Particles in small airways : Mechanisms for deposition and clearance & pharmacokinetic assessments of delivered dose to the lung

University dissertation from Stockholm : Karolinska Institutet, Department of Public Health Sciences

Abstract: BACKGROUND Knowledge about lung deposition and clearance from airways of inhaled particles/drugs are essential for evaluation of health effects of inhaled pollutants and to achieve optimal drug dose to the lung. The primary defence mechanism in the conducting airways is the mucociliary clearance (MCC). When MCC is defective, as in Cystic Fibrosis (CF) and Primary Ciliary Dyskinesia (PCD), cough can serve as back up in the larger airways. The importance of MCC from the small airways (< 2 mm in diameter) is still unknown. Most studies of lung deposition and clearance are performed with imaging methods using radiation, and are not suitable for routine clinical investigations. A simple pharmacokinetic method to evaluate the pulmonary dose would be beneficial. OBJECTIVE The aims of the studies were 1) to investigate the importance of mucociliary clearance to eliminate particles from the small airways, 2) to evaluate if the slow inhalation method is feasible for patients with high airway resistance, and 3) to develop a simple non-radioactive method to assess the deposited dose in the lung. METHODS Clearance in small airways was studied in patients with CF and PCD, using the extremely slow inhalation flow method (ESI). The inhalation method deposits particles mainly in the small ciliated airways. Clearance was evaluated by measuring lung retention up to 21 days after exposure, and the results were compared with data from age matched healthy controls. Inhaled sodium cromoclygate (SCG) was measured both in plasma and urine to estimate the bioavailibility and to evaluate what measurement had the best reproducibility. In another study the SCG method was used in asthmatic children to evaluate the relative humidity effect on droplet size distribution and the effect on lung deposition. RESULTS The particle retention (% of deposition) in the lung at 24 h was higher in patients with CF, 67±13%, and PCD, 79±1 1%, compared to the healthy subjects, 48±9% (P<0.001), probably due to their defective MCC. There was however a significant clearance after 24 h in all subjects with equivalent clearance rate during day 7 to day 21. The SCG method with individual plasma analyses showed best correlation between the two exposures and was easy to control. In the study with asthmatic children, the tidal volume corresponded to the deposited amount of drug. No difference in lung deposition measured with the SCG-method however was shown. CONCLUSIONS These studies show that despite defective mucociliary clearance, clearance continues in small airways. Apparently there are other clearance mechanisms present in the small airways. The extremely slow inhalation flow technique was shown to be feasible in patients with high airway resistance, and can be used for diagnostic purposes or for delivery of therapeutic drugs. The SCG-method, using plasma analyses, is a simple pharmacokinetic method that can be used in clinical situation, e.g when evaluating individual inhalation techniques. In asthmatic children a larger tidal volume can give greater lung deposition, provided that the droplets are not too small.

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