Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

The inhaled pharmacotherapy is fundamental in the management of obstructive lung diseases such as asthma bronchiale or chronic obstructive pulmonary disease. In this context short- and long-acting β2-agonists play a prominent role as relieve and control medication. Regarding the risk-benefit profile of an inhaled drug, the pattern of pulmonary deposition and the rate and extent of absorption into systemic circulation are essential parameters. New developments of drugs are characterized by high lung retention and improved efficacy. The aim of the present thesis was the parallel evaluation the pharmacokinetic (PK) and -dynamic (PD) properties of inhaled β2-agonists employing an isolated human lung perfusion model (IPL). The short-acting β2-agonist salbutamol and the newly developed ultra long-acting β2-agonist GW597901 were chosen for the analysis of pulmonary drug absorption and bronchodilation. In a pharmacokinetic enabling study an established human IPL setting was modified to monitor the pharmacokinetics of the β2-agonists by measuring the concentrations in perfusion fluid, lung tissue and BAL samples obtained during and after the experiments. The IPL model revealed differences in the pulmonary absorption behaviour of GW597901 and salbutamol. The lipophilic compound GW597901 was distributed to a lower extent into the perfusion fluid compared to the more hydrophilic compound salbutamol. The analyzed time profiles of nebulized salbutamol in the perfusate were consistent to with a clinical study if considering experimental conditions as the actual deposited doses and the differing volume of distribution. Thus, the suitability of the IPL model for the PK analysis of inhaled β2-agonists was confirmed. In a PK/PD study the human ex vivo model was employed for the first time for the evaluation of the clinical relevant bronchodilating effect induced by inhaled β2-agonists in addition to the analysis of their pharmacokinetics. Thereby the focus was to determine the onset and extent of bronchodilation. A new method was established to monitor changes in lung function parameters due to pharmacodynamic interventions over the duration of the experiment that allowed permanent online recording of the ventilation volume and lung mechanic parameters. Bronchial challenges with aerolised MCh were performed successfully in isolated ventilated human lung lobes, even though the responder rate was lower than expected despite high administered doses. The administration of the short acting agent salbutamol led to an immediate onset of action recognized as a sudden increase of the ventilation volumes. The bronchodilation following the application of GW597901 was observed delayed after about 6 min. Monitored lung function parameters considerably improved by both β2 - agonists in the IPL setting but not significantly different. Thus, in regard of the different applied doses GW597901 had a higher intrinsic activity and bronchodilating potency than salbutamol. The concentrations of salbutamol and GW597901 in the perfusate determined in the PK/PD study were significantly lower than those observed in the pharmacokinetic enabling study, while the tmax values and the course of the distribution profiles remained similar. Most likely, the application of nebulized MCh prior to the administration of the β2 - agonists had a substantial influence on their pharmacokinetic behaviour. It is yet not clear whether pharmacodynamic effects or molecular competition processes for the passage to the systemic circulation or both influenced the redistribution of the β2 - agonists as seen in the PK/PD study. The potential clinical relevance of this observation has to be further investigated. The development of pulmonary edema during the experiment was one limitation of the IPL model. For the determination of the onset of edema formation four potential biochemical markers, specifically surfactant-protein A (SP-A), angiotensin-converting enzyme (ACE), urea and lactate dehydrogenase, were measured in perfusion fluids. In this context, an ELISA method for the quantification of human