Abstract

Controlled release of lidocaine as a model drug from polyurethane matrices will be investigated as a novel approach for the therapy of experimental ventricular tachycardia (VT) and prevention of ventricular fibrillation (VF). Ventricular tachyarrhythmias are a leading cause of morbidity and mortality. Current therapy has been only partially effective in the management of this problem, and virtually all of the anti-arrhythmic agents have significant adverse effects related in part to systemic administration. The objective of this proposal will be to investigate this unique approach to antiarrhythmic administration in dogs. It is hypothesized that controlled release of minimal but drug doses will produce high local concentration at the site where it is needed will be effective while avoiding adverse effects associated with systemic administration.
The specific aims of the project are: 1) Formulate lidocaine- polyurethane controlled release matrices, with either a fixed or magnetically modulated release rate. 2) Investigate the effectiveness of controlled release lidocaine for experimental ventricular tachyarrhythmias in the dog. 3) Formulate a strategy for the computer controlled closed-loop feed-back modulation of site specific controlled release. The goal of this program will be to explore the advantages of controlled release for cardiac arrhythmias.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL041663-04
Application #
3359506
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1989-07-01
Project End
1994-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Perlstein, Itay; Burton, Denise Y; Ryan, Kenneth et al. (2005) Posttranslational control of a cardiac ion channel transgene in vivo: clarithromycin-hMiRP1-Q9E interactions. Hum Gene Ther 16:906-10
Cohen-Sacks, Hagit; Elazar, Victoria; Gao, Jianchuan et al. (2004) Delivery and expression of pDNA embedded in collagen matrices. J Control Release 95:309-20
Burton, Denise Y; Song, Cunxian; Fishbein, Ilia et al. (2003) The incorporation of an ion channel gene mutation associated with the long QT syndrome (Q9E-hMiRP1) in a plasmid vector for site-specific arrhythmia gene therapy: in vitro and in vivo feasibility studies. Hum Gene Ther 14:907-22
Panyam, Jayanth; Dali, Manisha M; Sahoo, Sanjeeb K et al. (2003) Polymer degradation and in vitro release of a model protein from poly(D,L-lactide-co-glycolide) nano- and microparticles. J Control Release 92:173-87
Abrahams, John M; Song, Cunxian; DeFelice, Suzanne et al. (2002) Endovascular microcoil gene delivery using immobilized anti-adenovirus antibody for vector tethering. Stroke 33:1376-82
Levy, R J; Song, C; Tallapragada, S et al. (2001) Localized adenovirus gene delivery using antiviral IgG complexation. Gene Ther 8:659-67
Ciftci, K; Levy, R J (2001) Enhanced plasmid DNA transfection with lysosomotropic agents in cultured fibroblasts. Int J Pharm 218:81-92
Cohen, H; Levy, R J; Gao, J et al. (2000) Sustained delivery and expression of DNA encapsulated in polymeric nanoparticles. Gene Ther 7:1896-905
Nielsen, L B; Sullivan, M; Vanni-Reyes, T et al. (1999) The DNA sequences required for apolipoprotein B expression in the heart are distinct from those required for expression in the intestine. J Mol Cell Cardiol 31:695-703
Labhasetwar, V; Strickberger, S A; Underwood, T et al. (1998) Prevention of acute inducible atrial flutter in dogs by using an ibutilide-polymer-coated pacing electrode. J Cardiovasc Pharmacol 31:449-55

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