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Pharmacokinetics of local intramyoca...

Altman, Peter A.

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Pharmacokinetics of local intramyocardial delivery.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Pharmacokinetics of local intramyocardial delivery./
Author:	Altman, Peter A.
Description:	142 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 5064.
Contained By:	Dissertation Abstracts International64-10B.
Subject:	Engineering, Biomedical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3109909

Pharmacokinetics of local intramyocardial delivery.
Altman, Peter A.

Pharmacokinetics of local intramyocardial delivery. - 142 p.

Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 5064.

Thesis (Ph.D.)--University of California, San Francisco with the University of California, Berkeley, 2003.

Local delivery of therapeutic cells, genes, and proteins is on the forefront of clinical medicine. These therapeutic strategies are dependent upon the local pharmacokinetics, or time course of agent distribution within the target tissue. Local pharmacokinetics is dependent on properties of the agents delivered, the method of delivery, and the tissue to which they are delivered. The goal of this work was to qualitatively and quantitatively explore the pharmacokinetics of local intramyocardial delivery that may be performed noninvasively with a percutaneous catheter system. Transepicardial intramyocardial deliveries were performed in <italic>in vitro</italic> swine studies using methylene blue dye, and in <italic>in vivo</italic> rat studies using fluorescent microspheres ranging from 20nm to 15000nm in diameter. These qualitative studies enabled investigation of the three dimensional redistribution after delivery and the pathways by which agents redistribute within the tissue. These in turn yielded practical considerations of import for cell based therapies, therapies for antirestenosis, and local delivery to promote therapeutic angiogenesis. A percutaneous transendocardial delivery system was then developed and the ability of this system to successfully pass skeletal muscle cells, plasmid based gene therapies, adenoviral gene therapies, and microspheres without degradation was performed. For two tracer agents, this percutaneous transendocardial system was then used in local intramyocardial <italic>in vivo</italic> swine delivery studies to quantify the retention, biodistribution, and distribution pathways out of the tissue. The first experiment using radiolabeled bovine serum albumin, incorporated sampling catheters at the venous and arterial egress of the heart tissue. The second experimental tracer was fluorescent 15μm diameter microspheres with seven distinct spectral emissivities, as they became trapped in the first capillary bed that they entered. Combined, these quantitative studies demonstrate that intramyocardial transport after delivery involves venous transport out of the tissue. On average, 15.2% of radiolabeled albumin and 11.1% of 15μm microspheres remained localized within the target tissue. Both results support that local transendocardial intramyocardial delivery significantly increases the therapeutic window when compared to other systemic or local delivery strategies for similar classes of therapeutics using percutaneous delivery strategies. These quantitative results support that transendocardial intramyocardial delivery may be a preferred route for future administration of biotherapeutic agents to the heart in routine clinical use.Subjects--Topical Terms:

1017684
Engineering, Biomedical.

Pharmacokinetics of local intramyocardial delivery.
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100 1 $a Altman, Peter A. $3 1947071
245 1 0 $a Pharmacokinetics of local intramyocardial delivery.
300 $a 142 p.
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500 $a Adviser: Dorian Liepmann.
502 $a Thesis (Ph.D.)--University of California, San Francisco with the University of California, Berkeley, 2003.
520 $a Local delivery of therapeutic cells, genes, and proteins is on the forefront of clinical medicine. These therapeutic strategies are dependent upon the local pharmacokinetics, or time course of agent distribution within the target tissue. Local pharmacokinetics is dependent on properties of the agents delivered, the method of delivery, and the tissue to which they are delivered. The goal of this work was to qualitatively and quantitatively explore the pharmacokinetics of local intramyocardial delivery that may be performed noninvasively with a percutaneous catheter system. Transepicardial intramyocardial deliveries were performed in <italic>in vitro</italic> swine studies using methylene blue dye, and in <italic>in vivo</italic> rat studies using fluorescent microspheres ranging from 20nm to 15000nm in diameter. These qualitative studies enabled investigation of the three dimensional redistribution after delivery and the pathways by which agents redistribute within the tissue. These in turn yielded practical considerations of import for cell based therapies, therapies for antirestenosis, and local delivery to promote therapeutic angiogenesis. A percutaneous transendocardial delivery system was then developed and the ability of this system to successfully pass skeletal muscle cells, plasmid based gene therapies, adenoviral gene therapies, and microspheres without degradation was performed. For two tracer agents, this percutaneous transendocardial system was then used in local intramyocardial <italic>in vivo</italic> swine delivery studies to quantify the retention, biodistribution, and distribution pathways out of the tissue. The first experiment using radiolabeled bovine serum albumin, incorporated sampling catheters at the venous and arterial egress of the heart tissue. The second experimental tracer was fluorescent 15μm diameter microspheres with seven distinct spectral emissivities, as they became trapped in the first capillary bed that they entered. Combined, these quantitative studies demonstrate that intramyocardial transport after delivery involves venous transport out of the tissue. On average, 15.2% of radiolabeled albumin and 11.1% of 15μm microspheres remained localized within the target tissue. Both results support that local transendocardial intramyocardial delivery significantly increases the therapeutic window when compared to other systemic or local delivery strategies for similar classes of therapeutics using percutaneous delivery strategies. These quantitative results support that transendocardial intramyocardial delivery may be a preferred route for future administration of biotherapeutic agents to the heart in routine clinical use.
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