Purpose: To determine the vascular reactivity (VR) capacity and visual function (VF) response to potent vasoconstrictor and vasodilatory provocations of retinal arterioles in healthy subjects. Methods: One hyperoxic hypocapnic and two graded hypoxic hypercapnic stimuli were administered. VR in response to gas provocation was assessed using the Canon Laser Blood Flowmeter. VF was assessed using high and low contrast ETDRS logMAR charts, Medmont C-100, and H.R.R. Pseudoisochromatic Plates. Results: Flow reduced by 23% (p=0.0001) during hyperoxic hypocapnia and increased by 18% (p=0.0129) during hypoxic hypercapnia. During hyperoxic hypocapnia, high contrast VA improved by -0.026 (p=0.0372). During hypoxic hypercapnia, high and low contrast VA were reduced (+0.033, p=0.0110; +0.025, p=0.0058, respectively). Colour vision was unaffected. Conclusions: The retinal arterioles demonstrated a greater capacity for vasoconstriction than vasodilation in response to the stimuli used in our study. Hyperoxic hypocapnia improved high contrast VA while hypoxic hypercapnia reduced high and low contrast VA.

Invasive Pulmonary Apsergillosis (IPA) is caused by inhalation of fungal conidia to the deep lung followed by germination and invasive hyphal growth in heavily immunosuppressed patients (e.g. those with hematologic malignancies, hematopoietic stem cell transplant recipients, and those undergoing solid organ transplantation). Hyphal growth into pulmonary capillaries often leads to dissemination of the infection and high mortality rates despite current treatment and prophylactic modalities. In addition, systemic antifungal therapy is often limited by drug toxicities, low and variable bioavailability, erratic pharmacokinetics, and drug interactions. Although targeted drug delivery to the lungs has been investigated to reduce adverse events and promote drug efficacy, inconsistent pharmacokinetic properties following inhalation of poorly water soluble antifungals has prompted variable drug efficacy. In this dissertation, inhaled voriconazole was investigated through in vitro and in vivo testing to evaluate pharmacokinetic properties, characterize drug safety and, determine drug efficacy as prophylaxis against IPA. In Chapter 2, the in vitro evaluation of solution properties and aerosol characterization of aqueous voriconazole was evaluated. Subsequent in vivo single and multiple dose pharmacokinetic studies demonstrated high drug concentrations were achieved in lung tissue and plasma following inhalation in contrast to previous reports of inhaled antifungals. Inhaled voriconazole was then administered twice daily (BID, at 08:00 and 16:00) in a murine model of IPA as described in Chapter 3 with significant improvements in animal survival over 12 days compared to both positive and negative control groups. As described in Chapter 4, voriconazole was then chronically administered BID at a high and low dose to rats over 21 days with a 7 day recovery period to assess dose tolerability through laboratory tests and histopathological changes to lung, liver, kidney, and spleen tissues. Inhaled voriconazole was well tolerated through all assessments but with signs of mild acute histiocytosis in lung tissue without other signs of inflammation. Chapter 5 expanded the single inhaled dose pharmacokinetic profile in lung tissue and plasma with determination of additional pharmacokinetic parameters through compartmental modeling. Peak and trough voriconazole concentrations were also evaluated in mice as well as rats following multiple doses administered over 12 hours (Q12H) as opposed to BID. / text

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Master of Science in Medicine / Rationale: Asthma management aims to achieve optimal control on the minimal effective dose of medication. We assessed the effectiveness of two algorithms to guide ICS dose in well-controlled patients on ICS+LABA in a double-blind study, comparing dose adjustment guided by exhaled nitric oxide (eNO) to clinical care algorithm(CCA) based on symptoms and lung function. Methods: We randomised non-smoking adult asthmatics on minimum FP dose 100μgs daily +LABA to ICS adjustment using eNO or CCA, assessed over 5 visits during 8 months treatment. Primary endpoints were asthma-free days and asthma related quality of life (QOL). Analysis was by mixed model regression and generalised estimating equations with log link. Results: 69 subjects were randomised (eNO:34, CCA:35) and 58 completed the study. At baseline mean FEV1 was 94% pred., mean eNO (200ml/sec) 7.1 ppb, median ACQ6 score 0.33. Median ICS dose was 500 μg (IQR 100-500) at baseline and 100 μg on both eNO (IQR 100-200) and CCA arms (IQR 100–100) at end of study. There were no significant differences between eNO and CCA groups in asthma-free days (RR=0.92, 95% CI 0.8–1.01), AQL (RRAQL<median = 0.95, 95% CI 0.8–1.1) or exacerbation-free days (HR = 1.03, 95%CI 0.6–1.7). Neither clinic FEV1 (overall mean difference FEV1 % pred. -0.24%, 95% CI -2.2–1.7) nor a.m. PEF (mean difference 1.94 L/min (95% CI -2.9–6.8) were significantly different. Similar proportions of subjects were treated for ≥1 exacerbation (eNO: 50%, 95% CI 32.1–67.9; CCA: 60%, 95% CI 43.9–76.2). Conclusion: Substantial reductions in ICS doses were achieved in well controlled asthmatics on ICS+LABA, with no significant differences in outcomes between eNO or clinically based algorithms.

