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Pharmacodynamics and pharmacogenomic...

Yao, Zhenling.

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Pharmacodynamics and pharmacogenomics of corticosteroids in rat skeletal muscle.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Pharmacodynamics and pharmacogenomics of corticosteroids in rat skeletal muscle./
Author:	Yao, Zhenling.
Description:	373 p.
Notes:	Adviser: William J. Jusko.
Contained By:	Dissertation Abstracts International67-11B.
Subject:	Health Sciences, Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3244262
ISBN:	9780542999543

Pharmacodynamics and pharmacogenomics of corticosteroids in rat skeletal muscle.
Yao, Zhenling.

Pharmacodynamics and pharmacogenomics of corticosteroids in rat skeletal muscle. - 373 p.

Adviser: William J. Jusko.

Thesis (Ph.D.)--State University of New York at Buffalo, 2007.

Glucocorticoids represent a class of drugs that are commonly debated between their potent anti-inflammatory and immunosuppressive functions and strong adverse effects. This thesis aims at using a mechanism based modeling approach to assist in the characterization of corticosteroid actions, with a focus on the detrimental effects in skeletal muscle. The common adverse effects including muscle atrophy and insulin resistance were evaluated at the molecular and genomic levels. Integrated pharmacokinetic/pharmacodynamic/pharmacogenomic (PK/PD/PG) models were applied extensively throughout the thesis to examine corticosteroid drug performance and molecular and genomic dynamics and seeking the opportunities in designing optimal dosing strategies to minimize adverse effects.

ISBN: 9780542999543Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

Pharmacodynamics and pharmacogenomics of corticosteroids in rat skeletal muscle.
LDR:03725nam 2200325 a 45 001 938900
005 20110512
008 110512s2007 eng d
020 $a 9780542999543
035 $a (UMI)AAI3244262
035 $a AAI3244262
040 $a UMI $c UMI
100 1 $a Yao, Zhenling. $3 1262870
245 1 0 $a Pharmacodynamics and pharmacogenomics of corticosteroids in rat skeletal muscle.
300 $a 373 p.
500 $a Adviser: William J. Jusko.
500 $a Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6334.
502 $a Thesis (Ph.D.)--State University of New York at Buffalo, 2007.
520 $a Glucocorticoids represent a class of drugs that are commonly debated between their potent anti-inflammatory and immunosuppressive functions and strong adverse effects. This thesis aims at using a mechanism based modeling approach to assist in the characterization of corticosteroid actions, with a focus on the detrimental effects in skeletal muscle. The common adverse effects including muscle atrophy and insulin resistance were evaluated at the molecular and genomic levels. Integrated pharmacokinetic/pharmacodynamic/pharmacogenomic (PK/PD/PG) models were applied extensively throughout the thesis to examine corticosteroid drug performance and molecular and genomic dynamics and seeking the opportunities in designing optimal dosing strategies to minimize adverse effects.
520 $a Corticosteroid-induced muscle atrophy was studied in both adrenalectomized (ADX) and normal rats using glutamine synthetase (GS) and myostatin as PD biomarkers. Temporary increases of both biomarkers were observed following treatment of various corticosteroids including methylprednisolone (MPL), dexamethasone and hydrocortisone. In addition, physiological circadian rhythm was present for GS with dependency on plasma corticosterone (CST) concentrations. An integrated model extended from the 5th-generation model was established. Simulations of various dosing times provide insights for future studies of corticosteroid dosing optimization.
520 $a An optimal dosing strategy necessitates the studies not only on detrimental effects but also on beneficial actions of corticosteroids, with the prerequisite of maintaining desired effects within therapeutic window. In this dissertation, lymphocytopenia was tested as a biomarker component of anti-inflammatory and immunosuppressive effects. A mechanism based PK/PD model incorporating cell trafficking and apoptosis was proposed and assessed the pharmacological differences between humans and rats in response to MPL.
520 $a The global pharmacogenomic actions of MPL in ADX rat skeletal muscle were evaluated using a microarray technique. Diverse gene dynamic profiles were observed indicating various complex regulatory mechanisms involved in corticosteroid actions. Genes regulated by MPL were also studied according to their functions. Dynamics of six insulin resistance related genes were closely examined and testable hypotheses of the regulatory cascades were proposed.
520 $a In summary, this dissertation allows for better understanding of the physiologic, pharmacological, and genomic mechanisms involved in glucocorticoid actions on skeletal muscle including muscle atrophy and insulin resistance. Sophisticated PK/PD models integrating drug exposure with biological signaling events may assist minimization of steroid-induced side effects.
590 $a School code: 0656.
650 4 $a Health Sciences, Pharmacology. $3 1017717
650 4 $a Health Sciences, Pharmacy. $3 1017737
690 $a 0419
690 $a 0572
710 2 0 $a State University of New York at Buffalo. $3 1017814
773 0 $t Dissertation Abstracts International $g 67-11B.
790 $a 0656
790 1 0 $a Jusko, William J., $e advisor
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3244262