CA2292481A1 - Use of fibrin adhesive for tissue regeneration - Google Patents
Use of fibrin adhesive for tissue regeneration Download PDFInfo
- Publication number
- CA2292481A1 CA2292481A1 CA002292481A CA2292481A CA2292481A1 CA 2292481 A1 CA2292481 A1 CA 2292481A1 CA 002292481 A CA002292481 A CA 002292481A CA 2292481 A CA2292481 A CA 2292481A CA 2292481 A1 CA2292481 A1 CA 2292481A1
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- CA
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- Prior art keywords
- fibrin adhesive
- fibrin
- regeneration
- injection
- occlusion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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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
-
- 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)
- A61K38/4833—Thrombin (3.4.21.5)
-
- 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
-
- 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
- A61K38/45—Transferases (2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Zoology (AREA)
- Pulmonology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Materials For Medical Uses (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The use of a fibrin adhesive for the regeneration is described. In the case of the treatment of liver damage, a fibrin adhesive occlusion is formed here by injection of a fibrin adhesive into the hepatobiliary system or by direct injection into the liver tissue. As a result of the fibrin adhesive occlusion in the hepatobiliary system, the expression of the hepatocyte growth factor (HGF) is increased and thus the regeneration of the liver tissue is promoted. The use of the fibrin adhevise by injection into lung, pancreas or skin tissue for the treatment of lung failure and of diabetes mellitus and also in plastic surgery is additionally described.
Description
CENTEON PHARMA GMBH 199812023-Ma 1196-C 31 Use of a fibrin adhesive for tissue regeneration The invention relates to a novel use of a fibrin adhesive for tissue regeneration.
It is known that in modern surgery fibrin adhesives are gaining increasingly in importance, since what is involved here is a highly tolerable and wound healing-promoting biomaterial. To date, fibrin adhesion is being employed for the hemostasis of heavily bleeding wounds in operations on parenchymatous, internal organs, in skin transplants, in emergency surgery on internal and external injuries, but especially also for the supportive sealing of sutures to avoid postoperative hemorrhages. In ENT and facial surgery, the fibrin adhesive is preferred for cosmetic reasons in the suture closure for the healing of external wounds. Moreover, the fibrin adhesive is increasingly employed in endoscopic surgery, for example for the hemostasis of gastric ulcers. The commercially available fibrin adhesives such as Beriplast~ contain the clotting factors fibrinogen, thrombin and factor XII I which are obtained from human plasma as main constituents.
It is moreover known that the regeneration of liver tissue destroyed by toxic effects is particularly dependent on the hepatocyte growth factor (HGF).
The production of HGFs can be increased by a system of different, activated proteins. At the beginning of this activating cascade, thrombin appears to play a not insignificant role. Despite this, to date it has not been attempted to employ the thrombin contained in the fibrin adhesive for the treatment of liver damage. As the mortality from acute liver failure is up to 80%, there is considerable need for prophylactic and therapeutic measures with which acute liver failure in particular can be prevented.
It is known that in modern surgery fibrin adhesives are gaining increasingly in importance, since what is involved here is a highly tolerable and wound healing-promoting biomaterial. To date, fibrin adhesion is being employed for the hemostasis of heavily bleeding wounds in operations on parenchymatous, internal organs, in skin transplants, in emergency surgery on internal and external injuries, but especially also for the supportive sealing of sutures to avoid postoperative hemorrhages. In ENT and facial surgery, the fibrin adhesive is preferred for cosmetic reasons in the suture closure for the healing of external wounds. Moreover, the fibrin adhesive is increasingly employed in endoscopic surgery, for example for the hemostasis of gastric ulcers. The commercially available fibrin adhesives such as Beriplast~ contain the clotting factors fibrinogen, thrombin and factor XII I which are obtained from human plasma as main constituents.
It is moreover known that the regeneration of liver tissue destroyed by toxic effects is particularly dependent on the hepatocyte growth factor (HGF).
The production of HGFs can be increased by a system of different, activated proteins. At the beginning of this activating cascade, thrombin appears to play a not insignificant role. Despite this, to date it has not been attempted to employ the thrombin contained in the fibrin adhesive for the treatment of liver damage. As the mortality from acute liver failure is up to 80%, there is considerable need for prophylactic and therapeutic measures with which acute liver failure in particular can be prevented.
In acute liver failure, two factors primarily determine the survival of the patient: the extent of the liver damage and the rate of hepatocyte regeneration (1 ). Hepatocyte regeneration can be markedly increased, for example, after bile duct ligature (2). In this case, bile duct cells show a 17-fold increase in proliferation after two days, accompanied by a 4-fold increase in hepatocyte regeneration.
The invention now relates to the use of a fibrin adhesive for regeneration of the liver tissue, in which a fibrin adhesive occlusion is formed by injection of a fibrin adhesive into the hepatobiliary system and/or fibrin adhesive is based on the observation that a fibrin adhesive occlusion is reversible within 24 hours and leads to a marked proliferation of the bile duct cells.
The increase associated therewith in the expression of the hepatocyte growth factor HGF and its receptor c-met leads to a rapid regeneration of the liver tissue. It was possible to show the success of the use according to the invention of a fibrin adhesive for the regeneration of the liver tissue by means of a hepatobiliary fibrin adhesive occlusion in thio-acetamide-induced acute liver failure. Moreover, additive factors mixed with the fibrin adhesive can thus become effective locally in the liver in high dose by means of a hepatobiliary occlusion and/or by direct injection.
Moreover, it has now been shown that the regeneration of other issues is also significantly improved by the intraparenchymatous administration of fibrin adhesive. Thus in a rat diabetes mode (streptozotocin), the glucose tolerance was significantly improved by intraductal/intraparenchymatous administration of fibrin adhesive. This shows that insulin-producing cells can be activated by the action of the fibrin adhesive from precursors. Thus a completely novel approach for the treatment of diabetes mellitus prsents itself.
In addition, it was possible in the case of acute lung failure of the rat to show that the oxygenation of the body is significantly improved by intrabronchial and intraparenchymatous administration of fibrin adhesive.
The invention now relates to the use of a fibrin adhesive for regeneration of the liver tissue, in which a fibrin adhesive occlusion is formed by injection of a fibrin adhesive into the hepatobiliary system and/or fibrin adhesive is based on the observation that a fibrin adhesive occlusion is reversible within 24 hours and leads to a marked proliferation of the bile duct cells.
The increase associated therewith in the expression of the hepatocyte growth factor HGF and its receptor c-met leads to a rapid regeneration of the liver tissue. It was possible to show the success of the use according to the invention of a fibrin adhesive for the regeneration of the liver tissue by means of a hepatobiliary fibrin adhesive occlusion in thio-acetamide-induced acute liver failure. Moreover, additive factors mixed with the fibrin adhesive can thus become effective locally in the liver in high dose by means of a hepatobiliary occlusion and/or by direct injection.
Moreover, it has now been shown that the regeneration of other issues is also significantly improved by the intraparenchymatous administration of fibrin adhesive. Thus in a rat diabetes mode (streptozotocin), the glucose tolerance was significantly improved by intraductal/intraparenchymatous administration of fibrin adhesive. This shows that insulin-producing cells can be activated by the action of the fibrin adhesive from precursors. Thus a completely novel approach for the treatment of diabetes mellitus prsents itself.
In addition, it was possible in the case of acute lung failure of the rat to show that the oxygenation of the body is significantly improved by intrabronchial and intraparenchymatous administration of fibrin adhesive.
It was furthermore observed that the regeneration ability of the skin after raising skin lesions is considerably improved by the subcutaneous administration of fibrin adhesives. In addition, the elasticity of the skin was markedly increased at the same time. A novel field of employment can thus be created for the fibrin adhesive in plastic surgery and regeneration of the skin.
Additive factors mixed with the fibrin adhesive can then become active locally in high concentration in the pancreas, in the lung or the skin.
To demonstrate the efficacy of a fibrin adhesive for the regeneration of the liver tissue, the following experiments and measurements were carried out.
Additive factors mixed with the fibrin adhesive can then become active locally in high concentration in the pancreas, in the lung or the skin.
