CA2281055A1 - Antithrombin iii-beta-comprising pharmaceutical preparation - Google Patents
Antithrombin iii-beta-comprising pharmaceutical preparation Download PDFInfo
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- CA2281055A1 CA2281055A1 CA002281055A CA2281055A CA2281055A1 CA 2281055 A1 CA2281055 A1 CA 2281055A1 CA 002281055 A CA002281055 A CA 002281055A CA 2281055 A CA2281055 A CA 2281055A CA 2281055 A1 CA2281055 A1 CA 2281055A1
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- beta
- iii
- isoform
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- antithrombin iii
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- 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
- A61K38/55—Protease inhibitors
-
- 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
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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Abstract
Pharmaceutical preparations for the parenteral administration of antithrombin III are described which either contain only the beta-isoform of antithrombin III or a mixture of the alpha-and the beta-isoform of antithrombin III. They can be used for the treatment of syndromes which are caused by a lack of the beta-isoform of antithrombin III, and can preferably also be employed for the therapeutic or prophylactic treatment of thrombotic complications or conditions which are associated with inflammatory reactions.
Description
CENTEON PHARMA GMBH 1998/Z011 - Ma 1184 - C19 Antithrombin III-beta-comprising pharmaceutical preparation The invention relates to a pharmaceutical preparation for the parenteral administration of antithrombin III-beta.
Antithrombin III (AT III) is one of the most important plasma inhibitors. AT
III belongs to the serine protease inhibitors family, which with their "target proteases" form a complex approximating to a covalent bond. This complex is very stable under physiological conditions and as a rule is eliminated rapidly from the blood circulation. The reaction between AT III and protease is drastically accelerated by heparin, the AT III undergoing a slight change in conformation after association with the heparin belonging to the glycosaminoglycans group and thus being able to enter into an accelerated reaction with the protease. These processes play a role physiologically, particularly on cell surfaces which contain glycosaminoglycans e.g. of the heparansulfate type and thereby protect the cells and the tissue from excessively increased proteolytic activity.
In addition, however, plasmatic coagulation and its regulation has an important meaning. In the healthy state, no or insignificant amounts of glycosaminoglycans circulate, such that these processes are especially determined by the progressive, i.e. heparin-independent, and thus far slower inhibition characteristics of antithrombin III. This is useful in order to guarantee wound closure while avoiding subsequent excessive activation of clotting.
The regulatory function of AT III is particularly clear when its plasma level sinks, which can be observed in the course of many diseases and particularly drastically, for exmaple, in the case of disseminated intravasal coagulation (DIC). Even falling below 70 % of the corresponding plasma concentration is associated with a drastic increase in the probability of mortality. A predominance of clotting processes frequently leads to thrombotic occlusions of vessels and thus to organ failure. The administration of AT III concentrates of human plasma has therefore proven very helpful, particularly in cases of inherited or acquired deficiency states.
In order to counteract the described pathophysiological processes, heparin - in addition to the abovementioned substitution with AT III concentrates -is sometimes also administered in order to reduce the predominance of the proteolytic potential to a normal degree. However, this can only be successful if adequate AT III is present. Since the administration of the heparin, however, is also associated with an increased risk of hemorrhage, which is all the higher, the more disregulated the blood clotting, a balance must continuously be sought between pro- and anticoagulatory processes.
The inhibition of the proteases of blood clotting, such as thrombin and the activated factors X and IX, by AT III is particularly important here. A
reinforcement of the progressive inhibitory properties, which contributes to the regulation of hemostasis, but does not significantly increase the proneness to hemorrhage, would be regarded as a considerable advance.
This also applies to inflammatory reactions, where both thrombin and FXa can be regarded as connecting links between clotting and inflammatory reactions. A moderate inhibition of these factors would thus also have an influence on both systems.
AT III circulates in the plasma in a concentration of about 150 mg/I.
Approximately 90 - 95 % of the AT III is glycosylated at four sites in the molecule. This isoform is called AT III-alpha. However, the beta-isoform only has three glycosylation sites. A comparison of these two isoforms has shown that one of the carbohydrate chains of the AT III-alpha is localized in the vicinity of the heparin-binding domain of the AT III, but is absent in the beta-isoform. In the end, an increased affinity of the beta-isoform for heparin results from this. Studies on the subendothelial tissue have shown that AT III-beta is preferably bound there, presumably to the exposed glycosaminoglycans. To date, however, it is not known whether the differing glycosylation has an influence on the progressive inhibition of plasmatic processes.
