavailability of aerosolized protein, as expressed by AUC, is a quantifiable function of lung dose and regional deposition as defined by planar scintigraphy.

Lung Deposition and Pharmacokinetics of Cyclosporine After Aerosolization in Lung Transplant Patients

AbstractPurpose. Aerosolized cyclosporine (aCsA) has proven to be an effective therapy for refractory acute and chronic rejection in lung transplant (LTx) patients. The objective of this study is to evaluate the lung deposition and systemic absorption of aCsA after aerosolized cyclosporine administration in LTx patients in the immediate postoperative period.nMethods. Cyclosporine (CsA) was administered intravenously (1.0 mg/kg) to eight LTx patients, and multiple blood samples were collected over 24 h. At least 24 h later, aCsA (300 mg in propylene glycol) was administered to the same patients using nebulization and multiple blood samples were obtained again. Five patients had an additional inhalational gamma scintigraphy study with aCsA and 99MTc-labeled albumin to measure drug deposition.nResults. Peak blood concentrations of CsA after aerosol administration ranged from 119-402 ng/ml, and concentrations at 24 h ranged from 9-48 ng/ml. The rate of decline in drug concentration in blood in the apparent elimination phase was notably slower after administration of aCsA than after IV infusion. Terminal disposition half life (t1/2 λz) values ranged from 4.1-9.9 h (mean 6.5 h) following IV administration and from 23.1 to 65.2 h (mean 40.7 h) following pulmonary administration, suggesting that drug absorption occurred throughout the 24-h sampling period following pulmonary administration. Deconvolution analysis indicated biphasic absorption of CsA from the lung in all patients, characterized by rapid initial absorption (absorption half-life 0.73 ± 0.38 h) over the first 4 to 6 h followed by slower, sustained absorption throughout the remainder of the sampling period (absorption half-life 16.2 ± 13.2 h). The absolute bioavailability of CsA after aerosol administration ranged from 5.4-11.2% (mean 8.2%) of the dose placed in the nebulizer. The total dose delivered to the lung estimated from scintigraphy ranged from 17.8-39.3 mg, and was in approximate agreement with the amount of drug absorbed, estimated using deconvolution. Essentially all drug deposited in the lungs was systemically absorbed.nConclusions. This study documents that cyclosporine can be effectively delivered by aerosolization to the lung of transplant patients in the early postoperative period. Part of the cyclosporine deposited in the lung is absorbed rapidly into systemic circulation and a portion is absorbed slowly but completely over a prolonged period.

Preservation of post-transplant lung function with aerosol cyclosporin

Post-lung transplant use of aerosol cyclosporin (ACsA) is considered by examining the relationship between deposited aerosol dose and effect. In a sub-study of placebo controlled trials of ACsA as a rejection prophylaxis, 15 drug subjects received aerosol dose quantification tests to gage their ability to effectively deposit the nebulised drug in their transplanted lung(s). A total of seven placebo subjects received mock deposition tests. The deposited doses and mock doses were compared to changes in the forced expiratory volume in one second, at six time points during the 2‐yr trial period (ACsA was started within 6 weeks post-transplant). Linear relationships were demonstrated between deposited dose and improvement in lung function in the drug subjects at all intervals. Mock dose data from placebo subjects did not demonstrate similar correlation. Based on these results, subjects were grouped by dose and compared. Subjects depositing ≥5u2005mg of the drug in the periphery of their transplant(s) had improving pulmonary function on average. Low-dose and placebo subjects demonstrated declines, more A2–A4 rejection events in the latter portion of the trial, and more chronic rejection beyond the end of the trial. A dose-to-effect relationship is demonstrated for aerosol cyclosporin in terms of pulmonary function and biopsy proven rejection.

Viewpoint: Unresolved mysteries

in an editorial in the March 2012 issue of the Journal of Applied Physiology , Nieman ([11][1]) highlighted a topic that has simmered below the surface for decades, i.e., how does the lung acinus expand with lung inflation. Indeed, the topic may be the last frontier of gross anatomy, but it is one

Evaluation of quantitative aerosol techniques for use in bronchoprovocation studies