Use of inhaled drugs in obstructive pulmonary diseases Author: Nikola Obertová 1 Tutor: Josef Malý 1 1 Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University Introduction and objectives: Chronic respiratory diseases are emerging health problem. The administration of the medication is mostly performed by the process of inhalation. Therefore, a proper inhalation technique plays a crucial role in symptom reduction and achievement of adequate control over the disease. The aim of the thesis was partly to assess the level of inhalation technique in elderly patients in nursing home settings, partly to evaluate the knowledge of nurses and their role in advice provision related to the proper inhalation technique. Methods: The data were collected from June to September 2016 from 18 nursing homes located in South Wales (Great Britain). The study was realized in two arms. The evaluated group (first arm) was composed of patients (residents) with having asthma bronchiale or chronic obstructive pulmonary disease diagnosed and being older than 65 years. Second arm consisted of nurses responsible for giving advices about inhalation technique to the residents. Nursing home visits were composed of three parts. First one was a controlled interview based on the...

This thesis is part of a larger series of studies being conducted by Kristine Tanner, PhD, Associate Professor in the Department of Communication Disorders at Brigham Young University (BYU). The larger project is funded by the National Institute on Deafness and Other Communication Disorders at the National Institutes of Health. This thesis primarily investigated the effects of combination inhaled corticosteroids (ICs) on aerodynamic measures of the voice. In recent years, an increase in the localized laryngeal side effects from IC treatment, including dysphonia, have been reported. This study employed a between-groups experimental design, with two groups of rabbit larynges having been exposed to either ICs or nebulized isotonic saline two times each day for eight weeks at The University of Utah. For this study, the independent variable is group condition (i.e., IC versus saline) and the dependent variables are two aerodynamic measurements made at the onset of phonation using a benchtop experimental setup, namely phonation threshold pressure (PTP; cmH2O) and phonation threshold flow (PTF; L/min). The results of this study indicate a significant difference in PTP and PTF between vocal folds treated with IC as compared to vocal folds treated with nebulized isotonic saline solution. Implications of this study suggest negative changes in the voice due to IC treatment.

The purpose of this thesis is to examine the effects of inhaled corticosteroid drugs (ICs) on the voice due to their frequent use in treating an increasing prevalence of asthma disorders. As part of a larger five-year study, the focus of this thesis is specifically on whether 8 weeks of in vivo exposure to ICs will cause changes in the sustained subglottal pressure, sustained airflow, and visual-perceptual ratings of edema and erythema in excised rabbit larynges. Researchers administered either ICs or a control nebulized isotonic saline solution to 22 rabbits in vivo, sacrificed them, and harvested their larynges for benchtop research. While ensuring proper tissue preservation, researchers then finely dissected the larynges to expose the true vocal folds and run phonation trials. Dependent variables included continuous acoustic signals (Hz), subglottal pressure (cm H2O), and airflow (L/min) data for 15 phonation trials per rabbit larynx. Researchers also collected still image photographs at this time and subsequently normalized them for use in the visual-perceptual portion of this thesis. For visual-perceptual ratings, raters used a 0-3 equal appearing interval scale to rate aspects of edema and erythema on left and right vocal fold and arytenoid tissues. Results indicate that, when compared to control larynges exposed to nebulized isotonic saline, experimental larynges treated with ICs require significantly higher subglottal pressure to maintain phonation, p < .05. Mean sustained phonation for experimental larynges is 11.24 cm H2O compared to 8.92 cm H2O for that of control larynges. Phonation trials for experimental larynges have significantly higher sustained airflow with a mean of 0.09 L/min compared to 0.07 L/min for that of control larynges, p < .05. Surprisingly, experimental larynges have higher average fundamental frequencies with less variability (mean: 519 Hz, standard deviation: 66 Hz) than that of control larynges (mean: 446 Hz, standard deviation: 130 Hz). On visual-perceptual ratings, experimental larynges have significantly higher severity ratings on all eight items rated, p < .0001 - p = .0305. Based on these results, it is concluded that ICs cause significant damage to rabbit vocal folds, as evidenced by higher sustained pressure, higher airflow, and higher severity ratings for experimental versus control larynges. The dependent variables in this thesis are novel in benchtop model research and demonstrate a unique perspective on this research question. Thus, this thesis informs future phonation, benchtop, and visual-perceptual research.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18852号 / 医博第3963号 / 新制||医||1007(附属図書館) / 31803 / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊達 洋至, 教授 中原 俊隆, 教授 山田 亮 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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

The purpose of this thesis is to investigate the reversibility of the adverse effects of combination inhaled corticosteroids (ICs) on vocal fold health as part of a five-year study. This pilot study tested the hypothesis that the adverse effects of ICs may be induced and then reversed, using a benchtop model and rabbit larynges measuring sustained subglottic pressure and airflow. Eighteen rabbits were assigned randomly to 5 subgroups, including baseline, induction experimental, induction control, reversibility experimental, and reversibility control. Baseline rabbits did not receive any treatment. Both experimental groups, induction and reversibility, were administered Advair until visual-perceptual ratings were noted. Their paired control groups were administered nebulized saline in the same dosage levels. Induction groups were immediately sacrificed, while reversibility groups entered a withdrawal phase until visual-perceptual ratings showed a return to baseline. Larynges were dissected and mounted on a benchtop model for phonation trials. Dependent variables included sustained phonatory pressure (cm/H2O) and sustained phonatory airflow (L/min). The results of phonation trials indicate that sustained pressure and flow were higher for both induction and reversibility experimental groups when compared to baseline and control groups. The reversibility experimental group had lower sustained pressure and flow than the induction experimental group. These results indicate a reduction of signs after a period of rest. These findings suggest that voice symptoms may be reversible to a degree after combination IC use. These are important preliminary data that support future studies with larger sample sizes to confirm findings.