Surprisingly, it has now been found that the beta-isoform of antithrombin III
inhibits the proteolytic activities of the activated coagulation factors F X
and F IX in the absence of heparin better than the alpha-isoform.
The invention therefore relates to a pharmaceutical preparation for parenteral administration of antithrombin III, which contains only the beta-isoform of antithrombin.
The invention further relates to a pharmaceutical preparation which contains a mixture of the alpha- and the beta-isoform of antithrombin III, in which the beta-isoform makes up at least 15 % by weight of the total amount of the antithrombin. The preparation of the two isoforms of antithrombin III and their inhibition properties are explained in greater detail in Example 1.
The significant, but moderately increased inhibitory capacity of the beta-isoform can be eliminated for the abovementioned reasons in patients with inherited or acquired AT III-beta deficiency states by the use of a pharmaceutical preparation which is to be administered parenterally and which only contains the beta-isoform of antithrombin or the beta-isoform in an amount of at least 15 % by weight of the total amount of the antithrombin. The administration of this mixture of the two isoforms is useful in AT III beta deficiency states, since this pharmaceutical preparation has a higher content of the beta-isoform of antithrombin than natural AT III concentrates.
The invention also relates to a pharmaceutical preparation which, in addition to the pure beta-isoform of antithrombin III or an antithrombin III
having a content of at least 15 % by weight of the beta-isoform of antithrombin, additionally contains a glycosaminoglycan, in particular heparin. Using a preparation of this type, the inhibitory reactions of the beta-isoform of antithrombin are considerably accelerated.
In pure form or as a constituent of an AT III concentrate, the beta-isoform can also be used for the prophylaxis or therapy of diseases which possibly exhibit no clear decrease in the AT III plasma concentration. This can, for example, be the case in leg vein thrombosis, in cardiac infarct prophylaxis, in rethrombosis prophylaxis or in septic conditions such as sepsis or septic shock. The increased inhibitory action against the activated blood clotting factor X or IX can make administration of the pure beta-isoform of antithrombin and also of an antithrombin concentrate enriched in beta-isoform appear useful. The administration of a pharmaceutical preparation which in the beta-isoform of antithrombin is not associated practically with any increased risk of proneness to hemorrhage. The more effective inhibition of the activated blood clotting factors IX and X is associated with an anti-inflammatory effect, which can therefore also be used for the prophylaxis and therapy of these conditions.
The pharmaceutical preparation according to the invention can be employed for injection or infusion. It is in general marketed as a dry substance in an injection vial together with a separately packed solvent.
The amount of the active compound intended for single administration in an injection vial is as a rule between 250 and 2500 I.E. Depending on the formulation of the lyophilized solution, the solvent used is water (for injection), a Ringer lactate solution or an isotonic aqueous solution which can contain sodium citrate, glucose, sodium monohydrogenphosphate, one or more amino acids but also human albumin (from plasma, prepared by recombinant or transgenic means) or a plasma substitute infusion solution such as Haemacel~. Antithrombin III-beta can also be supplied in the form of a liquid preparation to be administered parenterally. On simultaneous administration of heparin or another glycosaminoglycan, its dose should not exceed 500 I.U./hr.
The invention is explained in greater detail by the following examples.
Antithrombin III (AT III) is one of the most important plasma inhibitors. AT
III belongs to the serine protease inhibitors family, which with their "target proteases" form a complex approximating to a covalent bond. This complex is very stable under physiological conditions and as a rule is eliminated rapidly from the blood circulation. The reaction between AT III and protease is drastically accelerated by heparin, the AT III undergoing a slight change in conformation after association with the heparin belonging to the glycosaminoglycans group and thus being able to enter into an accelerated reaction with the protease. These processes play a role physiologically, particularly on cell surfaces which contain glycosaminoglycans e.g. of the heparansulfate type and thereby protect the cells and the tissue from excessively increased proteolytic activity.
