A mélyebb tüdőrégiókból tisztuló radon-leánytermékek dózisjáruléka a centrális légutakban

Epidemiológiai és kísérleti tanulmányok szerint ok-okozati összefüggés van a radonexpozíció magas szintje és a tüdőrák átlagosnál nagyobb előfordulási gyakorisága között(1). A hiszto-patológiai adatok szerint, a radon-indukálta tumorok rendszerint a centrális légutak első néhány generációjában fordulnak elő, leginkább a légúti elágazások csúcsaiban(2). Numerikus módszerekkel sikerült kimutatni, hogy a belélegzett részecskék depozíciósűrűség-eloszlásának maximumai is ezen elágazások csúcsaiban találhatók(3). Ez arra enged következtetni, hogy a primer kiülepedés-eloszlás és a rákkialakulás között szoros a korreláció. Felmerül azonban a kérdés, hogy a mélyebb tüdőrégiókban kiülepedett és onnan a mukociliáris tisztulással felfelé, azaz a garat felé, a nyákréteggel haladó radonleánytermékek dózisjáruléka a centrális légutakban nem adódhat-e érdemben hozzá a centrális légúti tüdőrák kialakulásának kockázatához. Azaz a primer depozícióhoz képest elhanyagolható-e a mukociliáris részecsketranszport okozta centrális légúti terhelés. Mukociliáris tisztulás alatt a bronchiális légutak falát borító nyákrétegnek a gége irányába történő mozgását és ezáltal a falra tapadt részecskék „kimosását” értjük(4). A nyák mozgását a hámszövetbe ágyazott csillószőrök összehangolt mozgása biztosítja. A rövid felezési idejű radonszármazékok esetében a mukociliáris gyors tisztulás a legfontosabb tisztulási mechanizmus. Jelen munka célja egy inhalált radonleánytermék tisztulási modell kifejlesztése és alkalmazása a fenti kérdés vizsgálatára

Simulation of Airway Deposition of an Aerosol Drug in COPD Patients

Medical aerosols are key elements of current chronic obstructive pulmonary disease (COPD) therapy. Therapeutic effects are conditioned by the delivery of the right amount of medication to the right place within the airways, that is, to the drug receptors. Deposition of the inhaled drugs is sensitive to the breathing pattern of the patients which is also connected with the patient's disease severity. The objective of this work was to measure the realistic inhalation profiles of mild, moderate, and severe COPD patients, simulate the deposition patterns of Symbicort((R)) Turbuhaler((R)) dry powder drug and compare them to similar patterns of healthy control subjects. For this purpose, a stochastic airway deposition model has been applied. Our results revealed that the amount of drug depositing within the lungs correlated with the degree of disease severity. While drug deposition fraction in the lungs of mild COPD patients compared with that of healthy subjects (28% versus 31%), lung deposition fraction characteristic of severe COPD patients was lower by a factor of almost two (about 17%). Deposition fraction of moderate COPD patients was in-between (23%). This implies that for the same inhaler dosage severe COPD patients receive a significantly lower lung dose, although, they would need more

