EP1143793A1 - Solutions organo-protectrices - Google Patents

Solutions organo-protectrices

Info

Publication number
EP1143793A1
EP1143793A1 EP00906200A EP00906200A EP1143793A1 EP 1143793 A1 EP1143793 A1 EP 1143793A1 EP 00906200 A EP00906200 A EP 00906200A EP 00906200 A EP00906200 A EP 00906200A EP 1143793 A1 EP1143793 A1 EP 1143793A1
Authority
EP
European Patent Office
Prior art keywords
mhc class
ifn
icam
glycosaminoglycans
heparin
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.)
Ceased
Application number
EP00906200A
Other languages
German (de)
English (en)
Inventor
Fokko J. Van Der Woude
Benito Yard
Dieter Herr
Volker Laux
Christian Peter Lorentz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Knoll GmbH filed Critical Knoll GmbH
Publication of EP1143793A1 publication Critical patent/EP1143793A1/fr
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
    • A01N1/0226—Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients

Definitions

  • the invention relates to the use of polysulfated glycosaminoglycans with a sulfur content of at least 12.5% for the production of pharmaceutical preparations for inhibiting the interferon- ⁇ -induced upregulation of the MHC class I, MHC class II proteins and ICAM-1.
  • the invention further relates to organ-protective solutions containing polysulfated glycosaminoglycans and a method for the ex-vivo protection of transplant organs.
  • glycosaminoglycans and especially of
  • Heparins and heparinoids for the manufacture of pharmaceutical preparations for the treatment of circulatory disorders are well known.
  • glycosaminoglycans in a number of other diseases has recently been described.
  • No. 5,236,910 claims the use of glycosaminoglycans in the treatment of diabetic nephropathy and neuropathy.
  • the use of low molecular weight heparins for the same indication is described by van der Pijl et al. (J. Americ. Soc. Nephrol. 1997, 8: 456-462).
  • tubular cells leads. Furthermore, the so-called "graft versus host reaction” results in a strong reaction of the donor's immune cells transmitted with the organ against the recipient. Cytotoxic T cells and antibodies against the host organism are formed.
  • the organs are cooled immediately after removal and stored under an organ protection solution.
  • the recipient is given medication to protect the immune system
  • This object was achieved by using polysulfated glycosaminoglycans with a sulfur content of at least 12.5% by weight for the production of pharmaceutical preparations for inhibiting the interferon- ⁇ -induced upregulation of the MHC class I, MHC class II proteins and ICAM-1 solved.
  • the invention also relates to organ-protective solutions containing a quantity of a suitable pharmaceutical preparation with a sulfur content of at least 12.5% by weight of a polysulfated glycosaminoglycan which is effective for maintaining cell integrity and vitality.
  • the pharmaceutical preparations prepared for the use according to the invention can contain the abovementioned compounds as free compounds, in the form of their physiologically active salts or esters, their tautomeric and / or isomeric forms or in the form of the Combination of the free compounds and the various salts included.
  • the Na, Ca or Mg salts may be mentioned by way of example as advantageous physiologically active salts. Salts with organic bases such as diethylamine, triethylamine or triethanolamine are also suitable.
  • the pharmaceutical preparations can advantageously contain at least one free substance or at least one compound in the form of their salt or mixtures thereof.
  • heparan sulfate corresponds to that of heparin, but it has fewer N- and O-sulfate groups and more N-acetyl groups.
  • Glycosaminoglycans can advantageously be isolated from tissues of animals 20 such as the intestinal mucosa or from ears of pigs or cattle.
  • the tissues used are, for example, autolyzed to isolate the glycosaminoglycans and extracted with alkali.
  • the protein is then allowed to coagulate and is precipitated, for example, by acidification. After the precipitate has been taken up in a polar, non-aqueous solvent, such as ethanol or acetone, the fats are removed by extraction with an organic solvent.
  • the proteins are finally removed by proteolytic digestion and the glycosaminoglycans are thus obtained. Charles et al. (Biochem. J., Vol.
  • glycosaminoglycans isolated from natural sources advantageously also receive a derivatization by polysulfation, as is described, for example, in US Pat. No. 5,013,724 or as described above.
  • the glycosaminoglycans have a sulfur content
  • Polysulfated glycosaminoglycans which have a sulfur content of at least 12.5% by weight are selected for the use according to the invention or for the pharmaceutical preparations. These polysulfated glycosaminoglycans advantageously have a sulfur content of 13 to
  • Low molecular weight polysulfated heparins and / or dermatan sulfates in the form of the free acid or in the form of a salt with physiologically compatible bases or mixtures of these compounds are particularly advantageous. These substances have a low anti-coagulant effect and are therefore particularly suitable for the treatment and prevention in the use according to the invention.
  • Preferred salts of the polysulfated glycosaminoglycans are, for example, the sodium, calcium and magnesium salts.
  • Low molecular weight glycosaminoglycans for example low molecular weight heparins and / or dermatan sulfates, can be produced by a number of methods. The production of low molecular weight heparins via depolymerization using nitrous acid is described, for example, in EP-B-0 037 319 or in Biochemistry Vol. 15, 1976: 3932. Low molecular weight heparin or low molecular weight glycosaminoglycans can also be produced with enzymes (Biochem. J. Vol. 108, 1968: 647), with sulfuric acid and chlorosulfonic acid (FRNo.
  • organ-protective solutions Another object of the invention is organ-protective solutions.
  • the advantageous addition of the polysulfated glycosaminoglycans to organ-protective solutions allows the organs to be stored after removal from the donor organism, that is to say ex vivo, by inhibiting the interferon- ⁇ -induced upregulation of the MHC class I, MHC class II proteins and Further improve ICAM-1.
  • the organs should advantageously be cooled, as is known to the person skilled in the art. A number of such solutions as described above are known from the literature.
  • the solutions generally contain salts, buffers, substances which are intended to stabilize the organs osmotically or which are intended to prevent oxidation, such as sugar or 5 sugar alcohols, proteins, amino acids, lower carboxylic acids, purines, pyrimidines or pharmaceutical active ingredients.
  • substances which are intended to stabilize the organs osmotically or which are intended to prevent oxidation, such as sugar or 5 sugar alcohols, proteins, amino acids, lower carboxylic acids, purines, pyrimidines or pharmaceutical active ingredients.
  • the following may be mentioned as examples of such substances: raffinose, glucose, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium chloride, potassium hydrogen carbonate, sodium hydrogen carbonate, magnesium sulfate, magnesium chloride, adenosine, albumin, mannitol, citrate, verapamil, allopurinol, insulin, dexethyl methasone, hydroxyl starch, hydroxyl Glucuronic acid.
  • organ-protective solutions 15 means that the organs can be transplanted in a better state or can be stored longer than previously, so that rejection reactions can be reduced.
  • the polysulfated glycosaminoglycans can, as far as possible, be administered orally or parenterally to transplant patients or transplant donors before the transplant. Post-treatment of the patients with the substances is also conceivable.
  • polysulfated glycosaminoglycans are in the organ-protective solutions or in the other pharmaceutical preparations in amounts of 10 mg / 1 to 10,000 mg / 1, advantageously in amounts of 10 mg / 1 to 5,000 mg / 1, preferably in amounts of
  • an osmotically stabilizing substance advantageously contain hydroxyethyl starch.
  • compositions have the following composition: a) 10 mg / 1 to 10,000 mg / 1 polysulfated glycosaminoglycans with a sulfur content of at least 12.5% by weight, 5 to 100 g / 1 hydroxyethyl starch and 5 to 100 mmol raffinose or b) 10 mg / 1 to 10,000 mg / 1 polysulfated
  • glycosaminoglycans with a sulfur content of at least 12.5% by weight 5 to 100 g / 1 hydroxyethyl starch, 5 to 100 mmol raffinose, 5 to 40 mmol KH 2 P0 4 , 1 to 50 mmol MgSOa, 1 to 50 mmol adenosine, 0.5 to 5 mmol allopurinol or 1 to 10 mmol glutathione.
  • polysulfated glycosaminoglycans can be used together with conventional formulation aids for the treatment of patients.
  • compositions used according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a customary manner; oral or intravenous applications are preferred.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the glycosaminoglycans are advantageously applied in a dose of 0.1 to 500 mg / kg body weight / day.
  • the glycosaminoglycans are advantageously administered in a dose of 0.1 to 30 mg / kg of body weight / day, in the case of oral use in a dose of 0.2 to 500 mg / kg of body weight / day, the administered Dose can be administered in a single dose or in multiple doses.
