Laleh Golshahi

In vitro lung delivery of bacteriophages KS4-M and ΦKZ using dry powder inhalers for treatment of Burkholderia cepacia complex and Pseudomonas aeruginosa infections in cystic fibrosis

Aims:  To determine the feasibility of formulating and aerosolizing powders containing bacteriophages KS4‐M and ΦKZ for lung delivery and treatment of pulmonary Burkholderia cepacia complex and Pseudomonas aeruginosa infections.

Toward Modern Inhalational Bacteriophage Therapy: Nebulization of Bacteriophages of Burkholderia cepacia Complex

Antibiotic-resistant bacterial infections have renewed interest in finding substitute methods of treatment. The purpose of the present in vitro study was to investigate the possibility of respiratory delivery of a Burkholderia cepacia complex (BCC) bacteriophage by nebulized aerosol administration. Bacteriophages in isotonic saline were aerosolized with Pari LC star and eFlow nebulizers, at titers with mean value (standard deviation) of 2.15 x 10(8) (1.63 x 10(8)) plaque-forming unit (PFU)/mL in 2.5-mL nebulizer fills. The breathing pattern of an adult was simulated using a pulmonary waveform generator. During breath simulation, the size distributions of the nebulized aerosol were measured using phase doppler anemometry (PDA). Efficiency of nebulizer delivery was subsequently determined by collection of aerosol on low resistance filters and measurement of bacteriophage titers. These filter titers were used as input data to a mathematical lung deposition model to predict regional deposition of bacteriophages in the lung and initial bacteriophage titers in the liquid surface layer of each conducting airway generation. The results suggest that BCC bacteriophages can be nebulized successfully within a reasonable delivery time and predicted titers in the lung indicate that this method may hold potential for treatment of bacterial lung infections common among cystic fibrosis patients.

An Idealized Child Throat that Mimics Average Pediatric Oropharyngeal Deposition

Copyright 2012 American Association for Aerosol Research

Deposition of Inhaled Ultrafine Aerosols in Replicas of Nasal Airways of Infants

Experimentally measured deposition of ultrafine particles, ranging from 13–100 nm in diameter, in nasal airway replicas of ten infants aged 3–18 months is presented. The replicas included the face, nostrils, and nasal airways including the upper trachea. A differential mobility analyzer (DMA) and a condensation particle counter (CPC) were used to quantify the nasal deposition by comparing the number of polydisperse sodium chloride particles, generated by evaporation from a Collison atomizer, at the inlet and outlet of the replicas. Particles were individually classified in size by DMA and subsequently were counted one size bin at a time by CPC upstream and downstream of each replica. Since in vivo data is not available for infants to compare to, we validated our experimental procedure instead by comparing deposition in nasal airway replicas of six adults with in vivo measurements reported in literature. In the infant replicas, tidal inhalation was simulated at two physiologically compatible flow rates and the effect of flow rate on deposition was found to be small. Deposition obtained at constant flow rates is lower than with tidal breathing, indicating the importance of unsteadiness, in contrast to similar data in adults where unsteadiness is known to be unimportant. An empirical equation, containing geometrical features of the nasal airways in the form of related non-dimensional dynamical parameters (Reynolds, Schmidt, and Womersley numbers), was best fitted to the infant data. This equation may be useful for a priori prediction of nasal deposition and intersubject variability during exposure of infants to ultrafine aerosols.

Intermittent Aerosol Delivery to the Lungs During High-Flow Nasal Cannula Therapy