In addition, however, plasmatic coagulation and its regulation has an important meaning. In the healthy state, no or insignificant amounts of glycosaminoglycans circulate, such that these processes are especially determined by the progressive, i.e. heparin-independent, and thus far slower inhibition characteristics of antithrombin III. This is useful in order to guarantee wound closure while avoiding subsequent excessive activation of clotting.
The regulatory function of AT III is particularly clear when its plasma level sinks, which can be observed in the course of many diseases and particularly drastically, for exmaple, in the case of disseminated intravasal coagulation (DIC). Even falling below 70 % of the corresponding plasma concentration is associated with a drastic increase in the probability of mortality. A predominance of clotting processes frequently leads to thrombotic occlusions of vessels and thus to organ failure. The administration of AT III concentrates of human plasma has therefore proven very helpful, particularly in cases of inherited or acquired deficiency states.
In order to counteract the described pathophysiological processes, heparin - in addition to the abovementioned substitution with AT III concentrates -is sometimes also administered in order to reduce the predominance of the proteolytic potential to a normal degree. However, this can only be successful if adequate AT III is present. Since the administration of the heparin, however, is also associated with an increased risk of hemorrhage, which is all the higher, the more disregulated the blood clotting, a balance must continuously be sought between pro- and anticoagulatory processes.
The inhibition of the proteases of blood clotting, such as thrombin and the activated factors X and IX, by AT III is particularly important here. A
reinforcement of the progressive inhibitory properties, which contributes to the regulation of hemostasis, but does not significantly increase the proneness to hemorrhage, would be regarded as a considerable advance.
This also applies to inflammatory reactions, where both thrombin and FXa can be regarded as connecting links between clotting and inflammatory reactions. A moderate inhibition of these factors would thus also have an influence on both systems.
AT III circulates in the plasma in a concentration of about 150 mg/I.
Approximately 90 - 95 % of the AT III is glycosylated at four sites in the molecule. This isoform is called AT III-alpha. However, the beta-isoform only has three glycosylation sites. A comparison of these two isoforms has shown that one of the carbohydrate chains of the AT III-alpha is localized in the vicinity of the heparin-binding domain of the AT III, but is absent in the beta-isoform. In the end, an increased affinity of the beta-isoform for heparin results from this. Studies on the subendothelial tissue have shown that AT III-beta is preferably bound there, presumably to the exposed glycosaminoglycans. To date, however, it is not known whether the differing glycosylation has an influence on the progressive inhibition of plasmatic processes.
Surprisingly, it has now been found that the beta-isoform of antithrombin III
inhibits the proteolytic activities of the activated coagulation factors F X
and F IX in the absence of heparin better than the alpha-isoform.
The invention therefore relates to a pharmaceutical preparation for parenteral administration of antithrombin III, which contains only the beta-isoform of antithrombin.
The invention further relates to a pharmaceutical preparation which contains a mixture of the alpha- and the beta-isoform of antithrombin III, in which the beta-isoform makes up at least 15 % by weight of the total amount of the antithrombin. The preparation of the two isoforms of antithrombin III and their inhibition properties are explained in greater detail in Example 1.
The significant, but moderately increased inhibitory capacity of the beta-isoform can be eliminated for the abovementioned reasons in patients with inherited or acquired AT III-beta deficiency states by the use of a pharmaceutical preparation which is to be administered parenterally and which only contains the beta-isoform of antithrombin or the beta-isoform in an amount of at least 15 % by weight of the total amount of the antithrombin. The administration of this mixture of the two isoforms is useful in AT III beta deficiency states, since this pharmaceutical preparation has a higher content of the beta-isoform of antithrombin than natural AT III concentrates.
The invention also relates to a pharmaceutical preparation which, in addition to the pure beta-isoform of antithrombin III or an antithrombin III
having a content of at least 15 % by weight of the beta-isoform of antithrombin, additionally contains a glycosaminoglycan, in particular heparin. Using a preparation of this type, the inhibitory reactions of the beta-isoform of antithrombin are considerably accelerated.
