application): To prevent heparin-induced postoperative bleeding, protamine is used in virtually all of 400,000 cardiac operations and 20-30% of the over 600,000 peripheral vascular operations to reverse the anticoagulant effects of heparin. Intravenous administration of protamine, however, can cause life-threatening adverse reactions. In fact, the combined use of heparin and protamine has been suggested as the major cause of morbidity and mortality for patients undergoing cardiovascular surgeries. Although a number of approaches have been attempted, protamine remains as the clinical drug of choice to heparin neutralization to date, due to its unmatched reliability, efficacy, and low costs. A recent authoritative review by clinical experts in the related field has concluded that the ideal heparin-neutralizing agent should be, quote: """"""""a compound providing all such advantages of protamine, yet lacking anaphylactic potential and preserving hemodynamic stability when infused rapidly."""""""" An explicit examination of the mechanisms of heparin neutralization and protamine toxicity suggests that a complete electrostatic neutralization of heparin may require only a small but intact arginine-rich fragment in protamine, whereas the toxicity of protamine is attributed primarily to its polycationic and polymeric nature. Thus, a chain-shortened low molecular weight protamine (LMWP) species, if can be derived from native protamine and contains solely the required heparin-neutralizing domain, may fulfill the requirements of the ideal heparin-neutralizing agent. In addition, such a LMWP species may also be devoid of antigenicity and immunogenicity; both are known to contribute significantly to the induced toxic effects. The ultimate goal of this project is therefore to develop LMWP as the ideal, effective and yet non-toxic heparin-neutralizing agent. In this STTR Phase I application, we plan to follow the precedent methodology in deriving low molecular weight heparin (LMWH) from heparin) to demonstrate the feasibility of the proposed approach. Once proven feasible, Phase II work will be focused on the complete development and testing of the LMWP species. In Phase III, ISTN Inc. will pursue with funds from industrial partners or licensee (identified during Phase II) the commercialization of the products.

Proposed Commercial Applications

NOT AVAILABLE

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
Project #
1R41HL059705-01A1
Application #
2767606
Study Section
Special Emphasis Panel (ZRG3-SSS-Z (01))
Project Start
1999-04-01
Project End
2000-09-30
Budget Start
1999-04-01
Budget End
2000-09-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Industrial Science & Technology Network
Department
Type
DUNS #
159817535
City
York
State
PA
Country
United States
Zip Code
17404
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