Gerald C Smaldone | PubMed Health

PubMed2003

Aerosol delivery and modern mechanical ventilation: in vitro/in vivo evaluation.

Aerosol delivery via a mechanical ventilator remains unregulated with no standards for drug delivery to intubated patients. Bench models predicting drug delivery have not been validated in vivo. For modern ventilator designs, we chose to identify, on the bench, the most important variables affecting aerosol delivery and to correlate in vitro predictions of aerosol delivery with in vivo end points independent of patient response. Test aerosols of albuterol and antibiotics were compared. Bench measurements of inhaled mass (percentage of nebulizer charge, mean +/- SEM) ranged from 5.7 +/- 0.5% to 37.4 +/- 1.6%, with breath-actuated nebulization and humidity identified as the most important factors determining aerosol delivery. In patients, sputum levels of deposited antibiotics varied from 1.10 to 19.6 microg/ml/mg. Variation in sputum levels correlated with predictions from the in vitro model. Aerosol delivery in ventilated patients can be efficient and reproducible only if defined ventilator parameters are tightly controlled. Key parameters can be determined via in vitro bench testing defining delivery standards for clinical trials of drugs with narrow therapeutic/toxicity ratios.

Administration, Inhalation↗

PubMed2003

Lung deposition and pharmacokinetics of cyclosporine after aerosolization in lung transplant patients.

PURPOSE: 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. METHOD: 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. RESULTS: 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 (t 1/2 lambda(z)) 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. CONCLUSIONS: 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.

Administration, Inhalation↗

PubMed2002

Smart nebulizers.

Physicians are familiar with conventional nebulizers, which deliver aerosols in a relatively uncontrolled manner. As aerosol medications evolve beyond bronchodilators, the need for control of dose variability, the possibility of overdose, and the need for efficient delivery have provoked the industry to redesign aerosol delivery systems. The need to target aerosol delivery to specific lung regions has focused efforts to coordinate aerosol delivery with defined breathing maneuvers. This review summarizes the major factors affecting aerosol deposition, discusses how those factors are guiding new designs for aerosol delivery systems, and describes some examples of the improved precision and efficiency of those systems.

Administration, Inhalation↗