In pure form or as a constituent of an AT III concentrate, the beta-isoform can also be used for the prophylaxis or therapy of diseases which possibly exhibit no clear decrease in the AT III plasma concentration. This can, for example, be the case in leg vein thrombosis, in cardiac infarct prophylaxis, in rethrombosis prophylaxis or in septic conditions such as sepsis or septic shock. The increased inhibitory action against the activated blood clotting factor X or IX can make administration of the pure beta-isoform of antithrombin and also of an antithrombin concentrate enriched in beta-isoform appear useful. The administration of a pharmaceutical preparation which in the beta-isoform of antithrombin is not associated practically with any increased risk of proneness to hemorrhage. The more effective inhibition of the activated blood clotting factors IX and X is associated with an anti-inflammatory effect, which can therefore also be used for the prophylaxis and therapy of these conditions.
The pharmaceutical preparation according to the invention can be employed for injection or infusion. It is in general marketed as a dry substance in an injection vial together with a separately packed solvent.
The amount of the active compound intended for single administration in an injection vial is as a rule between 250 and 2500 I.E. Depending on the formulation of the lyophilized solution, the solvent used is water (for injection), a Ringer lactate solution or an isotonic aqueous solution which can contain sodium citrate, glucose, sodium monohydrogenphosphate, one or more amino acids but also human albumin (from plasma, prepared by recombinant or transgenic means) or a plasma substitute infusion solution such as Haemacel~. Antithrombin III-beta can also be supplied in the form of a liquid preparation to be administered parenterally. On simultaneous administration of heparin or another glycosaminoglycan, its dose should not exceed 500 I.U./hr.
The invention is explained in greater detail by the following examples.
Example 1:
Antithrombin III-alpha and -beta were obtained by adsorption of the AT III
concentrate Kybernin~P (Centeon Pharma GmbH, Marburg) on heparin-Fractogel~ and stepwise elution. The differing affinity of the isoforms for heparin was used here for separation, AT III-alpha being eluted at lower and AT III-beta correspondingly at higher salt concentrations. The isoforms were characterized, inter alia, by means of their differing running behavior or band patterns, by SDS-PAGE and isoelectric focusing. The preparations were distinguished by very high purity. The protein concentrations were determined by the Kjeldahl method.
For the estimation of the inhibitory potencies of both isoforms, activated factors isolated from plasma and having increasing concentrations of the inhibitor isoforms (based on total protein content according to Kjeldahl) were treated in the absence or presence of heparin (2 IU/150 pg of ATIII) and the remaining amidolytic activities of the protease were determined photometrically with the aid of chromogenic peptide substrates.
For this, the activated forms of the factors II (thrombin), of F IX, of F X
and of plasminogen (plasmin) were used. The chromogenic substrate (3 mM) were purchased from the company Chromogenix AB (Sweden).
Table 1 Protease Source Conc. in Test Chromogenic (IUIML) substrate Human-a- Centeon 0.5 IU/ml S 2238 thrombin FIXa ERL (UK) 2 Ng/ml S 2288 Fxa Stago/ 0.05 IU/ml S 2765 Boehringer (Germany) Plasmin Centeon 0.1 CTA/ml S 2251 S 2238: H-D-Phe-Pip-Arg-pNA x 2HC1 S 2288: H-D-Ile-Pro-Arg-pNA x 2HC1 S 2765: Z-D-Arg-Gly-Arg-pNA x 2HC1 S 2251: H-D-Val-Leu-Lys-PNA x 2HC1 Part A
Test batch:
50 pl of ATIII-alpha or -beta + 100 pl of buffer + 50 NI of protease (see Table 1 ) + 50 NI of chromogenic substrate In the case of the batches containing heparin, the mixture was incubated for 10 min at room temperature before addition of the chromogenic substrate. Change in the absorption at 405 nm was recorded with time.
The inhibition (%) was quantified by comparison with the uninhibited batch.
The concentrations of AT III-alpha and AT III-beta which inhibited 50 % of _ g _ the protease activity were determined and expressed as an IC50 value (Table 2).
IC 50 (Nglml) AT III-a AT III-(3 -heparin / + heparin -heparin / +heparin Thrombin 220 1.5 200 0.8 F Xa 500 5.0 240 3.0 F IXa 490 10.0 175 7.0 Plasmin 900 55.0 900 45.0 Results:
As expected, all inhibitory reactions were strongly accelerated in the presence of heparin and led to a considerable decrease in the IC50 values.
Clear differences between both isoforms were not obvious due to the ranges of variability of the tests (Figures 1-4, in each case B), but relative to thrombin, F IXa and F Xa show a tendency to higher inhibitory potency of the beta-isoform.
In comparison with the alpha-isoform, AT III-beta concentrations reduced approximately by the factors 2 and 3 were necessary for the 50 inhibition of F Xa and F IXa (Figures 1-4, in each case A).
Part B
The stronger inhibitory potency of AT III-beta was further intensified by means of the following experiment, which was carried out in modified form according to Example 1A:
_ g _ While the total concentration of the AT Ills employed in the test batch was kept constant (at 100/250/500 Ng/ml), the content of AT III-beta was increased.
Figure 5 shows an inhibition of the F IXa activity increasing with the AT III-beta content. The curves of the absolute AT III specifications correspondingly run parallel.
Example 2 The influence of both AT III isoforms on the plasma recalcification time was determined according to Schnitger and Gross with the aid of coagulometers. For this, AT III-deficient plasma which contained no antithrombin III whatsoever was treated with increasing amounts of AT III-alpha or AT III-beta and with 100 pl of imidazole buffer, incubated at 37°C
for 1 minute and the reaction was then started by addition of 100 NI of calcium chloride (25 mM).
Result:
With increasing concentration, both AT III isoforms led to prolonged recalcification times, AT III-beta causing the more marked prolongation (Table 3).
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Antithrombin III-alpha and -beta were obtained by adsorption of the AT III
concentrate Kybernin~P (Centeon Pharma GmbH, Marburg) on heparin-Fractogel~ and stepwise elution. The differing affinity of the isoforms for heparin was used here for separation, AT III-alpha being eluted at lower and AT III-beta correspondingly at higher salt concentrations. The isoforms were characterized, inter alia, by means of their differing running behavior or band patterns, by SDS-PAGE and isoelectric focusing. The preparations were distinguished by very high purity. The protein concentrations were determined by the Kjeldahl method.
For the estimation of the inhibitory potencies of both isoforms, activated factors isolated from plasma and having increasing concentrations of the inhibitor isoforms (based on total protein content according to Kjeldahl) were treated in the absence or presence of heparin (2 IU/150 pg of ATIII) and the remaining amidolytic activities of the protease were determined photometrically with the aid of chromogenic peptide substrates.
For this, the activated forms of the factors II (thrombin), of F IX, of F X
and of plasminogen (plasmin) were used. The chromogenic substrate (3 mM) were purchased from the company Chromogenix AB (Sweden).
Table 1 Protease Source Conc. in Test Chromogenic (IUIML) substrate Human-a- Centeon 0.5 IU/ml S 2238 thrombin FIXa ERL (UK) 2 Ng/ml S 2288 Fxa Stago/ 0.05 IU/ml S 2765 Boehringer (Germany) Plasmin Centeon 0.1 CTA/ml S 2251 S 2238: H-D-Phe-Pip-Arg-pNA x 2HC1 S 2288: H-D-Ile-Pro-Arg-pNA x 2HC1 S 2765: Z-D-Arg-Gly-Arg-pNA x 2HC1 S 2251: H-D-Val-Leu-Lys-PNA x 2HC1 Part A
Test batch:
50 pl of ATIII-alpha or -beta + 100 pl of buffer + 50 NI of protease (see Table 1 ) + 50 NI of chromogenic substrate In the case of the batches containing heparin, the mixture was incubated for 10 min at room temperature before addition of the chromogenic substrate. Change in the absorption at 405 nm was recorded with time.
The inhibition (%) was quantified by comparison with the uninhibited batch.
The concentrations of AT III-alpha and AT III-beta which inhibited 50 % of _ g _ the protease activity were determined and expressed as an IC50 value (Table 2).
IC 50 (Nglml) AT III-a AT III-(3 -heparin / + heparin -heparin / +heparin Thrombin 220 1.5 200 0.8 F Xa 500 5.0 240 3.0 F IXa 490 10.0 175 7.0 Plasmin 900 55.0 900 45.0 Results:
As expected, all inhibitory reactions were strongly accelerated in the presence of heparin and led to a considerable decrease in the IC50 values.
Clear differences between both isoforms were not obvious due to the ranges of variability of the tests (Figures 1-4, in each case B), but relative to thrombin, F IXa and F Xa show a tendency to higher inhibitory potency of the beta-isoform.
In comparison with the alpha-isoform, AT III-beta concentrations reduced approximately by the factors 2 and 3 were necessary for the 50 inhibition of F Xa and F IXa (Figures 1-4, in each case A).
Part B
The stronger inhibitory potency of AT III-beta was further intensified by means of the following experiment, which was carried out in modified form according to Example 1A:
_ g _ While the total concentration of the AT Ills employed in the test batch was kept constant (at 100/250/500 Ng/ml), the content of AT III-beta was increased.
Figure 5 shows an inhibition of the F IXa activity increasing with the AT III-beta content. The curves of the absolute AT III specifications correspondingly run parallel.
Example 2 The influence of both AT III isoforms on the plasma recalcification time was determined according to Schnitger and Gross with the aid of coagulometers. For this, AT III-deficient plasma which contained no antithrombin III whatsoever was treated with increasing amounts of AT III-alpha or AT III-beta and with 100 pl of imidazole buffer, incubated at 37°C
for 1 minute and the reaction was then started by addition of 100 NI of calcium chloride (25 mM).
Result:
With increasing concentration, both AT III isoforms led to prolonged recalcification times, AT III-beta causing the more marked prolongation (Table 3).
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Claims (6)
1. A pharmaceutical preparation for the parenteral administration of antithrombin III, which contains only the beta-isoform of antithrombin III.
2. The pharmaceutical preparation as claimed in claim 1, which contains a mixture of the alpha-and the beta-isoform of antithrombin III in which the beta-isoform makes up at least 15% by weight of the total amount of the antithrombin.
3. The pharmaceutical preparation as claimed in claim 1 or 2, which contains a glycosaminoglycan as a further active compound.
4. The pharmaceutical preparation as claimed in claim 3, which contains heparin as a glycosaminoglycan.
5. The use of a pharmaceutical preparation as claimed in claims 1 to 4 for the treatment of syndromes which are caused by a lack of the beta-isoform of antithrombin III.
6. The use of a pharmaceutical preparation as claimed in claims 1 to 4, which is employed for the therapeutic or prophylactic treatment of thrombotic complications, septic conditions or conditions which are associated with inflammatory reactions.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19839337A DE19839337A1 (en) | 1998-08-28 | 1998-08-28 | Parenteral medicament for treating antithrombin III deficiency contains potent beta-isoform of antithrombin III |
| DE19839337.7 | 1998-08-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2281055A1 true CA2281055A1 (en) | 2000-02-28 |
Family
ID=7879113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002281055A Abandoned CA2281055A1 (en) | 1998-08-28 | 1999-08-27 | Antithrombin iii-beta-comprising pharmaceutical preparation |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0995446A3 (en) |
| JP (1) | JP2000103744A (en) |
| KR (1) | KR20000017598A (en) |
| AU (1) | AU4476399A (en) |
| CA (1) | CA2281055A1 (en) |
| DE (1) | DE19839337A1 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3901917A1 (en) * | 1989-01-24 | 1990-07-26 | Behringwerke Ag | MUTANTS OF HUMAN ANTITHROMBIN III |
-
1998
- 1998-08-28 DE DE19839337A patent/DE19839337A1/en not_active Withdrawn
-
1999
- 1999-08-13 EP EP99115942A patent/EP0995446A3/en not_active Withdrawn
- 1999-08-26 AU AU44763/99A patent/AU4476399A/en not_active Abandoned
- 1999-08-27 JP JP11240969A patent/JP2000103744A/en active Pending
- 1999-08-27 CA CA002281055A patent/CA2281055A1/en not_active Abandoned
- 1999-08-27 KR KR1019990035909A patent/KR20000017598A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000103744A (en) | 2000-04-11 |
| EP0995446A2 (en) | 2000-04-26 |
| KR20000017598A (en) | 2000-03-25 |
| AU4476399A (en) | 2000-03-16 |
| EP0995446A3 (en) | 2000-05-24 |
| DE19839337A1 (en) | 2000-03-02 |
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