SP-A in biological matrices was successfully established. The investigations showed that the concentrations of SP-A and ACE in the perfusate increased over time as a sign for lung tissue damage and correlated with the degree of edema formation. For the first time the IPL model was used for the evaluation of potential pulmonary edema marker and the results have shown that it is valuable tool for further investigations in this field. In conclusion, the pharmacokinetic and pharmacodynamic characterization of GW597901 and salbutamol was successfully achieved using the IPL model. This ex vivo methodology may contribute to further insights and understanding of the complex pharmacokinetic processes of inhaled β2 – agonists in the lung. / Die Inhalationstherapie stellt den grundlegenden Baustein in der Behandlung obstruktiver Lungenerkrankungen wie Asthma bronchiale oder chronisch obstruktiver Lungenerkrankung dar. Eine essentielle Rolle spielen dabei kurz- und langwirksame β2 – Agonisten, die sowohl als Bedarfs- und Kontrollmedikation eingesetzt werden. Bei Betrachtung des Nutzen-Risiko-Verhältnisses eines inhalativen Arzneistoffes sind das pulmonale Depositionsmuster und die Geschwindigkeit und das Ausmaß, mit welcher der Arzneistoff in die systemische Zirkulation gelangt, von zentraler Bedeutung. Das Ziel dieser Arbeit war die Bestimmung pharmakokinetischer (PK) und -dynamischer (PD) Eigenschaften inhalativer β2 – Agonisten anhand des isolierten humanen Lungenperfusionsmodells (IPL). Der kurzwirksame β2 – Agonist Salbutamol und der neue langwirksame Vertreter GW597901 dienten dabei als Modellsubstanzen für die Analyse der pulmonalen Absorption und den Effekt der Bronchodilatation. In einer ersten Versuchsreihe wurde das etablierte IPL Modell derart modifiziert, um mittels gemessener Konzentrationen in der Perfusions- und Lavageflüssigkeit sowie in Lungengewebsproben die Pharmakokinetik von β2 – Agonisten zu bestimmen. Das IPL Modell zeigte Unterschiede im pulmonalen Absorptionsverhalten von GW597901 und Salbutamol. Der lipophile Vertreter GW597901 wurde in geringerem Ausmaß in die Perfusionsflüssikeit umverteilt als das hydrophile Salbutamol. Das analysierte Absorptionsprofil von Salbutamol korrelierte dabei sehr gut mit Daten einer Humanstudie, wenn man die experimentellen Bedingungen wie die tatsächlich deponierte Dosis und das abweichende Verteilungsvolumen berücksichtigte. Dadurch war die Eignung des IPL Modells zur PK Analyse inhalativer β2 – Agonisten bestätigt. Zusätzlich zur Betrachtung der PK wurde das humane IPL Modell nun zum ersten Mal zur Untersuchung des klinisch relevanten Effekts der Bronchdilatation der β2 – Agonisten herangezogen. Dabei sollten vor allem der Beginn und das Ausmaß der induzierten Bronchodilatation bestimmt werden. Es konnte erfolgreich eine neue Methode etabliert werden, die es erlaubte durch permanente online Aufzeichnung von Ventilationsparameter Änderungen in der Lungenfunktion darzustellen, die durch pharmakodynamische Interventionen ausgelöst wurden. Erstmals wurde erfolgreich eine bronchiale Provokation an einem ex vivo ventilierten humanen Lungenlappen durchgeführt. Jedoch war trotz hoher verabreichter MCh Dosen die Responderrate niedriger als erwartet. Die Applikation des kurzwirksamen Vertreters Salbutamol führte zu einem sofortigen Effekt. Der Wirkeintritt der Bronchodilatation verursacht durch GW597901 war hingegen um ungefähr 6 Minuten verzögert. Unter Berücksichtigung der unterschiedlichen verabreichten Dosen zeigen diese Ergebnisse eine höhere intrinsische Aktivität und atemwegserweiternde Wirksamkeit von GW597901 im Vergleich zu Salbutamol. Die analysierten Konzentrationen von GW597901 und Salbutamol im Perfusat waren in der PK/PD Studie signifikant niedriger als diejenigen, die in der vorherigen PK Versuchsreihe gemessen wurden, während die jeweiligen Tmax Werte und Umverteilungsprofile unverändert blieben. Die wahrscheinlichste Erklärung hierfür ist, dass die Applikation von MCh vor der Vernebelung der β2 – Agonisten einen erheblichen Einfluß auf deren pharmakokinetischen Verhalten hatte. Gegenwärtig kann nicht mit Sicherheit eine