To investigate airway physiology by use of inhaled aerosols, it is frequently necessary to measure the actual amount of material deposited on the airway wall as well as the site of particle deposition. To satisfy these needs, radiolabeled aerosols and gamma camera techniques have been used to measure regional deposition of inhaled particles. To make quantitative measurements of the amount deposited, previous investigators have used a phantom technique to indirectly calibrate the gamma camera for the attenuation of gamma rays through the lungs and chest wall. For this calibration, the phantom is a simulated lung containing a known amount of radioactivity. Radioactive counts emitted from the phantom are assumed to be attenuated in the same manner as the intact human lung. The present article describes a technique to determine directly the amount of inhaled aerosol deposited in the lung and simultaneously to calibrate the gamma camera for each individual subject. We used right angle light scattering and a gamma camera to measure individual values of the deposition fraction (DF) of inhaled aerosol deposited in the lung and the coefficient of attenuation (AC) of gamma rays in normal and obstructed lungs of human subjects. Radiolabeled monodisperse aerosols 1 and 2 microns in diameter were used. Knowledge of the activity of the inhaled aerosol (microcurie per liter), the volume inhaled, and the measured DF determined each subjects AC (counts per minute per microcurie). DF varied by an order of magnitude in normal (0.04 to 0.48) and obstructed (0.16 to 0.75) of subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Deposition and clearance: unique problems in the proximal airways and oral cavity in the young and elderly.

Prospective longitudinal studies measuring aerosol behavior in the respiratory tract as humans age have not been performed. The present paper reviews observations related to aging of the respiratory tract and other effects more likely due primarily to disease and iatrogenic causes. Upper airway deposition was found to approximate 50% in children during inhalation of drugs thought to be designed primarily for deposition in the lower respiratory tract. In older subjects, aging per se did not have a major impact on the deposition of aerosols. Disease processes that develop with age were shown to be the primary cause of deposition abnormalities. Flow-limitation in central airways was proposed as a major factor responsible for central airway deposition as well as abnormal clearance in common obstructive lung diseases. The oral cavity, a source of pathogenic organisms causing pneumonia, was also studied in the elderly. Salivary clearance, often abnormal in the aged, was related to colonization with pathogenic bacteria. Salivary clearance was not obviously reduced by aging per se but by iatrogenic sources such as drug therapy for other diseases.

Inspiratory vs expiratory aerosol deposition in excised dog lungs

The difference between inspiratory and expiratory aerosol deposition efficiency (D) in the lung was analyzed. In excised dog lungs, from minimal lung volume, measurements of D for single breaths of a 0.9 μm monodisperse aerosol were made by Tyndallometry for a tidal volume of 0.5 TLC, and breathing periods, T, of 4, 6 and 8 s. At each T, D was measured for two combinations of inspiratory and expiratory times (ti and te): te >ti and te ti than for te < ti at T = 4 and 6 s. Thus, particles deposited primarily by time-dependent mechanisms and these particles were more likely to deposit during inspiration than expiration. Using both air and a helium-air mixture as the carrier gas, we measured D at (VT,T) = (0.5TLC, 4 s) for the two combinations of ti and te in an additional five lungs. Contrary to findings with air, we found that D was not different for the two combinations of ti and te in helium-air. In addition, D was greater in helium-air than in air even though particle mobility was similar in the two gases. We propose that the results are best explained by differences in the nature of inspiratory and expiratory flow profiles. However differences in airspace geometry between inspiration and expiration may also play a role.

Reliability of Vibrating Mesh Technology

BACKGROUND: For delivery of inhaled aerosols, vibrating mesh systems are more efficient than jet nebulizers are and do not require added gas flow. We assessed the reliability of a vibrating mesh nebulizer (Aerogen Solo, Aerogen Ltd, Galway Ireland) suitable for use in mechanical ventilation. METHODS: An initial observational study was performed with 6 nebulizers to determine run time and efficiency using normal saline and distilled water. Nebulizers were run until cessation of aerosol production was noted, with residual volume and run time recorded. Three controllers were used to assess the impact of the controller on nebulizer function. Following the observational study, a more detailed experimental protocol was performed using 20 nebulizers. For this analysis, 2 controllers were used, and time to cessation of aerosol production was noted. Gravimetric techniques were used to measure residual volume. Total nebulization time and residual volume were recorded. Failure was defined as premature cessation of aerosol production represented by residual volume of > 10% of the nebulizer charge. RESULTS: In the initial observational protocol, an unexpected sporadic failure rate was noted of 25% in 55 experimental runs. In the experimental protocol, a failure rate was noted of 30% in 40 experimental runs. Failed runs in the experimental protocol exhibited a wide range of retained volume averaging ± SD 36 ± 21.3% compared with 3.2 ± 1.5% (P = .001) in successful runs. Small but significant differences existed in nebulization time between controllers. CONCLUSIONS: Aerogen Solo nebulization was often randomly interrupted with a wide range of retained volumes.