CA2156991A1 - Compositions which are suitable for employment as antidotes to blood anticoagulants, and their use - Google Patents
Compositions which are suitable for employment as antidotes to blood anticoagulants, and their useInfo
- Publication number
- CA2156991A1 CA2156991A1 CA002156991A CA2156991A CA2156991A1 CA 2156991 A1 CA2156991 A1 CA 2156991A1 CA 002156991 A CA002156991 A CA 002156991A CA 2156991 A CA2156991 A CA 2156991A CA 2156991 A1 CA2156991 A1 CA 2156991A1
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- composition
- factor
- inhibitors
- lation
- group
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
- A61K38/37—Factors VIII
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
- A61K38/366—Thrombomodulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Abstract
Compositions are disclosed which are used as antidotes to blood anticoagulants and which exhibit a combination of different components which promote blood coagulation, with, in a preferred form, one of the components being prothrombin complex concentrate.
Description
21S69~1 EE~ W~K~ AKTIE~Gl~SEI,I,SC~laFT 1994/~013-Ma lC37 Dr. Bo/hg Compo3itions which are 3uitable for employment as antidotes to blood anticoagulants, and their use The invention relate3 to antidote3 to blood anticoagulant3 .
Blood coagulation is a complex process in which pla3ma proteins and cells are involved. Formation of a wound 10 closure is initiated by rapid adhesion of blood platelets to the damaged 6urfaces and by proteases and contact factors which are activated successively in a cascade-like reaction sequence. This course of events leads to the production of thrombin which, inter alia, catalyzes 15 activation of fibrinogen to form fibrin.
Proteins such as factors VIII and V contribute, as accelerators, to the ~ff;r~ ney of this system. In addition to the protein C system, inhibitors of the proteases involved essentially regulate the coagulation 20 proce3ses in such a way that, while wound clo3ure takes place, excessive reaction3 are avoided. Di3tur~ance of thi3 finely tuned equilibrium can lead to fibrin depo3ition or the formation of thrombose3. A3 i3 known, the vessel occlusions which result from thi3 are the 25 cause of many pathophy3iological proce33es 3uch as cardiac infarction, in particular. This problem assumes particular importance Ln tho3e patient3 who are 3ubject to increased risk of thrombosis, which often represents a po3t-operative complication.
30 Variou3 approache3 are taken for preventing the3e pathophysiological proce3se3. Thu3, anticoagulant3 which intervene in dif f erent way3 in the event of coagulation are often used in clinical practice to prevent the formation of a thrombu3 or el3e to 3upport its di3so-35 lution (thrombolysi3). In addition to reducing or pre-venting thromoocyte functions (aggregation, adhe3ion and activation and the 3ynthesi3 and 3ecretion of activation 21~991 products ), inhibitors o participating coagulation protease3, in particular of the thromboplastin/factor VI~a complex, of factor Xa and, in particular, of thrombin (factor IIa) are being investigated and applied.
5 E~irudin, which was originally isolated from the salivary gland3 of the leech E~irudo m~r~ n~ , is a particularly specific and potent inhibitor of thrombin. In the interim, a variety of dif f erent variant3, analogs, fragments and mutants of hirudin have become known and 10 are being investigated for their suitability. While hirudin is sulfated in its naturally occurring form, it has been observed that ~he advantageous biological activity is also retained in the non-sulfated form. As a conse~uence, hirudin or its derivatives can conveniently 15 be prepared by means of genetic manipulation.
The blood anticoagulants also include heparin, and its fragments and variants, as well a~ synthetic inhibitors which inhibit the catalytic activity of thrombin and other coagulation proteases, for example factor Xa. These 20 components can also be employed in the prophylaxis and/or therapy of thrombotic or pre-thrombotic complications.
The search for ever more specific and potent anticoagulant~ and antithrombotic agents ref lects the unsatisfactory situation that the ~1;nil-~lly established 25 substallces such as heparins or vitamin K antagonist ii are either insufficiently effective or else exhibit side e~ects which are undesirable and in some cases serious.
Eirudill is currently the most powerful known thrombin inhibitor which does not al~o interfere with the other 3 0 enzymes of the blood coagulation cascade . To date, hirudin has not been observed to have any appreciable side effects on pul3e rate, respiration, blood pres~ure, thrombocyte count or the content of ~ibrinogen or hemoglobin. For this reason, hirudin i9 a preferred blood 35 anticoagulant.
The u~e of anticoagulants or antithrombotic agents in a 215~991 ' .
patient naturally entails the risk of inGreasing the tendency to bleed which, in extreme situation~, for example in a3sociation with improper use or dosing, can lead to uncontrolled hemorrhages. In order to be able to counteract the undesirable tendency to bleed in such a situation, it is pos3ible rapidly to remove ~30me substances, whose constitution (molecular weight and structure) permits it, from the blood plasma of the patient by dialysis. However when this is not possible lp due to the lack of appropriate apparatus or Eor other reasons, an antidote must be made available.
Some substances or preparations have already bee~ pro-posed as antidotes. Thus, the thrombins and their blocked variants exhibit a certain hirudin-neutralizing e~fect;
however, on the one hand, the use of active thrombin in patients who are being treated with blood anticoagulants is contraindicated as a rule and, on the other, it is problematic to prepare inactive thrombin using low molecular weight inhibitors which enter into covalent 2 0 bond3, owing to the toxicity o~ these substances . In addition, there is a lack of experience with regard to whether these complexes possibly have an antigenic effect. Owing to their nature, the3e complexes are not suitable for neutralizing low molecular weight (synthetic1 antithrombins or antithrombotic agents. While meizothrombin, an int~r~ 3te which arises briefly when prothrombin i3 activated to form thrombin, po33es3e3 a certain antagoni3tic potency, it can tran3form rapidly into thrombin in vivo and, as 3uch, i3 contraindicated as 3 0 a rule .
Investigation o~ factor VII as a hirudin antidote in appropriate models failed to provide satisfactory results. European Patent Application EPA 89.810733.9 describes the u3e o~ Eactor VIII, or fragment3 of factor VIII, a3 antidote3 to blood anticoagulant3. It i3 al30 known that 3ubstances, 3uch as, for example, desmopre33in (Mannucci, P.M., ~rogress in E~aemo3tasi3 and Thrombosi3, ~, 21~6ggl 8 (lg86), pp. 19-45), can be u~ed which increase the concentration of factor VIII in the blood.
~owever, 3ince even these antidote3 are not adequate for all area3 of application, there i3 3till the need to make 5 available antidote3 to blood anticoagulant3, anti-thrombotic agent3 and platelet antagoni3t3 which are more effective and have fewer side effect3.
Within the 3cope of the pre3ent application, anti-coagulatory or antithrombotic sub3tance3 are under3tood to mean glyco3aminoglycan3 and 3ulfated poly3accharide3, including heparin3, in particular unractionated and low molecular weight (L~W) pento3an poly3ulfate, heparan 3ulfate, dermatan 3ulfate or chondroitin 3ulfate, and al30 hirudin3 and their ragment3, for example hirugen (J. Biol. Chem. 265 (1990), 13484-13487; EP-A-0 333 356), analog3 or mutant3, for example l~lirulog~ (W0 92/13952), coupled hirudin3, f or example PEG-hirudin or hirutonin3, natural or 3ynthetic inhibitor3 of the thrombo-pla3tin/factor VIIa complex, of factor Xa or o thrombin, 2 ~ components of the protein C sy3tem, namely activated protein C, protein S and thlu..~, l;n, inhibitor3 of fibrin aggregation or cro331inking, 3ub3tance3 from the vitamin K antagoni3t group, 3ub3tance3 which have an effect on platelet activation and/or platelet aggregation 25 or el3e platelet adhesion, 3uch a3, in particular, f ibrinogen receptor antagoni3t3, or which are able to increa3e the endogenou3 capacity for fibrinoly3i3, 3uch a3, in particular, PAI-l inhibitor3, or atimulator3 of the 3ynthe3i3 and 3ecretion Of pl ~pm; nogen activator 30 inhibitors, and thus have an indirect antithrom.botic ef ect .
It i~ particularly important to provide a 3uitable antidote to the 3aid coupled hirudin3, for example PEG-hirudin, 3ince the3e co,upled hirudin3 can only be removed 35 rom the organi3m with difficulty.