Aussage darüber getroffen werden, ob pharmakodynamische Effekte, Konkurrenzmechanismen um die Aufnahme in den systemischen Kreislauf auf molekularer Ebene oder beides zu einem veränderten Umverteilungsverhalten der β2 – Agonisten in der PK/PD Studie geführt haben. Die Entwicklung von Lungenödemen im Verlauf der Experimente war eine Einschränkung des IPL Modells. Um den Beginn einer Ödembildung besser bestimmen zu können, wurden vier potenzielle biochemische Marker in Perfusatproben untersucht, das Surfactant Protein-A (SP-A), das Angiotensin-konvertierende Enzym (ACE), Harnstoff und das Enzym Lactatdehydrogenase (LDH). Die Untersuchungen haben gezeigt, dass die Konzentrationen von SP-A und ACE im Perfusat über die Zeit als Anzeichen für eine Lungengewebsschädigung in Korrelation zum Ausmaß der Ödembildung anstiegen. Zum ersten Mal wurde das IPL Modell für die Bestimmung von biologischen Markern für pulmonale Ödementstehung herangezogen und die Ergebnisse haben gezeigt, dass dieses ex vivo Modell einen vielversprechenden Ansatz für weitere Untersuchungen in diesem Bereich bietet. Damit konnten erfolgreich Methoden entwickelt werden, um mit Hilfe des humanen IPL Modells die pharmakokinetischen und -dynamischen Eigenschaften von GW597901 und Salbutamol zu charakterisieren. Die angewandte ex vivo Methodik kann hierbei einen wertvollen Beitrag und weiterführende Erkenntnisse zum besseren Verständnis der komplexen pharmakokinetischen Vorgänge inhalativer β2 – Agonisten leisten.

Liu Hua. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 139-143). / Abstracts in English and Chinese. / Table of Contents --- p.I / Acknowledgement --- p.VII / Abstract --- p.VIII / Abstract (Chinese) --- p.X / List of Tables --- p.XV / List of Figures --- p.XXIV / List Symbols and Abbreviations / Chapter Chapter One --- Introduction / Chapter 1.1. --- Rationale of study --- p.2 / Chapter 1.2. --- Drug Delivery to the lungs --- p.5 / Chapter 1.3. --- Particle transport and deposition mechanisms --- p.8 / Chapter 1.4. --- Factors affecting particulate interactions --- p.9 / Chapter 1.4.1. --- Particle size --- p.9 / Chapter 1.4.2. --- Particle shape --- p.10 / Chapter 1.4.3. --- Surface texture --- p.10 / Chapter 1.4.4. --- Surface energy --- p.11 / Chapter 1.4.5. --- Contact area --- p.12 / Chapter 1.4.6. --- Relative humidity --- p.12 / Chapter 1.4.7. --- Electrical properties --- p.13 / Chapter 1.5. --- Fine powder production technologies applicable to dry powder inhalation formulations --- p.13 / Chapter 1.5.1. --- Batch crystallization and micronization --- p.14 / Chapter 1.5.2. --- Spray drying --- p.15 / Chapter 1.5.3. --- Supercritical fluid crystallization --- p.17 / Chapter 1.6. --- Physical characterization of aerosol powders --- p.18 / Chapter 1.6.1. --- Microscopy and particle size analysis --- p.19 / Chapter 1.6.2. --- Powder X-ray diffractometry --- p.19 / Chapter 1.6.3. --- Thermal analysis --- p.20 / Chapter 1.6.4. --- In-vitro deposition assessment --- p.20 / Chapter 1.6.5. --- Surface energy measurement by inverse gas chromatography (IGC) --- p.21 / Chapter 1.7. --- Scope of study --- p.22 / Chapter Chapter Two --- Materials and Methods / Chapter 2.1. --- Materials --- p.25 / Chapter 2.2. --- Equipment --- p.25 / Chapter 2.3. --- Methods --- p.27 / Chapter 2.3.1. --- Determination of aqueous solubility of salbutamol sulphate in water --- p.27 / Chapter 2.3.2. --- Preparation of spray-dried salbutamol sulphate powders under different operating conditions --- p.27 / Chapter 2.3.3. --- Preparation of spray-dried salbutamol sulphate powders at various lecithin concentrations --- p.30 / Chapter 2.3.4. --- Preparation of spray-dried salbutamol sulphate powders at various oleic acid concentrations --- p.32 / Chapter 2.3.5. --- Physical characterization of spray-dried salbutamol sulphate powders --- p.34 / Chapter 2.3.5.1. --- Scanning electron microscopy --- p.34 / Chapter 2.3.5.2. --- Specific surface area determination --- p.34 / Chapter 2.3.5.3. --- Particle size distribution measurements --- p.35 / Chapter 2.3.5.4. --- Water content determination --- p.36 / Chapter 2.3.5.5. --- Isothermal water