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  1. Article ; Online: A Quantitative Systems Physiology Model of Renal Function and Blood Pressure Regulation: Application in Salt-Sensitive Hypertension.

    Hallow, K M / Gebremichael, Y

    CPT: pharmacometrics & systems pharmacology

    2017  Volume 6, Issue 6, Page(s) 393–400

    Abstract: Salt-sensitivity (SS) refers to changes in blood pressure in response to changes in sodium intake. SS individuals are at greater risk for developing kidney disease, and also respond differently to antihypertensive therapies compared to salt-resistant (SR) ...

    Abstract Salt-sensitivity (SS) refers to changes in blood pressure in response to changes in sodium intake. SS individuals are at greater risk for developing kidney disease, and also respond differently to antihypertensive therapies compared to salt-resistant (SR) individuals. In this study we used a systems pharmacology model of renal function (presented in a companion article) to evaluate the ability of proposed mechanisms to produce salt-sensitivity. The model reproduced previously published data on renal functional changes in response to salt-intake, and also predicted that glomerular pressure, a variable that is not easily evaluated clinically but is a key factor in renal injury, increases with salt intake in SS hypertension. We then used the model to generate mechanistic insight into the differential blood pressure and glomerular pressure responses to angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, and calcium channel blockers observed in SS and SR hypertension.
    Language English
    Publishing date 2017-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2697010-7
    ISSN 2163-8306 ; 2163-8306
    ISSN (online) 2163-8306
    ISSN 2163-8306
    DOI 10.1002/psp4.12177
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A quantitative systems physiology model of renal function and blood pressure regulation: Model description.

    Hallow, K M / Gebremichael, Y

    CPT: pharmacometrics & systems pharmacology

    2017  Volume 6, Issue 6, Page(s) 383–392

    Abstract: Renal function plays a central role in cardiovascular, kidney, and multiple other diseases, and many existing and novel therapies act through renal mechanisms. Even with decades of accumulated knowledge of renal physiology, pathophysiology, and ... ...

    Abstract Renal function plays a central role in cardiovascular, kidney, and multiple other diseases, and many existing and novel therapies act through renal mechanisms. Even with decades of accumulated knowledge of renal physiology, pathophysiology, and pharmacology, the dynamics of renal function remain difficult to understand and predict, often resulting in unexpected or counterintuitive therapy responses. Quantitative systems pharmacology modeling of renal function integrates this accumulated knowledge into a quantitative framework, allowing evaluation of competing hypotheses, identification of knowledge gaps, and generation of new experimentally testable hypotheses. Here we present a model of renal physiology and control mechanisms involved in maintaining sodium and water homeostasis. This model represents the core renal physiological processes involved in many research questions in drug development. The model runs in R and the code is made available. In a companion article, we present a case study using the model to explore mechanisms and pharmacology of salt-sensitive hypertension.
    Language English
    Publishing date 2017-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2697010-7
    ISSN 2163-8306 ; 2163-8306
    ISSN (online) 2163-8306
    ISSN 2163-8306
    DOI 10.1002/psp4.12178
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A Tutorial on RxODE: Simulating Differential Equation Pharmacometric Models in R.

    Wang, W / Hallow, K M / James, D A

    CPT: pharmacometrics & systems pharmacology

    2016  Volume 5, Issue 1, Page(s) 3–10

    Abstract: This tutorial presents the application of an R package, RxODE, that facilitates quick, efficient simulations of ordinary differential equation models completely within R. Its application is illustrated through simulation of design decision effects on an ... ...

    Abstract This tutorial presents the application of an R package, RxODE, that facilitates quick, efficient simulations of ordinary differential equation models completely within R. Its application is illustrated through simulation of design decision effects on an adaptive dosing regimen. The package provides an efficient, versatile way to specify dosing scenarios and to perform simulation with variability with minimal custom coding. Models can be directly translated to Rshiny applications to facilitate interactive, real-time evaluation/iteration on simulation scenarios.
    MeSH term(s) Algorithms ; Computer Simulation ; Drug Dosage Calculations ; Models, Molecular ; Pharmaceutical Preparations/chemistry ; Software
    Chemical Substances Pharmaceutical Preparations
    Language English
    Publishing date 2016-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2697010-7
    ISSN 2163-8306 ; 2163-8306
    ISSN (online) 2163-8306
    ISSN 2163-8306
    DOI 10.1002/psp4.12052
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Influence of cytoskeletal structure and mechanics on epithelial cell injury during cyclic airway reopening.

    Yalcin, H C / Hallow, K M / Wang, J / Wei, M T / Ou-Yang, H D / Ghadiali, S N

    American journal of physiology. Lung cellular and molecular physiology

    2009  Volume 297, Issue 5, Page(s) L881–91

    Abstract: Although patients with acute respiratory distress syndrome require mechanical ventilation, these ventilators often exacerbate the existing lung injury. For example, the cyclic closure and reopening of fluid-filled airways during ventilation can cause ... ...

    Abstract Although patients with acute respiratory distress syndrome require mechanical ventilation, these ventilators often exacerbate the existing lung injury. For example, the cyclic closure and reopening of fluid-filled airways during ventilation can cause epithelial cell (EpC) necrosis and barrier disruption. Although much work has focused on minimizing the injurious mechanical forces generated during ventilation, an alternative approach is to make the EpC less susceptible to injury by altering the cell's intrinsic biomechanical/biostructural properties. In this study, we hypothesized that alterations in cytoskeletal structure and mechanics can be used to reduce the cell's susceptibility to injury during airway reopening. EpC were treated with jasplakinolide to stabilize actin filaments or latrunculin A to depolymerize actin and then exposed to cyclic airway reopening conditions at room temperature using a previously developed in vitro cell culture model. Actin stabilization did not affect cell viability but significantly improved cell adhesion primarily due to the development of more numerous focal adhesions. Surprisingly, actin depolymerization significantly improved both cell viability and cell adhesion but weakened focal adhesions. Optical tweezer based measurements of the EpC's micromechanical properties indicate that although latrunculin-treated cells are softer, they also have increased viscous damping properties. To further investigate the effect of "fluidization" on cell injury, experiments were also conducted at 37 degrees C. Although cells held at 37 degrees C exhibited no changes in cytoskeletal structure, they did exhibit increased viscous damping properties and improved cell viability. We conclude that fluidization of the actin cytoskeleton makes the EpC less susceptible to the injurious mechanical forces generated during cyclic airway reopening.
    MeSH term(s) Actins/metabolism ; Biomechanical Phenomena/drug effects ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Cell Adhesion/drug effects ; Cell Death/drug effects ; Cell Line ; Cytoskeleton/drug effects ; Cytoskeleton/metabolism ; Depsipeptides/pharmacology ; Elastic Modulus/drug effects ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Humans ; Microscopy, Fluorescence ; Optical Tweezers ; Stress, Mechanical ; Temperature ; Thiazolidines/pharmacology ; Vinculin/metabolism
    Chemical Substances Actins ; Bridged Bicyclo Compounds, Heterocyclic ; Depsipeptides ; Thiazolidines ; jasplakinolide (102396-24-7) ; Vinculin (125361-02-6) ; latrunculin A (SRQ9WWM084)
    Language English
    Publishing date 2009-08-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1013184-x
    ISSN 1522-1504 ; 1040-0605
    ISSN (online) 1522-1504
    ISSN 1040-0605
    DOI 10.1152/ajplung.90562.2008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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