Kitty Leung

Aerosol delivery of an enhanced helper-dependent adenovirus formulation to rabbit lung using an intratracheal catheter

Poor transduction of the ciliated airway epithelium and inefficient airway delivery of viral vectors are common difficulties encountered in lung gene therapy trials with large animals and humans.

Rapid Pulmonary Delivery of Inhaled Tobramycin for Pseudomonas Infection in Cystic Fibrosis : A Pilot Project

Patients with cystic fibrosis spend as much 30 min a day inhaling tobramycin. Could a new rapid system deposit the equivalent amount of tobramycin faster?

Higher Tobramycin concentration and vibrating mesh technology can shorten antibiotic treatment time in cystic fibrosis

Poor adherence to recommended therapy in cystic fibrosis (CF) is often because of the time demands of therapy. Tobramycin (TOBI®, 300 mg at 60 mg/ml) inhaled from the PARI LC PLUS® nebulizer requires about 20 min. This study determined if equivalent levels of pulmonary deposition could be achieved in shorter time using 1.5 ml of 100 mg/ml tobramycin solution delivered by an investigational eFlow® nebulizer. Sixteen males with stable CF, 8 children and 8 adults, and an FEV1 > 45% predicted inhaled both preparations on two occasions with 99mTc‐DTPA added to the tobramycin. Blood samples were taken for quantification of tobramycin in the serum. The PARI LC PLUS® delivered 45.4 (39.3–51.6), mean and 95% CI, mg to the lungs in 17.0 ± 2.5 min (mean ± SD) with serum levels of 1,089 ± 388 µg/L. The investigational eFlow® delivered 46.3(40.3–51.7) mg in 4.0 ± 1.0 min with blood levels of 909 ± 458 µg/L. Only the time of delivery was significantly different with P < 0.0001 (paired t‐test). Tolerability of the treatment was comparable for both inhalation regimes, but the shorter treatment was preferred by all patients. These results demonstrate the possibility of delivering equivalent levels of tobramycin much faster into the lungs of CF patients when using eFlow®, a very efficient electronic nebulizer. Pediatr Pulmonol. 2011; 46:401–408.

A Comparison of Amount and Speed of Deposition Between the PARI LC STAR® Jet Nebulizer and an Investigational eFlow® Nebulizer

BACKGROUND The potency and physical properties of many of the drugs used in the treatment of cystic fibrosis necessitates the use of nebulization, a relatively time-consuming pulmonary delivery method. Newer, faster, and more efficient delivery systems are being proposed. The purposes of this study was to compare the length of time it took to deliver the equivalent of normal saline nebulized for 10 min in a PARI LC STAR(®) nebulizer to that of an investigational PARI eFlow(®). METHODS Six normal adults inhaled a 4-mL (36-mg) charge volume of saline from the LC STAR(®) or a 2.5-mL (22.5-mg) charge volume from the investigational eFlow(®). The saline was mixed with (99m)Tc-DTPA to allow two-dimensional imaging. The inhalation was preceded by a xenon equilibration scan to allow more accurate separation of deposition into central and peripheral lung regions. RESULTS The investigational eFlow(®) delivered 8.6 ± 1.0 mg, approximately 90% of the lung dose compared to the LC STAR(®), 9.6 ± 1.0 mg, but did in less than half the time (p < 0.02 for both). There were no differences in central versus peripheral distribution for either device. CONCLUSIONS In conclusion the investigational eFlow(®) was both faster and more efficient than the LC STAR(®).

Efficient Gene Delivery to Pig Airway Epithelia and Submucosal Glands Using Helper-Dependent Adenoviral Vectors

Airway gene delivery is a promising strategy to treat patients with life-threatening lung diseases such as cystic fibrosis (CF). However, this strategy has to be evaluated in large animal preclinical studies in order to translate it to human applications. Because of anatomic and physiological similarities between the human and pig lungs, we utilized pig as a large animal model to examine the safety and efficiency of airway gene delivery with helper-dependent adenoviral vectors. Helper-dependent vectors carrying human CFTR or reporter gene LacZ were aerosolized intratracheally into pigs under bronchoscopic guidance. We found that the LacZ reporter and hCFTR transgene products were efficiently expressed in lung airway epithelial cells. The transgene vectors with this delivery can also reach to submucosal glands. Moreover, the hCFTR transgene protein localized to the apical membrane of both ciliated and nonciliated epithelial cells, mirroring the location of wild-type CF transmembrane conductance regulator (CFTR). Aerosol delivery procedure was well tolerated by pigs without showing systemic toxicity based on the limited number of pigs tested. These results provide important insights into developing clinical strategies for human CF lung gene therapy.

