Lung cellular disposition and anti-inflammatory pharmacology of inhaled corticosteroids (ICSs) is complex, comprised of a cascade of aerosol deposition and dissolution, followed by cellular uptake for local pharmacological action. This project hypothesized that the kinetics of dissolution for certain ICS aerosols generated from inhaler products were kinetically rate-determined for their cellular uptake and local pharmacological action. A novel dissolution testing system was developed to determine the dissolution kinetics for the ICS aerosols. A total of 5 ICSs aerosols generated from 6 inhaler products were collected in 2.1-3.3 or 4.7-5.8 µm of aerodynamic diameters at 0.7-19.8 µg on filter membranes by impaction using the Andersen cascade impactor. The filter membrane was then placed on the donor side of the transwell insert, with its face down, and the ICS dissolution in the limited 40 µL of the donor fluid was monitored over time. The dissolution kinetics overall conformed to the rank order of the aqueous solubility, while also being affected by ICS aerosol’s mass, size, formulation and dosage forms. For the readily soluble triamcinolone acetonide (TA), the kinetics was first-order, reaching ≥89 % dissolution in 5 h. In contrast, for the least soluble fluticasone propionate (FP), the kinetics was zero-order, reaching only 3 % dissolution in 10 h. The project then developed an air-interface culture of human bronchial epithelial cell line, Calu-3. Well-differentiated monolayers were formed with sufficiently “tight” barrier for restrictive solute diffusion while their mucosal surface was maintained semi-dry with 39.7±12.1 µL of the mucosal lining fluid in the 4.5 cm2 transwells. These monolayers were transfected with reporter plasmid of pNFκB-Luc to assess in vitro anti-inflammation via repression of pro-inflammatory NFκB by direct FP or TA aerosol deposition. The FP aerosols at 0.9 µg successfully exhibited significant 35.7±6.3 % repression. Notably, however, an identical ~0.5 µg of FP and TA aerosols caused comparable 15.5±2.2 and 10.4±2.6 % repression, respectively, despite FP’s 10-fold greater “intrinsic” anti-inflammatory potency over TA, reported in the literature. This was attributed to FP’s slow dissolution resulting in only 4.7 % cellular uptake, compared to 32.6 % for the TA aerosols. Hence, the FP aerosols were shown to be rate-determined by dissolution on the lung cell surface, resulting in reduced anti-inflammatory actions, which was not the case for the readily soluble TA aerosols.

This thesis examines the overarching theme of inhaled corticosteroid (ICS) dose response effects on a variety of asthma outcome measures; with further importance placed on the application of these findings to personalising ICS dosing for the individual asthmatic. The introduction provides a detailed summary of the current recommendations for the treatment of adult asthma, with particular reference to the mechanism of action and clinical utility of ICS for the treatment of asthma. Current methods of assessing ICS dose response are presented, as well as the common influences that affect these responses. Novel therapeutic theories and the identification of specific asthmatic phenotypes are also introduced, in order to demonstrate the shift towards personalising treatment for asthma. The first two studies examine the dose response of ICS on two specific factors that influence asthma. The third study presents an examination of pharmacological manipulation of the ICS dose response using an additional agent. The following two studies address: how asthma outcomes relate to each other in patients receiving ICS; in addition to an overall assessment of the ICS dose response across a broad range of both ICS moieties and outcome measures. The final study examines for any detrimental effect of an ICS dose ramp on bone metabolism, an important potential long-term adverse effect of higher ICS dosing. The discussion draws together all the results obtained in relation to ICS dose response in asthma, and how these apply to current clinical practice for the individual patient. Furthermore, hypotheses are generated for areas of future study based on the findings from this work.

http://olabout.wiley.com/WileyCDA/Section/id-820227.html / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19590号 / 医博第4097号 / 新制||医||1014(附属図書館) / 32626 / 京都大学大学院医学研究科医学専攻 / (主査)教授 山田 亮, 教授 清水 章, 教授 小池 薫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM