CN1304050C - Pharmaceutical composition comprising factor VII polypeptides and factor XI polypeptides - Google Patents
Pharmaceutical composition comprising factor VII polypeptides and factor XI polypeptides Download PDFInfo
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- CN1304050C CN1304050C CNB028185390A CN02818539A CN1304050C CN 1304050 C CN1304050 C CN 1304050C CN B028185390 A CNB028185390 A CN B028185390A CN 02818539 A CN02818539 A CN 02818539A CN 1304050 C CN1304050 C CN 1304050C
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- factor
- thromboplastin antecedent
- plasma thromboplastin
- polypeptide
- factor vii
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Abstract
The present invention relates to a composition comprising a factor VII or factor VII-related polypeptide and a factor XI or factor XI-related polypeptide, and the use thereof for treating bleeding episodes.
Description
Technical field
The present invention relates to contain the Pharmaceutical composition of factor VII or factor VII-dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide.The invention still further relates to factor VII or factor VII-dependency polypeptide and combine with factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide and be used to prepare treatment and suffer from the experimenter of bleeding episodes, or prevent the purposes in the medicine of its outbreak.The invention still further relates to the method for treatment experimenter bleeding episodes and promote the experimenter to form the method for blood coagulation.The invention still further relates to the test kit that contains these chemical compounds.
Background technology
Hemostasis is exposed to after by vascular damaged in tissue factor (TF) in the blood circulation and the circulation starts to form complex between the FVIIa that exists corresponding to about 1% total FVII protein quality.This complex anchor on the cell that carries TF and on cell surface and FX to be activated into FXa and FIX is activated into FIXa.FXa activates into thrombin with thrombinogen, and the latter activates FVIII, FV, FXI and FXIII.In addition, the limited amount thrombin that forms in the hemostasis initial step also activates platelet.Work its alteration of form of back and expose the charged phospholipid on its surface of thrombin on platelet.This activated platelet surface forms the template that FX further activates and thrombin fully produces.By forming the FIXa-FVIIIa complex, make and further activate FX that FXa still is transformed into thrombin on this surface with thrombinogen then at activated platelet surface at activated platelet surface.Thrombin is transformed into fibrinogen insoluble and stablizes the fibrin of initial platelet thromboembolism then.This process is compartmentalization, promptly is confined to the site that TF expresses or exposes, thereby makes general activate the risk minimization of blood coagulation system.The thromboembolism that insoluble fibrin forms is crosslinked further stable by the catalytic fibrin fiber of FXIII-.
FVIIa mainly exists with the strand proenzyme in blood plasma, and this proenzyme is cracked into its double-stranded activated form, i.e. FVIIa by FXa.Developed reorganization activation factor VIIa (rFVIIa) as short hemostasis (pro-haemostatic) agent.Can not use rFVIIa among the hemorrhage hemophilia experimenter with suffering from of thrombin product treatment owing to form antibody, can produce rapidly and short efficiently hemostasis reaction.Also can successfully treat the hemorrhage experimenter who suffers from factor VII deficiency or have normal blood coagulation system but the too much hemorrhage experimenter of generation with FVIIa.In these researchs, do not find the adverse side effect (thromboembolism particularly occurring) of rFVIIa.
The thrombin that the extra exogenous FVIIa of using is increased on the activated platelet surface forms.This takes place in the hemophilia experimenter of the effective way that lacks that thereby FIX or FVIII forfeiture thrombin fully forms.In addition, have under the situation of functional defect in platelet counts reduction or platelet, extra FVIIa increases thrombin and forms.
The article of commerce of recombined human FVIIa is sold (Novo NordiskA/S, Denmark) with NovoSeven .Novoseven indicates the bleeding episodes that is used for the treatment of hemophilia A and B patient.Novoseven is the obtainable unique reorganization FVIIa that is used for effectively and reliably treating bleeding episodes on the market.
FXI is the component of intrinsic coagulation approach.FXI lack with particularly in tissue with highly local fibrinolytic activity slightly to arrive the hemorrhage disorder of moderate relevant.On the contrary, it is believed that high-caliber FXI is the risk factor of venous thrombosis.FXI is by FXIIa, the proenzyme of thrombin and the activated trypsin-like serine protease of FXIa.Activatory FXI (FXIa) participates in the activation of FIX, and the latter (combines with FVIII) again and further activates FX and therefore cause thrombin generation.
Relevant with operation or the severe trauma experimenter who goes out hyperhematosis and need blood transfusion does not form more complication and knows than experiencing any hemorrhage experimenter.Yet the hemorrhage needs of moderate are used human blood or blood products (platelet, leukocyte, the concentrate that is used for the treatment of the blood plasma source of blood coagulation defective, Deng) also can cause and the relevant complication of danger of transmitting Human virus's (hepatitis, virus that HIV, parvovirus and other are unknown so far).The a large amount of blood transfusions of extensive hemorrhage needs can cause forming the depletion of a plurality of organs, comprise infringement lung and renal function.In case the experimenter forms these severe complications, the cascade event and the inflammatory reaction that relate to many cytokines just begin, make any treatment all very the difficulty and unfortunately all get nowhere usually.Therefore, the main target in operation and the treatment of serious tissue injury be avoid or minimize hemorrhage.For fear of or minimize this hemorrhagely, guarantee to form that to be not easy by the dissolved stabilization of solid tampon of fibrinoclase be important.And, importantly guarantee fast and effectively to form this thromboembolism or blood coagulation.
Now, the experimenter of experience bleeding episodes, comprise the wound victim and with the relevant hemorrhage experimenter of operation, treat with injection or infusion FVIIa several times usually, the hemostatic capability of certain level is kept in the administration more than need be once because of the half life of FVIIa short (2.5 hours).The quickening prevention is hemorrhage to have important benefits to this experimenter.It also is like this stopping minimizing hemorrhage and that keep the required administration number of times of hemostasis.
Japanese patent application 59-116213A relates to and contains the aerosol composition of coagulant as active ingredient as tissue adhesive.This coagulant is optional from thrombin I, II, III, IV, V, VII, VIII, IX, X, XI, XII, and XIII, prekallikrein, high polymer kininogen and thrombin.The combination of preferred F XIII and thrombin.
The compositions and being used for the treatment of that European patent 225.160 (Novo Nordisk) relates to FVIIa is not the method for the hemorrhagic disease that caused by thrombin defective or blood coagulation factor inhibitors.
The compositions that European patent 82.182 (Baxter Travenol Lab.) relates to factor VIIa in the experimenter to the purposes of anticoagulin defective or as the influence of inhibitor to thrombin.
International Patent Application WO 93/06855 (Novo Nordisk) relates to the topical application of FVIIa.
United States Patent (USP) 5,252,217 relate to the method that preparation is used for the treatment of people's factor XI, plasma thromboplastin antecedent concentrate of purposes.
This area still needs the experimenter of experience bleeding episodes is carried out the modified form treatment, comprises the bleeding episodes that is caused by following reason: by operation, and wound, or the tissue injury of other form causes; The induction type coagulopathy is included in the coagulopathy among the experimenter who repeatedly transfuses blood; Congenital or acquired blood coagulation or hemorrhagic disease comprise that liver function reduces (" hepatic disease "); Deficiency platelet function or number of platelets reduce; Main blood coagulation " chemical compound " (for example, platelet or Feng. von willebrand's factor albumen) shortage or unusual; Fibrinolysis increases; Anticoagulant therapy or thrombolytic therapy; Or stem cell transplantation.
This area still needs to improve, reliably and the method that extensively is suitable for be used to strengthen blood coagulation, strengthen or guarantee to form stable tampon, or improve treatment experimenter's convenience, or, particularly realize hemostasis fully among the experimenter that thrombin generation reduces the experimenter.Also need to reduce the method for the FVIIa amount that realizes stopping blooding required fully and shortened and stoped hemorrhage time method.
Summary of the invention
An object of the present invention is to provide the compositions that can be effective to treat or prevent bleeding episodes and blood coagulation disease.
Second purpose of the present invention provides the compositions of single unit dosage form, and it can be effective to treatment or prevention bleeding episodes or as procoagulant.Another object of the present invention provides the compositions that shows cooperative effect, Therapeutic Method or test kit.
Another object of the present invention provides and shows no remarkable side effect, and for example high-caliber general activates compositions, Therapeutic Method or the test kit of blood coagulation system.
Other purpose of the present invention will be conspicuous when reading this description.
Aspect first, the invention provides the Pharmaceutical composition that contains factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide.
Aspect second, the invention provides the test kit that contains the parts for the treatment of bleeding episodes, comprise
A) goods of the factor VII of the effective dose in first unit dosage form or factor VII dependency polypeptide and medicinal on acceptable carrier;
B) goods of the factor XI, plasma thromboplastin antecedent of the effective dose in second unit dosage form or factor XI, plasma thromboplastin antecedent dependency polypeptide and medicinal on acceptable carrier; With
C) contain the case of described first and second dosage forms.
In its different embodiment, this test kit also contains the TFPI-inhibitor and/or the Factor IX of effective dose; This TFPI-inhibitor or Factor IX (or both combinations) can be present in separately the unit dosage form or can be present in and contain factor VII or factor VII dependency polypeptide, perhaps in the unit dosage form of factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide.
Aspect the 3rd, the invention provides the purposes for preparing in the medicine for the treatment of experimenter's bleeding episodes that is combined in of factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide.On the other hand, the invention provides the purposes that each described compositions of claim 1 to 18 is used for preparing the medicine for the treatment of experimenter's bleeding episodes.
In its different embodiment, this medicine is used to shorten clotting time, prolongs the blood coagulation dissolution time and increases blood coagulation intensity.
In another embodiment, this medicine is mixed with and is used for intravenous administration, preferably injection or infusion, particularly injection.
In one embodiment, this medicine is mixed with single unit dosage form; It is mixed with first unit dosage form that contains factor VII or factor VII dependency polypeptide product and the form that contains second unit dosage form of factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product in another embodiment.
In different embodiments, this medicine is used for the treatment of the experimenter who experiences bleeding episodes, and described bleeding episodes is caused by following reason: operation, wound, or the tissue injury of other form; Coagulopathy is included in the coagulopathy among the experimenter who repeatedly transfuses blood; Congenital or acquired blood coagulation or hemorrhagic disease comprise that liver function reduces (" hepatic disease "); Deficiency platelet function or number of platelets reduce; Main blood coagulation " chemical compound " (for example, platelet or Feng. von willebrand's factor albumen) shortage or unusual; Fibrinolysis increases; Anticoagulant therapy or thrombolytic therapy; Stem cell transplantation.In a series of embodiment, hemorrhage occurring in such as brain, interior ear field, eye, liver, lung, tumor tissues is in the gastrointestinal organ; In another serial embodiment, it is that diffusion-type is hemorrhage, for example hemorrhagic gastritis and too much metrorrhagia.In another serial embodiment, bleeding episodes is to have acute hemorrhagic arthrosis (arthrorrhagia), chronic hemophilia arthrosis, hematoma, (muscle for example is behind the peritoneum, Sublingual and pharynx back) the experimenter in operation or wound interrelate hemorrhage, hemorrhage in other tissue, hematuria (the kidney road is hemorrhage), cerebral hemorrhage, operation (for example, hepatectomy), exodontia, and gastrointestinal hemorrhage (for example, UGI is hemorrhage).In one embodiment, this medicine is used for the treatment of among the experimenter because wound, or operation, or platelet count or the active bleeding episodes that causes that reduces.
On the other hand, the invention provides the method for treatment experimenter bleeding episodes, this method comprises that the experimenter to needs uses the factor VII of first amount or goods and the factor XI, plasma thromboplastin antecedent of second amount or the goods of factor XI, plasma thromboplastin antecedent dependency polypeptide of factor VII-dependency polypeptide, and wherein first and second amounts are hemorrhage effective to treating together.
On the other hand, the invention provides the method that shortens experimenter's clotting time, the experimenter that this method comprises to needs uses the factor VII of first amount or goods and the factor XI, plasma thromboplastin antecedent of second amount or the goods of factor XI, plasma thromboplastin antecedent dependency polypeptide of factor VII-dependency polypeptide, and wherein first and second amounts are effective to shortening clotting time together.
On the other hand, the invention provides and in the experimenter, strengthen the hemostatic method, the experimenter that this method comprises to needs uses the factor VII of first amount or goods and the factor XI, plasma thromboplastin antecedent of second amount or the goods of factor XI, plasma thromboplastin antecedent dependency polypeptide of factor VII-dependency polypeptide, and wherein first and second amounts are together to strengthening hemostasis effectively.
On the other hand, the invention provides the method that in the experimenter, prolongs the blood coagulation dissolution time, the experimenter that this method comprises to needs uses the factor VII of first amount or goods and the factor XI, plasma thromboplastin antecedent of second amount or the goods of factor XI, plasma thromboplastin antecedent dependency polypeptide of factor VII-dependency polypeptide, and wherein first and second amounts are effective to prolonging the blood coagulation dissolution time together.
On the other hand, the invention provides the method that in the experimenter, increases blood coagulation intensity, the experimenter that this method comprises to needs uses the factor VII of first amount or goods and the factor XI, plasma thromboplastin antecedent of second amount or the goods of factor XI, plasma thromboplastin antecedent dependency polypeptide of factor VII-dependency polypeptide, and wherein first and second amounts are effective to increasing blood coagulation intensity together.
In a series of embodiments of this method, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are with single unit dosage form administration.
In another serial embodiment, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are with first unit dosage form that contains factor VII or factor VII-dependency polypeptide product and the form administration that contains second unit dosage form of factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product.In the embodiment of an one series, first unit dosage form and second the interval administration of unit dosage form to be no more than 15 minutes.
On the other hand, the invention provides and contain the test kit for the treatment of bleeding episodes, comprise
D) factor XI, plasma thromboplastin antecedent of the factor VII of the effective dose in a unit dosage form or factor VII dependency polypeptide and effective dose or factor XI, plasma thromboplastin antecedent dependency polypeptide and medicinal on acceptable carrier; With
E) contain the case of a described unit dosage form.
In the embodiment of a series of the present invention, factor VII or factor VII dependency polypeptide are factor VII dependency polypeptide.In the embodiment of a series of the present invention, factor VII dependency polypeptide is a factor VII variant amino acid sequence body.In one embodiment, the ratio between the activity of the activity of factor VII dependency polypeptide and natural human factor VIIa (wild type FVIIa) is about at least 1.25 when detecting in this description described " extracorporeal hydrolysis test ".
In the embodiment of a series of the present invention, factor VII or factor VII dependency polypeptide are factor VII.In one embodiment, described factor VII is a human factor VII.In one embodiment, factor VII is a cattle, pig, dog, horse, Mus or salmon factor VII.In another embodiment, factor VII is the reorganization preparation.In another embodiment, factor VII derives from blood plasma.In a preferred embodiment, factor VII is the reorganization human factor VII.In the embodiment of a series of the present invention, factor VII or factor VII dependency polypeptide are its activated form.In a preferred embodiment of the invention, factor VII is the recombined human factor VIIa.
In the embodiment of a series, factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are factor XI, plasma thromboplastin antecedent dependency polypeptide.In one embodiment, factor XI, plasma thromboplastin antecedent dependency polypeptide is a factor XI, plasma thromboplastin antecedent variant amino acid sequence body.In one embodiment, the ratio between the activity of the activity of described factor XI, plasma thromboplastin antecedent dependency polypeptide and natural human plasma factor X I (wild type FXI) is about at least 1.25 when detecting in this description described " FXI produces colour test ".In one embodiment, factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are the factor XI, plasma thromboplastin antecedent polypeptide.In one embodiment, factor XI, plasma thromboplastin antecedent is people's factor XI, plasma thromboplastin antecedent.In one embodiment, factor XI, plasma thromboplastin antecedent is a cattle, pig, dog, horse, Mus or salmon factor XI, plasma thromboplastin antecedent.In a preferred embodiment, factor XI, plasma thromboplastin antecedent is the reorganization preparation.In another embodiment, factor XI, plasma thromboplastin antecedent derives from blood plasma.In another embodiment, factor XI, plasma thromboplastin antecedent is platelet-derived factor XI, plasma thromboplastin antecedent.In a preferred embodiment, factor XI, plasma thromboplastin antecedent is a recombined human blood plasma factor XI, plasma thromboplastin antecedent.In the embodiment of a series of the present invention, factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are its activated form.In one embodiment, factor XI, plasma thromboplastin antecedent dependency polypeptide is the segment of factor XI, plasma thromboplastin antecedent.In one embodiment, factor XI, plasma thromboplastin antecedent dependency polypeptide is a heterozygosis factor XI, plasma thromboplastin antecedent polypeptide, for example pig/people's heterozygote.In one embodiment, factor XI, plasma thromboplastin antecedent is human plasma activation factor XI (FXIa).
In one embodiment, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide were with about 100: 1 to about 1: 100 (w/w factor VII: the mass ratio existence factor XI, plasma thromboplastin antecedent).
In one embodiment, factor VII dependency polypeptide is to compare with wild type factor VII to have to be no more than 20 aminoacid replacement, and disappearance or the variant amino acid sequence body that inserts (that is, have U.S. Patent number 4, the polypeptide of disclosed aminoacid sequence in 784,950).In another embodiment, factor VII variant has and is no more than 15 amino acid whose replacements, disappearance or insert; In another embodiment, factor VII variant is compared with wild type factor VII has the replacement that is no more than 10 aminoacid (for example 8,6,5, or 3 aminoacid), disappearance or insertion.In one embodiment, factor VII variant is selected from L305V-FVIIa, L305V/M306D/D309S-FVIIa, L305I-FVIIa, L305T-FVIIa, F374P-FVIIa, V158T/M298Q-FVIIa, V158D/E296W/M298Q-FVIIa, K337A-FVIIa, M298Q-FVIIa, V158D/M298Q-FVIIa, L305V/K337A-FVIIa, V158D/E296V/M298Q/L305V-FVIIa, V158D/E296V/M298Q/K337A-FVIIa, V158D/E296V/M298Q/L305V/K337A-FVIIa, K157A-FVII, E296V-FVII, E296V/M298Q-FVII, V158D/E296V-FVII, V158D/M298K-FVII, and S336G-FVII.
In another embodiment, factor VII dependency polypeptide is compared the activity that does not rely on tissue factor with increase with natural human proconvertin a.In another embodiment, this activity increase is not accompanied by the change of substrate specificity.In another embodiment of the present invention, factor VII dependency polypeptide does not reduce with combining of tissue factor and factor VII dependency polypeptide has the activity of wild type factor VIIa when combining with tissue factor at least.
In a preferred embodiment, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are recombined human factor VIIa and recombined human blood plasma factor XI, plasma thromboplastin antecedent or recombined human factor VIIa and recombined human blood plasma factor XI, plasma thromboplastin antecedent a.
In one embodiment, the clotting time in the mammalian shortens.In another embodiment, the hemostasis in the mammalian strengthens.In another embodiment, the blood coagulation dissolution time in the mammalian prolongs.In another embodiment, the blood coagulation intensity in the mammalian improves.In one embodiment, mammalian is a human blood.In another embodiment, mammalian is normal human blood; In one embodiment, this blood is the blood from the experimenter with thrombin generation minimizing.In one embodiment, blood is the blood from the experimenter with one or more thrombin defectives; In another embodiment, blood is from the blood that has at the experimenter of the inhibitor of one or more thrombins; In one embodiment, blood is the blood from the experimenter with fibrinogen concentration reduction; In one embodiment, blood is the human blood of factor XI deficiency.In the embodiment of a series, blood is blood plasma.
In one embodiment, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide have prolonged the dissolution time of external blood coagulation in the human normal plasma.In another embodiment, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide have improved the external maximum blood coagulation intensity blood coagulation dissolution time among the human normal plasma.In another embodiment, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide have shortened human normal plasma's external clotting time.
In one embodiment of the invention, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent-dependency polypeptide unique hemorrhage of being in the said composition to be comprised.In another embodiment, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide unique active hemorrhage of being in the said composition to be comprised.In another embodiment, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are unique thrombins of using to the experimenter.In one embodiment of the invention, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are unique activating agents of using to the patient.In one embodiment, the essentially no thrombinogen of said composition; In another embodiment, the essentially no FX of said composition; In another embodiment, the essentially no FXa of said composition.
In another embodiment, this pharmaceutical composition is mixed with and is used for intravenously administrable, preferably injection or infusion, particularly injection.In one embodiment, said composition contains at least a medicinal acceptable excipient or the carrier.
In one embodiment of the invention, said composition is single unit dosage form, and wherein single unit dosage form contains two kinds of thrombins.In one embodiment of the invention, said composition is the assembling kit form, wherein contain factor VII or factor VII dependency polypeptide product as first unit dosage form and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product as second unit dosage form, and comprise case and be used to hold described first and second unit dosage forms.In one embodiment, said composition or test kit can further contain the description of using said composition respectively or separating component as required.
In one embodiment of the invention, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are with single dosage form administration.In one embodiment of the invention, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent-dependency polypeptide are with first unit dosage form of the goods that contain factor VII or factor VII dependency polypeptide with contain the form administration of second unit dosage form of the goods of factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide.
In one embodiment of the invention, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide administration simultaneously.In another embodiment, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or the administration successively of factor XI, plasma thromboplastin antecedent dependency polypeptide.In one embodiment, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide to be being no more than 15 minutes, and be preferred 10, and more preferably 5, more preferably 2 minutes interval administration.In one embodiment, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide be with up to 2 hours, preferred 1 to 2 hour, more preferably up to 1 hour, more preferably 30 minutes to 1 hour, more preferably up to 30 minutes, more preferably 15 to 30 minutes interval administration.
In one embodiment, the effective dose of factor VII or factor VII dependency polypeptide is the amount from about 0.05mg/ days to about 500mg/ days (experimenter of 70-kg).In one embodiment, the effective dose of factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product is from about 0.01mg/ days to about 500mg/ days (experimenter of 70-kg).
In one embodiment, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide were with about 100: 1 to about 1: 100 (w/w factor VII: the mass ratio existence factor XI, plasma thromboplastin antecedent).
In one embodiment of the invention, this Pharmaceutical composition is a single dosage form and basically by factor VII or factor VII dependency polypeptide product and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product, and be selected from medicinal acceptable excipient or the carrier, stabilizing agent, detergent, neutral salt, antioxidant, one or more compositions in antiseptic and the protease inhibitor are formed.
In another embodiment, the experimenter is the people; In another embodiment, experimenter's thrombin generation is impaired; In one embodiment, the plasma concentration of experimenter's fibrinogen reduces (for example, the experimenter who repeatedly transfuses blood); In one embodiment, the plasma concentration of experimenter's factor VII reduces.
On the other hand, the present invention relates to reply the treatment of carrying out as unique blood coagulating protein with factor VII with this experimenter among the syndromic experimenter and compare and strengthen the hemostatic method suffering from factor VII, this method comprises that the experimenter to needs uses the factor VII of first amount or goods and the factor XI, plasma thromboplastin antecedent of second amount or the goods of factor XI, plasma thromboplastin antecedent dependency polypeptide of factor VII dependency polypeptide, and wherein first and second amounts are together to strengthening hemostasis effectively.
On the other hand, the present invention relates in the experimenter, strengthen the method that thrombin forms, this method comprises that the experimenter to needs uses the factor VII of first amount or goods and the factor XI, plasma thromboplastin antecedent of second amount or the goods of factor XI, plasma thromboplastin antecedent dependency polypeptide of factor VII dependency polypeptide, and wherein first and second amounts form effectively strengthening thrombin together.
On the other hand, the present invention relates to reply the treatment of carrying out as unique blood coagulating protein with factor VII with this experimenter among the syndromic experimenter and compare and strengthen the method that thrombin forms suffering from factor VII, this method comprises that the experimenter to needs uses the factor VII of first amount or goods and the factor XI, plasma thromboplastin antecedent of second amount or the goods of factor XI, plasma thromboplastin antecedent dependency polypeptide of factor VII dependency polypeptide, and wherein first and second amounts form effectively strengthening thrombin together.
On the other hand, the present invention relates to, reply among the syndromic experimenter suffering from factor VII, using factor VII with this experimenter compares as the administration number of times that unique coagulation factor protein needs, reduce the method for finishing the required coagulation factor protein administration number of times of hemostasis, this method comprises that the experimenter to needs uses the factor VII of first amount or goods and the factor XI, plasma thromboplastin antecedent of second amount or the goods of factor XI, plasma thromboplastin antecedent dependency polypeptide of factor VII dependency polypeptide, and wherein first and second amounts are effective to reducing the coagulation factor protein administration number of times together.
On the other hand, the present invention relates to reply the hemorrhage method of treatment among the syndromic experimenter suffering from factor VII, this method comprises that the experimenter to needs uses the factor VII of first amount or goods and the factor XI, plasma thromboplastin antecedent of second amount or the goods of factor XI, plasma thromboplastin antecedent dependency polypeptide of factor VII dependency polypeptide, and wherein first and second amounts are hemorrhage effective to treating together.
In one embodiment, factor VII is people's recombinant factor VIIa (rFVIIa).In another embodiment, rFVIIa is NovoSeven (Novo Nordisk A/S, Bagsvaerd, a Denmark).
In one embodiment, this Pharmaceutical composition is mixed with intravenous administration.In one embodiment, said composition also contains the inhibitor of fibrinolytic system, includes, but not limited to aprotinin, episilon amino caproic acid or tranexamic acid.In one embodiment, said composition also contains TFPI inhibitor and/or FVIII.
In one embodiment, said composition also contains factor VII.In one embodiment, Factor IX is that (Factor IX a) for activation factor VIII.In another embodiment, Factor IX is recombinant factor VIIIa.In another embodiment, Factor IX is recombined human Factor IX a.
In another embodiment, the present invention relates to factor VIIa and factor XI, plasma thromboplastin antecedent and be combined in the purposes for preparing in the medicine that strengthens fibrin blood coagulation formation in the mammalian plasma.
On the other hand, the present invention relates to strengthen the method that the fibrin blood coagulation forms among the experimenter, this method comprises that the experimenter to needs uses the factor VII of first amount or goods and the factor XI, plasma thromboplastin antecedent of second amount or the goods of factor XI, plasma thromboplastin antecedent dependency polypeptide of factor VII dependency polypeptide, and wherein first and second amounts are effective in treatment is hemorrhage together.
In one embodiment of the invention, this pharmaceutical composition (with the form of single goods time) is basically by factor VIIa and factor XI, plasma thromboplastin antecedent, with medicinal acceptable excipient or the carrier of choosing any one kind of them, with the stabilizing agent of choosing any one kind of them, with detergent and the choose any one kind of them neutral salt and the antioxidant of choosing any one kind of them of choosing any one kind of them, the antiseptic and the protease inhibitor of choosing any one kind of them are formed with choosing any one kind of them.
In another embodiment of the present invention, this pharmaceutical composition (with the form of single goods time) is basically by factor VIIa and factor XI, plasma thromboplastin antecedent, with medicinal acceptable excipient or the carrier of choosing any one kind of them, with stabilizing agent and the choose any one kind of them detergent and the neutral salt of choosing any one kind of them of choosing any one kind of them, with the antioxidant of choosing any one kind of them, with antiseptic and choose any one kind of them protease inhibitor and the TFPI inhibitor composition of choosing any one kind of them.
In another embodiment of the present invention, this pharmaceutical composition (with the form of single goods time) is basically by factor VIIa and factor XI, plasma thromboplastin antecedent, with medicinal acceptable excipient or carrier and the choose any one kind of them stabilizing agent and the detergent of choosing any one kind of them of choosing any one kind of them, with the neutral salt of choosing any one kind of them, with antioxidant and the choose any one kind of them antiseptic and the protease inhibitor of choosing any one kind of them of choosing any one kind of them, and Factor IX and the TFPI inhibitor of choosing any one kind of them composition.
In another embodiment, this Pharmaceutical composition (with the form of test kit time) is by basically by the factor VIIa and medicinal acceptable excipient or the carrier of choosing any one kind of them, with the stabilizing agent of choosing any one kind of them, with the detergent of choosing any one kind of them, with the neutral salt of choosing any one kind of them, with the antioxidant of choosing any one kind of them, with the antiseptic of choosing any one kind of them, first unit dosage form with the protease inhibitor composition of choosing any one kind of them, basically by the factor XI, plasma thromboplastin antecedent and medicinal acceptable excipient or the carrier of choosing any one kind of them, with the stabilizing agent of choosing any one kind of them, with detergent and the choose any one kind of them neutral salt and the antioxidant of choosing any one kind of them of choosing any one kind of them, form with second unit dosage form that the choose any one kind of them antiseptic and the protease inhibitor of choosing any one kind of them are formed.
In another embodiment, this Pharmaceutical composition (with the form of test kit time) is by basically by the factor VIIa and medicinal acceptable excipient or the carrier of choosing any one kind of them, with the stabilizing agent of choosing any one kind of them, with the detergent of choosing any one kind of them, with the neutral salt of choosing any one kind of them, with the antioxidant of choosing any one kind of them, with the antiseptic of choosing any one kind of them, first unit dosage form with the protease inhibitor composition of choosing any one kind of them, basically by the factor XI, plasma thromboplastin antecedent and medicinal acceptable excipient or the carrier of choosing any one kind of them, with the stabilizing agent of choosing any one kind of them, with detergent and the choose any one kind of them neutral salt and the antioxidant of choosing any one kind of them of choosing any one kind of them, form with second unit dosage form that the choose any one kind of them antiseptic and the protease inhibitor of choosing any one kind of them are formed; Wherein first unit dosage form or second unit dosage form or two dosage forms all further contain Factor IX and/or TFPI inhibitor.
Description of drawings
Fig. 1: add FVIIa and cause the dose dependent of blood coagulation dissolution time to prolong.This effect is best under 10nMFVIIa.
Fig. 2: in the presence of 10nM FVIIa, add FXI and cause the blood coagulation dissolution time further to prolong.This effect is a dose dependent and best under 30nM FXI.
Fig. 3: use thromboelastography (roTEG) to measure, analyze FVIIa and FXI maximum blood coagulation hardness (MCF), and to the influence of the dissolved blood coagulation resistance of t-PA mediation.
Fig. 4: shorten clotting time among the NHP with cooperative mode when these results have confirmed that FVIIa and FXI add blood plasma.
Detailed Description Of The Invention
The too much hemorrhage and experimenter that therefore need transfuse blood who interrelates with operation or severe trauma does not form more complication than experiencing any hemorrhage experimenter.Yet, moderate is hemorrhage to give human blood or blood products (platelet at needs, leukocyte, the concentrate that is used for the treatment of the blood plasma source of blood coagulation defective, etc.) situation under also can cause complication because this with (for example transmit the Human virus, hepatitis, HIV, parvovirus, or other unknown so far virus) and the danger of non-viral pathogen relevant.The a large amount of blood transfusions of extensive hemorrhage needs can cause forming the depletion of a plurality of organs, comprise infringement lung and renal function.In case the experimenter forms these severe complications, the cascade event and the inflammatory reaction that relate to many cytokines just begin, make any treatment all very the difficulty and unfortunately all get nowhere usually.The patient that experience loses blood seriously is unstable clinically.There is the danger of experiencing auricular fibrillation in this patient, and it can cause that fatal cardiomotility stops; Impaired renal function; Or the lung intravenous extravasation (is also referred to as " wet lung " or ARDS).Therefore, the main target in operation and the treatment of serious tissue injury be avoid or minimize hemorrhage.For fear of or minimize this unwanted hemorrhagely, guarantee to form that to be not easy by the dissolved stabilization of solid tampon of fibrinoclase be important.And, importantly guarantee fast and effectively to form this thromboembolism or blood coagulation.
Experimenter (platelet count or active the reduction) with thrombocytopenia also has impaired thrombin generation and fibrin bolt stabilisation defective, causes tampon dissolving too early easily.In addition, the experimenter who is subjected to severe trauma or organ injury and therefore often accepts blood transfusion has the platelet count of reduction and the fibrinogen of reduction, Factor IX and other blood coagulating protein level usually.The thrombin generation that these experimenters experience impaired (or reduction).Therefore, these experimenters have deficiency, or the lower hemostasis of efficient, cause forming easily and too early by the dissolved fibrin thrombosis of proteolytic enzyme, and this proteolytic enzyme further extensively discharges under the situation that with wound and organ injury on a large scale is feature.
Organize the hemorrhage hematoma that also can cause forming.The degree of injury of the size of hematoma (particularly between cranium and spinal column) and function of nervous system, the rehabilitation difficulty, and/or the seriousness of function of nervous system's permanent damage is closely related with degree after the rehabilitation.The serious consequence that hematoma when hematoma is arranged in brain, occurs, they in addition can cause death.
Therefore, the main purpose in treatments for bleeding is to stop blooding in the shortest time, keeps minimum thereby make to lose blood.
Therefore the invention provides composition beneficial, its purposes and the Therapeutic Method of treatment bleeding episodes in the experimenter of needs treatment.Said composition, purposes is relevant with some beneficial effects with method, it is less to lose blood before described effect is for example stopped blooding, and intra-operative needs blood less, and blood pressure maintains acceptable level before the hemostasis, the blood pressure stabilization quickening, the patient who is treated shortens recovery time, and patient's rehabilitation duration of being treated shortens, and comprises that the hematoma formation minimizing of hematoma in the brain or the hematoma that forms are less, hemorrhage termination is accelerated, and stops the hemorrhage administration number of times required with keeping hemostasis and reduces.
Factor VII or factor VII dependency polypeptide product, for example factor VIIa combines the clotting time of administration with separately with factor VIIa or factor XI, plasma thromboplastin antecedent administration the time with factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product, blood coagulation hardness is compared with resistance provides the clotting time that shortens, bigger blood coagulation hardness and Fibrinolytic resistance increased.
Factor VII or factor VII dependency polypeptide product (for example factor VIIa) and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product are compared in conjunction with the situation of administration with separately with factor VIIa or factor XI, plasma thromboplastin antecedent administration the time, stop the hemorrhage required time to shorten, keep the required administration number of times of hemostasis and reduce.The invention provides simultaneously or the beneficial effect of the goods of the goods of administration factor XI, plasma thromboplastin antecedent successively or factor XI, plasma thromboplastin antecedent dependency polypeptide and factor VII or factor VII dependency polypeptide.Can be the form of single compositions or can be the kit form (test kit of assembling) of a plurality of components according to Pharmaceutical composition of the present invention.Compositions according to the present invention is used as therapeutic and preventative procoagulant in comprising such as the mammal of the mankind's primates.The present invention also provides the method for treatment in comprising human experimenter (comprise prophylactic treatment or prevent) bleeding episodes.
No matter when mention the first or second or the 3rd in this manual, etc., unit dose, it does not represent preferred order of administration, and only is for convenience.
The combination of factor VII or factor VII dependency polypeptide product and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product is to guarantee that clotting time shortens, and tampon forms and form a kind of useful product of stable tampon rapidly.The inventor has had been found that the combination of factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide is to guarantee that formation is hard, the useful product of tampon stable and that form fast.
The inventor shows that the combination of factor VIIa and factor XI, plasma thromboplastin antecedent can more effectively shorten human normal plasma's clotting time than independent factor VIIa or factor XI, plasma thromboplastin antecedent.The combination that also shows factor VIIa and factor XI, plasma thromboplastin antecedent can more effectively strengthen blood coagulation hardness than independent factor VIIa or factor XI, plasma thromboplastin antecedent.Combine with also being in the factor XI, plasma thromboplastin antecedent of observing under the concentration that blood coagulation hardness no longer further increases by being in the factor VIIa observed under the concentration that blood coagulation hardness no longer further increases, the unexpected blood coagulation hardness of finding further strengthens.Shown that also the combination of factor VIIa and factor XI, plasma thromboplastin antecedent can more effectively prolong external blood coagulation dissolution time among the human normal plasma than independent factor VIIa or factor XI, plasma thromboplastin antecedent.Shown that also the combination of factor VIIa and factor XI, plasma thromboplastin antecedent can more effectively prolong half blood coagulation dissolution time among the human normal plasma than independent factor VIIa or factor XI, plasma thromboplastin antecedent.Shown that also the combination of factor VIIa and factor XI, plasma thromboplastin antecedent is than independent factor VIIa or factor XI, plasma thromboplastin antecedent more effectively anticoagulative fibrinolysis in the human normal plasma, the particularly fibrinolysis of tPA-mediation.
Therefore, by strengthening blood coagulation, can obtain hemorrhage more effective treatment to the experimenter.
Do not wish to be bound by theory, it is believed that abundant generation thrombin is to form hardly, stable tampon is necessary, and therefore is that to keep hemostasis necessary.The fibrin structure of this thrombosis depend on formation thrombin amount and begin to produce the speed of thrombin.Under the impaired condition of thrombin generation, form highly permeable porous fibrin thrombosis.The fibrinoclase that generally is present in the fibrin surface dissolves this fibrin thrombosis easily.Therefore the formation of stable fibrin thrombosis also depends on the existence of factor XIIIa, and factor XIIIa is by thrombin activation and also depend on thrombin and fully produce.In addition, the fibrinolysis inhibitor of the nearest thrombin activation of describing, promptly TAFI needs quite high thrombin amount be used for its activation.Therefore form under the sufficient inadequately situation at thrombin, TAFI is not activated, and the tampon that causes forming is than easier by the active normal dissolving of normal fiber protein dissolution.Under the situation that number of platelets reduces, i.e. thrombocytopenia, the extraneous factor VIIa of administration of exogenous can start thrombin generation faster.Yet even under high concentration, factor VIIa can not make overall thrombin generation normalization.
In experimenter that the plasma concentration of fibrinogen reduces (because many places wound or operation on a large scale repeatedly experimenter of blood transfusion) thrombin not taking place fully activates.And obtained more effective hemostasis by the administering drug combinations of factor VII and factor XI, plasma thromboplastin antecedent.
The experimenter who suffers from thrombocytopenia has impaired thrombin generation and fibrin thrombosis stabilisation defective, causes tampon dissolving too early easily.In addition, be subjected to the impaired and experimenter that therefore often accept blood transfusion of severe trauma or organ and have the platelet count of reduction and the fibrinogen of reduction usually, Factor IX and other blood coagulating protein level.These experimenters experience the thrombin generation of impaired (reduction).In addition, the activation of the fibrinogen levels negative sense interference factor XIII of its reduction.Therefore, these experimenters have the hemostasis deficiency, or hemostasis efficient is lower, and the fibrin thrombosis that causes forming is dissolved by proteolytic enzyme easily and prematurely, and this proteolytic enzyme is further extensively discharged under the situation that with wound and organ injury on a large scale is feature.
In order to help in the experimenter, to form abundant stable thrombosis, can use according to compositions of the present invention with the whole abilities of the hemostatic kept.Said composition is useful especially in the experimenter that the blood plasma level of experimenter that number of platelets reduces and fibrinogen and/or other blood coagulating protein reduces.
Under the condition that factor XI, plasma thromboplastin antecedent exists, but it is believed that the factor VIIa sufficient to guarantee of low concentration fully stops blooding.
Factor VII polypeptides:
Implementing when of the present invention, can use prevention or treat hemorrhage in effective any factor VII polypeptides.It comprises coming autoblood or blood plasma, perhaps the factor VII polypeptides that produces with recombination form.
The present invention includes factor VII polypeptides, for example, have U.S. Patent number 4,784, the polypeptide of disclosed aminoacid sequence in 950 (the wild type human factor VIIs).In some embodiments, factor VII polypeptides is for example, U.S. Patent number 4,784, disclosed human factor VII a among 950 (the wild type factor VII).In a series of embodiments, factor VII polypeptides comprises that the specific biological that shows human factor VII a is active about at least 10%, and is preferably about at least 30%, more preferably about at least 50%, and about at least 70% polypeptide most preferably.In a series of embodiments, factor VII polypeptides comprises that the specific biological that shows human factor VII a is active about at least 90%, and is preferably about at least 100%, preferably about at least 120%, more preferably about at least 140%, and about at least 160% polypeptide most preferably.In a series of embodiments, factor VII polypeptides comprises and U.S. Patent number 4,784, the sequence table of disclosed wild type factor VII reveals about at least 70% in 950, preferably about at least 80%, more preferably about at least 90%, and the polypeptide of about at least 95% homogeny most preferably.
" factor VII polypeptides " used herein includes, but not limited to factor VII, and factor VII dependency polypeptide.Term " factor VII " is attempted to include, but not limited to have the wild type human factor VII (at U.S. Patent number 4,784, open in 950) the polypeptide of aminoacid sequence 1-406, and the wild type factor VII that comes from other species, for example cattle, pig, dog, Mus and salmon factor VII, described factor VII comes from blood or blood plasma, perhaps produces with recombination form.The natural allelic variation body of the factor VII that exists it also comprises from body one by one to another individuality and occur.In addition, glycosylated degree and position or other post translational modification can change according to the selected host cell and the characteristic of host cell environment.Term " factor VII " is also attempted to comprise the factor VII polypeptides of its not cracking (proenzyme) form and has been processed producing its biologically active form separately by Proteolytic enzyme, and the those polypeptides of called after factor VIIa.In general, factor VII between residue 152 and 153 cracking to produce factor VIIa.
" factor VII-dependency polypeptide " comprises, but be not limited to, contain one or more aminoacid sequences changes (promptly with respect to human factor VII by chemical modification and/or with respect to human factor VII, factor VII variant), and/or contain the factor VII polypeptides of the aminoacid sequence (that is factor VII segment) of truncate with respect to human factor VII.This factor VII dependency polypeptide can show different qualities with respect to human factor VII, comprises stability, and phospholipids incorporate changes than living, etc.This polypeptide of its not cracking (proenzyme) form attempted to comprise in term " factor VII dependency polypeptide ", processed producing its biologically active form separately by Proteolytic enzyme, but and the those polypeptides of called after " factor VIIa dependency polypeptide " or " activated factor VII dependency polypeptide ".
" factor VII dependency polypeptide " used herein comprises, but be not limited to, show the polypeptide of substantially the same or the biologic activity that improves with respect to the wild type human factor VII, and the biologic activity of the factor VIIa polypeptide being modified or reduce basically with respect to the activity of wild type human factor VII a.These polypeptide include, but not limited to by the factor VII of chemical modification or factor VIIa and have imported to modify or to destroy the factor VII variant that the bioactive specific amino acids sequence of this polypeptide changes.
It also comprises the polypeptide that has slightly the aminoacid sequence of modifying, and for example, has the polypeptide of the modified N-terminal that comprises the-terminal amino acid disappearance or add, and/or with respect to human factor VII a by the polypeptide of chemical modification.
No matter show substantially the same or better biological activity than wild type factor VII, still select to show the biologic activity of modifying or reducing basically with respect to wild type factor VII, the factor VII dependency polypeptide that comprises the variant of factor VII comprises, but be not limited to, have by one or more amino acid whose insertions, disappearance, or replace and be different from the polypeptide of the aminoacid sequence of wild type factor VII sequence.
Factor VII dependency polypeptide (comprising variant), those have been contained at above-mentioned one or more thrombotests, Proteolytic enzyme test, or TF is when detecting in the test, the wild type factor VIIa in the performance same cell type than live about at least 10%, at least about 20%, at least about 25%, about at least 30%, about at least 40%, at least about 50%, at least about 60%, about at least 70%, about at least 75%, at least about 80%, at least about 90%, about at least 100%, about at least 110%, at least about 120%, or about at least 130% polypeptide.
The factor VII dependency polypeptide (comprising variant) that has substantially the same or improved biologic activity with respect to wild type factor VIIa, those have been contained at above-mentioned one or more thrombotests, the Proteolytic enzyme test, or TF is in conjunction with in the test when detecting, wild type factor VIIa in the performance same cell type compares about at least 25% of work, preferably about at least 50%, more preferably about at least 75%, more preferably about at least 100%, more preferably about at least 110%, more preferably about at least 120%, and about at least 130% polypeptide most preferably.
The factor VII dependency polypeptide (comprising variant) that has the biologic activity that reduces basically with respect to wild type factor VIIa is, at above-mentioned one or more thrombotests, the Proteolytic enzyme test, or TF is in conjunction with in the test when detecting, wild type factor VIIa in the performance same cell type is more about below 25% than what live, preferred about below 10%, the polypeptide below 1% below 5% and most preferably from about more preferably from about.The factor VII variant that has basically a biologic activity of modifying with respect to wild type factor VII includes, but not limited to show the factor VII variant of TF dependent form factor X protein hydrolysing activity and those variants of factor lytic X in conjunction with TF but not.
In some embodiments, factor VII polypeptides is a factor VII dependency polypeptide, variant particularly, the ratio when wherein detecting in " extracorporeal hydrolysis test " (" test " vide infra) between the activity of the activity of described factor VII polypeptides and natural human factor VIIa (wild type FVIIa) is about at least 1.25; In other embodiments, this ratio is about at least 2.0; In other embodiments, this ratio is about at least 4.0.In some embodiments of the present invention, factor VII polypeptides is a factor VII dependency polypeptide, variant particularly, the ratio when wherein detecting in " external Proteolytic enzyme test " (" test " vide infra) between the activity of the activity of described factor VII polypeptides and natural human factor VIIa (wild type FVIIa) is about at least 1.25; In other embodiments, this ratio is about at least 2.0; In other embodiments, this ratio is about at least 4.0; In other embodiments, this ratio is about at least 8.0.
In some embodiments, factor VII polypeptides is for example, U.S. Patent number 4,784, disclosed human factor VII among 950 (the wild type factor VII).In some embodiments, factor VII polypeptides is human factor VII a.In a series of embodiments, factor VII polypeptides is that to show the specific biological of human factor VII a active about at least 10%, and is preferably about at least 30%, more preferably about at least 50%, and about at least 70% factor VII dependency polypeptide most preferably.In some embodiments, factor VII polypeptides has by one or more amino acid whose insertions, disappearance, or replace and be different from the aminoacid sequence of wild type factor VII sequence.
The non-limitative example of comparing the factor VII variant with substantially the same or better biologic activity with wild type factor VIIa comprises, but be not limited to, at those variants described in Danish Patent Application PA 2,000 00734 and PA 2,000 01360 (corresponding to WO 01/83725) and the PA 2,000 01361 (corresponding to WO02/22776).VII compares with wild type factor, and the non-limitative example with factor VII variant of substantially the same or higher biologic activity comprises S52A-FVII, S60A-FVII (lino etc., Arch.Biochem.Biophys.352:182-192,1998); L305V-FVII, L305V/M306D/D309S-FVII, L305I-FVII, L305T-FVII, F374P-FVII, V158T/M298Q-FVII, V158D/E296V/M298Q-FVII, K337A-FVII, M298Q-FVII, V158D/M298Q-FVII, L305V/K337A-FVII, V158D/E296V/M298Q/L305V-FVII, V158D/E296V/M298Q/K337A-FVII, V158D/E296V/M298Q/L305V/K337A-FVII, K157A-FVII, E296V-FVII, E296V/M298Q-FVII, V158D/E296V-FVII, V158D/M298K-FVII, and S336G-FVII; U.S. Patent number 5,580 disclosedly in 560 shows the FVIIa variant that Proteolytic enzyme stability increases; Between residue 290 and 291 or between residue 315 and 316 through the factor VIIa (Mollerup etc., Biotechnol.Bioeng.48:501-505,1995) of proteolytic cleavage; Oxidised form (Kornfelt etc., Arch.Biochem.Biophys.363:43-54,1999) with factor VIIa.The non-limitative example that has the factor VII variant of the biologic activity that reduces basically or modify with respect to wild type factor VII comprises R152E-FVIIa (Wildgoose etc., Biochem 29:3413-3420,1990), S344A-FVIIa (Kazama etc., J.Biol.Chem.270:66-72,1995), FFR-FVIIa (Holst etc., Eur.J.Vasc.Endovasc.Surg.15:515-520,1998), with the factor VIIa that lacks the Gla domain (Nicolaisen etc., FEBS Letts.317:245-249,1993).The factor VII polypeptides of chemical modification and the non-limitative example of sequence variant be for example, and U.S. Patent number 5,997 is described in 864.
The biologic activity of factor VIIa in blood coagulation comes from its (i) and combines with tissue factor (TF) and the proteolytic cleavage generation activation factor IX of (ii) catalysis factors IX or factor X or the ability of X (being respectively factors IX a or Xa).
To achieve the object of the present invention, by for example U.S. Patent number 5, insufficient blood plasma of 997,864 described usage factor VII and tissue thromboplastin are by the quantitative biologic activity of factor VII polypeptides (" factor VII biologic activity ") of the ability measuring these goods and promote blood coagulation.In this test, biologic activity is expressed as with respect to the shortening of control sample clotting time and by relatively converting " factor VII unit " to the human blood standard that contains 1 unit/active collection of ml factor VII.In addition, the biologic activity of factor VIIa can be quantitatively as follows:
(i) measure factor VIIa or factor VIIa dependency polypeptide produce activated factor X (factor Xa) in the system that contains the TF that is embedded in the adipose membrane and factor X ability.(Persson etc., J.Biol.Chem.272:19919-19924,1997);
(ii) in aqueous system, measure the hydrolysis (" external Proteolytic enzyme test " sees below) of factor X;
(iii) use physical bond (Persson, FEBS Letts.413:359-363,1997) based on apparatus measures factor VIIa or the factor VIIa dependency polypeptide and the TF of surface plasmon resonance; With
(iv) measure the hydrolysis (" extracorporeal hydrolysis test " sees below) of factor VIIa and/or factor VIIa dependency polypeptide to synthetic substrate; With
(v) measure the generation of thrombin in not relying on the vitro system of TF.
Term " factor VII biologic activity " or " factor VII activity " attempt to comprise the ability that produces thrombin; This term is also included within the ability that produces thrombin under the condition that does not have tissue factor at activatory platelet surface.
The factor VIIa goods are that (Novo Nordisk A/S, Bagsvaerd Denmark), and is not limited thereto NovoSeven used according to the present invention.
The factor XI, plasma thromboplastin antecedent polypeptide:
Implementing when of the present invention, can use prevention or treat hemorrhage in effective any factor XI, plasma thromboplastin antecedent polypeptide.It comprises coming autoblood or blood plasma, perhaps the factor XI, plasma thromboplastin antecedent polypeptide that produces with recombination form.In addition, platelet can contain the structurally different form (may be because the selectable montage of FXI gene) of FXI.Platelet factor XI is at Lipscomb, M.S.﹠amp; Walsh, P.N. (1979), Journal of ClinicalInvestigation, 63, describe among the 1006-1014.
" factor XI, plasma thromboplastin antecedent polypeptide " used herein comprises, but is not limited to, factor XI, plasma thromboplastin antecedent, and factor XI, plasma thromboplastin antecedent dependency polypeptide.Term " factor XI, plasma thromboplastin antecedent " is attempted to comprise, but is not limited to, and has at Sun Y.﹠amp; Gailani, D. (1996), the polypeptide of the aminoacid sequence described in the J.Biol.Chem.271:29023-29028 (wild type people factor XI, plasma thromboplastin antecedent, blood plasma), and the wild type factor XI that comes from other species, for example, cattle, pig, dog, Mus and salmon factor XI, plasma thromboplastin antecedent.In some embodiments, the factor XI, plasma thromboplastin antecedent polypeptide is for example, Sun, Y.﹠amp; Gailani, D. (1996), disclosed wild type people factor XI, plasma thromboplastin antecedent among the J.Biol.Chem.271:29023-29028.
The natural allelic variation body of the factor XI, plasma thromboplastin antecedent that exists it also comprises from body one by one to another individuality and occur.In addition, glycosylated degree and position or other post translational modification can change according to the selected host cell and the characteristic of host cell environment.Term " factor XI, plasma thromboplastin antecedent " is also attempted to comprise the factor XI, plasma thromboplastin antecedent polypeptide of its not cracking (proenzyme) form and has been processed producing its biologically active form separately by Proteolytic enzyme, but and the those polypeptides of called after factor XI, plasma thromboplastin antecedent a.
" factor XI, plasma thromboplastin antecedent-dependency polypeptide " comprises, but be not limited to, contain one or more aminoacid sequences changes (promptly with respect to people's factor XI, plasma thromboplastin antecedent by chemical modification and/or with respect to people's factor XI, plasma thromboplastin antecedent, the factor XI, plasma thromboplastin antecedent variant), and/or contain the factor XI, plasma thromboplastin antecedent polypeptide of the aminoacid sequence (that is factor XI, plasma thromboplastin antecedent segment) of truncate with respect to people's factor XI, plasma thromboplastin antecedent.This factor XI, plasma thromboplastin antecedent dependency polypeptide can show different qualities with respect to people's factor XI, plasma thromboplastin antecedent, comprises stability, and phospholipids incorporate changes than living, etc.
This polypeptide with its not cracking (proenzyme) form attempted to comprise in term " factor XI, plasma thromboplastin antecedent dependency polypeptide ", processed producing its biologically active form separately by Proteolytic enzyme, but and the those polypeptides of called after " factor XI, plasma thromboplastin antecedent a dependency polypeptide " or " activated factor XI dependency polypeptide ".
" factor XI, plasma thromboplastin antecedent dependency polypeptide " used herein comprises, but be not limited to, show the polypeptide of substantially the same or the biologic activity that improves with respect to wild type people factor XI, plasma thromboplastin antecedent, and the biologic activity of the factor XI, plasma thromboplastin antecedent polypeptide being modified or reduce basically with respect to the activity of wild type people factor XI, plasma thromboplastin antecedent.These polypeptide include, but not limited to by the factor XI, plasma thromboplastin antecedent of chemical modification or factor XI, plasma thromboplastin antecedent a and have imported to modify or to destroy the factor XI, plasma thromboplastin antecedent variant that the bioactive specific amino acids sequence of this polypeptide changes.
It also comprises the polypeptide that has slightly the aminoacid sequence of modifying, and for example, has the polypeptide of the modified N-terminal that comprises the-terminal amino acid disappearance or add, and/or with respect to people's factor XI, plasma thromboplastin antecedent by the polypeptide of chemical modification.
No matter show substantially the same or better biological activity than wild type factor XI, still select to show the biologic activity of modifying or reducing basically with respect to wild type factor XI, the factor XI, plasma thromboplastin antecedent dependency polypeptide that comprises the variant of factor XI, plasma thromboplastin antecedent comprises, but be not limited to, have by one or more amino acid whose insertions, disappearance, or replace and be different from the polypeptide of the aminoacid sequence of wild type factor XI sequence.
The factor XI, plasma thromboplastin antecedent dependency polypeptide that comprises variant is included in when detecting in the described factor XI, plasma thromboplastin antecedent activity test of this description and shows about at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about at least 100%, about at least 110%, at least about 120%, and the ratio of about at least 130% the wild type factor XI that in the same cell type, the produces those polypeptides of living.
The factor XI, plasma thromboplastin antecedent dependency polypeptide that comprises variant that has substantially the same or an improved biologic activity with respect to wild type factor XI is included in when detecting in described one or more atopen XI activity test and shows about at least 25%, preferably about at least 50%, more preferably about at least 75%, more preferably about at least 100%, more preferably about at least 110%, more preferably about at least 120%, and the active those polypeptides of specific biological of about at least 130% the wild type people factor XI, plasma thromboplastin antecedent that in the same cell type, produces most preferably.For the purposes of the present invention, the biologic activity of factor XI, plasma thromboplastin antecedent can be by described subsequently quantitatively (" test portion ") in this description.
The factor XI, plasma thromboplastin antecedent dependency polypeptide that comprises variant that has basically a biologic activity that reduces with respect to wild type factor XI is to show when detecting in above-mentioned one or more atopen XI activity tests to be not less than about 25%, preferably be not less than approximately 10%, more preferably be not less than about 5% and most preferably be not less than the those polypeptides that the ratio of about 1% the wild type factor XI that produces is lived in the same cell type.
The non-limitative example of factor XI, plasma thromboplastin antecedent polypeptide for example is included in, Gailani﹠amp; Broze (1993), BloodCoagul.Fibrinolysis, 4:15-20, or Kerbiriou﹠amp; Griffin (1979), J.Biol.Chem., people's factor XI, plasma thromboplastin antecedent in the blood plasma source described in the 254:12020-12207.
In some embodiments, factor XI, plasma thromboplastin antecedent is a factor XI, plasma thromboplastin antecedent dependency polypeptide, and the ratio when wherein detecting in " FXI produces colour test " (vide infra) between the activity of the activity of described factor XI, plasma thromboplastin antecedent polypeptide and natural human factor XI, plasma thromboplastin antecedent (wild type factor XI) is about at least 1.25; In other embodiments, this ratio is about at least 2.0; In other embodiments, this ratio is about at least 4.0.
Factor XI, plasma thromboplastin antecedent dependency polypeptide also comprises the factor XI, plasma thromboplastin antecedent of its characteristic hemostasis related activity of reservation or the segment of factor XI, plasma thromboplastin antecedent dependency polypeptide.For example, use described in this manual factor XI, plasma thromboplastin antecedent activity test can measure the hemostasis related activity of factor XI, plasma thromboplastin antecedent polypeptide.
In preferred embodiments, factor XI, plasma thromboplastin antecedent is human plasma factor XI, plasma thromboplastin antecedent or activatory human plasma factor XI, plasma thromboplastin antecedent a.In one embodiment, FXI is platelet factor XI.In another embodiment, FXI is the reorganization preparation.
Definition
In this article, amino acid whose trigram or single-letter code are pressed its conventional sense use shown in the table 1.Unless clearly show, the aminoacid that this paper mentions is L-aminoacid.Should understand, for example, first letter among the K337 represents wild type factor VII at the naturally occurring aminoacid in described position, and for example, [K337A]-FVIIa represents the FVII-variant, wherein shown in the aminoacid replacement represented of the naturally occurring aminoacid coverlet letter code A that represents by single-letter code K in position.
Table 1: amino acid whose abbreviation:
Aminoacid | The trigram code | The single-letter code |
Glycine | Gly | G |
Proline | Pro | P |
Alanine | Ala | A |
Valine | Val | V |
Leucine | Leu | L |
Isoleucine | Ile | I |
Methionine | Met | M |
Cysteine | Cys | C |
Phenylalanine | Phe | F |
Tyrosine | Tyr | Y |
Tryptophan | Trp | W |
Histidine | His | H |
Lysine | Lys | K |
Arginine | Arg | R |
Glutamine | Gln | Q |
Agedoite | Asn | N |
Glutamic acid | Glu | E |
Aspartic acid | Asp | D |
Term " factor VIIa " or " FVIIa " are used interchangeably.The term factor VIIa comprises proenzyme factor VII (strand factor VII).Term " factor XI, plasma thromboplastin antecedent " or " FXI " are used interchangeably.This term " Factor IX " or " FVIII " are used interchangeably.Term " Factor IX " or " FVIII " comprise activated factor VIII (FVIIIa), kept the variant and the clipped form of the relevant styptic activity of characteristic FVIII-; This term comprises the FVIII of reorganization preparation and the FVIII in blood plasma source.Preferred people FVIII and the people FVIII that recombinates.
In this article, " experimenter that thrombin generation is impaired " is meant the experimenter that can not produce sufficient thrombin outburst at activatory platelet surface, and comprise than normal haemostatic system with complete function, the thrombin that comprises normal amount and function, the thrombin experimenter still less of experimenter's generation of platelet and fibrinogen (for example, in the human normal plasma who collects), and comprise, but be not limited to, lack the experimenter of Factor IX; Number of platelets reduces or platelet has the experimenter (for example, thrombocytopenia or the graceful Thromboasthenia of Glan thatch or the experimenter that goes out hyperhematosis) of functional defect; Thrombinogen, the experimenter that FX or FVII level reduce; The experimenter that some thrombin levels reduce (for example, because wound or operative hemorrhage is too much on a large scale); The experimenter who reduces with the plasma concentration of fibrinogen (for example, repeatedly the experimenter of blood transfusion).
" thrombin generation level " or " normal thrombin generation " is meant the level of comparing patient's thrombin generation with health volunteer's level.This level is called normal level percent.If suitable, this term is used interchangeably.
Term " enhancing of hemostasis system " is meant that the ability that produces thrombin strengthens.Term " strengthens hemostasis " to be attempted to comprise, when in identical thrombin generation test, detecting, the measured thrombin generation of test specimen that contains factor VII or factor VII-dependency polypeptide product and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product, for the single thrombin generation of the control sample that only contains factor VII or factor VII-dependency polypeptide or factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide respectively, the situation of prolongation.Thrombin generation can be by measure (referring to " test portion ") described in the thrombin generation test of this description.
" unique " reagent used herein or the factor are meant, factor VII or factor VII-dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are the unique hemorrhage that comprises in Pharmaceutical composition or the test kit together, or active hemorrhage, or thrombin, or in the specific course of treatment, for example unique hemorrhage of in specific bleeding episodes process, using, or active hemorrhage, or thrombin to the patient.Should understand that these situations comprise, the amount of other adaptable hemorrhage or thrombin or active those situations that are not enough to obviously influence one or more coagulation parameters.