Calculating expected lung deposition of aerosolized administration of AAV vector in human clinical studies

Cystic fibrosis is an autosomal recessive disease affecting approximately 1 in 2500 live births. Introducing the cDNA that codes for normal cystic fibrosis transmembrane conductance regulator (CFTR) to the small airways of the lung could result in restoring the CFTR function. A number of vectors for lung gene therapy have been tried and adeno‐associated virus (AAV) vectors offer promise. The vector is delivered to the lung using a breath‐actuated jet nebulizer. The purpose of this project was to determine the aerosolized AAV (tgAAVCF) particle size distribution (PSD) in order to calculate target doses for lung delivery.

Testing of Nebulizers for Delivering Magnesium Sulfate to Pediatric Asthma Patients in the Emergency Department

BACKGROUND: As the use of intravenous magnesium sulfate (MgSO4) for the treatment of refractory asthma is becoming more common, the incidence of MgSO4-related systemic hypotension is also rising. One option is to deliver MgSO4 via aerosol, but compared to most inhaled medications, which are active in the microgram dose range, the MgSO4 dose requirement is in the milligram range. This, along with inefficient aerosol delivery systems, may be the reason that some studies have found lack of efficacy with aerosol MgSO4. In preparation for a multicenter study of inhaled MgSO4 in asthmatic children 2–17 years old, we conducted an in vitro study to choose the best MgSO4 nebulizer system that would be effective over the entire age range. METHODS: We tested the Pari LC Star jet nebulizer, Omron MicroAir vibrating-mesh nebulizer, and the Aeroneb Go vibrating-mesh nebulizer with the Idehaler valve-less holding chamber. Aerosol delivery was via face mask. RESULTS: The Pari LC Star had an appropriate particle size distribution but a very slow aerosol output rate. The Omron MicroAir had an even slower output rate and a larger particle size distribution, which would be inappropriate for smaller children. In vitro lung deposition with the Aeroneb Go with Idehaler was 16.0 ± 0.4 mg/min in older children and approximately a fifth of that in toddlers. CONCLUSIONS: The Aeroneb Go with Idehaler was chosen for the multicenter clinical study.

Aerosolized liposomal Amphotericin B: a potential prophylaxis of invasive pulmonary aspergillosis in immunocompromised patients.

Aerosolized liposomal Amphotericin B may reduce the incidence of invasive pulmonary Aspergillosis in adults with chemotherapy‐induced prolonged neutropenia with less nephrotoxicity. The breath‐actuated AeroEclipse® BAN nebulizer is very efficient and minimizes environmental drug contamination since no aerosol is produced, unless the patient is inspiring through the device. Our aim is to develop an appropriate delivery system suitable for children that does not disrupt the liposomes due to the shear forces in nebulization.

Respiratory System Deposition with a Novel Aerosol Delivery System in Spontaneously Breathing Healthy Adults

BACKGROUND: Intravenous magnesium sulfate (MgSO4) in children and adults with refractory acute asthma is effective, but therapy may be limited by systemic hypotension that might be avoided with the aerosol route. Inhaled MgSO4 has a relatively high dose (volume) requirement. This, plus the use of inefficient delivery systems, may explain the lack of efficacy of inhaled MgSO4 in some studies. An in vitro study suggested that the AeroNeb Go with the Idehaler Pocket and a face mask would deliver 16 mg/min of MgSO4 to the respiratory system in older children, and approximately a fifth for toddlers, but no in vivo data exist. METHODS: Saline mixed with a radiolabel was used as a proxy for the 100 mg/mL MgSO4 solution. In 5 adult males the rate of deposition was measured using nuclear medicine techniques. The radiolabel deposition below the vocal cords was converted to the rate of deposition of MgSO4 and compared to the results from an in vitro model using adult respiratory patterns. RESULTS: The mean ± SD rate of deposition was 12.6 ± 1.9 mg/min. The reasons for this lower deposition, compared to the in vitro estimate, was most likely the exhalation of anatomical dead space aerosol, which would have been captured on the inspiratory filter in vitro. CONCLUSIONS: These in vivo data confirm the deposition data predicted in the in vitro study, although caution should be used in extrapolating the results to children. This device appears suitable for the clinical trial of inhaled MgSO4 in children and adults with refractory asthma.