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Abstract

Grant Number: 5R44HL059705-03
PI Name: ZHANG, RUIYUN
PI Email:
PI Title:
Project Title: Effective and Non-toxic Antagonist to Heparin and LMWH

Abstract: To prevent heparin-induced bleeding, protamine is used in nearly 2,000,000 cardiac/vascular operations to reverse the anticoagulant effects of heparin. Intravenous use of protamine, however, can cause life-threatening adverse reactions. In fact, the combined use of heparin and protamine was suggested as the major cause of morbidity and mortality for patients undergoing such surgeries. Although many attempts have been made, to date, protamine remains as the sole clinical heparin antidote; due to its unmatched reliability, efficacy, and low costs. A recent authoritative review by clinicians concluded that the ideal heparin-neutralizing agent should be a compound that provided all advantages and yet lacked anaphylactic potential of protamine. An explicit examination of the mechanism of heparin neutralization and protamine toxicity by us suggests that complete heparin neutralization may require only a small 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), if it can be derived from protamine to contain only the heparin-neutralizing domain, could be this ideal heparin- neutralizing agent. Further, this LMWP may also be devoid of antigenicity and immunogenicity; both are known to contribute significantly to protamine toxicity. The ultimate goal of this SBIR project is therefore to develop LMWP to be a non-toxic, wholesale protamine substitute. During the Phase I work, the feasibility of this approach was successfully demonstrated. In this Phase II application, the focus is to demonstrate the utility of the approach in aborting all patients, either diabetic or non-diabetic, with or without pre- development of anti-protamine antibodies in their system, from possible attack of protamine allergy. In Phase III, ISTN will team up with identified industrial partners to proceed FDA-approved clinical trials, standarization of the compound under GMP, and commercialization of the final LMWP products. PROPOSED COMMERCIAL APPLICATION: Our assessment made in Section 3.5.3.3 indicates that the annual protamine production totals 1 metric ton in the US and 10 metric tons worldwide. The main objective of this SBIR project is to develop LMWP as a non-toxic protamine substitute without the risk of protamine allergy. If proves successful, it is expected that LMWP would become a wholesale replacement of protamine in all its pharmacological and clinical uses. The commencial potential of this project is therefore enormous.

Thesaurus Terms:
cytotoxicity, drug design /synthesis /production, drug screening /evaluation, hemodynamics, heparin, immunologic substance development /preparation, inhibitor /antagonist, molecular weight, protamine
anticoagulant, antigen, arginine, biotherapeutic agent, blood coagulation, cross immunity, drug quality /standard, extracorporeal circulation, immunogenetics, insulin dependent diabetes mellitus, pharmacokinetics
laboratory mouse, laboratory rat

Institution: INDUSTRAIL SCIENCE & TECHNOLOGY NETWORK
2101 PENNSYLVANIA AVE
YORK, PA 17404
Fiscal Year: 2003
Department:
Project Start: 01-APR-1999
Project End: 31-DEC-2004
ICD: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
IRG: ZRG1


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