vapour sorption studies --- p.37 / Chapter 2.3.5.6. --- Powder X-ray diffraction --- p.37 / Chapter 2.3.5.7. --- Thermal analysis --- p.38 / Chapter 2.3.5.8. --- Surface energy measurement by inverse gas chromatography --- p.39 / Chapter 2.3.5.8.1. --- Calculation of surface thermodynamic parameters --- p.40 / Chapter 2.3.5.8.1.1. --- Standard Free Energy of Adsorption and Related Thermodynamic Parameters --- p.40 / Chapter 2.3.5.8.1.2. --- Dispersive Component of Surface Free Energy and Related Thermodynamic Parameters --- p.41 / Chapter 2.3.5.8.1.3. --- Specific Interactions and Associated Acid-Base Properties --- p.42 / Chapter 2.3.5.9. --- In-vitro deposition measurement by multi-stage liquid impinger --- p.43 / Chapter Chapter Three --- Results and discussion / Chapter 3.1. --- Influence of spray drying operating parameters --- p.46 / Chapter 3.1.1. --- Drying temperature --- p.46 / Chapter 3.1.1.1. --- "Particle size, particle morphology, and specific surface area" --- p.46 / Chapter 3.1.1.2. --- "Crystallinity, moisture sorption and thermal behaviour" --- p.53 / Chapter 3.1.1.3. --- Surface thermodynamic properties --- p.60 / Chapter 3.1.1.4. --- Aerodynamic properties and in-vitro deposition --- p.64 / Chapter 3.1.2. --- Feed solution concentration --- p.67 / Chapter 3.1.2.1. --- "Particle size, particle morphology and specific surface area" --- p.69 / Chapter 3.1.2.2. --- "Crystallinity, moisture sorption and thermal behaviour" --- p.69 / Chapter 3.1.2.3. --- Surfacethermodynamicproperties --- p.70 / Chapter 3.1.2.4. --- Aerodynamic properties and in-vitro deposition --- p.70 / Chapter 3.1.3. --- Feed speed --- p.72 / Chapter 3.1.3.1. --- "Particle size, particle morphology, and specific surface area" --- p.72 / Chapter 3.1.3.2. --- "Crystallinity, moisture sorption and thermal behaviour" --- p.73 / Chapter 3.1.3.3. --- Surfacethermodynamicproperties --- p.73 / Chapter 3.1.3.4. --- Aerodynamic properties and in-vitro deposition --- p.73 / Chapter 3.2. --- Influence of formulation additives --- p.78 / Chapter 3.2.1. --- Influence of lecithin as additive --- p.78 / Chapter 3.2.1.1. --- "Particle morphology, particle size and specific surface area" --- p.79 / Chapter 3.2.1.2. --- "Crystallinity, moisture sorption and thermal behaviour" --- p.84 / Chapter 3.2.1.3. --- Surfacethermodynamicproperties --- p.90 / Chapter 3.2.1.4. --- Aerodynamic properties and in-vitro deposition --- p.94 / Chapter 3.2.2. --- Influence of oleic acid as additive --- p.101 / Chapter 3.2.2.1. --- "Particle morphology, particle size and specific surface area" --- p.101 / Chapter 3.2.2.2. --- "Crystallinity, moisture sorption and thermal behaviour" --- p.106 / Chapter 3.2.2.3. --- Surfacethermodynamicproperties --- p.123 / Chapter 3.2.2.4. --- Aerodynamic properties and in-vitro deposition --- p.127 / Chapter Chapter Four --- Conclusion and Future Work / Chapter 4.1. --- Conclusion --- p.134 / Chapter 4.1.1. --- Influence of spray drying operating parameters --- p.134 / Chapter 4.1.2. --- Influence of formulation additives --- p.135 / Chapter 4.2. --- Future Work --- p.137 / References --- p.139

Although the production of polychlorinated biphenyl (PCB) technical mixtures has been banned in the U.S. since the 70’s, they remain ubiquitous in the environment, particularly in indoor and ambient air. Due to the presence of PCB’s in air, inhalation is a significant route of exposure. PCBs released from various building materials have been shown to contaminate the indoor air in homes and schools. In the AESOP Study, an epidemiologic study of PCB exposures among school children and their mothers, PCB28 was found in the serum of over 20% of participants. Data are lacking on the absorption, distribution, metabolism, and excretion (ADME) of inhaled PCBs and on the biological fate and dose-specific toxicological endpoints. In order to inform toxicokinetic modeling for risk-assessment, we are conducting ADME toxicological studies with lung exposure to a representative trichlorobiphenyl, and evaluating the uptake from the lung and the distribution, metabolism, and excretion. Male Sprague-Dawley rats were exposed