-_ 5 _ 21~;6991 The present invention therefore relate3 to compositions which are used as antidotes to blood anticoagulants, it being possible for these blood antieoagulants to be selected from the group consisting of glycosaminoglycans 5 and sulfated polysaccharides, such as hirudins, and their fragments, analogs or mutants, natural or synthetie inhibitors of the thromboplastin/factor VIIa complex, of faetor Xa or of thrombin, eomponents of the protein C
systeIn, namely aetivated protein C, protein S and 10 thL~ ~vl,Ludulin, inhibitors of fibrin aggregation or erosslinking, substances from the vitamin 1~ antagonist group, substances which have an effeet on platelet aetivation and/or platelet aggregation or else platelet adhesion, sueh as, in particular, fibrinogen reeeptor 15 antagonists, or which are able to inerease the endogenous eapaeity for fibrinolysis, such as, in particular, PAI-l inhibitors, or s~; m~ lrs of the synthesis and seeretion of plasminogen activator inhibitors, whieh eompositions exhibit a prothrQmbin complex concentrate and at least 20 one additional eomponent which promote~ blood coagulation .
The prothrombin eomplex concentrates which are used in aeeordanee with the invention are isolated from the eorresponding blood prepzLrations by means of enriehment.
25 The prothrombin eomplex eoneentrates eontain, in par-tieular, faetors II, VII, IX and X. The prothrombin eomplex eoneentrates (ppss) ean be present in non--activated f orm or in aetivated f orm with activation eustomarily being effeeted by reaeting the prothrombin 3 0 eomplex eoncentrate with thrombin or eontact activators, f or example . The activated prothrombin eomplex eoneen-trates therefore reaet eonsiderably faster and are eorre~pondingly more diffieult to eontrol. ~owever, the non-aetivated prothrombin complex concentrates are 3~ preferred within the scope of the present invention.
In a preferred embodiment, the additional component which promotes blood coagulation is factor VIII, with the 21~6991 additional component which promotes blood coagulation particularly preferably being a combination of factor VIII and the von Willebrand factor (vWF~.
In other, likewise preferred, embodiments, the additional 5 component which promotes blood coagulation is factor V, factor Va, von W~ hr~n~ factor, factor XI, factor XII
or factor XIII, in particular factor3 V and VIII. Where appropriate, mixtures of these components can al30 be used .
10 These components can also be present in the form of active fragments or variants which can, in particular, be prepared by genetic manipulation . In another pref erred embodiment of the present invention, the additional component which promotes blood coagulation i8 at least 15 one lipid or a mixture of lipids, with negatively charged lipids or lipid mixtures being preferred.
In another preferred embodiment of the present invention, the additional component which promotes blood coagulation is at least one diuretic agent.
20 Compoæitions are particularly preferred which comprise a pro~hrt ; n complex concentrate and at least two additional components - as described above - which promote blood coagulation.
In the compositions according to the invention, the 25 prothrombin complex concentrates are employed in a concentration of ~rom 1 to 2 0 0 0 international units ( IU ) per kilogram of the bodyweight of the patient to be treated, with concentrations of the prothrombin complex concentrate ln a quantity of irom 10 to 1000 IU/kg being 3 C particularly pref erred .
The additional component which promote~ blood coagulation is customarily present in a concentration of in each case from 1 to 2000 IU/kg, with concentrations of from 10 to 2156~91 1000 IU/kg being particularly preferred in this case as well .
The diuretic agent and/or the lipid or lipid mixture is customarily present in a concentration of from 0.01 to 5 100 mg/kg of patient bodyweight, with concentrations of the diuretic agent and/or the lipid or the lipid mixture ln a quantity of from 0.1 to 10 mg/kg being particularly pref erred .
In a further embodiment, the present invention ralates to 10 compositions which are used as antidotes to blood anti-coagulants, it being possible for the blood anticoagu-lants to be 3elected from the group consisting of glycos-aminoglycans and sulfated polys~ h~ri ~e3, 3uch as hirudins, and their fragments, analogs or mutants, 15 natural and synthetic inhibitors of the thrombo-plastin/factor VIIa complex, of factor Xa or of thrombin, components of the protein C 3ystem, namely activated protein C, protein S and th~ lulin~ inhibitors of fibriLI aggregation or crosslinking, substances from the 20 vitamin ~ antagonist group, substances which have an effect on platelet activation and/or platelet aggregation or else platelet adhesion, such as, in particular, fibrinogen receptor antagonists, or which are able to increase the endogenous capacity for fibrinolysis, such 25 as, in particular, PAI-1 inhibitors or stimulators of the 3ynthesis and secretion of pl~3Tn;no~en activator inhihitors, which compositions comprise, on the one hand, at least one ~- _ nn~nt selected from the group lipid, lipid mixture and diuretic agent, and, on the other hand, 30 at least one component selected from the group pro-thrombin complex concentrate, one of factors II, V, Va, VIII, IX, X, XI, XII or XIII, and von Willebrand factor, as a single factor, or as mixtures of these factors.
In a further ~mho~ -nt, the present invention relates to 35 a composition which is used as an antidote to blood anticoagulants, it being possible f or the anticoagulants ~ 21~6991 to be selected from the group consisting of glycosamino-glycans and sulfated polysaccharides, such as hirudins, and their fragment3, analogs or mutants, natural and synthetic inhibitors of the thromboplastin/factor VIIa 5 complex, of factor Xa or of thrombin, components of the protein C system, namely activated protein C, protein S
and th~ 1; n, inhibitors of f ibrin aggregation or crosslinking, substances from the vitamin K antagoni3t group, substances which have an ef f ect on platelet 10 activation and~or platelet aggregation or else platelet adhesion, such a3, in particular, fibrinogen receptor antagonists, or which are able to increase the endogenous capacity for fibrinolysis, such as, in particular, PAI-1 inhibitors or stimulators of the synthesis and secretion 15 of plasminogen activator inhibitors, which compositions each comprise at least one c~ n~T3t selected from one of the t~o groups A and B, where group A comprises f actors II, V, Va, VIII and IX, and group B comprises factors II, V, Va, VII, VIIa and VIII, von Willebrand factor, and 20 factors IX, X, XI, XII and XIII, with the proviso that the component or the components from group A is/are not identical to the component or components f rom group B .
The invention also relates to the use of one of the abovedescribed compositions as an antldote to blood 25 anticoagulants.
rhe present invention is further illustrated by the following examples.
~xample 1 In this in vitro experiment, the potential of F VIII
30 (Beriate'!g), a non-activated prothrombin complex concen-trate ~PeSB/heparin-free Beriplex'!g), and a combination of the two, to antagonize the coagulation-inhibiting effect of hirudin was tested in standard human plasma lS~P).
For this purpose, 100 ~Ll volumes of citrate-SllP were 35 brought, after the addition of in each case 2 ~1 of an approp~iately concentrated stock solution, to f Lnal concentration~ of 3 and 20 ,ug/ml hirudin, respectively.
After mixing together with 50 1~l of a concentrated solution containing F VIII and/or PPSB, and adding 100 1ll of Pathromtin<9/kaolin suspension, the whole was incubated 5 at 37C for 2 min. The reaction was started by i~1m;~in~
50 ~1 of a 50 mM solution of CaCl2. The (mo~;f;ed) acti-vated partial thromboplastin time (aPTT) was det~-rm;n-~in accordance with Schnitger and Gross.
The coagulation times listed in Table 1 make clear that 10 the extension in the aPTT (as compared with the control) which was brought about by 3 ~g/ml hirudin was shortened by 2 IU of F VIII. The extension produced by PPSB on its own may possibly be attributed to an in vitrQ effect which has not previously been completely elucidated. The 15 combination of the 2 compounds was f ound to be particu-larly effective. This effect became all the more apparent when very high hirudin concentrations (20 ~g/ml) were employed which prevented non-antagonized plasma f rom clotting even after 2000 seconds. l~ere! 1 IU of PPSB on 20 its own exhibited a certain shortening effect while, on the other hand, 2 IU of F VIII on its own was not able to elicit any clotting. By contrast, the combination F VIII/PPSB was once again found to have a markedly ~etter ef f ect than the individual components .
2 5 Table aPTT ( sec . ) ~iru~lin Control 2 IU F VIII 1 IU PPss 2 IU F VIII
conc. /ml /ml + 1 IU
~g/ml ~ PPSB/ml 036.4 31.5 31.4 24.7 30 3 9~.1 76.0 121.1 57.7 20>2000 >2000 313.6 92.7 Table 2 show~3 different combinations of F VIII/PPSB
concentrations which supplement the above experimental 2ls699l series and confirm the results (using 10 ~g/ml hirudin ~nd comp~rlng w~tt th~ control~.
2ls6 /-Table 2 PPSB
(IU ml) 0 0.25 0.5 1.0 F VIII
5( IU~ml ) 037.734.1 31.9 31.4 170 . 1 181 . 5 196 . 6 225 . 5 1.033.8 28.0 27.1 26.7 140.0101.1 83.9 86.2 2.031.7 26.1 24.2 24.2 123.289.6 67.8 69.7 4.028.g 22.9 21.3 22.1 107.286.1 54.6 56.6 10 normal: (control~, without hirudin bold: 10 ~g/ml hirudin Fxa~le 2 a) In a corresponding manner to that employed in Example 1, rat citrate plasma to which 10 l~g/ml hirudin were added was used in the aPTT test to . investigate the antagonizing effect of F VIII, PPSB
and combinations of the two. The coagulation times shown in Table 3 demonstrate once again that the combination produces a more effective n~ l; 7~tion 2 0 than do the individual components .
21~6991 Table 3 Rat citrate plasma/aPTT
Pl?SB
(IU/ml) 0 0.25 0.5 l.0 F VIII
Blood coagulation is a complex process in which pla3ma proteins and cells are involved. Formation of a wound 10 closure is initiated by rapid adhesion of blood platelets to the damaged 6urfaces and by proteases and contact factors which are activated successively in a cascade-like reaction sequence. This course of events leads to the production of thrombin which, inter alia, catalyzes 15 activation of fibrinogen to form fibrin.
Proteins such as factors VIII and V contribute, as accelerators, to the ~ff;r~ ney of this system. In addition to the protein C system, inhibitors of the proteases involved essentially regulate the coagulation 20 proce3ses in such a way that, while wound clo3ure takes place, excessive reaction3 are avoided. Di3tur~ance of thi3 finely tuned equilibrium can lead to fibrin depo3ition or the formation of thrombose3. A3 i3 known, the vessel occlusions which result from thi3 are the 25 cause of many pathophy3iological proce33es 3uch as cardiac infarction, in particular. This problem assumes particular importance Ln tho3e patient3 who are 3ubject to increased risk of thrombosis, which often represents a po3t-operative complication.
30 Variou3 approache3 are taken for preventing the3e pathophysiological proce3se3. Thu3, anticoagulant3 which intervene in dif f erent way3 in the event of coagulation are often used in clinical practice to prevent the formation of a thrombu3 or el3e to 3upport its di3so-35 lution (thrombolysi3). In addition to reducing or pre-venting thromoocyte functions (aggregation, adhe3ion and activation and the 3ynthesi3 and 3ecretion of activation 21~991 products ), inhibitors o participating coagulation protease3, in particular of the thromboplastin/factor VI~a complex, of factor Xa and, in particular, of thrombin (factor IIa) are being investigated and applied.
5 E~irudin, which was originally isolated from the salivary gland3 of the leech E~irudo m~r~ n~ , is a particularly specific and potent inhibitor of thrombin. In the interim, a variety of dif f erent variant3, analogs, fragments and mutants of hirudin have become known and 10 are being investigated for their suitability. While hirudin is sulfated in its naturally occurring form, it has been observed that ~he advantageous biological activity is also retained in the non-sulfated form. As a conse~uence, hirudin or its derivatives can conveniently 15 be prepared by means of genetic manipulation.
The blood anticoagulants also include heparin, and its fragments and variants, as well a~ synthetic inhibitors which inhibit the catalytic activity of thrombin and other coagulation proteases, for example factor Xa. These 20 components can also be employed in the prophylaxis and/or therapy of thrombotic or pre-thrombotic complications.
The search for ever more specific and potent anticoagulant~ and antithrombotic agents ref lects the unsatisfactory situation that the ~1;nil-~lly established 25 substallces such as heparins or vitamin K antagonist ii are either insufficiently effective or else exhibit side e~ects which are undesirable and in some cases serious.
Eirudill is currently the most powerful known thrombin inhibitor which does not al~o interfere with the other 3 0 enzymes of the blood coagulation cascade . To date, hirudin has not been observed to have any appreciable side effects on pul3e rate, respiration, blood pres~ure, thrombocyte count or the content of ~ibrinogen or hemoglobin. For this reason, hirudin i9 a preferred blood 35 anticoagulant.
The u~e of anticoagulants or antithrombotic agents in a 215~991 ' .
patient naturally entails the risk of inGreasing the tendency to bleed which, in extreme situation~, for example in a3sociation with improper use or dosing, can lead to uncontrolled hemorrhages. In order to be able to counteract the undesirable tendency to bleed in such a situation, it is pos3ible rapidly to remove ~30me substances, whose constitution (molecular weight and structure) permits it, from the blood plasma of the patient by dialysis. However when this is not possible lp due to the lack of appropriate apparatus or Eor other reasons, an antidote must be made available.
Some substances or preparations have already bee~ pro-posed as antidotes. Thus, the thrombins and their blocked variants exhibit a certain hirudin-neutralizing e~fect;
however, on the one hand, the use of active thrombin in patients who are being treated with blood anticoagulants is contraindicated as a rule and, on the other, it is problematic to prepare inactive thrombin using low molecular weight inhibitors which enter into covalent 2 0 bond3, owing to the toxicity o~ these substances . In addition, there is a lack of experience with regard to whether these complexes possibly have an antigenic effect. Owing to their nature, the3e complexes are not suitable for neutralizing low molecular weight (synthetic1 antithrombins or antithrombotic agents. While meizothrombin, an int~r~ 3te which arises briefly when prothrombin i3 activated to form thrombin, po33es3e3 a certain antagoni3tic potency, it can tran3form rapidly into thrombin in vivo and, as 3uch, i3 contraindicated as 3 0 a rule .
Investigation o~ factor VII as a hirudin antidote in appropriate models failed to provide satisfactory results. European Patent Application EPA 89.810733.9 describes the u3e o~ Eactor VIII, or fragment3 of factor VIII, a3 antidote3 to blood anticoagulant3. It i3 al30 known that 3ubstances, 3uch as, for example, desmopre33in (Mannucci, P.M., ~rogress in E~aemo3tasi3 and Thrombosi3, ~, 21~6ggl 8 (lg86), pp. 19-45), can be u~ed which increase the concentration of factor VIII in the blood.
~owever, 3ince even these antidote3 are not adequate for all area3 of application, there i3 3till the need to make 5 available antidote3 to blood anticoagulant3, anti-thrombotic agent3 and platelet antagoni3t3 which are more effective and have fewer side effect3.
Within the 3cope of the pre3ent application, anti-coagulatory or antithrombotic sub3tance3 are under3tood to mean glyco3aminoglycan3 and 3ulfated poly3accharide3, including heparin3, in particular unractionated and low molecular weight (L~W) pento3an poly3ulfate, heparan 3ulfate, dermatan 3ulfate or chondroitin 3ulfate, and al30 hirudin3 and their ragment3, for example hirugen (J. Biol. Chem. 265 (1990), 13484-13487; EP-A-0 333 356), analog3 or mutant3, for example l~lirulog~ (W0 92/13952), coupled hirudin3, f or example PEG-hirudin or hirutonin3, natural or 3ynthetic inhibitor3 of the thrombo-pla3tin/factor VIIa complex, of factor Xa or o thrombin, 2 ~ components of the protein C sy3tem, namely activated protein C, protein S and thlu..~, l;n, inhibitor3 of fibrin aggregation or cro331inking, 3ub3tance3 from the vitamin K antagoni3t group, 3ub3tance3 which have an effect on platelet activation and/or platelet aggregation 25 or el3e platelet adhesion, 3uch a3, in particular, f ibrinogen receptor antagoni3t3, or which are able to increa3e the endogenou3 capacity for fibrinoly3i3, 3uch a3, in particular, PAI-l inhibitor3, or atimulator3 of the 3ynthe3i3 and 3ecretion Of pl ~pm; nogen activator 30 inhibitors, and thus have an indirect antithrom.botic ef ect .
It i~ particularly important to provide a 3uitable antidote to the 3aid coupled hirudin3, for example PEG-hirudin, 3ince the3e co,upled hirudin3 can only be removed 35 rom the organi3m with difficulty.
-_ 5 _ 21~;6991 The present invention therefore relate3 to compositions which are used as antidotes to blood anticoagulants, it being possible for these blood antieoagulants to be selected from the group consisting of glycosaminoglycans 5 and sulfated polysaccharides, such as hirudins, and their fragments, analogs or mutants, natural or synthetie inhibitors of the thromboplastin/factor VIIa complex, of faetor Xa or of thrombin, eomponents of the protein C
systeIn, namely aetivated protein C, protein S and 10 thL~ ~vl,Ludulin, inhibitors of fibrin aggregation or erosslinking, substances from the vitamin 1~ antagonist group, substances which have an effeet on platelet aetivation and/or platelet aggregation or else platelet adhesion, sueh as, in particular, fibrinogen reeeptor 15 antagonists, or which are able to inerease the endogenous eapaeity for fibrinolysis, such as, in particular, PAI-l inhibitors, or s~; m~ lrs of the synthesis and seeretion of plasminogen activator inhibitors, whieh eompositions exhibit a prothrQmbin complex concentrate and at least 20 one additional eomponent which promote~ blood coagulation .
The prothrombin eomplex concentrates which are used in aeeordanee with the invention are isolated from the eorresponding blood prepzLrations by means of enriehment.
25 The prothrombin eomplex eoneentrates eontain, in par-tieular, faetors II, VII, IX and X. The prothrombin eomplex eoneentrates (ppss) ean be present in non--activated f orm or in aetivated f orm with activation eustomarily being effeeted by reaeting the prothrombin 3 0 eomplex eoncentrate with thrombin or eontact activators, f or example . The activated prothrombin eomplex eoneen-trates therefore reaet eonsiderably faster and are eorre~pondingly more diffieult to eontrol. ~owever, the non-aetivated prothrombin complex concentrates are 3~ preferred within the scope of the present invention.
In a preferred embodiment, the additional component which promotes blood coagulation is factor VIII, with the 21~6991 additional component which promotes blood coagulation particularly preferably being a combination of factor VIII and the von Willebrand factor (vWF~.
In other, likewise preferred, embodiments, the additional 5 component which promotes blood coagulation is factor V, factor Va, von W~ hr~n~ factor, factor XI, factor XII
or factor XIII, in particular factor3 V and VIII. Where appropriate, mixtures of these components can al30 be used .
10 These components can also be present in the form of active fragments or variants which can, in particular, be prepared by genetic manipulation . In another pref erred embodiment of the present invention, the additional component which promotes blood coagulation i8 at least 15 one lipid or a mixture of lipids, with negatively charged lipids or lipid mixtures being preferred.
In another preferred embodiment of the present invention, the additional component which promotes blood coagulation is at least one diuretic agent.
20 Compoæitions are particularly preferred which comprise a pro~hrt ; n complex concentrate and at least two additional components - as described above - which promote blood coagulation.
In the compositions according to the invention, the 25 prothrombin complex concentrates are employed in a concentration of ~rom 1 to 2 0 0 0 international units ( IU ) per kilogram of the bodyweight of the patient to be treated, with concentrations of the prothrombin complex concentrate ln a quantity of irom 10 to 1000 IU/kg being 3 C particularly pref erred .
The additional component which promote~ blood coagulation is customarily present in a concentration of in each case from 1 to 2000 IU/kg, with concentrations of from 10 to 2156~91 1000 IU/kg being particularly preferred in this case as well .
The diuretic agent and/or the lipid or lipid mixture is customarily present in a concentration of from 0.01 to 5 100 mg/kg of patient bodyweight, with concentrations of the diuretic agent and/or the lipid or the lipid mixture ln a quantity of from 0.1 to 10 mg/kg being particularly pref erred .
In a further embodiment, the present invention ralates to 10 compositions which are used as antidotes to blood anti-coagulants, it being possible for the blood anticoagu-lants to be 3elected from the group consisting of glycos-aminoglycans and sulfated polys~ h~ri ~e3, 3uch as hirudins, and their fragments, analogs or mutants, 15 natural and synthetic inhibitors of the thrombo-plastin/factor VIIa complex, of factor Xa or of thrombin, components of the protein C 3ystem, namely activated protein C, protein S and th~ lulin~ inhibitors of fibriLI aggregation or crosslinking, substances from the 20 vitamin ~ antagonist group, substances which have an effect on platelet activation and/or platelet aggregation or else platelet adhesion, such as, in particular, fibrinogen receptor antagonists, or which are able to increase the endogenous capacity for fibrinolysis, such 25 as, in particular, PAI-1 inhibitors or stimulators of the 3ynthesis and secretion of pl~3Tn;no~en activator inhihitors, which compositions comprise, on the one hand, at least one ~- _ nn~nt selected from the group lipid, lipid mixture and diuretic agent, and, on the other hand, 30 at least one component selected from the group pro-thrombin complex concentrate, one of factors II, V, Va, VIII, IX, X, XI, XII or XIII, and von Willebrand factor, as a single factor, or as mixtures of these factors.
In a further ~mho~ -nt, the present invention relates to 35 a composition which is used as an antidote to blood anticoagulants, it being possible f or the anticoagulants ~ 21~6991 to be selected from the group consisting of glycosamino-glycans and sulfated polysaccharides, such as hirudins, and their fragment3, analogs or mutants, natural and synthetic inhibitors of the thromboplastin/factor VIIa 5 complex, of factor Xa or of thrombin, components of the protein C system, namely activated protein C, protein S
and th~ 1; n, inhibitors of f ibrin aggregation or crosslinking, substances from the vitamin K antagoni3t group, substances which have an ef f ect on platelet 10 activation and~or platelet aggregation or else platelet adhesion, such a3, in particular, fibrinogen receptor antagonists, or which are able to increase the endogenous capacity for fibrinolysis, such as, in particular, PAI-1 inhibitors or stimulators of the synthesis and secretion 15 of plasminogen activator inhibitors, which compositions each comprise at least one c~ n~T3t selected from one of the t~o groups A and B, where group A comprises f actors II, V, Va, VIII and IX, and group B comprises factors II, V, Va, VII, VIIa and VIII, von Willebrand factor, and 20 factors IX, X, XI, XII and XIII, with the proviso that the component or the components from group A is/are not identical to the component or components f rom group B .
The invention also relates to the use of one of the abovedescribed compositions as an antldote to blood 25 anticoagulants.
rhe present invention is further illustrated by the following examples.
~xample 1 In this in vitro experiment, the potential of F VIII
30 (Beriate'!g), a non-activated prothrombin complex concen-trate ~PeSB/heparin-free Beriplex'!g), and a combination of the two, to antagonize the coagulation-inhibiting effect of hirudin was tested in standard human plasma lS~P).
For this purpose, 100 ~Ll volumes of citrate-SllP were 35 brought, after the addition of in each case 2 ~1 of an approp~iately concentrated stock solution, to f Lnal concentration~ of 3 and 20 ,ug/ml hirudin, respectively.
After mixing together with 50 1~l of a concentrated solution containing F VIII and/or PPSB, and adding 100 1ll of Pathromtin<9/kaolin suspension, the whole was incubated 5 at 37C for 2 min. The reaction was started by i~1m;~in~
50 ~1 of a 50 mM solution of CaCl2. The (mo~;f;ed) acti-vated partial thromboplastin time (aPTT) was det~-rm;n-~in accordance with Schnitger and Gross.
The coagulation times listed in Table 1 make clear that 10 the extension in the aPTT (as compared with the control) which was brought about by 3 ~g/ml hirudin was shortened by 2 IU of F VIII. The extension produced by PPSB on its own may possibly be attributed to an in vitrQ effect which has not previously been completely elucidated. The 15 combination of the 2 compounds was f ound to be particu-larly effective. This effect became all the more apparent when very high hirudin concentrations (20 ~g/ml) were employed which prevented non-antagonized plasma f rom clotting even after 2000 seconds. l~ere! 1 IU of PPSB on 20 its own exhibited a certain shortening effect while, on the other hand, 2 IU of F VIII on its own was not able to elicit any clotting. By contrast, the combination F VIII/PPSB was once again found to have a markedly ~etter ef f ect than the individual components .