INTRODUCTION: Use of submicrometer particles combined with condensational growth techniques has been proposed to reduce drug losses within components of high-flow nasal cannula therapy systems and to enhance the dose reaching the lower respiratory tract. These methods have been evaluated using continuous inhalation flow rather than realistic inhalation/exhalation breathing cycles. The goal of this study was to evaluate in vitro aerosol drug delivery using condensational growth techniques during high-flow nasal cannula therapy using realistic breathing profiles and incorporating intermittent aerosol delivery techniques. METHODS: A mixer-heater combined with a vibrating mesh nebulizer was used to generate a submicrometer aerosol using a formulation of 0.2% albuterol sulfate and 0.2% sodium chloride in water. Delivery efficiency of the aerosol for 1 min through a nasal cannula was considered using an intermittent delivery regime with aerosol being emitted for either the entire inhalation time (2 s) or half of the inhalation period (1 s) and compared with continuous delivery. The deposition of the aerosol was evaluated in the nasal delivery components (ventilator tubing and cannula) and an in vitro adult nose-mouth-throat (NMT) model using 3 realistic breathing profiles. RESULTS: Significant improvements in dose delivered to the exit of the NMT model (ex-NMT) were observed for both condensational growth methods using intermittent aerosol delivery compared with continuous delivery, and increasing the tidal volume was found useful. The combination of the largest tidal volume with the shortest intermittent delivery time resulted in the lowest respiration losses and the highest ex-NMT delivered dose. CONCLUSIONS: Intermittent aerosol delivery using realistic breathing profiles of submicrometer condensational growth aerosols was found to be efficient in delivering nasally administered drugs in an in vitro airway model.

Improving Aerosol Drug Delivery During Invasive Mechanical Ventilation With Redesigned Components

INTRODUCTION: Patients receiving invasive mechanical ventilation with an endotracheal tube (ETT) can often benefit from pharmaceutical aerosols; however, drug delivery through the ventilator circuit is known to be very inefficient. The objective of this study was to improve the delivery of aerosol through an invasive mechanical ventilation system by redesigning circuit components using a streamlining approach. METHODS: Redesigned components were the T-connector interface between the nebulizer and ventilator line and the Y-connector leading to the ETT. The streamlining approach seeks to minimize aerosol deposition and loss by eliminating sharp changes in flow direction and tubing diameter that lead to flow disruption. Both in vitro experiments and computational fluid dynamic (CFD) simulations were applied to analyze deposition and emitted dose of drug for multiple droplet size distributions, flows, and ETT sizes used in adults. RESULTS: The experimental results demonstrated that the streamlined components improved delivery through the circuit by factors ranging from 1.3 to 1.5 compared with a commercial system for adult ETT sizes of 8 and 9 mm. The overall delivery efficiency was based on the bimodal aspect of the aerosol distributions and could not be predicted by median diameter alone. CFD results indicated a 20-fold decrease in turbulence in the junction region for the streamlined Y resulting in a maximum 9-fold decrease in droplet deposition. The relative effectiveness of the streamlined designs was found to increase with increasing particle size and increasing flow, with a maximum improvement in emitted dose of 1.9-fold. CONCLUSIONS: Streamlined components can significantly improve the delivery of pharmaceutical aerosols during mechanical ventilation based on an analysis of multiple aerosol generation devices, ETT sizes, and flows.

Examining the ability of empirical correlations to predict subject specific in vivo extrathoracic aerosol deposition during tidal breathing

ABSTRACT The accuracy of five extrathoracic deposition equations was examined by comparing model predictions with in vivo deposition measurements of 99mTc-DTPA radiolabeled 0.9% saline delivered via PARI LC Sprint nebulizers in 19 healthy human subjects. The average extrathoracic deposition fraction measured in vivo was 0.19 ± 0.10 (average ± standard deviation). Comparing to this average value, the extrathoracic deposition fraction predicted by Golshahi et al. equation was the most accurate (0.18 ± 0.08), followed by the model described by the ICRP (0.16 ± 0.03). However, prediction of subject-specific deposition proved more challenging; the Golshahi et al. model performed the best of the examined equations, yet showed only a small positive correlation between measured and predicted deposition in individual subjects with a Pearson correlation coefficient of 0.34. The difficulties in predicting subject-specific deposition likely result from geometric dissimilarity both within and between subjects, and may require more complicated modeling methods than algebraic equations of the kind examined in this study. Copyright

Development of a Transient Flow Aerosol Mixer-Heater System for Lung Delivery of Nasally Administered Aerosols Using a Nasal Cannula

