Protamine fragment compositions and methods of use

Abstract

Provided are bioactive, low-toxicity protamine fragments, compositions, combinations, kits and methods of using these components in a variety of embodiments, including neutralizing heparin and reducing post-operative bleeding. Improved protamine fragment-insulin solutions and methods for treating diabetes are also provided.

Description

[0001] The present application claims priority to provisional application Ser. No. 60 / 124,873, filed Mar. 17, 1999, the entire specification, claims and figures of which are each incorporated herein by reference without disclaimer.[0002] The U.S. Government owns rights in the present invention pursuant to grant numbers RO1 HL38353 and RO1 HL55461 from the National Institutes of Health.BACKGROUND OF THE INVENTION [0003] 1. Field of the Invention [0004] The present invention relates generally to the fields of protein biochemistry and medicine. More particularly, it concerns bioactive, low-toxicity fragments of protamine, and a number of different uses of such protamine fragment compositions. Provided are protamine fragments, compositions, combinations and kits and various methods and uses of such fragments, e.g., in the neutralization of heparin and for association with a variety of therapeutic proteins, including insulin. [0005] 2. Description of Related Art [0006] Heparin has become...

AI Technical Summary

Benefits of technology

[0018] The present invention overcomes one or more of these and other shortcomings in the art by providing bioactive protamines and compositions, combinations and kits thereof, in which the protamines have reduced immunogenicity, antigenicity and / or toxicity compared to native protamine. Preferably, the bioactive, low-toxicity protamines and compositions thereof are low molecular weight protamines. Various methods and uses of such low molecular weight bioactive protamines, compositions, combinations and kits are also provided, including antagonizing heparin functions to reduce post-operative bleeding and prolonging the adsorption of insulin to treat diabetes.

Problems solved by technology

Systemic heparinization, however, results in a high incidence of bleeding complications (Hirsh, 1984; Kelton and Hirsh, 1984).

Aside from hemorrhage, there are also other complications associated with the use of heparin, particularly when the drug is administered over a long period.

However, it is of insufficient length to bind thrombin and catalyze the inhibition of thrombin by ATIII.

A major drawback of LMWH lies in the absence of an appropriate clinical antidote to combat the potential risk of induced bleeding.

Protamine, however, cannot completely neutralize the anticoagulant activities of low molecular weight heparins (Lechner et al., 1995; Ryn-McKenna et al., 1990; Harenberg et al., 1985; Diness and Ostergaard, 1986; Wakefield et al., 1994), apparently due to an insufficient binding affinity between protamine and LMWH.

However, despite its nearly universal use in clinical practice, current formulations of protamine are nevertheless toxic.

Anaphylactic types of responses produced via the second pathway, however, are unpredictable, not preventable, and always life-threatening.

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