  • Mixtures of, for example, at least one low molecular weight heparin and / or its polysulfated derivative and / or at least one low molecular weight dermatan sulfate and / or its polysulfated derivative are also used in a dose of 0.1 to 30 mg / kg body weight / day with parenteral administration or in one Dose of 0.2 to 500 mg / kg / day administered orally.
  • pharmaceutical preparations containing the polysulfated glycosaminoglycans for the treatment and prevention of diseases in connection with organ transplants are to be understood as all galenical forms of application customary for oral or parenteral use, whether solid or liquid, such as tablets, film-coated tablets, capsules, powders, granules, dragees , Suppositories, solutions or suspensions. These are manufactured in the usual way.
  • the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (cf. H.
  • the polysulfated glycosaminoglycans can also be processed with pharmaceutically inert, inorganic or organic excipients. Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof can be used as such excipients for tablets, dragees and hard gelatin capsules. Vegetable oils, waxes, fats, semi-solid and liquid polyols are suitable excipients for soft gelatin capsules.
  • Suitable excipients for the production of solutions and syrups are e.g. Water, polyols, sucrose, invert sugar, glucose and the like.
  • Suitable excipients for injection solutions are water, alcohols, polyols, glycerin, vegetable oils. Natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like are suitable as excipients for suppositories.
  • the pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers. Wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents. Contain salts for changing the osmotic pressure, buffers, coating agents and / or antioxidants.
  • PTEC poximal tubular epithelial cells
  • HUVEC human umbilical vein endothelial cells
  • the culture medium consisted of the Dulbecco modified "Eagle's Medium” and Ham's F12 medium (both from Gibco BRL) in a 1: 1 ratio, supplemented with insulin (5 ⁇ g / ml), transferrin (5 ⁇ g / ml), selenium (5 ng / ml), hydrocortisone (36 ng / ml), triidothyronine (4 pg / ml), epidermal growth factor (10 ng / ml) and penicillin / streptomycin [(5IE / ml, 5 ⁇ g / ml), all of Sigma].
  • the endothelial cells were isolated from umbilical cord veins by digestion with Collagenase V (Sigma, St. Louis MO, 20 minutes at 37 ° C). The veins were then rinsed with sterile culture medium and the endothelial cells were collected.
  • FCS fetal calf serum
  • the cells were cultured in 25 cm 2 bottles coated with 1% gelatin (Sigma, St. Louis Mo).
  • HUVEC cells were characterized by their positive staining using the factor VIII-related antigen (Dako, High Wycombe, UK) and the endothelial marker EN4 (CD31).
  • Confluent monolayers from PTEC or HUVEC cells were treated with trypsin and seeded in 24-well plates. When confluence was reached, the cells were stimulated with IFN- ⁇ (Sigma, St. Louis MO) for 72 h in the presence or absence of various concentrations of different heparinoids, which were found in various heparins such as Heparin-Braun ® from Braun-Melsungen, Melsungen, Germany, low molecular weight heparin Fragmin ® P from Pfrimmer Kabi, Er Weg, Germany and modified low molecular weight heparin from Knoll AG, Ludwigshafen, Germany.
  • IFN- ⁇ Sigma, St. Louis MO
  • the chlorate was used in concentrations of 50 to 150 mM. It was added to the medium 24 hours before the addition of IFN- ⁇ . The stimulation with IFN- ⁇ was carried out in the presence of chlorate.
  • Sodium chloride was used as an osmolar control.
  • the cultivated cells were obtained after cultivation with a trypsin EDTA treatment for flow cytometry.
  • the cells of the individual batches were brought together and then divided into two test tubes and washed. Antibodies that do not bind to cell isotypes and that are coupled to RPE and FITC (from Dako, Glostrup, Denmark) and Cy-5 (from Dianowa, Hamburg, Germany) were added to the first test tube. This approach was taken as a negative control for the FACS background.
  • the cells in the second batch were antibodies against MHC class I (RPE-conjugated, W6 / 32, Dako), against MHC class II (Cy-5-conjugated, CR3 / 43, Dianova) and against ICAM 1 (FITC-conjugated, Dianova) marked in concentrations according to the manufacturer.
  • MHC class I, class II and ICAM-1 proteins were modulated in PTEC by IFN- ⁇ depending on the dose.
  • the MHC class I and ICAM-1 expression was already regulated by a concentration of 50 ng / ml IFN- ⁇ .