2 5 Table aPTT ( sec . ) ~iru~lin Control 2 IU F VIII 1 IU PPss 2 IU F VIII
conc. /ml /ml + 1 IU
~g/ml ~ PPSB/ml 036.4 31.5 31.4 24.7 30 3 9~.1 76.0 121.1 57.7 20>2000 >2000 313.6 92.7 Table 2 show~3 different combinations of F VIII/PPSB
concentrations which supplement the above experimental 2ls699l series and confirm the results (using 10 ~g/ml hirudin ~nd comp~rlng w~tt th~ control~.
2ls6 /-Table 2 PPSB
(IU ml) 0 0.25 0.5 1.0 F VIII
5( IU~ml ) 037.734.1 31.9 31.4 170 . 1 181 . 5 196 . 6 225 . 5 1.033.8 28.0 27.1 26.7 140.0101.1 83.9 86.2 2.031.7 26.1 24.2 24.2 123.289.6 67.8 69.7 4.028.g 22.9 21.3 22.1 107.286.1 54.6 56.6 10 normal: (control~, without hirudin bold: 10 ~g/ml hirudin Fxa~le 2 a) In a corresponding manner to that employed in Example 1, rat citrate plasma to which 10 l~g/ml hirudin were added was used in the aPTT test to . investigate the antagonizing effect of F VIII, PPSB
and combinations of the two. The coagulation times shown in Table 3 demonstrate once again that the combination produces a more effective n~ l; 7~tion 2 0 than do the individual components .
21~6991 Table 3 Rat citrate plasma/aPTT
Pl?SB
(IU/ml) 0 0.25 0.5 l.0 F VIII
5,( I~J/ml ) 025.9 31.0 33.8 35.1 111.0 133.6 138.6 141.5 1.0 23.0 23.2 25.4 27.2 76.1 49.8 52.6 54.1 2.0 21.3 21.6 23.8 25.1 62 . 1 42 . 6 45 . 8 47 . l 4.0 19.9 20.0 20.8 23.0 56.0 38.7 37.6 23.1 normal: without hirudin (control~
bold: 10 ~g/ml hirudin b) Experiments with rat whole blood, which was investi-gated in a thromboelastograph (TEG) in order to approach more closely to the in vivo situation, confirm the results obtained in the aPTT test (Table 4 ) . The r value (reaction time) es#entially denote3 the time until clotting begins i . e . the time from initiation of the reaction (blood removal or r~lr;f;~ation) to the widening of the TEG curve by l mm. The k value (clot forming time) corresponds to the time which elapses from the endpoint of the r value until the curve has widened to 20 mm.
For this purpose, 200 ,ul of rat citrate whole blood were mixed with 5 0 ~Ll of an appropriately concen-trated stock solution of hirudin (in diethyl bar-~iturate buf f er, pE~ 7 . 6; 1 96 human serum albumin ) and with 50 ~l of antidote (F VIII, PPSB or F VIII
+ PPSB) and subjected to preincubation at 37C for 3 min. The reaction was started by adding 50 ~l of a 100 mM solution of CaCl2.
Table 4: Rat whole blood/TEG
Elirudin Control 2 IU 1 IU 1 I~ PPSB
(llg/ml) F VIII/ml PPSB/ml 2 IIJ
F VIII/ml 10 r>40.0 min. >40.0 min. 3.7 min. 2.0 min.
k>4 0 . 0 min >4 0 . 0 min . 2 . 4 min . 1. 5 min .
5 Example 3 The antagoni~ing effect of the combination of factor V
and PPS33 was tested in a manner corresponding to that employed in Example 1. Once again, it was found that use of the combination was superior to use of the individual 10 components. The results are presented in Table 5.
Tahle 5 aPTT ( sec. ) ~irudin Control 2 IU F V 1 I~ PPSB Z IU F V +
conc. /ml /ml 1 IU
(~g/ml) PPSB/ml 15 0 36.4 3~.3 31.4 28.9 20 >2000 >2000 313.6 156.3 Example 4 In principle, an undesirable, excessive anticoagulatory reaction which is o~tained using a low molecular weight 20 thromoin inhibitor, for example argatroban (MD 805, (2R,4R) -4-methyl-1-{N-{3-methyl-1,2,3,4-tetrahydro-8-quinolinyl) sulfonyl}-L-argininyl}-2-pip~r; ~; nerA~hoxylic acid), can also be countered using the described com-ponents; however the combination o~ the two is most 25 effective. Typical eifects on the aPTT of S~P
( implementation as described in Example 1 ) are presented in Table 6.
Table 6 PPSB aPTT tsec. ) IU/ml ) F VIII 0 0.25 0.5 5( IU/ml ) 036.5 32.6 31.2 217.7 216.5 228.3 l.Q 33.4 26.9 26.1 18g . 8 164 . 4 161 . 7 2.0 31.1 24.2 23.8 177 . 2 137 . 4 135 . 2 4.0 28.1 21.6 20.0 164 . 1 122 . 4 114 . 8 10 normal: without 2aD 805, control bold: lO ~g/ml M~ 805 A similar ef f ect can also be achieved when bivalent thrombin inhibitors of the ~Iiruloge~!3 type, such as D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-15 Pro-Glu-Glu-Tyr-Leu (analog), are uged, as tl~.ri.~ y way of Example in Table 7.
Table 7 aPT~ ( 3ec. ) Analog Control 2 IU 1 IU PPSB 2 IU F VIII
( ~g/ml ) F VIII/ml /ml 1 IU
PPSB/ml 203.0 g7.0 77.0 107.1 66.6 Example 5 In a corresponding manner to that employed in Example 1, Sh~ to which 10 ~g/ml hirudin were added was investigated in the aPTT test for the antagonizing effect of F VIII, 25 F IX and the combination of the two. The coagulation 2~56991 times shown in rra~le 8 demonstrate once again that, while F IX also has a certain antagonizing effect, the combination of the individual romronl~ntS is superior.
Table 8 F IX aPTT ( sec . ) - ( IU~
( IU/IIL1 ~
0137.5 121.7 113.0 107.3 10 2 103.3 90.6 86.2 78.3 ~irudin concentration: 10 ~g/ml Example 6 In a corresponding manner to that employed in Example 1, S~IP to which 20 ~g/ml hirudin were added was investigated 15 in the aPTT test for the antagonizing effect of F II, F V, F VII, F VIII, F IX and F X and combi3rations of these compounds. The coagulation times shown in Table 9 demonstrate oncc again that the combinations of the compounds are superior to the individual components. The 20 combination of all 6 components was found to be the most ef f ecti~e .
Table 9 aPTT ( sec ) 2 IU factor V i 2000.0 25 2 IU factor V ~ -2 IU factor II 182 . 0 2 IU f actor V +
2 IU f actor II +
2 IU factor VII 152 . 0 -2~6991 Continuation of Table 9 aPTT ( ~ee ) 2 IU f aetor V +
2 IU f aetor II +
52 IU faetor VII +
2 IU faetor VIII 53 . 0 2 IU faetor V +
2 IU faetor II +
2 IU faetor VIr +
2 IU faetor VIII +
2 IU f actor X 3 9 .1 2 IU f aetor V f 2 IU f aetor II +
2 IU faetor VII +
2 IU faetor VIII +
2 IU f aetor IX +
2 IU factor X 29 . 6 2 IU f aetor V +
2 0 2 IU f aetor II +
2 IU faetor VIII 105 . 0 2 IU f aetor V +
2 IU faetor II +
2 IU faetor VIII +
2 IU faetor IX 51. 0 2 IU f actor V +
2 IU faetor II +
2 IU faetor VIII +
2 IU factor IX +
2 IU faetor X 32 . 0 2 IU f aetor V +
2 IU f aetor II +
2 IU faetor IX +
3!~ 2 IU faetor X 91.3 21~6991 Continuation of Table 9 aPTT ( 3ec ) 2 IU factor V +
2 IU factor VII > 2000 . 0 5 2 IU f actor V +
2 IU factor VIII i 2000 . O
2 IU factor V +
2 IU factor VIII +
2 IU factor IX > 2000.0 2 IU factor V +
2 IU f actor VIII +
2 IU factor IX +
2 IU factor X > 2000.0 2 IU factor VII ~ > 2000 . 0 2 IU f actor VII +
2 IU factor II 202.8 2 IU factor VII +
2 IU factor II +
2 IU factor VIII 141.0 2 IU factor VII +
2 IU f actor II +
2 IU factor IX 173 . 5 2 IU f actor VII +
2 IU factor II +
2 IU factor X 173 . 0 2 I~ factor VII +
2 IU factor VIII > 2000 . 0 2 IU factor VII +
2 IU factor IX > 2000.0 21~69gl C--nt i n~ tion of Table 9 aPTT ( see ) 2 IU factor VII +
2 IU faetor X > 200~ . 0 5 2 IU faetor VIII +
2 IU faetor II +
2 IU faetor IX +
2 IU faetor X 84 . 0 10 2 IU fae~or IX +
2 IU faetor II 210.3 2 IU faetor IX +
2 IU f actor II +
2 IU faetor X 148.0 2 IU f actor X > 2 0 0 0 . 0 2 IU factor X +
~ lU ~actor II 196,0
bold: 10 ~g/ml hirudin b) Experiments with rat whole blood, which was investi-gated in a thromboelastograph (TEG) in order to approach more closely to the in vivo situation, confirm the results obtained in the aPTT test (Table 4 ) . The r value (reaction time) es#entially denote3 the time until clotting begins i . e . the time from initiation of the reaction (blood removal or r~lr;f;~ation) to the widening of the TEG curve by l mm. The k value (clot forming time) corresponds to the time which elapses from the endpoint of the r value until the curve has widened to 20 mm.