to [14C]PCB28 via intratracheal instillation at two different doses (42 µg/rat and 4.2 µg/rat). Digestive matter from five separate compartments of the gastrointestinal tract and thirty-six tissue types were excised and measured by scintillation counting. Exhaled air and excreta were also collected and analyzed. Measurements for the high dose were made at 12, 25, 50, 100, 200, 400, 720, and 1440 min, and for the low dose at 2, 12, 50, 200, and 720 min post-exposure. Data show that pulmonary uptake exceeded 99% in both doses. [14C]PCB28 entered the blood stream and distributed quickly to all tissues within minutes of dosing. In the high dose, the majority of radioactivity initially went to the muscle and liver, while in the low dose [14C]PCB28 initially distributed to the muscle, esophagus, and trachea, before being redistributed to the skin and adipose tissue, where it accumulated in both doses. In most tissues, elimination was biphasic, consisting of an initial fast phase with a half-life (t1/2) of 7-93 min (high dose) and t1/2 of 6-60 min (low dose), followed by a slower phase with t1/2 of 5-18 hours (high dose) and t1/2 of 3-18 hours (low dose). The metabolism of PCB28 was not extensive, with the parent compound as the major component in liver, kidney, serum, and adipose tissue. Excretion via urine and feces was limited, with 92% (high dose) and 88% (low dose) of radioactivity remaining in the tissues by the end of the time course, primarily in skin and adipose tissue. Low urinary concentration relative to serum, suggested that parent PCB28 in serum would serve as an accurate biomarker for assessment of exposure to inhaled trichlorobiphenyls. The time course and tissue distribution is comparable to [14C]PCB11, while metabolism and excretion of [14C]PCB28 is much less extensive.

Inhalation exposure to semi-volatile polychlorobiphenyls (PCBs) that ubiquitously exist in the environment has the potential to cause adverse health effects. Recently identified sources of airborne PCBs, especially non-legacy sources, stress the importance of risk assessment for inhalation exposure. However, the fate of inhaled airborne PCBs in biological systems and the resultant toxicity remain unexplored. The objective of this thesis research was to investigate the distribution and elimination of semi-volatile PCBs in biological systems after inhalation exposure and evaluate the biologic and toxicologic consequences. This objective was achieved by conducting the following inhalation studies in rats: a short-term exposure study of the body burden and elimination; a subchronic exposure toxicity study; an acute exposure study of PCB11 metabolism; and a mass balance study of [14C]PCB11 following lung exposure. PCBs found in technical Aroclor mixtures and PCB11 were readily absorbed and distributed following nose-only inhalation exposure. PCBs accumulated in adipose tissue, but decayed in other tissues with biological half-lives of several hours. Their elimination was dependent on the structure of the PCB congeners and the metabolic nature of the organ. Lower-chlorinated PCBs exhibited more rapid clearance than higher-chlorinated congeners yet differential rates of elimination were also seen within the homologue. A distinct congener pattern was found in tissues, ranging from tri- to pentachorobiphenyls after subacute and subchronic exposure. Rapid elimination of PCB11 and its metabolite, 4-OH-CB11, were detected in liver following nose-only inhalation exposure by our established methodology. Further investigation revealed that [14C]PCB11 was 99.8% absorbed in lung. Elimination of the [14C]PCB11 and products consisted of an initial fast phase followed by a slow clearance phase. [14C]PCB11 underwent rapid and extensive metabolism in liver. The major products were phase II metabolites which dominated in the non-adipose tissues and were eliminated via the large intestine and urine. Overall, differential congener elimination was found after inhalation of airborne PCBs, with minimal toxicity. Lower-chlorinated congeners were rapidly and extensively metabolized to phase II products and eliminated within hours.