The blood coagulation dissolution time, blood coagulation intensity, the fibrin blood coagulation forms and clotting time is to be used to measure the stop blooding clinical parameter of system mode of patient.Blood sample from patient's extraction and by measuring one or more parameters such as methods such as thromboelastographys, is for example pressed Meh etc., BloodCoagulation﹠amp with suitable interval; Fibrinolysis 2001; 12:627-637; Vig etc., Hematology, Vol.6 (3), 205-213 page or leaf (2001); Vig etc., Blood coagulation﹠amp; Fibrinolysis, Vol.12 (7), 555-561 page or leaf (2001) Oct; Glidden etc., Clinical and applied thrombosis/hemostasis, Vol.6 (4), 226-233 page or leaf (2000) Oct; McKenzie etc., Cardiology, Vol.92 (4), 240-247 page or leaf (1999) Apr; Or Davis etc., Journal of the American Society ofNephrology, Vol.6 (4), 1250-1255 page or leaf (1995) is described.
Term " prolongs the blood coagulation dissolution time " to be attempted to comprise, when in identical blood coagulation solubility test, detecting, the situation that the blood coagulation dissolution time of measuring for the test specimen that contains factor VII or factor VII-dependency polypeptide product and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product prolongs with respect to the single blood coagulation dissolution time of the control sample that only contains factor VII or factor VII-dependency polypeptide or factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide respectively.The blood coagulation dissolution time can be by said determination.
Term " strengthens blood coagulation intensity " and attempts to be included in when detecting in the identical blood coagulation strength test, for the blood coagulation intensity that the test specimen that contains factor VII or factor VII-dependency polypeptide product and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product is measured, for example mechanical strength is with respect to the strengthened situation of single blood coagulation of the control sample that only contains factor VII or factor VII-dependency polypeptide or factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide respectively.Blood coagulation intensity can be by for example, Carr etc., 1991. (Carr ME, Zekert SL, the blood plasma blood coagulation during forming platelet-mediated intensity form AM J MED SCI 1991; 302:13-8) described, perhaps measure by thromboelastography by above-mentioned.
Term " strengthening the fibrin blood coagulation forms " is attempted to be included in when detecting in the identical thrombotest, and speed that the fibrin blood coagulation of measuring for the test specimen that contains factor VII or factor VII-dependency polypeptide product and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product forms or degree are with respect to the speed of the single fibrin blood coagulation formation of the control sample that only contains factor VII or factor VII-dependency polypeptide or factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide respectively or the situation that degree improves.The fibrin blood coagulation forms can be by said determination.
Term " shortening clotting time " is attempted to be included in when detecting in the identical thrombotest, the blood coagulation formation time of measuring for the test specimen that contains factor VII or factor VII-dependency polypeptide product and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product (clotting time) shortens the situation of (annotate: original text is " increase ", may be wrong) with respect to the single clotting time of the control sample that only contains factor VII or factor VII-dependency polypeptide or factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide respectively.Clotting time can be tested by means of the known standard P T of those of ordinary skill or aPTT and measure.
Term " platelet count or active the reduction " is meant number and this activity hematoblastic biological, that blood coagulation is relevant of the platelet (blood platelet) that exists in experimenter's blood plasma.It may be that because for example platelet destruction increases that counting reduces, and platelet is produced and reduced and than the bigger gathering of the normal part of platelet in the spleen.For example, thrombocytopenia is defined as every microlitre and is not less than 150,000 hematoblastic platelet counts; The upper limit of orthoplastocyte counting be it is generally acknowledged between 350,000 to 450,000 platelet of every microlitre.Platelet count can be measured by automatic platelet counter; It is a method well-known to those having ordinary skill in the art.Platelet count reduces the syndrome that causes and includes, but are not limited to thrombocytopenia, coagulopathy." activity " includes, but not limited to hematoblastic gathering, adhere to, and blood coagulation activity.Active decline may be because, for example, glycoprotein is unusual, cell membrane-cytoskeleton interacts unusual, the granule of platelet is unusual, the platelet blood coagulation activity is unusual, signal transduction and diacrisis.Biologically active pdgf comprises gathering, adheres to and blood coagulation activity, measure by standard method known to the skilled, for example, referring to Platelets.A Practical Approach, Ed.S.P.Watson﹠amp; K.S.Authi:ClinicalAspects of Platelet Disorders (K.J.Clemetson) 15:299-318,1996, OxfordUniversity Press; Williams Hematology, Sixth Edition, Eds.Butler, Lichtman, Coller, Kipps﹠amp; Seligsohn, 2001, McGraw-Hill.Biologically active pdgf reduces the syndrome that causes and includes, but not limited to the graceful Thromboasthenia of Glan thatch, Bernard Soulier syndrome, anticoagulant treatment and thrombolytic therapy." reduction " is meant in identical test when measuring the counting in the plasma sample with normal collection or the counting or the activity of the active test plasma sample of comparing.
Term used herein " hemorrhage disorder " is meant the cell that occurs or molecule source in bleeding episodes, congenital, acquired or epigamic any defective.The example of hemorrhage disorder comprises, but be not limited to, deficiency of coagulation factors (for example, blood coagulation factor VIII, IX, XI or VII lack), blood coagulation factor inhibitors, deficiency platelet function (for example, graceful Thromboasthenia of Glan thatch and Bernard Soulier syndrome), thrombocytopenia, Feng. von Willebrand's disease, with such as by blood coagulating protein dilution, fibrinolysis increases and because the number of platelets of hemorrhage and/or blood transfusion reduces the coagulopathy that (for example, in the experimenter of the repeatedly blood transfusion of experience operation or wound) causes.
The hemorrhage blood that is meant overflows from any composition of blood circulation.Term " bleeding episodes " is meant and comprises and operation, wound, or the tissue injury of other form interrelates, and unwanted, uncontrolled and normally too much is hemorrhage, and unwanted hemorrhage in having the experimenter of hemorrhage disorder.Bleeding episodes can have basically normal blood coagulation system but experienced among the experimenter of (temporarily) coagulopathy, and takes place in the experimenter with congenital or acquired blood coagulation or hemorrhage disorder.In experimenter with deficiency platelet function, hemorrhage be similar to by hemophilia cause hemorrhage, because with the same in the hemophilia, the hemostasis system lack or have unusual essential blood coagulation " chemical compound " (for example, platelet or Feng. von willebrand's factor albumen).In the experimenter of experience such as the extensive tissue injury that interrelates with operation or severe trauma, instant hemostatic require to exceed normal hemostatic mechanism and no matter basically (before the wound or before the operation) normal hemostatic mechanism whether to exist them all can form too much hemorrhage.This experimenter also accepts repeatedly blood transfusion usually, because hemorrhage and/or blood transfusion formation (temporarily) coagulopathy (that is, because hemorrhage and/or blood transfusion dilution blood coagulating protein, fibrinolysis increases and the number of platelets reduction).Hemorrhage also may appearing at such as brain, in the organ of interior ear field and eye, they are that the limited regional and hemostasis therefore realization satisfaction of surgical hemostasis probability is a problem.Identical problem can appear in the process of getting biopsy from various organs (liver, lung, tumor tissues, gastrointestinal tract) and in laparoscopic surgery and free retropubic prostatectomy.The common ground of all these situations is to be difficult to stop blooding by surgical technic (sew up, mosquito forceps, etc.), and situation also is like this when hemorrhage diffusion (for example, hemorrhagic gastritis and too much metrorrhagia).Among the hemorrhage experimenter that also may appear at anticoagulant treatment; Wherein induced the hemostasis defective by the treatment that provides; These are hemorrhage normally acute and too much.Anticoagulant therapy is generally used for preventing thromboembolic disorders.This therapy can comprise heparin, the Dan Baijutang of other form, and the vitamin K antagonist of warfarin or other form and aspirin and other anticoagulant, for example, active other inhibitor of antibody or GP IIb/IIIa.Hemorrhage also can be since comprise with anti-platelet agents (for example aspirin), anticoagulant (for example, heparin), and fibrinolytic agent (for example, tissue plasminogen activator, tPA) the so-called thrombolytic therapy of therapeutic alliance causes.Bleeding episodes also means and includes, but are not limited to have acute hemorrhagic arthrosis (arthrorrhagia), chronic hemophilia arthrosis, hematoma, (muscle for example is behind the peritoneum, Sublingual and pharynx back) the experimenter in operation or wound interrelate uncontrolled and too much hemorrhage, hemorrhage in other tissue, hematuria (the kidney road is hemorrhage), cerebral hemorrhage, operation (for example, hepatectomy), exodontia, and gastrointestinal hemorrhage (for example, UGI is hemorrhage).Bleeding episodes can with the inhibitor of anti-Factor IX; Hemophilia A; Hemophilia A with inhibitor; The hemophilia B; Factor VII deficiency; Factor XI deficiency; Thrombocytopenia; Feng. the von willebrand's factor shortage (Feng. the von Willebrand disease); Serious tissue injury; Severe trauma; The hands art; Laparoscopic surgery; Hemorrhagic gastritis; Carry out biopsy; Anticoagulant therapy; Upper stomach intestinal bleeding (UGI); Or stem cell transplantation interrelates.Bleeding episodes can be too much metrorrhagia; In the limited organ of machinery hemostasis probability, take place; Take place at brain; Take place at interior ear field; Or in eye, take place.Term " bleeding episodes " and " hemorrhage " are if suitable being used interchangeably.
In this article, term " treatment " means and comprises in order to suppress or to minimize hemorrhage and stop hemorrhage (as in the operation hemorrhage) of expection and regulate taken place hemorrhage (as outer damaging the spleen and stomach hemorrhage)." expection hemorrhage " mentioned above can be to be expected at take place in particular organization or the organ hemorrhage, perhaps can be nonspecific hemorrhage.Therefore in term " treatment ", comprise preventative factor VII or factor VII dependency polypeptide product and factor XI, plasma thromboplastin antecedent or the factor XI, plasma thromboplastin antecedent dependency polypeptide product used.
Term used herein " experimenter " is meant any animal, particularly mammal, people for example, and if suitable, can exchange with term " patient " and use.
Factor VII that limits in this description or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or the administration simultaneously or sequentially of factor XI, plasma thromboplastin antecedent dependency polypeptide.This factor can provide by single dosage form, wherein single dosage form contains two kinds of thrombins, perhaps provides as the goods of first unit dosage form and factor XI, plasma thromboplastin antecedent or the factor XI, plasma thromboplastin antecedent dependency polypeptide assembling kit form as second unit dosage form with the goods that contain factor VII or factor VII dependency polypeptide.No matter when mention the first or second or the 3rd in this manual, etc., unit dose, it does not represent preferred order of administration, and only is for convenience.
" simultaneously " goods of using the goods of factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are meant with single dosage form and use coagulation factor protein matter, perhaps use the first coagulation factor protein matter earlier, then be no more than 15 minutes, preferred 10, more preferably 5, more preferably use the second coagulation factor protein matter in 2 minutes the interval.Can at first use arbitrary factor.
" in proper order " administration is meant and uses the first coagulation factor protein matter earlier, then at nearly 2 hours, and preferred 1 to 2 hour, more preferably reach 1 hour, more preferably 30 minutes to 1 hour, more preferably reach 30 minutes, more preferably use the second coagulation factor protein matter in 15 to 30 minutes the interval.Can at first use in two kinds of unit dosage forms or the coagulation factor protein matter any.Preferably, by injecting two kinds of products with an intravenous route.
" level of factor XI, plasma thromboplastin antecedent " or " factor XI, plasma thromboplastin antecedent level " is meant patient's plasma thromboplastin antecedent activity level of comparing with health volunteer's level.This level is called the percent of normal level.Be used interchangeably if this term is suitable.
The level of the factor XI, plasma thromboplastin antecedent " reduce " or " the factor XI, plasma thromboplastin antecedent level of reduction " is meant and do not have the plasma thromboplastin antecedent defective or compare factor XI, plasma thromboplastin antecedent or its active minimizing that exists in the blood flow at the average factor XI, plasma thromboplastin antecedent level in the population of subjects of the inhibitor of plasma thromboplastin antecedent.The level of repetition factor XI can be measured by in blood coagulation or the immunological testing any.The procoagulant activity of factor XI, plasma thromboplastin antecedent measures by the ability of the clotting time of patient's blood plasma improvement factor XI deficiency blood plasma that (for example, APTT test sees below; Also referring to this description " test portion ").
The factor XI, plasma thromboplastin antecedent of a unit is defined as the amount (the factor XI, plasma thromboplastin antecedent level corresponding to 100%) of the factor XI, plasma thromboplastin antecedent that exists in 1 milliliter of normal (collection) human plasma.
The factor VII of a unit is defined as the amount of the factor VII that exists in the 1ml normal plasma, corresponding to about 0.5 μ g protein.After the activation, 50 units are corresponding to about 1 μ g protein.
" shortage " is meant and for example compares in the blood plasma existence of factor XI, plasma thromboplastin antecedent or active the minimizing with the normal health individuality.If suitable can the exchange with " reduction of factor XI, plasma thromboplastin antecedent level " of this term used.
" APTT " or " aPTT " is meant (for example, Proctor RR, Rapaport SI: with the kaolinic portion of tissue Thromboplastin time of activatory portion of tissue Thromboplastin time; The simple screening test of phase I plasma coagulation factors defective.Am J Clin Pathol 36:212,1961 is described).
" factor XI, plasma thromboplastin antecedent response syndrome " be to show the exogenous factor XI that the experimenter that needs uses can prevent, and cures or improve expection or exist, by any symptom that this syndrome causes, the syndrome of situation or disease.Include, but not limited to reduce the syndrome cause by the factor XI, plasma thromboplastin antecedent level, for example, the hemorrhage disorder that causes by the inhibitor of factor XI, plasma thromboplastin antecedent.The factor XI, plasma thromboplastin antecedent response syndrome is also available according to combination treatment of the present invention.
" factor VII response syndrome " is to show the exogenous factor VII that the experimenter that needs uses, preferred factor VIIa can prevent, and cures or improves expection or exist, by any symptom that this syndrome causes, the syndrome of situation or disease.Include, but not limited to by blood coagulation factor VIII, IX, XI or VII level reduce, blood coagulation factor inhibitors, and the syndrome that the deficiency platelet function causes is (for example, graceful Thromboasthenia of Glan thatch and Bernard Soulier syndrome), thrombocytopenia, Feng. von Willebrand's disease and such as diluting by blood coagulating protein, fibrinolysis increases and because the number of platelets of hemorrhage and/or blood transfusion reduces the coagulopathy that (for example, in the experimenter of the repeatedly blood transfusion of experiencing operation or wound) causes.
" half life " is meant that the plasma concentration of factor VII or factor VII dependency polypeptide or factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide reduces to half required time of this value from particular value.
" elementary hemostasis " is meant by FXa and TF: factor VIIa tentatively produces thrombin, then activates platelet and activatory, and the platelet of adhering to forms preliminary loose thrombosis, and it is also infirm by fibrin, and the fibrin that finally is crosslinked is firm.If by the fibrin firm (keeping hemostasis) that forms during second step of hemostasis, this thrombosis is not dissolved by fibrinolytic system easily.
" secondary hemostasis " or " keeping hemostasis " be meant take place at activatory platelet surface and secondary by factor VIIa and the catalytic thrombin of Factor IX a, fully and main outburst or generation, form fibrin and firm preliminary platelet thrombus subsequently.The firm thrombosis of fibrin causes stopping blooding fully.
" hemostasis " fully is meant in injury site and forms effective hemostasis and be not easy by dissolved stable and hard fibrin blood coagulation or the thrombosis of fibrinolytic system.In this manual, the term hemostasis can be used for representing above-mentioned hemostasis fully.
Proteinic total amount can be used known method in the goods, for example, measures by measuring light density.The amount of plasma thromboplastin antecedent or factor VII protein (" antigen ") can be by measuring such as the known method of standard ELISA immunoassay.In general, this algoscopy contacts with anti-FXI antibody on being fixed to elisa plate by making the solution that for example contains the factor XI, plasma thromboplastin antecedent protein articles, fixed antibody-factor XI, plasma thromboplastin antecedent complex is contacted with the second anti-FXI antibody that carries labelling, in the 3rd step, measure the amount of this labelling and carry out.The amount of each thrombin can use suitable antibody to measure in a similar manner.The total amount of the coagulation factor protein matter that exists in the goods can be measured by the amount that adds each coagulation factor protein matter.In one embodiment, these goods comprise isolating thrombin.In another embodiment, these goods do not contain prothrombin and prothrombin a (thrombinogen and thrombin) and/or factor X or Xa.
Term used herein " isolating " is meant from the cell that synthesizes them or isolating thrombin such as factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide in their medium of natural discovery (for example, blood plasma or blood).By any method known in the art, include, but not limited to from the attached cell culture, take out the cell culture medium that contains required product; Centrifugal or filter to remove non-adherent cell; Wait and finish from its derived cell isolated polypeptide.By any method known in the art, include, but not limited to such as the affinity chromatography on anti-factor VII or anti-factor XI, plasma thromboplastin antecedent antibody column respectively; Hydrophobic interaction chromatography; Ion exchange chromatography; The size exclusion chromatography; Electrophoresis method (for example, preparation type isoelectrofocusing (IEF)), differential dissolving (for example, ammonium sulfate precipitation), or extraction etc. can be finished isolated polypeptide from its naturally occurring medium.
Term " TFPI inhibitor " is meant the chemical compound of the anticoagulant active that suppresses TFPI (tissue factor approach restrainer).This term comprises such as at european patent number 558,529, WO 96/28153 and US5, those disclosed chemical compound in 622,988.The commutative use of " TFPI " and " EPI " (extrinsic pathway inhibitor).
" effective dose " of factor VII polypeptides and factor XI, plasma thromboplastin antecedent polypeptide is defined as factor VII polypeptides among the present invention, and for example FVIIa and factor XI, plasma thromboplastin antecedent polypeptide are enough to together prevent or reduce hemorrhage or lose blood, and is enough to cure, and alleviates or part is controlled the amount of this disease and complication thereof.
Term " activity of factor VIIa " or " factor VIIa activity " comprise the ability that produces thrombin; This term is also included within the ability that produces thrombin when not having tissue factor at activatory platelet surface.
Also comprise the TFPI-inhibitor according to compositions of the present invention.Also comprise Factor IX according to compositions of the present invention.Said composition is preferably given the experimenter's administration that does not have at the inhibitor of Factor IX.
Abbreviation
The TF tissue factor
FVII is with its strand, not the factor VII of activated form
FVIIa is with the factor VII of its activated form
RFVIIa is with the recombinant factor VII of its activated form
FXI is with its proenzyme, not the factor XI, plasma thromboplastin antecedent of activated form
FXIa is with the factor XI, plasma thromboplastin antecedent of its activated form
The rFXI FXI that recombinates
The rFXIa FXIa that recombinates
FVIII is with its proenzyme, not the Factor IX of activated form
The rFVIII FVIII that recombinates
FVIIIa is with the Factor IX of its activated form
The rFVIIIa FVIIIa that recombinates
The TFPI tissue factor approach restrainer
The preparation of chemical compound:
Be applicable to that people's purification of factor VIIa of the present invention preferably with the DNA recombinant technique, for example presses Hagen etc.,
Proc.Natl.Acad.Sci.USA 83: 2412-2416,1986 is described, perhaps presses european patent number 200,421 (ZymoGenetics, Inc.) described preparation.
Factor VII also can be by Broze and Majerus,
J.Biol.Chem.255(4): 1242-1247,1980 and Hedner and Kisiel,
J.Clin.lnvest.71: 1836-1841,1983 described methods produce.These methods produce factor VII, but do not contain other thrombin of detection limit.By comprising that extra gel filtration can obtain as final purification step even the factor VII goods of purification more.Then by known method, for example by some different plasma proteinss, factor XI, plasma thromboplastin antecedent Ia for example, IX or Xa can be transformed into the factor VII activation factor FVIIa.In addition, press Bjoern etc. (Research Disclosure,
269, in JIUYUE, 1986,564-565 page or leaf) described, with its by such as Mono Q (Pharmacia fineChemicals) but etc. ion-exchange chromatography activation factor VII.
Factor VII dependency polypeptide can be by modifying wild type factor VII or producing by recombinant technique.The factor VII dependency polypeptide of comparing the aminoacid sequence with change with wild type factor VII can pass through known method, for example changes amino acid code in the nucleic acid of the natural factor VII of coding by direct mutagenesis or removes some amino acid code and modify the nucleotide sequence of encoding wild type factor VII and produce.
Can replace and still produce active polypeptide outside the key zone of function of factor VIIa or factor XI, plasma thromboplastin antecedent molecule be conspicuous to those skilled in the art.According to methods known in the art, for example direct mutagenesis or alanine scanning mutagenesis can identify the activity of factor VII or factor VII dependency polypeptide or factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide essential, and the therefore preferred amino acid residue that does not replace (referring to, for example, Cunningham and Wells, 1989, Science 244:1081-1085).In one technology of back, import sudden change at each positively charged residue place of this molecule, and detect the blood coagulation of the mutant molecule of gained, crosslinking active separately is to identify the active crucial amino acid residue to this molecule.Substrate-enzyme interacting site also can be by analyzing with such as nuclear magnetic resonance spectroscopy, the three dimensional structure of the technical measurement of crystallography or photoaffinity labeling measure (referring to, for example, de Vos etc., 1992, Science 255:306-312; Smith etc., 1992, Journal of Molecular Biology 224:899-904; Wlodaver etc., 1992, FEBS Letters 309:59-64).
Using arbitrary method known in the art can finish by direct mutagenesis imports nucleotide sequence with sudden change and makes and replace another nucleotide with a nucleotide.Useful especially is to utilize to contain the method that purpose is inserted pulsating superhelix double-stranded DNA carrier and contained two synthetic primers of required sudden change.During temperature cycles, extend by means of the Pfu archaeal dna polymerase with the complementary oligonucleotide primers of the opposite strand of this carrier respectively.When this primer mixes, produce the mutant plasmid that contains staggered breach.After the temperature cycles, use and handle this product so that digestion parent's dna profiling and selection contain the synthetic DNA of sudden change with the specific DpnI of hemimethylation DNA methylating.Also can use generation known in the art, other method of evaluation and dissociation body, for example, gene reorganization or display technique of bacteriophage.
By arbitrary method known in the art, include, but not limited to take out the cell culture medium that contains required product from the attached cell culture; Centrifugal or filter to remove non-adherent cell; Deng can finishing from its cell source isolated polypeptide.
Optional is to be further purified factor VII or factor VII dependency polypeptide.Use any method known in the art, include, but not limited to such as the affinity chromatography on anti-factor VII antibody column (referring to, for example, Wakabayashi etc., J.Biol.Chem.261:11097,1986; With Thim etc., Biochem.27:7785,1988); Hydrophobic interaction chromatography; Ion exchange chromatography; The size exclusion chromatography; Electrophoresis method (for example, preparation type isoelectrofocusing (IEF)), differential dissolving (for example, ammonium sulfate precipitation), or extraction etc. can be finished purification.In general, referring to Scopes, Protein Purification, Springer-Verlag, New York, 1982; With Protein Purification, J.C.Janson and LarsRyden, editors, VCH Publishers, New York, 1989.Behind the purification, these goods preferably contain has an appointment below 10% weight, more preferably from about below 5%, and non-factor VII or the factor VII dependency polypeptide below 1% most preferably from about from host cell.
But factor VII or factor VII dependency polypeptide usage factor XIIa or have specific other protease of trypsin-like, for example, factors IX a, kallikrein, factor Xa and thrombin activate by proteolytic cleavage.Referring to, for example, Osterud etc., Biochem.11:2853 (1972); Thomas, U.S. Patent number 4,456,591; With Hedner etc., J.Clin.Invest.71:1836 (1983).In addition, factor VII or factor VII dependency polypeptide can activate it by the ion-exchange chromatography that waits such as Mono Q (Pharmacia).The activation factor VII of gained or factor VII dependency polypeptide can be by hereinafter described preparation and administrations then.
The factor XI, plasma thromboplastin antecedent of using among the present invention can be according to known method, (the Biochemistry 16:2279-2286 such as Koide that quote as a reference of this paper for example, 1977) and (J.Biol.Chem.252:6432-6437,1977) those disclosed method such as Bouma from blood plasma, prepare.Yet, preferably use recombinant factor XI to avoid using the blood that has pathophoresis danger or tissue-derived product.The method for preparing recombinant factor XI is known in the art.Referring to, for example, (Gene 139 (2): 275-279 for Kemball-Cook etc., 1994), Fujikawa etc. (Biochemistry 25:2417-2424,1986), Meijers etc. (Blood 79 (6): 1435-1440,1992), this paper quotes with its integral body as a reference.
Factor XI, plasma thromboplastin antecedent dependency polypeptide can be by modifying wild type factor XI or producing by recombinant technique.The factor XI, plasma thromboplastin antecedent dependency polypeptide of comparing the aminoacid sequence with change with wild type factor XI can pass through known method by more detailed description above, for example change amino acid code in the nucleic acid of the natural factor XI, plasma thromboplastin antecedent of coding or remove some amino acid code, modify the nucleotide sequence of encoding wild type factor XI, plasma thromboplastin antecedent and produce by direct mutagenesis.By arbitrary method known in the art, include, but not limited to take out the cell culture medium that contains required product from the attached cell culture; Centrifugal or filter to remove non-adherent cell; Deng can finishing from its cell source isolated polypeptide.Optional is to be further purified factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide.Can use any method known in the art by more detailed description above, include, but not limited to such as the affinity chromatography on anti-factor XI, plasma thromboplastin antecedent antibody column; Hydrophobic interaction chromatography; Ion exchange chromatography; The size exclusion chromatography; Electrophoresis method (for example, preparation type isoelectrofocusing (IEF)), differential dissolving (for example, ammonium sulfate precipitation), or purification is finished in extraction etc.Behind the purification, these goods preferably contain has an appointment below 10% weight, more preferably from about below 5%, and non-factor XI, plasma thromboplastin antecedent or the factor XI, plasma thromboplastin antecedent dependency polypeptide below 1% most preferably from about from host cell.The activation factor XI of gained or factor XI, plasma thromboplastin antecedent dependency polypeptide can be by hereinafter described preparation and administrations then.
Those skilled in the art will reckon with, the preferred risk of reacting with the reduction induction of immunity with homologous factor XI, plasma thromboplastin antecedent of experimenter and factor VIIa protein of using.The preparation of inhuman factor XI, plasma thromboplastin antecedent and identify that by for example, Gailani (Blood 90 (3): 1055-1064,1997) is open.The present invention also comprises this factor XI, plasma thromboplastin antecedent and the purposes of factor VIIa protein in veterinary's method.
Pharmaceutical composition and using method
Goods of the present invention can be used for treating any factor VII response syndrome, for example hemorrhage disorder, comprise, but be not limited to by blood coagulation factor VIII, IX, XI or VII level reduce, blood coagulation factor inhibitors, the syndrome that the deficiency platelet function causes (for example, graceful Thromboasthenia of Glan thatch and Bernard Soulier syndrome), thrombocytopenia, Feng. von Willebrand's disease, with such as by blood coagulating protein dilution, fibrinolysis increases and because the number of platelets of hemorrhage and/or blood transfusion reduces the coagulopathy that (for example, in the experimenter of the repeatedly blood transfusion of experience operation or wound) causes.The Pharmaceutical composition that contains factor VII or factor VII dependency polypeptide product and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product according to the present invention is mainly used in parenteral and is used for preventative and/or therapeutic treatment.Preferably, this Pharmaceutical composition is by parenteral, and promptly intravenous is subcutaneous, or intramuscular; Intravenous administration most preferably.They also can be by continuous or pulsation infusion administration.
Comprise with single unit dosage form or with the form preparation of assembling test kit according to Pharmaceutical composition of the present invention or preparation, preferably be dissolved in the medicinal acceptable carrier of going up, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide in preferred aqueous carrier or the diluent.Briefly, being suitable for can be by with factor VIIa according to the Pharmaceutical composition of purposes of the present invention, or factor XI, plasma thromboplastin antecedent, and the perhaps combination of factor VIIa and factor XI, plasma thromboplastin antecedent (preferably purified form) prepares with suitable adjuvant and suitable carriers or mixing diluents.Can use various aqueous carriers, water for example, buffered water, 0.4% saline, 0.3% glycine etc.Goods of the present invention also can use the nonaqueous carrier preparation, for example, are used for administration or are directed to injury site with the form of gel or as liposome product.Liposome product is generally for example pressed, U.S. Patent number 4,837, and 028,4,501,728 and 4,975, described in 282.Said composition can be routinely, the sterilization technology sterilization known.The aqueous solution of packing gained is standby or filter also lyophilizing under aseptic condition, and this freeze-dried products mixes with aseptic aqueous solution before administration.
Said composition can contain medicinal acceptable auxiliary substance or the adjuvant, and includes, but not limited to pH regulator and buffer agent and/or tension regulator, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, etc.
Preparation also can comprise one or more diluent, emulsifying agent, and antiseptic, buffer agent, excipient etc. and can be used as such as liquid, powder, Emulsion, the form of slow releasing agent etc. provides.Those skilled in the art with suitable manner and according to such as
Remington ' s Pharmaceutical Sciences.Gennaro, ed., Mack Publishing Co., Easton, PA, disclosed generally acknowledged practice can be prepared compositions of the present invention in 1990.Therefore, the typical Pharmaceutical composition that is used for intravenous infusion can be mixed with aseptic Ringer's solution and these goods of 10mg that contain 250ml.
Can use the compositions that contains goods of the present invention is used for preventative and/or therapeutic treatment.In treatment is used, use for healing for the experimenter who has suffered from above-mentioned disease, alleviate or partly stop the compositions of the clinical manifestation q.s of this disease and complication thereof.The q.s of realizing this point is defined as " treatment effective dose ".The effective dose of each purpose depends on the seriousness of this i or I and experimenter's body weight and general state.Should understand that measuring proper dosage can use normal experiment to finish by the difference of setting up numerical matrix and test in this matrix.
The topical of goods of the present invention, for example, topical application can by means of spraying, be poured into by for example, double balloon catheter, support (stent) inserts blood vessel graft or support, is used for the hydrogel of coating gas ductus bursae, and perhaps other method of fully determining is carried out.In either case, this Pharmaceutical composition should provide the product amount that is enough to effectively treat this situation.
Factor VII or factor VII dependency polypeptide in these preparations, factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide, perhaps the concentration of the combination of factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide can change on a large scale, promptly from the weight of deficiency about 0.5%, be generally or be at least about 1% weight to up to 15 or 20% weight and according to selected concrete administering mode mainly by liquid volume, viscosity etc. are selected.Preferably by injection or infusion, particularly drug administration by injection.Therefore, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are to be suitable for the form preparation of intravenous administration, for example these goods can be dissolved freeze-dried powder end or the liquid formulations that contains factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide in a kind of dosage form simultaneously, or contain the dissolved freeze-dried powder end or the liquid formulations of factor VII or factor VII dependency polypeptide and contain factor XI, plasma thromboplastin antecedent or the dissolved freeze-dried powder end or the liquid formulations of factor XI, plasma thromboplastin antecedent dependency polypeptide in another dosage form in a kind of dosage form.
Should understand that the amount of factor VII or factor VII dependency polypeptide and the amount of factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide comprise the total effective dose for the treatment of bleeding episodes together.
Must remember that material of the present invention generally can be used for serious disease or faulted condition, i.e. life-threatening or the life-threatening situation of possibility.In this case, in view of exogenous material minimizes and the immunogenicity of human body factor VIIa and factor XI, plasma thromboplastin antecedent totally lacks, the attending doctor may and think and need use excessive basically said composition.
In prophylactic use, the compositions that contains factor VII or factor VII dependency polypeptide product and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product can be given morbid state or damage susceptibility or this dangerous experimenter's administration be arranged to strengthen experimenter's self blood coagulation ability.This amount is defined as " prevention effective dose ".Should understand that the amount of factor VII or factor VII dependency polypeptide and the amount of factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide comprise the total effective dose that prevents bleeding episodes together.
Dosage level that available attending doctor selectes and mode are carried out the single or multiple administration of said composition.But said composition every day or be administered once weekly or repeatedly.The effective dose of this Pharmaceutical composition provides bleeding episodes obvious and effective amount clinically.This amount depends in part on the concrete symptom of being treated, experimenter's age, and body weight and general health state, and to the conspicuous other factors of those skilled in the art.
Compositions of the present invention generally before expection is hemorrhage or during in hemorrhage beginning with single dosed administration.Yet, also can be according to dosage that provides and experimenter's situation, preferably with 2-4-6-12 hour interval repeat administration (being multiple dose).
Be equipped with to get involved in the relevant treatment with having, the generally administration in about 24 hours before intervention of factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide, and after this continue to reach 7 days or longer.Administration as anticoagulant can be undertaken by various approach as herein described.
Said composition can be the single goods form (single dosage form) that contains goods and the factor XI, plasma thromboplastin antecedent or the factor XI, plasma thromboplastin antecedent dependency polypeptide product of factor VII or factor VII dependency polypeptide with suitable concentration simultaneously.Said composition also can be by first unit dosage form that contains factor VII or factor VII dependency polypeptide product and is contained the form of the assembling test kit that second unit dosage form of factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide product forms.In this case, factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are answered a then administration, and be preferred each other in about 15 minutes interval, for example, each other in 10 minutes, perhaps preferably in 5 minutes, or more preferably each other in 2 minutes.Can at first use in two unit dosage forms any.
This test kit comprises at least two isolating pharmaceutical compositions.This test kit comprises the case that contains this compositions of separating such as bottle that separates or the Foilpac that separates.In general, this test kit comprises the administration explanation of the composition that this separates.When this composition that separates preferably with different dosage form administrations, during with different dosing interval administration, perhaps during the titration value of each composition that need make up as the attending doctor, this kit form advantageous particularly.
The amount of the amount of factor VII that uses according to the present invention or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide can change in the ratio between about 1: 100 to about 100: 1 (w/w).Therefore the ratio of factor VII and factor XI, plasma thromboplastin antecedent can be, for example, and about 1: 100, or 1: 90, or 1: 80, or 1: 70 or 1: 60, or 1: 50, or 1: 40, or 1: 30, or 1: 20, or 1: 10, or 1: 5, or 1: 2, or 1: 1, or 2: 1, or 5: 1, or 10: 1, or 20: 1, or 30: 1, or 40: 1, or 50: 1, or 60: 1, or 70: 1, or 80: 1, or 90: 1, or 100: 1; Perhaps between about 1: 90 to about 1: 1, perhaps between about 1: 80 to about 1: 2, perhaps between about 1: 70 to about 1: 5, perhaps between about 1: 60 to about 1: 10, perhaps between about 1: 50 to about 1: 25, perhaps between about 1: 40 to about 1: 30, perhaps between about 90: 1 to about 1: 1, perhaps between about 80: 1 to about 2: 1, perhaps between about 70: 1 to about 5: 1, perhaps between about 60: 1 to about 10: 1, perhaps between about 50: 1 to about 25: 1, perhaps between about 40: 1 to about 30: 1.
The dosage of factor VII or factor VII dependency polypeptide for the experimenter of 70-kg as loading and maintenance dose, can be dependent on experimenter's body weight, the seriousness of situation and symptom corresponding to about 0.05mg to about 500mg/ days wild type factor VII, for example, from about 1mg to approximately 200mg/ days, perhaps, for example, change the dosage from about 5mg to approximately 175mg/ days.
The dosage of factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide for the experimenter of 70-kg as loading and maintenance dose, can be dependent on experimenter's body weight, the seriousness of situation and symptom corresponding to about 0.05mg to about 500mg/ days wild type factor XI, for example, from about 1mg to approximately 200mg/ days, perhaps, for example, change the dosage from about 1mg to approximately 175mg/ days.
Being combined in external blood coagulation hardness and the fibrinolysis time test of factor VIIa and factor XI, plasma thromboplastin antecedent shows cooperative effect.And being combined in of factor VIIa and factor XI, plasma thromboplastin antecedent forms stable fibrin blood coagulation, prolongs half blood coagulation dissolution time, increases blood coagulation intensity and enhancing to showing cooperative effect in the Fibrinolytic resistance.
Said composition can be the single goods form that contains factor VIIa and factor XI, plasma thromboplastin antecedent with suitable concentration simultaneously.Said composition also can and contain the form of second unit dosage form and the test kit that optional one or more other unit dosage forms that contain Factor IX and/or TFPI inhibitor are formed of factor XI, plasma thromboplastin antecedent by first unit dosage form that contains factor VIIa.In this case, factor VIIa and factor XI, plasma thromboplastin antecedent should the order administrations, and be preferred each other in approximately 1-2 hour interval, for example, and each other in 30 minutes, perhaps preferably in 10 minutes, or more preferably each other in 5 minutes.Can at first use in two unit dosage forms any.
But, therefore, the invention still further relates to form combination Pharmaceutical composition separately with test kit owing to the present invention relates to handle by carrying out the prevention or the treatment of bleeding episodes with the Combined Treatment of the active ingredient of separate administration or be used for blood coagulation.This test kit comprises at least two Pharmaceutical compositions that separate.This test kit comprises the case that contains this compositions of separating such as bottle that separates or the Foilpac that separates.In general, this test kit comprises the administration explanation of the composition that this separates.When this composition that separates preferably with different dosage form administrations, during with different dosing interval administration, perhaps during the titration value of each composition that need make up as the attending doctor, this kit form advantageous particularly.
Test:
Detect the activity of factor VIIa:
In in vitro tests, carry out suitable test with detection factor VIIa activity, thereby select suitable factor VIIa variant with simple prerun:
The extracorporeal hydrolysis test
Can measure the ratio of natural (wild type) factor VIIa and factor VIIa variant (both hereinafter all are called " factor VIIa ") lives.But also parallel assay they in case directly relatively its than work.(MaxiSorp, Nunc carry out this mensuration on Denmark) at microtitration plate.(S-2288, Chromogenix Sweden) add to be dissolved in final concentration 1mM and contain 0.1M NaCl, 5mM CaCl with chromogenic substrate D-Ile-Pro-Arg-p-nitroanilide
2With the 50mMHepes of 1mg/ml bovine serum albumin, in the factor VIIa among the pH 7.4 (final concentration is 100nM).At SpectraMax
TM340 flat bed readers (Molecular Devices, USA) absorbance under the last continuous measurement 405nm.The absorbance that incubation formed during 20 minutes deducts the ratio that is used to calculate behind the absorbance in the blank well that does not contain enzyme between variant and the wild type factor VIIa activity:
Ratio=(A
405nmThe factor VIIa variant)/(A
405nmThe factor VIIa wild type).
On this basis, identified activity is equivalent to or is higher than the factor VIIa variant of natural factor VIIa, and for example, the ratio between the activity of the activity of variant and natural factor VII (wild type FVII) is approximately, perhaps is higher than 1.0 variant.
The activity of factor VIIa or factor VIIa variant also can be used the physiology substrate such as factor X, measures with the suitable concn of 100-1000nM, and wherein (for example, S-2765) factor Xa that produces is measured in the back adding suitable product color substrate.In addition, can under physiological temp, carry out activity test.
External Proteolytic enzyme test
Natural (wild type) factor VIIa of parallel assay and factor VIIa variant (both hereinafter all are called " factor VIIa ") are so that directly compare it than work.(MaxiSorp, Nunc carry out this mensuration on Denmark) at microtitration plate.Contain 0.1M NaCl at 100 microlitres, 5mM CaCl
2With the 50mM Hepes of 1mg/ml bovine serum albumin, among the pH 7.4, with factor VIIa (10nM) and factor X (0.8 micromole) incubation 15 minutes.Add 50 microlitres then and contain 0.1M NaCl, the 50mM Hepes of 20mM EDTA and 1mg/ml bovine serum albumin, the cracking of pH 7.4 termination factor X.By adding the chromogenic substrate Z-D-Arg-Gly-Arg-p-nitroanilide that final concentration is 0.5mM (S-2765, Chromogenix, Sweden) amount of the factor Xa of measurement generation.At SpectraMax
TM340 flat bed readers (MolecularDevices, USA) absorbance under the last continuous measurement 405nm.The absorbance that forms during 10 minutes deducts the ratio between the proteolytic activity that is used to calculate variant and wild type factor VIIa behind the absorbance in the blank well that does not contain FVIIa:
Ratio=(A405nm factor VIIa variant)/(A405nm factor VIIa wild type).
On this basis, identified activity is equivalent to or is higher than the factor VIIa variant of natural factor VIIa, and for example, the ratio between the activity of the activity of variant and natural factor VII (wild type FVII) is approximately, perhaps is higher than 1.0 variant.
The thrombin generation test:
Factor VII or factor VII dependency polypeptide or factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide are (for example, variant) produces to measure in the test of all relevant thrombins that the ability of thrombin can be under comprising physiological concentration and inhibitor and activated blood platelet and (press (1997) Brit.J.Haematol.99 such as Monroe, among the 542-547 the 543rd page described, this paper quotes for your guidance).
Detect the activity of factor XI, plasma thromboplastin antecedent:
For example use, (Blood 97 (10): 3117-3122 for Gailani etc., 2001) (" FXI produces colour test ") described product color substrate can carry out the amide decomposition activity of suitable test with the detection factor XI, plasma thromboplastin antecedent simply in vitro tests, thereby selects suitable factor XI, plasma thromboplastin antecedent variant.
By for example, Gailani etc. (Blood 97 (10): 3117-3122,2001) are described to activate into the Determination of biological activity that also can carry out factor XI, plasma thromboplastin antecedent in the in vitro tests of IXa simply measuring factors IX.
Detect the activity of Factor IX:
For example press Kirkwood TBL, Rizza CR, Snape TJ, Rhymes IL, the source of Austen DEG. identification experiment chamber differences in the Factor IX test.B J Haematol 1981; 37; 559-68; Or Kessels etc., British Journal of Haematology, the described activity that in vitro tests, can carry out suitable test with the detection Factor IX simply of Vol.76 (Suppl.1) pp.16 (1990), thus the method for selecting to be used for suitable Factor IX variant of the present invention is provided.The activity of Factor IX also can be produced colour test by two steps based on the amide decomposition activity of the FXa that produces and be measured (Wagenvoord etc., 1989, Haemostasis, 19 (4): 196-204).
For example press Nilsson etc., 1959. (Nilsson IM, Blombaeck M, Thilen A, vonFrancken I., hemophilia A carrier-laboratory research, Acta Med Scan 1959; The ability of the clotting time by measuring goods correction factor VIII deficiency blood plasma 165:357) is the quantitative biologic activity of Factor IX also.In this test, the biologic activity unit of being expressed as/ml blood plasma (amount of the FVIII that exists in 1 blood plasma of unit) corresponding to normal collection.
Aspect of the present invention:
Aspect 1: the Pharmaceutical composition that contains factor VII or factor VII dependency polypeptide and factor XI, plasma thromboplastin antecedent or factor XI, plasma thromboplastin antecedent dependency polypeptide.
Embodiment 2: the compositions in the aspect 1, wherein said factor VII or factor VII dependency polypeptide are factor VII dependency polypeptide.
Embodiment 3: the compositions of aspect 1, wherein factor VIIa is human factor VII a.
Embodiment 4: the compositions in aspect 1 or the aspect 3, wherein factor VIIa and factor XI, plasma thromboplastin antecedent are recombined human factor VIIa and recombined human factor XI, plasma thromboplastin antecedent.
Embodiment 5: each compositions among the aspect 1-4, wherein factor XI, plasma thromboplastin antecedent is platelet factor XI.
Embodiment 6: each compositions among the aspect 1-5, wherein factor XI, plasma thromboplastin antecedent is activated factor XI.
Embodiment 7: each compositions among the aspect 1-6, wherein said composition also contains the TFPI inhibitor.
Embodiment 8: each compositions among the aspect 1-7, wherein said composition also contains Factor IX.
Aspect 2: contain the test kit for the treatment of bleeding episodes, comprise
A) factor VIIa of the effective dose in first unit dosage form and medicinal on acceptable carrier;
B) factor XI, plasma thromboplastin antecedent of the effective dose in second unit dosage form and medicinal on acceptable carrier; With
C) contain the case of described first and second dosage forms.
Embodiment 10: the compositions in the aspect 2 comprises
A) factor VIIa of the effective dose in first unit dosage form and medicinal on acceptable carrier;
B) factor XI, plasma thromboplastin antecedent of the effective dose in second unit dosage form and medicinal on acceptable carrier;
C) the TFPI inhibitor of the effective dose in the 3rd unit dosage form and medicinal on acceptable carrier; With
D) contain described the first, the second and the case of the 3rd dosage form.
Aspect 3: contain the test kit for the treatment of bleeding episodes, comprise
A) factor VIIa of the effective dose in first unit dosage form and TFPI inhibitor and medicinal on acceptable carrier;
B) factor XI, plasma thromboplastin antecedent of the effective dose in second unit dosage form and medicinal on acceptable carrier; With
C) contain the case of described first and second dosage forms.
Aspect 4: contain the test kit for the treatment of bleeding episodes, comprise
A) factor VIIa of the effective dose in first unit dosage form and medicinal on acceptable carrier;
B) factor XI, plasma thromboplastin antecedent of the effective dose in second unit dosage form and TFPI inhibitor and medicinal on acceptable carrier; With
C) contain the case of described first and second dosage forms.
Embodiment 9: each test kit among the embodiment 2-4, also contain with the preparation of the unit dosage form that separates, perhaps be included in also to contain and be selected from factor VIIa, the Factor IX in the unit dosage form of one or more chemical compounds in factor XI, plasma thromboplastin antecedent or the TFPI inhibitor.
Aspect 6: the purposes in the medicine that is combined in preparation treatment experimenter bleeding episodes of factor VIIa and factor XI, plasma thromboplastin antecedent.
Aspect 7: being combined in of factor VIIa and factor XI, plasma thromboplastin antecedent prepares the purposes that is used in the medicine of experimenter's shortening clotting time.
Aspect 8: being combined in of factor VIIa and factor XI, plasma thromboplastin antecedent prepares the purposes that is used in the medicine of normal mammalian blood plasma prolongation blood coagulation dissolution time.
Aspect 9: being combined in of factor VIIa and factor XI, plasma thromboplastin antecedent prepares the purposes that is used in the medicine of normal mammalian blood plasma increase blood coagulation intensity.
Aspect 10: being combined in of factor VIIa and factor XI, plasma thromboplastin antecedent prepares the purposes that is used in the medicine that the blood coagulation of human normal plasma's enhancing fibrin forms.
Aspect 11: strengthen the method that the blood coagulation of experimenter's fibrin forms, this method comprises the combination of using the factor XI, plasma thromboplastin antecedent of the factor VIIa of effective dose and effective dose to the experimenter.
Aspect 12: the method for treatment experimenter bleeding episodes comprises the combination of using the factor XI, plasma thromboplastin antecedent of the factor VIIa of effective dose and effective dose to the experimenter.
Embodiment 10: aspect 19 or 20 method, wherein factor VIIa and factor XI, plasma thromboplastin antecedent are with single dosage form administration.
Embodiment 11: aspect 19 or 20 method, the wherein administration of factor VIIa and factor XI, plasma thromboplastin antecedent order.
Can further specify the present invention by the following examples, yet they can not be construed to the limiting protecting scope.Describe in the above and following embodiment in disclosed feature can separate and with its combination in any as with its multi-form realization basis of the present invention.
Embodiment
By proconvertin a and XI are made up the stability that improves the blood coagulation of hemostasis type
Method:
Blood coagulation solubility test: will be with containing Innovin (Dade Behring, 2000-doubly dilutes), rFVIIa (Novo Nordisk A/S, Bagsvaerd, Denmark; Various concentration) and t-PA (AmericanDiagnostics, (the 20mM HEPES of buffer 8nM), 150mM NaCl, 5mM CaCl, pH7.4) human normal plasma of 10 times of dilutions adds the turbidity a period of time of also at room temperature measuring in the 96 hole ELISA flat boards under the 650nm.In indicated position, comprise the people FXI (HaematologicTechnologies, various concentration) of purification.
Rotation (Rotatonal) thromboelastography (roTEG): measure in the Citrated human normal plasma who has added 5nM t-PA, analysis is made up the effect that adds 1nM FVIIa separately or with 30nM FXI (Haematologic Technologies).Be added in 20mM HEPES, 150mM NaCl, the Innovin in pH 7.4 buffer (final concentration that 2000-doubly dilutes, Dade Behring#526945) and calcium (final concentration of 15mM) beginning blood coagulation.
The result:
Blood coagulation solubility test: add FVIIa and cause the dose dependent of blood coagulation dissolution time to prolong (Fig. 1).This effect is best under 10nM FVIIa.In the presence of 10nM FVIIa, add FXI and cause the blood coagulation dissolution time further to prolong (Fig. 2).This effect is a dose dependent and best under 30nM FXI.
Thromboelastography: the roTEG measurement is used to analyze FVIIa and FXI to maximum blood coagulation hardness (MCF), and blood coagulation is to the influence of the dissolved resistance of t-PA mediation type.Before adding FVIIa/FXI, MCF is that to dissolve half required time be 12.3 minutes (Fig. 3) for 25mm and blood coagulation.Adding FXI (30nM) does not change MCF but half blood coagulation dissolution time is extended to 16.1 minutes (Fig. 3).Equally, add FVIIa (1nM) and cause blood coagulation protected and be not subjected to the fibrinolysis (half blood coagulation dissolution time: 16.7 minutes) of t-PA mediation, to MCF have no effect (Fig. 3).Yet FVIIa (1nM) adds with FXI (30nM) increases MCF (29mm), and half blood coagulation dissolution time (24.2 minutes, Fig. 3).
Conclusion:
These results prove in FVIIa and the FXI adding blood plasma and improve the mechanical strength of blood coagulation and the Fibrinolytic resistance that t-PA is mediated in collaborative mode.
Embodiment 2
By the clotting time among combination proconvertin a and the XI shortening human normal plasma
Method:
Thrombotest: independent rFVIIa (1 μ g/ml), independent FXI (25nM), or rFVIIa and FXI are at 50mM Pipes, 100mM NaCl, 2mM EDTA, 1%BSA, the aliquot among the pH 7.2 (55 μ l) with in same buffer, contain 100 μ M PC/PS vesicle and 50mM CaCl
255 μ l aliquot incubations 5 minutes.The aliquot that adds 55 μ l human normal plasmas (NHP) is then used the blood coagulation 400 seconds in ACL blood coagulation machine of standard A PTT program.
The result:
Thrombotest: before adding rFVIIa or FXI, NHP not blood coagulation in 400 seconds monitoring time.After adding FXI (25nM), clotting time still was longer than 400 seconds.Add FVIIa (1 μ g/ml) clotting time is shortened to 159.4 ± 1.4 seconds (Fig. 4).Add FVIIa (1 μ g/ml) and FXI (25nM) simultaneously clotting time is shortened to 95.0 ± 1.4 seconds (Fig. 4).
Conclusion:
These results proof adds FVIIa and FXI and shortens clotting time among the NHP in collaborative mode in blood plasma.
Claims (35)
1. the Pharmaceutical composition that contains proconvertin and plasma thromboplastin antecedent.
2. according to the compositions of claim 1, wherein said proconvertin is a human blood coagulation factor VII.
3. according to the compositions of claim 2, wherein said proconvertin is a recombinant human blood coagulation factor VII.
4. according to each compositions of claim 1-3, wherein said proconvertin is its activated form.
5. according to the compositions of claim 4, wherein said proconvertin is recombinant human blood coagulation factor VII a.
6. according to the compositions of claim 1, wherein said plasma thromboplastin antecedent is human blood coagulation XI.
7. according to the compositions of claim 6, wherein said plasma thromboplastin antecedent is a recombined human blood plasma plasma thromboplastin antecedent.
8. according to the compositions of claim 6, wherein said plasma thromboplastin antecedent is the recombination human platelet plasma thromboplastin antecedent.
9. according to each compositions of claim 1 to 8, wherein said proconvertin and described plasma thromboplastin antecedent exist with the mass ratio between 100: 1 to 1: 100.
10. according to the compositions of claim 9, wherein said composition also contains and is suitable for injecting or infusion medicinal acceptable excipient.
11. according to each the purposes of compositions in the medicine of preparation treatment experimenter bleeding episodes of claim 1 to 10.
12. according to the purposes of claim 11, wherein this medicine is used to shorten clotting time.
13. according to the purposes of claim 11, wherein this medicine is used to prolong the blood coagulation dissolution time.
14. according to the purposes of claim 11, wherein this medicine is used to increase blood coagulation intensity.
15. according to each purposes of claim 11-14, wherein this medicine is mixed with and is used to inject or the dosage form of infusion.
16. according to each purposes of claim 11-14, wherein bleeding episodes is because wound or operation or enumeration of thrombocytes or active the reduction.
17. according to each purposes of claim 11-14, wherein this medicine is a single dose form.
18. be used for the treatment of the assembling test kit of bleeding episodes, comprise
F) goods of the proconvertin of the effective dose in first unit dosage form and medicinal on acceptable carrier;
G) goods of the plasma thromboplastin antecedent of the effective dose in second unit dosage form and medicinal on acceptable carrier; With
H) contain the case of described first and second dosage forms.
19. according to the test kit of claim 18, wherein said proconvertin is a human blood coagulation factor VII.
20. according to the test kit of claim 19, wherein said proconvertin polypeptide is a recombinant human blood coagulation factor VII.
21. according to each test kit of claim 18 to 20, wherein said proconvertin is its activated form.
22. according to the test kit of claim 21, wherein said proconvertin is recombinant human blood coagulation factor VII a.
23. according to the test kit of claim 18, wherein said plasma thromboplastin antecedent is human blood coagulation XI.
24. according to the test kit of claim 23, wherein said plasma thromboplastin antecedent is a recombined human blood plasma plasma thromboplastin antecedent.
25. according to the test kit of claim 23, wherein said plasma thromboplastin antecedent is the recombination human platelet plasma thromboplastin antecedent.
26. according to the test kit of claim 18, wherein said proconvertin and plasma thromboplastin antecedent exist with the mass ratio between 100: 1 to 1: 100.
27. the purposes in the medicine that is combined in preparation treatment experimenter bleeding episodes of proconvertin and plasma thromboplastin antecedent.
28. according to the purposes of claim 27, wherein this medicine is used to shorten clotting time.
29. according to the purposes of claim 27, wherein this medicine is used to prolong the blood coagulation dissolution time.
30. according to the purposes of claim 27, wherein this medicine is used to increase blood coagulation intensity.
31. according to each purposes of claim 27 to 30, wherein this medicine is mixed with and is used to inject or the dosage form of infusion.
32. according to each purposes of claim 27 to 30, wherein bleeding episodes is because wound or operation or enumeration of thrombocytes or active the reduction.
33. according to each purposes of claim 27 to 30, wherein this medicine is with the form preparation of first unit dosage form that contains the proconvertin goods and second unit dosage form that contains the plasma thromboplastin antecedent goods.
34. the goods of the plasma thromboplastin antecedent of the goods of the proconvertin of first amount and second amount are used for strengthening the purposes of experimenter's hemostatic medicine in preparation, wherein first and second amounts are together to strengthening hemostasis effectively.
35. be used for the treatment of the test kit of bleeding episodes, comprise
A) plasma thromboplastin antecedent of the proconvertin of the effective dose in a unit dosage form and effective dose and medicinal on acceptable carrier; With
B) contain the case of a described unit dosage form.
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CA2378249A1 (en) | 1999-07-14 | 2001-01-25 | Mirella Ezban | Use of fviia or a tissue factor antagonist for regulating gene expression and cell migration or chemotaxis |
CN1863908B (en) | 2003-09-09 | 2010-08-04 | 诺和诺德医疗保健公司 | Coagulation factor vii polypeptides |
JP2007513881A (en) * | 2003-11-20 | 2007-05-31 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | Therapeutic use of factor XI |
AU2005210175A1 (en) * | 2004-02-05 | 2005-08-18 | Novo Nordisk Health Care Ag | Use of factor VIIa for treating late complications of trauma |
WO2006128497A1 (en) * | 2005-06-01 | 2006-12-07 | Novo Nordisk A/S | Pharmaceutical formulation of factor xi |
BRPI0922344A2 (en) | 2008-12-19 | 2017-10-24 | 3B Pharmaceuticals Gmbh | tfpi inhibitors and methods of use |
ES2983470T3 (en) | 2010-03-19 | 2024-10-23 | Takeda Pharmaceuticals Co | TFPI inhibitors and methods of use |
PL2624859T3 (en) * | 2010-10-06 | 2017-09-29 | Medimmune Limited | Factor ii alone or in combination with further factors for treatment of impaired haemostasis associated with dilutional coagulopathy |
JP2015514070A (en) | 2012-03-21 | 2015-05-18 | バクスター・インターナショナル・インコーポレイテッドBaxter International Incorp0Rated | TFPI inhibitors and methods of use |
CA2936871A1 (en) * | 2014-01-31 | 2015-08-06 | Dana-Farber Cancer Institute, Inc. | Dihydropteridinone derivatives and uses thereof |
AU2016276963C1 (en) | 2015-06-12 | 2021-08-05 | Dana-Farber Cancer Institute, Inc. | Combination therapy of transcription inhibitors and kinase inhibitors |
SG11201803210YA (en) | 2015-11-25 | 2018-05-30 | Dana Farber Cancer Inst Inc | Bivalent bromodomain inhibitors and uses thereof |
US11958911B2 (en) | 2017-02-10 | 2024-04-16 | Shanghai Benemae Pharmaceutical | Anti-coagulation factor XI antibody |
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US5252217A (en) * | 1991-05-07 | 1993-10-12 | Association Pour L'essor De La Transfusion Sanguine Dans La Region Du Nord | Blood coagulation factor XI concentrate having high specific activity, suitable for therapeutic use, and process for preparing same |
US5580560A (en) * | 1989-11-13 | 1996-12-03 | Novo Nordisk A/S | Modified factor VII/VIIa |
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JPS59116213A (en) * | 1982-12-24 | 1984-07-05 | Unitika Ltd | Aerosol composition |
CA1281647C (en) * | 1985-11-26 | 1991-03-19 | Novo Nordisk A/S | Compositions and methods for the treatment of bleeding disorders |
WO2002022776A2 (en) * | 2000-09-13 | 2002-03-21 | Novo Nordisk A/S | Human coagulation factor vii variants |
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2002
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- 2002-07-19 JP JP2003513588A patent/JP2004534855A/en active Pending
- 2002-07-19 CA CA002452677A patent/CA2452677A1/en not_active Abandoned
- 2002-07-19 PL PL02369077A patent/PL369077A1/en not_active Application Discontinuation
- 2002-07-19 HU HU0400976A patent/HUP0400976A3/en unknown
- 2002-07-19 AU AU2002354846A patent/AU2002354846B2/en not_active Ceased
- 2002-07-19 WO PCT/DK2002/000505 patent/WO2003007983A1/en not_active Application Discontinuation
- 2002-07-19 MX MXPA04000415A patent/MXPA04000415A/en unknown
- 2002-07-19 RU RU2004105031/15A patent/RU2298416C2/en not_active IP Right Cessation
- 2002-07-19 EP EP02750844A patent/EP1411973A1/en not_active Withdrawn
- 2002-07-19 BR BR0211256-6A patent/BR0211256A/en not_active IP Right Cessation
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- 2002-07-19 IL IL15962202A patent/IL159622A0/en unknown
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2004
- 2004-01-05 ZA ZA200400012A patent/ZA200400012B/en unknown
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US5580560A (en) * | 1989-11-13 | 1996-12-03 | Novo Nordisk A/S | Modified factor VII/VIIa |
US5252217A (en) * | 1991-05-07 | 1993-10-12 | Association Pour L'essor De La Transfusion Sanguine Dans La Region Du Nord | Blood coagulation factor XI concentrate having high specific activity, suitable for therapeutic use, and process for preparing same |
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RU2298416C2 (en) | 2007-05-10 |
HUP0400976A2 (en) | 2004-08-30 |
HUP0400976A3 (en) | 2006-01-30 |
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AU2002354846B2 (en) | 2007-08-02 |
MXPA04000415A (en) | 2004-11-22 |
ZA200400012B (en) | 2004-08-17 |
CZ200439A3 (en) | 2005-03-16 |
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IL159622A0 (en) | 2004-06-01 |
CA2452677A1 (en) | 2003-01-30 |
JP2004534855A (en) | 2004-11-18 |
RU2004105031A (en) | 2005-04-20 |
NO20040235L (en) | 2004-03-17 |
BR0211256A (en) | 2004-07-27 |
CN1556710A (en) | 2004-12-22 |
PL369077A1 (en) | 2005-04-18 |
EP1411973A1 (en) | 2004-04-28 |
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