For this purpose, 200 ,ul of rat citrate whole blood were mixed with 5 0 ~Ll of an appropriately concen-trated stock solution of hirudin (in diethyl bar-~iturate buf f er, pE~ 7 . 6; 1 96 human serum albumin ) and with 50 ~l of antidote (F VIII, PPSB or F VIII
+ PPSB) and subjected to preincubation at 37C for 3 min. The reaction was started by adding 50 ~l of a 100 mM solution of CaCl2.
Table 4: Rat whole blood/TEG
Elirudin Control 2 IU 1 IU 1 I~ PPSB
(llg/ml) F VIII/ml PPSB/ml 2 IIJ
F VIII/ml 10 r>40.0 min. >40.0 min. 3.7 min. 2.0 min.
k>4 0 . 0 min >4 0 . 0 min . 2 . 4 min . 1. 5 min .
5 Example 3 The antagoni~ing effect of the combination of factor V
and PPS33 was tested in a manner corresponding to that employed in Example 1. Once again, it was found that use of the combination was superior to use of the individual 10 components. The results are presented in Table 5.
Tahle 5 aPTT ( sec. ) ~irudin Control 2 IU F V 1 I~ PPSB Z IU F V +
conc. /ml /ml 1 IU
(~g/ml) PPSB/ml 15 0 36.4 3~.3 31.4 28.9 20 >2000 >2000 313.6 156.3 Example 4 In principle, an undesirable, excessive anticoagulatory reaction which is o~tained using a low molecular weight 20 thromoin inhibitor, for example argatroban (MD 805, (2R,4R) -4-methyl-1-{N-{3-methyl-1,2,3,4-tetrahydro-8-quinolinyl) sulfonyl}-L-argininyl}-2-pip~r; ~; nerA~hoxylic acid), can also be countered using the described com-ponents; however the combination o~ the two is most 25 effective. Typical eifects on the aPTT of S~P
( implementation as described in Example 1 ) are presented in Table 6.
Table 6 PPSB aPTT tsec. ) IU/ml ) F VIII 0 0.25 0.5 5( IU/ml ) 036.5 32.6 31.2 217.7 216.5 228.3 l.Q 33.4 26.9 26.1 18g . 8 164 . 4 161 . 7 2.0 31.1 24.2 23.8 177 . 2 137 . 4 135 . 2 4.0 28.1 21.6 20.0 164 . 1 122 . 4 114 . 8 10 normal: without 2aD 805, control bold: lO ~g/ml M~ 805 A similar ef f ect can also be achieved when bivalent thrombin inhibitors of the ~Iiruloge~!3 type, such as D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-15 Pro-Glu-Glu-Tyr-Leu (analog), are uged, as tl~.ri.~ y way of Example in Table 7.
Table 7 aPT~ ( 3ec. ) Analog Control 2 IU 1 IU PPSB 2 IU F VIII
( ~g/ml ) F VIII/ml /ml 1 IU
PPSB/ml 203.0 g7.0 77.0 107.1 66.6 Example 5 In a corresponding manner to that employed in Example 1, Sh~ to which 10 ~g/ml hirudin were added was investigated in the aPTT test for the antagonizing effect of F VIII, 25 F IX and the combination of the two. The coagulation 2~56991 times shown in rra~le 8 demonstrate once again that, while F IX also has a certain antagonizing effect, the combination of the individual romronl~ntS is superior.
Table 8 F IX aPTT ( sec . ) - ( IU~
( IU/IIL1 ~
0137.5 121.7 113.0 107.3 10 2 103.3 90.6 86.2 78.3 ~irudin concentration: 10 ~g/ml Example 6 In a corresponding manner to that employed in Example 1, S~IP to which 20 ~g/ml hirudin were added was investigated 15 in the aPTT test for the antagonizing effect of F II, F V, F VII, F VIII, F IX and F X and combi3rations of these compounds. The coagulation times shown in Table 9 demonstrate oncc again that the combinations of the compounds are superior to the individual components. The 20 combination of all 6 components was found to be the most ef f ecti~e .
Table 9 aPTT ( sec ) 2 IU factor V i 2000.0 25 2 IU factor V ~ -2 IU factor II 182 . 0 2 IU f actor V +
2 IU f actor II +
2 IU factor VII 152 . 0 -2~6991 Continuation of Table 9 aPTT ( ~ee ) 2 IU f aetor V +
2 IU f aetor II +
52 IU faetor VII +
2 IU faetor VIII 53 . 0 2 IU faetor V +
2 IU faetor II +
2 IU faetor VIr +
2 IU faetor VIII +
2 IU f actor X 3 9 .1 2 IU f aetor V f 2 IU f aetor II +
2 IU faetor VII +
2 IU faetor VIII +
2 IU f aetor IX +
2 IU factor X 29 . 6 2 IU f aetor V +
2 0 2 IU f aetor II +
2 IU faetor VIII 105 . 0 2 IU f aetor V +
2 IU faetor II +
2 IU faetor VIII +
2 IU faetor IX 51. 0 2 IU f actor V +
2 IU faetor II +
2 IU faetor VIII +
2 IU factor IX +
2 IU faetor X 32 . 0 2 IU f aetor V +
2 IU f aetor II +
2 IU faetor IX +
3!~ 2 IU faetor X 91.3 21~6991 Continuation of Table 9 aPTT ( 3ec ) 2 IU factor V +
2 IU factor VII > 2000 . 0 5 2 IU f actor V +
2 IU factor VIII i 2000 . O
2 IU factor V +
2 IU factor VIII +
2 IU factor IX > 2000.0 2 IU factor V +
2 IU f actor VIII +
2 IU factor IX +
2 IU factor X > 2000.0 2 IU factor VII ~ > 2000 . 0 2 IU f actor VII +
2 IU factor II 202.8 2 IU factor VII +
2 IU factor II +
2 IU factor VIII 141.0 2 IU factor VII +
2 IU f actor II +
2 IU factor IX 173 . 5 2 IU f actor VII +
2 IU factor II +
2 IU factor X 173 . 0 2 I~ factor VII +
2 IU factor VIII > 2000 . 0 2 IU factor VII +
2 IU factor IX > 2000.0 21~69gl C--nt i n~ tion of Table 9 aPTT ( see ) 2 IU factor VII +
2 IU faetor X > 200~ . 0 5 2 IU faetor VIII +
2 IU faetor II +
2 IU faetor IX +
2 IU faetor X 84 . 0 10 2 IU fae~or IX +
2 IU faetor II 210.3 2 IU faetor IX +
2 IU f actor II +
2 IU faetor X 148.0 2 IU f actor X > 2 0 0 0 . 0 2 IU factor X +
~ lU ~actor II 196,0
Claims (25)
1. A composition which is used as an antidote to blood anticoagulants, with the anticoagulants being selected from the group consisting of glycos-aminoglycans and sulfated polysaccharides, such as hirudins, and their fragments, analogs or mutants, natural and synthetic inhibitors of the thrombo-plastin/factor VIIa complex, of factor Xa or of thrombin, components of the protein C system, namely activated protein C, protein S and thrombomodulin, inhibitors of fibrin aggregation or crosslinking, substances from the vitamin K antagonist group, substances which have an effect on platelet activation and/or platelet aggregation or else platelet adhesion, such as, in particular, fibrinogen receptor antagonists, or which are able to increase the endogenous capacity for fibrinolysis, such as, in particular, PAI-1 inhibitors, or stimulators of the synthesis and secretion of plasminogen activator inhibitors, which composition exhibits a prothrombin complex concentrate and at least one additional component which promotes blood coagulation.