To demonstrate the efficacy of a fibrin adhesive for the regeneration of the liver tissue, the following experiments and measurements were carried out.
1st experiment The model of acute liver failure was induced in Sprague Dawley rats by means of thioacetamide (3). Two groups of six rats each were treated in the following manner here. On three successive days, the rats of group A
received thioacetamide in doses of 500 mg/kg, 500 mg/kg and 250 mg/kg intraperitoneally at the same time of day. After laparotomy under pentobarbital anesthesia, a slowly hardening fibrin adhesive (Beriplast~) was injected into the hepatobiliary system of animals of group B 24 hours before the start of thioacetamide administration.
The following results were observed: the histological findings on the hepatocytes of the rats of group A showed a swelling of the nucleus with highly prominent nucleoli, and an extensive loss of parenchyma from the center of the lobe with more or less compact round-celled infiltration. In group B, the portal areas showed a slight edema and discrete round-cell infiltration, while the hepatocytes were distinguished by a noticeable lightening with isolated centrilobular individual cell necrosis.
The mortality of group A was 100% after five days, while all animals of group B survived. The conclusion is to be drawn from this that a hepatobiliary fibrin adhesive occlusion can prophylactically prevent the lethal thioacetamide-induced liver failure in the rat.
2nd experiment 40 SD rats each day received an injection of 100 mglkg of thioacetamide intraperitoneally. On the seventh day, 20 animals were laparotomized under ether anesthesia, the bile duct was microsurgically dissected, canulated and 0.2 ml of Beriplast~ fibrin adhesive was subsequently injected. 20 animals were only laparotomized (control group). The continuation of the thioacetamide treatment was then carried out up to the 14th day. On the 14th day, laparotomy with removal of blood from the aorta was carried out and, after exsanguination of the animals had been carried out, organ removal. The determinations of glutamate oxalacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), gamma-glutamyl transferase (yGT), alkaline phosphatase, bilirubin, urea and creatinine were carried out using routine methods. For the immunohistochemical workup of the livers fixed in liquid nitrogen, these were cut into 5 ~m thin preparations using a freezing microtome and two preparations in each case were mounted on Superfrost plus slides. Seven slides from each animal were prepared for staining and a further seven slides as a negative or isotype control.
Dilution stages:
HGF-alpha: 1:200; HGF-beta: 1:100; c-met: 1:200.
The starting concentration in each case was 200 ~g/ml. The evaluation of immunohistochemical stains was carried out without knowledge of the group association in a semiquantitative manner using five graduations.
Results:
Table 1 (data as mean values ~ 1 SD) *p<0.005 GOT GPT yGT AP Bilirubin Control 406 199 30.9 23742 0.70.1 Occlusion 35 17 5 3 0.9 335 149 0.4 0.1 Table 2 (data as mean values ~ 1 SD) *p<0.05 c-met HGF-alpha HGF-beta Control 3.33 0.62 2.67 1.18 0.33 0.47 Occlusion 3.73 0.44 3.73 0.44* 2.27 1.06*
These experiments show that the hepatobiliary fibrin adhesive occlusion increases the expression of HGF in the thioacetamide-damaged liver.
Application possibilities of the fibrin adhesive for the regeneration of liver tissue result from this.
References:
1. Lake J. and Sussman N. (1995) Editorial: Determining Prognosis in Patients with Fulminant Hepatic Failure: When you Absolutely, Positively Have to Know the Answer; Hepatology 21, 879-881 2. Polimeno L., Azzarone A., Zeng Q.H., Panella C., Subbotin V., Carr B., Bouzahzah B., Francavilla A., Starzl T.E. (1995), Cell Proliferation and Oncogene Expression after Bile Duct Ligation in the Rat: Evidence of a Specific Growth Effect on Bile Duct Cells; Hepatology 21, 1070-1078 3. Zimmermann Ch., Ferenci P., Pifl Ch., Yurdaydin C., Ebner J., Lassmann H., Roth E., Hortnagl H. (1989), Hepatic Encephalopathy in Thioacetamide-Induced Acute Liver Failure in Rats: Characterization of an Improved Model and Study of Amino Acidergic Neurotransmission;
Hepatology 9, 594-601
received thioacetamide in doses of 500 mg/kg, 500 mg/kg and 250 mg/kg intraperitoneally at the same time of day. After laparotomy under pentobarbital anesthesia, a slowly hardening fibrin adhesive (Beriplast~) was injected into the hepatobiliary system of animals of group B 24 hours before the start of thioacetamide administration.