  • the same concentration of IFN- ⁇ the MHC class II expression in PTEC increased (see Figure 1).
  • Corresponding results were obtained with the cultivated HUVEC cells.
  • both HUVEC and PTEC cultures were stimulated with IFN- ⁇ in the presence or absence of heparin.
  • the addition of heparin in concentrations of 0.03 to 3 mg / ml to HUVEC cultures completely prevents the "upregulation" of MHC class I and ICAM-1 proteins caused by 100 ng / ml IFN- ⁇ .
  • the induction of the MHC class II proteins was also suppressed in these cells by the addition of heparin.
  • Heparin itself had no influence on the expression of the three antigens examined (FIG. 2) in the absence of IFN- ⁇ .
  • the heparinoids were all tested at 3 mg / ml for their ability to inhibit MHC class I and ICAM-1 after iFN- ⁇ stimulation.
  • the MHC Class II tests were performed with 10 ng / ml IFN- ⁇ stimulation.
  • the supersulfated GAG (GAG 6-8) were able to inhibit the expression of MHC and ICAM-1 in both HUVEC and PTEC after IFN- ⁇ stimulation.
  • desulfated-N-acetylated GAG GAG 1-5) could not influence the MHC and ICAM-1 expression in these cells after IFN- ⁇ stimulation (FIGS. 4a-c and 5a-c).
  • 125 IFN- ⁇ can bind.
  • Desulfated-N-acetylated GAGs that have very few sulfate groups (GAG 3-5) can no longer do this.
  • Desulfated-N-acetylated GAG with a higher sulfate content (GAG 1 and 2) still bind 125 IFN- ⁇ , but significantly less than heparin or supersulfated GAG.
  • the binding of 125 IFN- ⁇ to heparin or GAG bound to nitrocellulose filters can be blocked by a 3000-fold excess of heparin in the binding solution. Under these conditions, there was no longer any binding to GAG 1 and 2, while the binding to heparin, fragmin and supersulfated GAG was significantly reduced (FIG. 8).
  • Tab. 1 Properties of the various heparins and glycosaminoglycans used in this study *)
  • IFN- ⁇ stimulated HUVEC cells Effect of heparin on MHC and ICAM-1 expression of IFN- ⁇ stimulated HUVEC cells.
  • IFN- ⁇ stimulated (100 ng / ml, for 72 hours, gray bars) or non-stimulated (white bars) HUVEC were incubated with different heparin concentrations during the stimulation.
  • the MHC and ICAM-1 expression was then determined using the FACS. The results are shown in the figure as the average fluorescence intensity of a representative experiment.
  • IFN- ⁇ stimulated PTEC cells Effect of heparin on the MHC and ICAM-1 expression of IFN- ⁇ stimulated PTEC cells.
  • the MHC and ICAM-1 expression of three replicated cultures were then determined using the FACS.
  • 3a shows the MHC class I expression.
  • 3b shows the MHC class II expression.
  • 3c shows the ICAM-1 expression. The results are shown in the figure as an average fluorescence intensity +/- 2 SD.
  • IFN- ⁇ stimulated HUVEC cells Effect of various heparins and glycosaminoglycans on the MHC and ICAM-1 expression of IFN- ⁇ stimulated HUVEC cells.
  • IFN- ⁇ stimulated (10 ng / ml, for 72 hours, filled bars) or non-stimulated (hatched bars) HUVEC cells were incubated with various heparins or glycosaminoglycans in a concentration of 3 mg / ml during the stimulation period.
  • the MHC and ICAM-1 expression was then determined using the FACS.
  • 4a shows the MHC class I expression.
  • 4b shows the MHC class II expression.
  • 4c shows the ICAM-1
  • IFN- ⁇ stimulated PTEC cells Effect of various heparins and glycosaminoglycans on the MHC and ICAM-1 expression of IFN- ⁇ stimulated PTEC cells.
  • IFN- ⁇ stimulated (10 ng / ml, for 72 hours, filled bars) or non-stimulated (hatched bars) PTEC cells were incubated with various heparins or glycosaminoglycans in a concentration of 3 mg / ml during the stimulation period.
  • the MHC and ICAM-1 expression was then with the FACS determined.
  • Fig. 5a shows the MHC class I expression.
  • 5b shows the MHC class II expression.
  • 5c shows the ICAM-1 expression. The results are shown in the figure as the average fluorescence intensity of a representative experiment.
  • GAG 6-8 and heparin in their effect to inhibit the MHC and ICAM-1 expression of IFN- ⁇ (10 ng / ml, for 72 hours) PTEC cells.
  • the PTEC cells were incubated with various concentrations of GAG6 (), GAG7 (), GAG8 () and heparin () during the stimulation period.
  • the MHC and ICAM-1 expression was then determined using the FACS. Expression of these antigens was also determined in the absence of GAG (-GAG) or in the absence of IFN- ⁇ (-IFN).
  • 6a shows the MHC class I expression.
  • 6b shows the MHC class II expression.
  • 6c shows the ICAM-1 expression. The results are shown in the figure as an average fluorescence intensity +/- 2 SD.
  • Heparin Heparin
  • GAG glycosaminoglycan 1 to 8
  • Fragmin Fragmin

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Environmental Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Dentistry (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Biophysics (AREA)
  • Physiology (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des solutions organo-protectrices contenant des glycosaminoglycanes polysulfatés.
EP00906200A 1999-01-20 2000-01-14 Solutions organo-protectrices Ceased EP1143793A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE29900874U DE29900874U1 (de) 1999-01-20 1999-01-20 Organprotektive Lösungen
DE29900874U 1999-01-20
US09/235,235 US6313104B1 (en) 1999-01-20 1999-01-22 Organoprotective solutions
PCT/EP2000/000264 WO2000042842A1 (fr) 1999-01-20 2000-01-14 Solutions organo-protectrices

Publications (1)

Publication Number Publication Date
EP1143793A1 true EP1143793A1 (fr) 2001-10-17

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP00906200A Ceased EP1143793A1 (fr) 1999-01-20 2000-01-14 Solutions organo-protectrices

Country Status (7)

Country Link
US (1) US6313104B1 (fr)
EP (1) EP1143793A1 (fr)
AU (1) AU2796900A (fr)
BR (1) BR0007615A (fr)
DE (1) DE29900874U1 (fr)
NO (1) NO20013530L (fr)
WO (1) WO2000042842A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103478118B (zh) * 2013-10-09 2014-11-26 山东省农业科学院畜牧兽医研究所 一种用于细胞培养的组织块的冷冻保存方法

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2478646A2 (fr) 1980-03-20 1981-09-25 Choay Sa Composition mucopolysaccharidique ayant une activite regulatrice de la coagulation, medicament la contenant et procede pour l'obtenir
US4948881A (en) 1982-12-28 1990-08-14 Sanofi Process for the depolymerization and sulfation of polysaccharides
FR2538404B1 (fr) 1982-12-28 1985-08-23 Anic Spa
FR2584728B1 (fr) * 1985-07-12 1987-11-20 Choay Sa Procede de sulfatation de glycosaminoglycanes et de leurs fragments
US4879283A (en) * 1985-10-03 1989-11-07 Wisconsin Alumni Research Foundation Solution for the preservation of organs
US4798824A (en) 1985-10-03 1989-01-17 Wisconsin Alumni Research Foundation Perfusate for the preservation of organs
IT1213384B (it) 1986-11-24 1989-12-20 Lab Derivati Organici Mediolan Processo per la preparazione controllata di gilcosaminoglicani a basso peso molecolare.
DE3882310T2 (de) 1987-09-18 1994-01-27 Eastman Kodak Co Polymerteilchen, auf die Gelatine aufgepfropft ist.
DE3744119A1 (de) 1987-12-24 1989-07-06 Basf Ag Verwendung von polysulfatierten heparinen
US5032679A (en) 1988-12-15 1991-07-16 Glycomed, Inc. Heparin fragments as inhibitors of smooth muscle cell proliferation
US5104787A (en) * 1990-03-05 1992-04-14 Lindstrom Richard L Method for apparatus for a defined serumfree medical solution useful for corneal preservation
IT1245907B (it) 1991-05-17 1994-10-25 Alfa Wassermann Spa Uso dei glicosaminoglicani nel trattamento della nefropatia diabetica e della neuropatia diabetica.
US5200398A (en) 1991-09-12 1993-04-06 Mount Sinai Hospital Corporation Composition for the preservation of organs comprising glucuronic acid or a physiologically tolerated salt or ester thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CASU ET AL: "Glycosaminoglycans from Pig Duodenum", ARZNEIM.-FORSCH. / DRUG RES., vol. 30 (II), no. 11, 1980, pages 1889 - 1892 *
See also references of WO0042842A1 *

Also Published As

Publication number Publication date
NO20013530D0 (no) 2001-07-17
US6313104B1 (en) 2001-11-06
DE29900874U1 (de) 1999-07-22
AU2796900A (en) 2000-08-07
BR0007615A (pt) 2001-10-30
WO2000042842A1 (fr) 2000-07-27
NO20013530L (no) 2001-09-19

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