2. A composition as claimed in claim 1, wherein the prothrombin complex concentrate is a non-activated prothrombin complex concentrate.
3. A composition as claimed in claim 1, wherein the additional component which promotes blood coagu-lation is factor VIII.
4. A composition as claimed in claim 1, wherein the additional component which promotes blood coagu-lation is factor VIII and von Willebrand factor (vWF).
5. A composition as claimed in claim 1, wherein the additional component which promotes blood coagu-lation is factor V.
6. A composition as claimed in claim 1, wherein the additional component which promotes blood coagu-lation is factor Va.
7. A composition as claimed in claim 1, wherein the additional component which promotes blood coagu-lation is von Willebrand factor.
8. A composition as claimed in claim 1, wherein the additional component which promotes blood coagu-lation is factor XI.
9. A composition as claimed in claim 1, wherein the additional component which promotes blood coagu-lation is factor XII.
10. A composition as claimed in claim 1, wherein the additional component which promotes blood coagu-lation is factor XIII.
11. A composition as claimed in claim 1, wherein the additional component which promotes blood coagu-lation is at least one lipid or a mixture of lipids.
12. A composition as claimed in claim 11, wherein the component is negatively charged lipids or lipid mixtures.
13. A composition as claimed in claim 1, wherein the additional component which promotes blood coagu-lation is at least one diuretic agent.
14. A composition as claimed in claim 1, which comprises a prothrombin complex concentrate and at least two additional components which promote blood coagulation as claimed in one of claims 3 to 13.
15. A composition as claimed in claim 1, wherein the prothrombin complex concentrate is present in a concentration of from 1 to 2000 international units (IU) per kilogram of the bodyweight of the patient to be treated.
16. A composition as claimed in claim 15, wherein the prothrombin complex concentrate is present in a quantity of from 10 to 1000 IU/kg.
17. A composition as claimed in claim 1, wherein the additional component which promotes blood coagu-lation is present in a concentration of from 1 to 2000 IU/kg.
18. A composition as claimed in claim 17, wherein the additional component which promotes blood coagu-lation is present in a quantity of from 10 to 1000 IU/kg.
19. A composition as claimed in claim 11, wherein the lipid or lipid mixture is present in a concentration of from 0.01 to 100 mg/kg of the bodyweight of the patient to be treated.
20. A composition as claimed in claim 13, wherein the diuretic agent is present in a quantity of from 0.01 to 100 mg/kg of the bodyweight of the patient to be treated.
21. A composition as claimed in claim 19, wherein the lipid or lipid mixture is present in a quantity of from 0.1 to 10 mg/kg of the bodyweight of the patient to be treated.
22. A composition as claimed in claim 20, wherein the diuretic agent is present in a quantity of from 0.1 to 10 mg/kg of the bodyweight of the patient to be treated.
23. A composition which is used as an antidote to blood anticoagulants, with the anticoagulants being selected from the group consisting of glycosamino-glycans and sulfated polysaccharides, such as hirudins, and their fragments, analogs or mutants, natural and synthetic inhibitors of the thrombo-plastin/factor VIIa complex, of factor Xa or of thrombin, components of the protein C system, namely activated protein C, protein S and thrombomodulin, inhibitors of fibrin aggregation or crosslinking, substances from the vitamin K antagonist group, substances which have an effect on platelet acti-vation and/or platelet aggregation or else platelet adhesion, such as, in particular, fibrinogen receptor antagonists, or which are able to increase the endogenous capacity for fibrinolysis, such as, in particular, PAI-1 inhibitors or stimulators of the synthesis and secretion of plasminogen activator inhibitors, which composition comprises, on the one hand, at least one component selected from the group lipid, lipid mixture and diuretic agent, and, on the other hand, at least one component selected from the group prothrombin complex concentrate, one of factors II, V, Va, VIII, IX, X, XI, XII or XIII, and von Willebrand factor, as a single factor, or as mixtures of these factors.
24. A composition which is used as an antidote to blood anticoagulants, it being possible to select the anticoagulants from the group consisting of glycos-aminoglycans and sulfated polysaccharides, such as hirudins, and their fragments, analogs or mutants, natural and synthetic inhibitors of the thromboplastin/factor VIIa complex, of factor Xa or of thrombin, components of the protein C system, namely activated protein C, protein S and thrombomodulin, inhibitors of fibrin aggregation or crosslinking, substances from the vitamin K
antagonist group, substances which have an effect on platelet activation and/or platelet aggregation or else platelet adhesion, such as, in particular, fibrinogen receptor antagonists, or which are able to increase the endogenous capacity for fibrinolysis, such as, in particular, PAI-1 inhibitors or stimulators of the synthesis and secretion of plasminogen activator inhibitors, which composition comprises in each case at least one component selected from one of the two groups A and B, where group A comprises factors II, V, Va, VIII
and IX, and group B comprises factors II, V, Va, VII, VIIa and VIII, von Willebrand factor, and factors IX, X, XI, XII and XIII, with the proviso that the component or the components from group A
is/are not identical to the component or components from group B.
antagonist group, substances which have an effect on platelet activation and/or platelet aggregation or else platelet adhesion, such as, in particular, fibrinogen receptor antagonists, or which are able to increase the endogenous capacity for fibrinolysis, such as, in particular, PAI-1 inhibitors or stimulators of the synthesis and secretion of plasminogen activator inhibitors, which composition comprises in each case at least one component selected from one of the two groups A and B, where group A comprises factors II, V, Va, VIII
and IX, and group B comprises factors II, V, Va, VII, VIIa and VIII, von Willebrand factor, and factors IX, X, XI, XII and XIII, with the proviso that the component or the components from group A
is/are not identical to the component or components from group B.