Source Specific Risk Assessment of Indoor Aerosol Particles

In the urban environment, atmospheric aerosols consist mainly of pollutants from anthropogenic sources. The majority of these originate from traffic and other combustion processes. A fraction of these pollutants will penetrate indoors via ventilation. However, indoor air concentrations are usually predominated by indoor sources due to the small amount of dilution air. In modern societies, people spend most of their time indoors. Thus, their exposure is controlled mainly by indoor concentrations from indoor sources. During the last decades, engineering of nanosized structures has created a new field of material science. Some of these materials have been shown to be potentially toxic to human health. The greatest potential for exposure to engineered nanomaterials (ENMs) occurs in the workplace during production and handling of ENMs. In an exposure assessment, both gaseous and particulate matter pollutants need to be considered. The toxicities of the particles usually depend on the source and age. With time, particle morphology and composition changes due to their tendency to undergo coagulation, condensation and evaporation. The PM exposure risk is related to source specific emissions, and thus, in risk assessment one needs to define source specific exposures. This thesis describes methods for source specific risk assessment of airborne particulate matter. It consists of studies related to workers ENM exposures during the synthesis of nanoparticles, packing of agglomerated TiO2 nanoparticles, and handling of nanodiamonds. Background particles were distinguished from the ENM concentrations by using different measurement techniques and indoor aerosol modelings. Risk characterization was performed by using a source specific exposure and calculated dose levels in units of particle number and mass. The exposure risk was estimated by using non-health based occupational exposure limits for ENMs. For the nanosized TiO2, the risk was also assessed from dose-biological responses which had been extrapolated from inhalation studies conducted in mice. The ENM exposure levels were compared with background particle concentrations in order to determine the relevant ENM exposure metrics and exposure scenarios.Sisäilman epäpuhtaudet koostuvat ilmanvaihdon mukana tulevista ulkoilman epäpuhtauksista ja sisätilan lähteistä. Koska sisätilassa on vähän laimennosilmaa, niin sisätilan lähteet yleensä määräävät sisätilan pitoisuustasot. Koska modernissa yhteiskunnassa ihmiset viettävät valtaosan ajasta sisätiloissa, niin heidän altistuminen määräytyy suurelta osin sisätilan lähteiden aiheuttamista päästöistä. Viime vuosikymmenien aikana materiaalitekniikka on alkanut hyödyntämään synteettisiä nanohiukkasia (SNH). Jotkut näistä SNH:ta on mahdollisesti myrkyllisiä ihmisille jo pienissä pitoisuuksissa. Altisuminen näille SNH tapahtuu pääosin työpaikoilla tuotannon ja käsittelyn yhteydessä. Koska hiukkasien haitallisuudet vaihtelevat voimakkaasti niiden syntyperän mukaan niin altistuksen ja riskin arviointi tulisi tehdä lähdekohtaisten päästöjen mukaisesti. Tässä väitöskirjassa esitetään eri menetelmiä ilmassa olevien hiukkasten lähdekohtaiseen riskinarviointiin. Menetelmiä sovellettiin työntekijöiden SNH altistuksen arvioinnissa SNH:n tuotannossa, pakkauksessa ja käsittelyssä. Työntekijöiden altistuksesta aiheutunutta riskiä arvioitiin lähdekohtaisesti käyttämällä laskennallisia annoksia sekä annosvastetta, jota oltiin arvioitu altistuskokeilla. Altistuksen arvioinnissa käytettävää mittausmetriikan sopivuutta arvioitiin eri altistustapahtumille ja altistumistasoja verrattiin epävirallisiin altistusraja-arvoihin. Tutkimus tuotti tietoa SNH:n riskinarviointiin, riskimallinnuksiin, raja-arvojen sekä säädöksien määrittämiseen

Aerosol formulation and clinical efficacy of bronchodilators

This thesis subject is the improvement of the formulation of inhaled aerosols. It is well known that the formulation of inhaled drugs is not optimal: the major part of the mass delivered does not reach the lower airways. This phenomenon is due to the particle size of the inhaled particles, which is too large. Reduction of the size is the answer to this problem, but size reduction has its limits: too small particles do not deposit and are exhaled. The optimum between too large and too small is not known and has been the main object of this research project. The optimal particle size of a ß2-mimetic aerosol was determined in 8 stable asthmatics with a FEV1 of 72% of the predicted and it was shown that in these mild asthmatics the particle size of choice for a ß2-mimetic aerosol should be around 2.8 m m. Based on the distribution of the pulmonary receptors we expected that for parasympathicolytic aerosol a more central deposition pattern would be best. The latter being equivalent to a large optimal particle size. However, in mild asthmatics the optimal particle size for an ipratropium bromide aerosol also proved to be # 2.8 mm. Based deposition theories, we hypothesised that the optimal particle size of a 82-agonist or parasympathicolytic aerosol in patients with severe airflow obstruction had to be smaller, because these particles must pass obstructed airways. 7 stable patients with a mean FEV1 of 37.9% of predicted value inhaled three types of monodisperse salbutamol and ipratropium bromide aerosols, with particle sizes of 1.5 :m, 2.8 :m and 5 :m, respectively, and a placebo aerosol. Greater improvements in FEV1 were induced by the 2.8 :m aerosol than by the other particle sizes. The dilatations in the previous experiments were already clinically relevant at low dosages. To discover whether the bronchodilator effects of these low dosed monodisperse aerosols differed from those of standard dosages delivered by metered dose inhalers, we carried out a comparative trial. 10 stable outpatients, with a mean FEV1 of 58.1 % of predicted, inhaled a placebo aerosol, 8 µg of a 2.8 µm monodisperse ipratropium bromide aerosol and 40 µg from a metered dose inhaler plus spacer, followed by lung function measurements. We were able to show that the low dosed 2.8 µm aerosol proved to be equivalent to the higher dosed metered dose inhaler. Subsequently we compared the adverse effects of 160 µg fenoterol in the form of a 2.8 µm monodispers aerosol to those of 800 µg as a conventional metered dose inhaler aerosol. In twelve healthy volunteers changes in serum potassium, finger tremor, blood pressure, heart rate and specific airway conductance were measured before and 15 min after administration. Potassium levels decreased by 0.27 mmol/l after the monodispers aerosol, while the MDI lowered it by 0.67 mmol/l (p=0.001). Finger tremor also increased less. There was no significant specific airway conductance differences between the two actives. The overall conclusion of these experiments is that the best choice for a bronchodilator aerosol size are particles of 2.8 µm. When aerosols are composed of these particles, the dose of inhaled bronchodilators, relative to metered dose inhalers, can be reduces by 80%. This is accompanied by a major reduction in adverse effects

CFD Assessment of Respiratory Drug Delivery Efficiency in Adults and Improvements Using Controlled Condensational Growth

Pharmaceutical aerosols provide a number of advantages for treating respiratory diseases that include targeting high doses directly to the lungs and reducing exposure of other organs to the medication, which improve effectiveness and minimize side effects. However, difficulties associated with aerosolized drug delivery to the lungs include drug losses in delivery devices and in the extrathoracic region of human upper airways. Intersubject variability of extrathoracic and thoracic drug deposition is a key issue as well and should be minimized. Improvements to respiratory drug delivery efficiency have been recently proposed by Dr. P. Worth Longest and Dr. Michael Hindle through the use controlled condensational growth methods, which include enhanced condensational growth (ECG) and excipient enhanced growth (EEG). These methods reduce inhaled drug loss through the introduction of an aerosol with an initial submicrometer aerodynamic diameter, which then experiences condensational growth to increase droplet size and enhance thoracic deposition. Tracheobronchial and nasal human airway computational models were developed for this study to assess drug delivery using conventional and EEG methods. Computational versions of these models are used to assess drug delivery and variability with computational fluid dynamics (CFD) simulations, which are validated with experimental data where possible. Using CFD, steady state delivery of albuterol sulfate (AS) during high flow therapy (HFT) through a nasal cannula was characterized with four nasal models developed for this study, with results indicating an increase in average delivered dose from 24.0% with a conventional method to 82.2% with the EEG technique and an initially sized 0.9 µm aerosol, with a corresponding decrease in the coefficient of variation from 15% to 3%. Transient CFD simulations of nebulized AS administration through a mask during noninvasive positive pressure ventilation (NPPV) were performed and validated with experimental data, which resulted in 40.5% delivered dose with the EEG method as compared with 19.5% for a conventional method and a common inhalation profile. Using two newly created face-nose-mouth-throat models, dry powder delivery of ciprofloxacin during NPPV was assessed for the first time with steady state CFD predictions, which showed an increase in average delivered lung dose through a new mask design of 78.2% for the EEG method as compared with 36.2% for conventional delivery, while corresponding differences in delivered dose between the two models were reduced from 45.4% to 12.8% with EEG. In conclusion, results of this study demonstrate (i) the use of highly realistic in silico and in vitro models to predict the lung delivery of inhaled pharmaceutical aerosols, (ii) indicate that the EEG approach can reduce variability in nose-to-lung aerosol delivery through a nasal cannula by a factor of five, and (iii) introduce new high efficiency methods for administering aerosols during NPPV, which represents an area of current clinical need