Browsing by Subject "Lungs"
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Item Mechanical signals for compensatory lung growth assessed by high resolution computed tomography(2008-09-18) Ravikumar, Priya; Hsia, Connie C.W.This dissertation involves the use of high resolution computed tomography (HRCT) to understand the role of intra-thoracic mechanical force and its distribution in regenerative growth in dogs i.e. to quantify lobar lung volumes and density gradients in normal and post-pneumonectomy (following lung resection) lungs. HRCT was used to quantitatively assess regional distribution of lung volume and density gradients among lobes of the lung in order to follow the expansion of remaining lobes following lung resection with a high degree of anatomical precision, and to determine the relationships between lung expansion and alveolar tissue growth. I also extended this work by relating regional lung expansion and growth assessed by radiology to regional alveolar tissue growth assessed by detailed quantitative histology under light and electron microscopy. This study illustrates for the first time a powerful and novel use of in vivo imaging to quantify regional lung distortion and changes in local volume, lung compliance as well as soft tissue density. These changes can be followed non-invasively and serially in a wide range of clinical and investigational applications, such as a) assessing the extent and progression of regional heterogeneity in lung disease or injury; b) assessing local response to treatment or surgical intervention; or c) assessing normal or abnormal patterns of lung growth.Item Pulmonary delivery of aqueous voriconazole solution(2009-05) Tolman, Justin Andrew; Williams, Robert O., 1956-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.Item Total and segmented direct cost-of-care for stage IV non-small cell lung cancer in a privately insured population(2011-05) Bell, Allison Miriam; Koeller, Jim; Frei, Christopher; Ryan, Laurajo; Penrod, JohnIntroduction: New treatments for stage IV (adv) NSCLC have emerged this past decade. Recent pharmacoeconomic research has focused on cost of treatment, comparative costs of therapies, and cost/cost effectiveness of adding a biologic to traditional therapy. Drug cost is thought to be a primary driver of cost change in NSCLC, yet to our knowledge, characterization of the direct cost of NSCLC has not been published since the new treatments have emerged in the guidelines. Our primary objective was to characterize the direct and segmented cost of adv NSCLC from 2000-9. We also want to determine cost impact of new therapies, and cost trend from 2000-9. Methods: This PharMetrics claims database study includes diagnosed NSCLC patients [greater than or equal to] 20 yo. Small cell lung cancer was excluded. Claims were divided into disease segments and time periods representative of changes in therapy ("pre" (2000-2), "transition" (2003-5), and "current" (2006-9) periods). Descriptive statistics (median, interquartile range (IQR)), chi-square test (nominal data), and Wilcoxan rank sum tests were performed on the data. To adjust for baseline confounders, multivariate least squares regression models were created. Results: Costs are reported as medians in terms of per patient per month (pppm). Overall monthly cost (n=969) was $10,281 pppm. Diagnosis cost $6,601 pppm, active treatment cost $9,287 pppm, and end-of life cost $12,215 pppm. There was no difference in cost between the “transition” (n=439) and “current” (n=503) periods overall or for any segment of disease. Comorbidities had no effect on cost. For patients receiving at least 5 months of active treatment medication (n=316) total median cost was $144,147 per patient ($9,371 pppm). Discussion: There was no difference in cost between the transition and current periods, in regards to either overall cost or segmented cost. The most expensive segment was end-of-life, with a median cost exceeding $12,000 pppm. Surprisingly, comorbidities had no effect on cost. Newer agents (biologics, TKIs, and pemetrexed) represent only a modest portion of cost, with a majority of cost for stage IV NSCLC comprised of non-drug costs.