Anxiety sensitivity, defined as the fear of anxiety-related sensations and their consequences (Reiss & McNally, 1985), has been consistently shown to be associated with risk for anxiety psychopathology as well as other mental health problems. The primary objective of the present secondary prevention trial sought to examine strategies to reduce anxiety sensitivity among persons with elevated anxiety sensitivity by testing the singular and combined efficacy of two commonly used strategies in multi-component interventions for reducing anxiety sensitivity: (a) anxiety psychoeducation emphasizing the benign nature of stress and (b) interoceptive exposure (i.e. repeated inhalations of 35% CO₂ gas mixture). To provide a stringent control for non-specific effects associated with anxiety psychoeducation and interoceptive exposure with CO₂, two control strategies were included in the study design: general health and nutrition education and repeated inhalations of regular room air. Utilizing a 2X2 design, participants were randomly assigned to receive an education component and intervention sessions consisting of one of two gas mixtures. The current study did not support the relative efficacy of hypothesized active intervention strategies. Rather, all conditions led to significant reductions in anxiety sensitivity. In addition, within-condition effect sizes for conditions in the present study were comparable to effect sizes of active interventions that were efficacious in previous research. Findings from the present study support that anxiety sensitivity is malleable following brief, cost-efficient interventions and these reductions are maintained over a one-month follow-up period. Data from the present study suggest that in the presence of stringent control conditions, hypothesized active intervention strategies provided little additional benefit. The present study has implications for methodological considerations for future secondary prevention trials for the reduction of anxiety sensitivity. The absence of stringent control groups might lead to premature conclusions that reductions in anxiety sensitivity are due to the specific effects of active interventions. Further research is needed to elucidate specific effects of intervention strategies for the reduction of anxiety sensitivity in at risk populations in order to refine secondary prevention interventions aimed to reduce risk for psychopathology. / text

One of the most elusive challenges in the diagnosis and treatment of dysphagia is the reliable identification of silent aspiration (aspiration in the absence of cough). The citric acid inhalation cough challenge offers potential for aiding in identification of silent aspiration; however clinical application of this technique is currently problematic due to an absence of normative data. Therefore, this study aimed to establish a normative data set for the Citric- Acid Inhalation Cough Challenge, as administered with facemask method. 80 healthy subjects will participate in this study, constituting 2 age groups: above and below 60 years, with equal gender representation. On 3 separate trials, they will be asked to passively inhale, via a facemask, nebulised citric acid of concentrations ranging from 08M to 2.6M with placebo interspersed. ‘Natural cough thresholds’ (NCT) and ‘Suppressed Cough Thresholds’ (SCT) will be reached when subjects cough on at least 2 out of 3 trials. The majority (92.5%) of participants reached Natural Cough Threshold by 0.8M, with 68% demonstrating Suppressed Cough Threshold also at this concentration. There were no significant differences found between males and females (p<0.05) for either NCT (p=0.9885) or SCT (p=0.44). Whilst no difference was found between youngers and elders for NCT (p=0.7254), there was a significant difference for SCT (p=0.018), with youngers better able to suppress cough. Over 90% of healthy people were found to elicit cough at 0.8M, inferring that this level would be an adequate guide for use by clinicians testing for presence/absence of cough.

Thesis (M.S.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 34 pages. Includes bibliographical references.

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Cerrahi Tıp Bilimleri Anesteziyoloji ve Reanimasyon Anabilim Dalı, 2002. / Bibliyografya var.

Thesis (M.S.)--University of Michigan, 1981.