US5504064A
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US
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Treatment of bleeding with modified tissue factor in combination with an activator of FVII
Assignee: Oklahoma Medical Research Foundation
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Filing: 1993-02-19
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Granted: 1996-04-02
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Expires: 2013-02-19
Abstract
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 μg 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.
Inventors
- 👤 James H. Morrissey
- 👤 Philip C. Comp
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 10:13
CPC Classifications
A; A61; A61K; A61K38/00; A61K38/16; A61K38/43; A61K38/46; A61K38/48; A61K38/482; A61K38/4846; A61P; A61P7/00; A61P7/04; G; G01; G01N; G01N33/00; G01N33/48; G01N33/50; G01N33/68; G01N33/86; G01N2333/00; G01N2333/435; G01N2333/745; G01N2333/90; G01N2333/914; G01N2333/948; G01N2333/95; G01N2333/964; G01N2333/96425; G01N2333/96427; G01N2333/9643; G01N2333/96433; G01N2333/96441; G01N2333/96447; G01N2405/00; G01N2405/04
Claims Analysis
Total Claims: 25
Claim 1
Independent Claim
107 words
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.
Claim 2
Independent Claim
107 words
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.
Claim 3
Independent Claim
74 words
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.
Claim 4
Independent Claim
74 words
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.
Claim 5
Independent Claim
101 words
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.
Claim 6
Independent Claim
101 words
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.
Claim 7
Dependent Claim
31 words
A method for treating a patient to control bleeding according to claim 3 wherein said truncated tissue factor and said activator of endogenous Factor VII are administered simultaneously to said patient.
Claim 8
Dependent Claim
31 words
A method for treating a patient to control bleeding according to claim 3 wherein said truncated tissue factor and said activator of endogenous Factor VII are administered sequentially to said patient.
Claim 9
Dependent Claim
31 words
A method for treating a patient to control bleeding according to claim 3 wherein said truncated tissue factor and said activator of endogenous Factor VII are administered systemically to said patient.
Claim 10
Dependent Claim
76 words
A method for treating a patient to control bleeding according to claim 6 wherein a sufficient amount of said truncated tissue factor is administered to produce a level of from about 1 microgram to about 10 micrograms truncated tissue factor per milliliter of plasma and wherein a sufficient amount of said activator of endogenous Factor VII is administered to produce a level of between about 40 nanograms and 700 nanograms Factor VIIa per milliliter of plasma.
Claim 11
Dependent Claim
32 words
A method for treating a patient to control bleeding according to claim 3 wherein said truncated tissue factor and said activator of endogenous Factor VII are administered topically to a wound site.
Claim 12
Dependent Claim
85 words
A method for treating a patient to control bleeding according to claim 8 wherein a sufficient amount of said truncated tissue factor is administered to produce a local concentration in said wound site of from about 10 to about 50 micrograms truncated tissue factor per milliliter of plasma and a sufficient amount of said activator of endogenous Factor VII is administered to produce a local concentration in said wound site of from about 40 nanograms to about 700 nanograms Factor VIIa per milliliter of plasma.
Claim 13
Dependent Claim
34 words
A method for treating a patient to control bleeding according to claim 3, wherein said truncated tissue factor and said activator of endogenous Factor VII are administered to control surgical bleeding from the microvasculature.
Claim 14
Dependent Claim
31 words
A method for treating a patient to control bleeding according to claim 3, wherein said truncated tissue factor and said activator of endogenous Factor VII are administered to control postoperative bleeding.
Claim 15
Dependent Claim
33 words
A method for treating a patient to control bleeding according to claim 3, wherein said truncated tissue factor and said activator of endogenous Factor VII are administered to control bleeding secondary to thrombocytopenia.
Claim 16
Dependent Claim
35 words
A method for treating a patient to control bleeding according to claim 3, wherein said truncated tissue factor and said activator of endogenous Factor VII are administered to control bleeding of patients with platelet dysfunction.
Claim 17
Dependent Claim
48 words
The method of claim 3, wherein said activator of endogenous Factor VII is selected from the group consisting of Factor Xa in combination with phospholipid, Factor IXa in combination with phospholipid, thrombin, Factor XIIa, and an FVII activator from the venom of Oxyuranus scutellatus in combination with phospholipid.
Claim 18
Dependent Claim
16 words
The method of claim 3, wherein said activator of Factor VII comprises Factor Xa and phospholipid.
Claim 19
Dependent Claim
39 words
The method of claim 15, wherein from about 12 to about 26 pmoles Factor Xa and from about 19 to about 40 pmoles phospholipid per kg body weight of said patient are administered as said activator of Factor VII.
Claim 20
Dependent Claim
70 words
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.
Claim 21
Dependent Claim
70 words
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.
Claim 22
Dependent Claim
66 words
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.
Claim 23
Dependent Claim
66 words
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.
Claim 24
Dependent Claim
68 words
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.
Claim 25
Dependent Claim
68 words
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.
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