The following results were observed: the histological findings on the hepatocytes of the rats of group A showed a swelling of the nucleus with highly prominent nucleoli, and an extensive loss of parenchyma from the center of the lobe with more or less compact round-celled infiltration. In group B, the portal areas showed a slight edema and discrete round-cell infiltration, while the hepatocytes were distinguished by a noticeable lightening with isolated centrilobular individual cell necrosis.
The mortality of group A was 100% after five days, while all animals of group B survived. The conclusion is to be drawn from this that a hepatobiliary fibrin adhesive occlusion can prophylactically prevent the lethal thioacetamide-induced liver failure in the rat.
2nd experiment 40 SD rats each day received an injection of 100 mglkg of thioacetamide intraperitoneally. On the seventh day, 20 animals were laparotomized under ether anesthesia, the bile duct was microsurgically dissected, canulated and 0.2 ml of Beriplast~ fibrin adhesive was subsequently injected. 20 animals were only laparotomized (control group). The continuation of the thioacetamide treatment was then carried out up to the 14th day. On the 14th day, laparotomy with removal of blood from the aorta was carried out and, after exsanguination of the animals had been carried out, organ removal. The determinations of glutamate oxalacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), gamma-glutamyl transferase (yGT), alkaline phosphatase, bilirubin, urea and creatinine were carried out using routine methods. For the immunohistochemical workup of the livers fixed in liquid nitrogen, these were cut into 5 ~m thin preparations using a freezing microtome and two preparations in each case were mounted on Superfrost plus slides. Seven slides from each animal were prepared for staining and a further seven slides as a negative or isotype control.
Dilution stages:
HGF-alpha: 1:200; HGF-beta: 1:100; c-met: 1:200.
The starting concentration in each case was 200 ~g/ml. The evaluation of immunohistochemical stains was carried out without knowledge of the group association in a semiquantitative manner using five graduations.
Results:
Table 1 (data as mean values ~ 1 SD) *p<0.005 GOT GPT yGT AP Bilirubin Control 406 199 30.9 23742 0.70.1 Occlusion 35 17 5 3 0.9 335 149 0.4 0.1 Table 2 (data as mean values ~ 1 SD) *p<0.05 c-met HGF-alpha HGF-beta Control 3.33 0.62 2.67 1.18 0.33 0.47 Occlusion 3.73 0.44 3.73 0.44* 2.27 1.06*
These experiments show that the hepatobiliary fibrin adhesive occlusion increases the expression of HGF in the thioacetamide-damaged liver.
Application possibilities of the fibrin adhesive for the regeneration of liver tissue result from this.
References:
1. Lake J. and Sussman N. (1995) Editorial: Determining Prognosis in Patients with Fulminant Hepatic Failure: When you Absolutely, Positively Have to Know the Answer; Hepatology 21, 879-881 2. Polimeno L., Azzarone A., Zeng Q.H., Panella C., Subbotin V., Carr B., Bouzahzah B., Francavilla A., Starzl T.E. (1995), Cell Proliferation and Oncogene Expression after Bile Duct Ligation in the Rat: Evidence of a Specific Growth Effect on Bile Duct Cells; Hepatology 21, 1070-1078 3. Zimmermann Ch., Ferenci P., Pifl Ch., Yurdaydin C., Ebner J., Lassmann H., Roth E., Hortnagl H. (1989), Hepatic Encephalopathy in Thioacetamide-Induced Acute Liver Failure in Rats: Characterization of an Improved Model and Study of Amino Acidergic Neurotransmission;
Hepatology 9, 594-601
Claims (9)
1. The use of a fibrin adhesive for the regeneration of tissue.
2. The use as claimed in claim 1, wherein the fibrin adhesive causes activation of insulin-producing cells as a result of injection into the pancreas.
3. The use as claimed in claim 1, wherein the fibrin adhesive improves the oxygenation of the body as a result of injection into the intrabronchial tissue.
4. The use as claimed in claim 1, wherein the regeneration ability of the skin is improved by subcutaneous injection of the fibrin adhesive.
5. The use of a fibrin adhesive for the regeneration of the liver tissue.
6. The use as claimed in claim 5, wherein a fibrin adhesive occlusion is formed by injection of a fibrin adhesive into the hepatobiliary system.
7. The use as claimed in claims 5 and 6, wherein the expression of the hepatocyte growth factor (HGF) and of its receptor c-met is increased by the formation of a fibrin adhesive occlusion in the hepatobiliary system.
8. The use as claimed in claims 5 to 7, wherein additive factors are additionally mixed with the fibrin adhesive and thus, as va result of a heptobiliary occlusion, can be effective locally in the liver in a high dose.
9. The use as claimed in claims 1 to 4, wherein additive factors mixed with the fibrin adhesive can be locally active in a high dose in the skin or in the lung.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19858463.6 | 1998-12-18 | ||
| DE19858463A DE19858463A1 (en) | 1998-12-18 | 1998-12-18 | Use of a fibrin glue to regenerate the liver tissue |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2292481A1 true CA2292481A1 (en) | 2000-06-18 |
Family
ID=7891554
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002292481A Abandoned CA2292481A1 (en) | 1998-12-18 | 1999-12-16 | Use of fibrin adhesive for tissue regeneration |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1016415A3 (en) |
| JP (1) | JP2000178201A (en) |
| KR (1) | KR20000057069A (en) |
| AU (1) | AU6528899A (en) |
| CA (1) | CA2292481A1 (en) |
| DE (1) | DE19858463A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7745106B2 (en) | 1997-06-24 | 2010-06-29 | Cascade Medical Enterprises, Llc | Methods and devices for separating liquid components |
| US6979307B2 (en) | 1997-06-24 | 2005-12-27 | Cascade Medical Enterprises Llc | Systems and methods for preparing autologous fibrin glue |
| EP1959634A1 (en) * | 1999-09-28 | 2008-08-20 | AT&T Corp. | H.323 user, service and service provider mobility framework for the multimedia intelligent networking |
| WO2004050102A2 (en) * | 2002-06-27 | 2004-06-17 | Roberto Beretta | Methods for preparing a solid-fibrin web |
| EP3645491B1 (en) | 2017-10-19 | 2021-09-15 | Dow Silicones Corporation | Polyorganosiloxane compositions containing a 2-substituted-1-alkynyl-1-cyclohexanol useful as a hydrosilylation reaction inhibitor |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6013619A (en) * | 1988-01-06 | 2000-01-11 | The Scripps Research Institute | Pulmonary surfactants and therapeutic uses, including pulmonary lavage |
| CN1091315A (en) * | 1992-10-08 | 1994-08-31 | E·R·斯奎布父子公司 | Fibrin sealant compositions and using method thereof |
| US5817303A (en) * | 1995-05-05 | 1998-10-06 | Protein Polymer Technologies, Inc. | Bonding together tissue with adhesive containing polyfunctional crosslinking agent and protein polymer |
-
1998
- 1998-12-18 DE DE19858463A patent/DE19858463A1/en not_active Withdrawn
-
1999
- 1999-12-11 EP EP99124688A patent/EP1016415A3/en not_active Withdrawn
- 1999-12-16 CA CA002292481A patent/CA2292481A1/en not_active Abandoned
- 1999-12-17 KR KR1019990058617A patent/KR20000057069A/en not_active Application Discontinuation
- 1999-12-17 AU AU65288/99A patent/AU6528899A/en not_active Abandoned
- 1999-12-17 JP JP11358587A patent/JP2000178201A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000178201A (en) | 2000-06-27 |
| DE19858463A1 (en) | 2000-06-21 |
| AU6528899A (en) | 2000-06-22 |
| KR20000057069A (en) | 2000-09-15 |
| EP1016415A3 (en) | 2001-02-21 |
| EP1016415A2 (en) | 2000-07-05 |
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| EEER | Examination request | ||
| FZDE | Dead |