25. Use of a composition as claimed in claim 1 for preparing a pharmaceutical as an antidote to blood anticoagulants.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4430205.3 | 1994-08-26 | ||
| DE4430205A DE4430205A1 (en) | 1994-08-26 | 1994-08-26 | Compositions suitable as antidotes for blood anticoagulants and their use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2156991A1 true CA2156991A1 (en) | 1996-02-27 |
Family
ID=6526564
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002156991A Abandoned CA2156991A1 (en) | 1994-08-26 | 1995-08-25 | Compositions which are suitable for employment as antidotes to blood anticoagulants, and their use |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0700684A3 (en) |
| JP (1) | JP3859176B2 (en) |
| KR (1) | KR960006938A (en) |
| AU (1) | AU3025795A (en) |
| CA (1) | CA2156991A1 (en) |
| DE (1) | DE4430205A1 (en) |
| IL (1) | IL115058A0 (en) |
| ZA (1) | ZA957139B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7371722B2 (en) | 2002-07-23 | 2008-05-13 | Bio & Bio Licensing S.A. | Pharmaceutical preparations and medicine capable of generating and/or containing thrombin |
| US7494971B2 (en) | 2002-07-23 | 2009-02-24 | Bio & Bio Licensing Sa | Pharmaceutical preparations and medicines capable of generating, and/or containing, thrombin |
| US20100125052A1 (en) * | 2008-11-14 | 2010-05-20 | Portola Pharmaceuticals, Inc. | Antidotes for factor xa inhibitors and methods of using the same in combination with blood coagulating agents |
| US8153590B2 (en) | 2007-09-28 | 2012-04-10 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
| US8268783B2 (en) | 2007-09-28 | 2012-09-18 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
| US8268362B2 (en) | 1997-11-12 | 2012-09-18 | Bio-Products & Bio-Engineering Aktiengesellschaft | Medicinal product for the promotion of wound healing |
| US8394768B2 (en) | 2006-12-22 | 2013-03-12 | Csl Behring Gmbh | Synergistic therapeutic use of Prothrombin Complex Concentrates with FVIII concentrates |
| US8603979B2 (en) | 2008-07-10 | 2013-12-10 | Csl Behring Gmbh | von Willebrand factor or factor VIII and von Willebrand factor for the treatment of coagulopathy induced by inhibitors of thrombocytes |
| US9878017B2 (en) | 2013-04-22 | 2018-01-30 | Csl Ltd. | Covalent complex of von Willebrand Factor and factor VIII, compositions, and uses relating thereto |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT404673B (en) * | 1996-03-20 | 1999-01-25 | Immuno Ag | Pharmaceutical product for treating blood clotting disorders |
| ES2241030T3 (en) * | 1996-03-20 | 2005-10-16 | Baxter Aktiengesellschaft | PHARMACEUTICAL PREPARATION FOR THE TREATMENT OF ALTERATIONS OF THE SANGUINEA COAGULATION. |
| DE19710190A1 (en) * | 1997-03-12 | 1998-09-17 | Immuno Ag | Activated vitamin K-dependent blood factor and method for its production |
| AT409334B (en) * | 1997-09-19 | 2002-07-25 | Immuno Ag | PHARMACEUTICAL PREPARATION CONTAINING VITAMIN K-DEPENDENT INDIVIDUAL FACTORS |
| JPWO2003099324A1 (en) * | 2002-05-23 | 2005-09-22 | 中外製薬株式会社 | Tissue factor inhibitor neutralizing agent and active blood coagulation factor VII neutralizing agent |
| US20140128732A1 (en) | 2012-11-06 | 2014-05-08 | Cross Bay Medical, Inc. | Biopsy and sonography method and apparatus for assessing bodily cavities |
| FR3000895B1 (en) | 2013-01-11 | 2017-02-24 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies Sa | USE OF ANTIDOTES OF COAGULATION INHIBITORS INDICATED IN THE PREVENTION OR TREATMENT OF THROMBOEMBOLIC PATHOLOGIES |
| ES2907190T3 (en) * | 2014-07-31 | 2022-04-22 | Haemonetics Corp | Detection of anticoagulant reversal by ecarin and factor Xa coagulation tests |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE443293B (en) * | 1978-01-25 | 1986-02-24 | Blombaeck E G B | Blood fraction FRONT TELL NING |
| WO1981002105A1 (en) * | 1980-01-28 | 1981-08-06 | Baxter Travenol Lab | Therapeutic compositions & methods for manufacture and use |
| US4386068A (en) * | 1980-02-26 | 1983-05-31 | Cutter Laboratories, Inc. | Antihemophilic factor concentrate and method for preparation |
| EP0333356A3 (en) | 1988-03-04 | 1990-12-19 | Biogen, Inc. | Hirudin peptides |
| GB8823480D0 (en) * | 1988-10-06 | 1988-11-16 | Ciba Geigy Ag | Antidote |
| US5240913A (en) | 1989-08-18 | 1993-08-31 | Biogen, Inc. | Inhibitors of thrombin |
| FR2651437A1 (en) * | 1989-09-05 | 1991-03-08 | Lille Transfusion Sanguine | PROCESS FOR PREPARING A CONCENTRATE OF THE VON WILLEBRAND FACTOR VIII-FACTOR COMPLEX OF BLOOD COAGULATION FROM TOTAL PLASMA. |
| DE4203965A1 (en) * | 1992-02-11 | 1993-08-12 | Max Planck Gesellschaft | ANTIDOT FOR HIRUDIN AND SYNTHETIC THROMBIN INHIBITORS |
| AU3129393A (en) * | 1992-11-12 | 1994-06-08 | Sheldon Goldstein | Multiple coagulation test device and method |
| IL113010A (en) * | 1994-03-31 | 1999-10-28 | Pharmacia & Upjohn Ab | Pharmaceutical formulation comprising factor viii with an activity of at least 500iu/ml and an enhancer for improved subcutaneous intramuscular or intradermal administration |
| DE4416166C2 (en) * | 1994-05-06 | 1997-11-20 | Immuno Ag | Stable preparation for the treatment of blood clotting disorders |
-
1994
- 1994-08-26 DE DE4430205A patent/DE4430205A1/en not_active Withdrawn
-
1995
- 1995-08-10 EP EP95112570A patent/EP0700684A3/en not_active Withdrawn
- 1995-08-24 AU AU30257/95A patent/AU3025795A/en not_active Abandoned
- 1995-08-24 IL IL11505895A patent/IL115058A0/en unknown
- 1995-08-25 JP JP21683895A patent/JP3859176B2/en not_active Expired - Fee Related
- 1995-08-25 CA CA002156991A patent/CA2156991A1/en not_active Abandoned
- 1995-08-25 ZA ZA957139A patent/ZA957139B/en unknown
- 1995-08-25 KR KR1019950026510A patent/KR960006938A/en not_active Application Discontinuation
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|---|---|---|---|---|
| US8268362B2 (en) | 1997-11-12 | 2012-09-18 | Bio-Products & Bio-Engineering Aktiengesellschaft | Medicinal product for the promotion of wound healing |
| US7494971B2 (en) | 2002-07-23 | 2009-02-24 | Bio & Bio Licensing Sa | Pharmaceutical preparations and medicines capable of generating, and/or containing, thrombin |
| US7371722B2 (en) | 2002-07-23 | 2008-05-13 | Bio & Bio Licensing S.A. | Pharmaceutical preparations and medicine capable of generating and/or containing thrombin |
| US8580737B2 (en) | 2006-12-22 | 2013-11-12 | Csl Behring Gmbh | Synergistic therapeutic use of prothrombin complex concentrates with FVIII concentrates |
| US8394768B2 (en) | 2006-12-22 | 2013-03-12 | Csl Behring Gmbh | Synergistic therapeutic use of Prothrombin Complex Concentrates with FVIII concentrates |
| US8455441B2 (en) | 2007-09-28 | 2013-06-04 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
| US8268783B2 (en) | 2007-09-28 | 2012-09-18 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
| US10954503B2 (en) | 2007-09-28 | 2021-03-23 | Alexion Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
| US9587233B2 (en) | 2007-09-28 | 2017-03-07 | Portola Pharmaceuticals, Inc. | Antidotes for factor XA inhibitors and methods of using the same |
| US8153590B2 (en) | 2007-09-28 | 2012-04-10 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
| US11839646B2 (en) | 2007-09-28 | 2023-12-12 | Alexion Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
| US8889129B2 (en) | 2007-09-28 | 2014-11-18 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
| US9062298B2 (en) | 2007-09-28 | 2015-06-23 | Portola Pharmaceuticals, Inc. | Antidotes for factor XA inhibitors and methods of using the same |
| US10675335B2 (en) | 2007-09-28 | 2020-06-09 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
| US9109046B2 (en) | 2007-09-28 | 2015-08-18 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
| US10190111B2 (en) | 2007-09-28 | 2019-01-29 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
| US9388401B2 (en) | 2007-09-28 | 2016-07-12 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same |
| US8603979B2 (en) | 2008-07-10 | 2013-12-10 | Csl Behring Gmbh | von Willebrand factor or factor VIII and von Willebrand factor for the treatment of coagulopathy induced by inhibitors of thrombocytes |
| US9095564B2 (en) | 2008-07-10 | 2015-08-04 | Csl Behring Gmbh | von Willebrand factor or factor VIII and von Willebrand factor for the treatment of coagulopathy induced by inhibitors of thrombocytes |
| AU2009314153B2 (en) * | 2008-11-14 | 2015-09-17 | Alexion Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same in combination with blood coagulating agents |
| US8455439B2 (en) * | 2008-11-14 | 2013-06-04 | Portola Pharmaceuticals, Inc. | Antidotes for factor Xa inhibitors and methods of using the same in combination with blood coagulating agents |
| US20100125052A1 (en) * | 2008-11-14 | 2010-05-20 | Portola Pharmaceuticals, Inc. | Antidotes for factor xa inhibitors and methods of using the same in combination with blood coagulating agents |
| US9878017B2 (en) | 2013-04-22 | 2018-01-30 | Csl Ltd. | Covalent complex of von Willebrand Factor and factor VIII, compositions, and uses relating thereto |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3025795A (en) | 1996-04-04 |
| EP0700684A2 (en) | 1996-03-13 |
| IL115058A0 (en) | 1995-12-08 |
| JP3859176B2 (en) | 2006-12-20 |
| JPH0859504A (en) | 1996-03-05 |
| KR960006938A (en) | 1996-03-22 |
| ZA957139B (en) | 1996-03-26 |
| EP0700684A3 (en) | 1997-01-08 |
| DE4430205A1 (en) | 1996-02-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |