Treatment of bleeding with modified tissue factor in combination with an activator of FVII
AssigneeOklahoma Medical Research Foundation
InventorsJames H. Morrissey, Philip C. Comp
Life of this patent
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Abstract
It has been discovered that it is possible to administer truncated tissue factor (not having the transmembrane region) (tTF) in combination with factor VIIa (FVIIa) or an activator of endogenous factor VII to treat bleeding disorders such as those resulting from hemophilia or cirrhosis of the liver. The tTF is administered to produce up to 10 .mu.g tTF/ml of plasma. The FVIIa or FVII activator is administered to produce levels of between 40 ng FVIIa/ml and 700 ng FVIIa/ml of plasma. The effective dosages of both tTF and FVIIa/factor VII activator are significantly and surprisingly less than the administration of either alone to stop bleeding. Examples demonstrate safety and efficacy in normal and hemophilic dogs.
Claims19
A method for treating a patient for excessive bleeding occurring at a site, comprising the step of:
- administering an effective amount of a truncated tissue factor protein having an amino acid sequence differing from that of native tissue factor in that sufficient transmembrane amino acids which function to bind native tissue factor to phospholipid membranes are lacking from said truncated tissue factor protein so that said truncated tissue factor protein does not bind to phospholipid membranes, and an effective amount of an activator of endogenous Factor VII to said patient to effect clotting of said patient's blood at said site and subsequent reduction of said excessive bleeding.
A method for treating a patient for excessive bleeding occurring at a site, comprising the step of:
- administering an effective amount of a truncated tissue factor protein having the amino acid sequence set forth in SEQ ID NO:2 from position 1 to 219 and an effective amount of an activator of endogenous Factor VII to said patient to effect clotting of said patient's blood at said site and subsequent reduction of said excessive bleeding.
A method for treating a patient to control bleeding, comprising administering a truncated tissue factor having the amino acid sequence set forth in SEQ ID NO:2 from position 1 to 219 and an activator of endogenous Factor VII to said patient, said truncated tissue factor in a sufficient amount to produce a level of from about 100 nanograms to about 50 micrograms of said truncated tissue factor per milliliter of plasma and said activator of endogenous Factor VII in a sufficient amount to produce a level of from about 20 nanograms to about 700 nanograms Factor VIIa per milliliter of plasma.
A pharmaceutical composition for treating excessive bleeding comprising a truncated tissue factor protein having an amino acid sequence which differs from that of native tissue factor in that sufficient transmembrane amino acids which function to bind native tissue factor to phospholipid membranes are lacking from said truncated tissue factor protein so that said truncated tissue factor protein does not bind to phospholipid membranes, and an activator of endogenous Factor VII.
A pharmaceutical composition for systemic administration to a patient to control bleeding, comprising a combination of a truncated tissue factor having the amino acid sequence of SEQ ID NO:2 from position 1 to 219 and an activator of endogenous Factor VII, said truncated tissue factor and said activator of endogenous Factor VII in sufficient quantity to effect clotting of said patient's blood at a desired site.
A pharmaceutical composition for topical administration to a patient comprising a pharmaceutically acceptable carrier for topical administration, about 100 nanograms to about 50 micrograms of a truncated tissue factor having the amino acid sequence of SEQ ID NO:2 from position 1 to 219 per milliliter of said carrier and from about 1 to about 10 micrograms of an activator of endogenous Factor VII per milliliter of said carrier.
Dependencies are inferred from the claim text.