Previous studies have demonstrated improved nose-to-lung aerosol drug delivery with controlled condensational growth methods using a mixer-heater developed to synchronize aerosol delivery with patient inhalation. The goal of this study was to develop a new mixer-heater that delivers aerosols with a transient flow profile similar to a sinusoidal breathing waveform. The mixer-heater consisted of a chamber with two blowers delivering aerosol during the inhalation cycle of three sinusoidal breathing profiles. The effects of breathing profiles and mode of condensational growth delivery were studied using two in vitro extrathoracic airway models (closed- and open-mouth options). In excipient enhanced growth (EEG) delivery mode, increasing peak exhalation breathing flow rate decreased the emitted dose from the mixer-heater using the closed-mouth model. The mean (SD) emitted doses were 92 (2)%, 77 (2)%, and 70 (2)%, with 23, 35, and 44 L/min peak exhalation breathing flow rates, respectively. Using the in vitro open-mouth model mitigated the effect of breathing and the emitted doses were 93 (0.5)%, 83 (3)%, and 90 (4)% using the breathing profiles. The emitted doses in enhanced condensational growth (ECG) delivery mode using the breathing profiles with peak flow rates of 23, 35, and 44 L/min were 63 (4)%, 58 (2)%, and 58 (1)%, which were consistently lower than with EEG. Similarly, using the open-mouth model in ECG mode increased emitted doses to 77 (3)%, 73 (2)%, and 77 (8)%, respectively. The developed aerosol mixer-heater delivered greater than 50% of the nominal dose using a flow profile of sinusoidal inhalation, which represents a significant improvement compared to the current methods. Copyright 2014 American Association for Aerosol Research

Recent Advances in Understanding Gas and Aerosol Transport in the Lungs: Application to Predictions of Regional Deposition

Recent developments in understanding the physical processes responsible for gas and aerosol transport in the alveolar region of the lung are reviewed. Predicting regional deposition in the lungs is important both for environmental exposure and respiratory drug delivery. There is a strong connection between transport and deposition in the lung; thus, a large number of experiments, theoretical developments and computational studies on gas and aerosol transport, both in animals and with human subjects, have been developed so far to enhance our understandings of possible adverse effects of toxic particulate matter inhalation and determining therapeutic strategies for inhalation drug delivery (i.e. aerosol administration). Due to the intrinsic limitations of accurate measurement of detailed regional deposition in the lung, mathematical models have been favored extensively for prediction of regional deposition. The goal of the present article is to review recent advances in model development for predicting the regional deposition in the lung with a focus on the lung parenchyma. These advances build on recent model predictions considering the complex structure, time-varying, and cyclic process of alveolar expansion and contraction. Since validation of the developed mathematical models has improved with the advent of an experimental technique known as aerosol bolus dispersion, the latter subject has been linked to the review of the subject.

Advanced testing method to evaluate the performance of respirator filter media

ABSTRACT Filter media for respirator applications are typically exposed to the cyclic flow condition, which is different from the constant flow condition adopted in filter testing standards. To understand the real performance of respirator filter media in the field it is required to investigate the penetration of particles through respirator filters under cyclic flow conditions representing breathing flow patterns of human beings. This article reports a new testing method for studying the individual effect of breathing frequency (BF) and peak inhalation flow rate (PIFR) on the particle penetration through respirator filter media. The new method includes the use of DMA (Differential Mobility Analyzer)-classified particles having the most penetrating particle size, MPPS (at the constant flowrate of equivalent mean inhalation flow rate, MIFR) as test aerosol. Two condensation particle counters (CPCs) are applied to measure the particle concentrations at the upstream and downstream of test filter media at the same time. Given the 10 Hz sampling time of CPCs, close-to-instantaneous particle penetration could be measured. A pilot study was performed to demonstrate the new testing method. It is found that the effect of BF on the particle penetration of test respirator filter media is of importance at all the tested peak inhalation flow rates (PIFRs), which is different from those reported in the previous work.