AU595382B2 - Use of polysulfated low molecular weight dextran sulfates - Google Patents
Use of polysulfated low molecular weight dextran sulfates Download PDFInfo
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- AU595382B2 AU595382B2 AU79456/87A AU7945687A AU595382B2 AU 595382 B2 AU595382 B2 AU 595382B2 AU 79456/87 A AU79456/87 A AU 79456/87A AU 7945687 A AU7945687 A AU 7945687A AU 595382 B2 AU595382 B2 AU 595382B2
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- dextran
- molecular weight
- low molecular
- weight
- sulfur content
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- 229920002307 Dextran Polymers 0.000 title description 37
- -1 dextran sulfates Chemical class 0.000 title description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 230000033115 angiogenesis Effects 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 4
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 4
- 229960000633 dextran sulfate Drugs 0.000 claims description 4
- 230000001939 inductive effect Effects 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 235000009917 Crataegus X brevipes Nutrition 0.000 claims 1
- 235000013204 Crataegus X haemacarpa Nutrition 0.000 claims 1
- 235000009685 Crataegus X maligna Nutrition 0.000 claims 1
- 235000009444 Crataegus X rubrocarnea Nutrition 0.000 claims 1
- 235000009486 Crataegus bullatus Nutrition 0.000 claims 1
- 235000017181 Crataegus chrysocarpa Nutrition 0.000 claims 1
- 235000009682 Crataegus limnophila Nutrition 0.000 claims 1
- 235000004423 Crataegus monogyna Nutrition 0.000 claims 1
- 240000000171 Crataegus monogyna Species 0.000 claims 1
- 235000002313 Crataegus paludosa Nutrition 0.000 claims 1
- 235000009840 Crataegus x incaedua Nutrition 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229960002086 dextran Drugs 0.000 description 33
- 239000000126 substance Substances 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000005012 migration Effects 0.000 description 9
- 238000013508 migration Methods 0.000 description 9
- 230000035755 proliferation Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 229960002897 heparin Drugs 0.000 description 7
- 229920000669 heparin Polymers 0.000 description 7
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 210000003038 endothelium Anatomy 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000000489 anti-atherogenic effect Effects 0.000 description 3
- 230000002429 anti-coagulating effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940041984 dextran 1 Drugs 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000002262 Thromboplastin Human genes 0.000 description 2
- 108010000499 Thromboplastin Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000001858 anti-Xa Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000014508 negative regulation of coagulation Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000036523 atherogenesis Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Vascular Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Description
1 i i C- L' Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE
SPECIFICATION
(ORIGINAL)
Class Application Number: Lodged: Int. Class Complete Specification Lodged: Accepted: Published: "Priority 4 595382 -iendments qa ,op 1 icrA e*"C 4 Related Art: t Name of Applicant: It Address of Applicant: 'Actual Inventor: Address for Service KNOLL AG D-6700 Ludwigshafen, Federal Republic of Germany DIETER HERR, CLAUS D. MUELLER,EBERHARD BETZ and HUGO
HAEMMERLE
EDWD. WATERS SONS, QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
Complete Specification for the invention entitled: USE OF POLYSULFATED LOW MOLECULAR WEIGHT DEXTRAN SULFATES The following statement is a full description of this invention, including the best method of performing it known to 1 O.Z. 0480/01027 Use of polysulfated low molecular weight dextran sulfates The present invention relates to a novel use of low molecular weight dextran sulfates.
Low molecular weight dextran sulfates and their use as anticoagulants are disclosed in U.S. Patent 2,715,091.
The present invention relates to the use of low molecular weight dextran sulfate and its salts with physiologically tolerated bases in the treatment of arteriosclerosis and/or for inducing angiogenesis and for the preparation of drugs for the treatment of arteriosclerosis and/or for inducing angiogenesis.
The dextran sulfates to be used according to the invention have a molecular weight of about 1,500-20,000, preferably 2,000-9,000, dalton and a sulfur content of from 0.5 to 20, preferably from 7 to 17, in particular from 7 to 8, by weight. They are prepared by sulfatr ing the corresponding dextrans (cf. U.S. Patent 2,715,091).
r* Physiologically tolerated bases, such as alkali metal and alkaline earth metal hydroxides, in particular sodium hydroxide and calcium hydroxide, are suitable for salt formation.
Using the novel compounds, the formation of •t atheromas in the vessel wall and the progression of existing arteriosclerotic changes can be inhibited or their regression promoted. Moreover, by promoting the proliferat.4 tion of endothelium cells, angiogenesis can be stimulated and the vascularization of organs whose circulation is reduced, for example by arteriosclerotic processes, can be improved. The novel compounds also promote endothelialization after surgical replacement of vessels.
To demonstrate these effects, cultures of smooth arterial muscle cells (SMC) and of arterial endothelium cells (EC) were incubated with the substances in a concentration of 5 x 10 M. The increase in the number of cells within 7 days from administration of the substance was determined. The relative change in comparison with untreated control cultures served as a measure of 2 O.Z. 0480/01027 the effect or the test substances on proliferation (inhibition, stimulation).
The effect of the compounds on the migration behavior of SMC and EC was also determined. To do this, the cells were grown in culture dishes until a multilayer (SMC) or monolayer (EC) had formed. Thereafter, the cultures were incubated for 48 hours with the substances to be investigated. The cell sheet was then cut with a razor blade to give a sharp edge and a free surface into which the cells were able to migrate. The cells which had migrated were counted after a further 72 hours. The relative change in the number of migrated cells in comparison with the untreated control cultures served as a measure of the effect of the test substances on migration.
SThe anticoagulant activity of the novel compounds was determined via the activated partial thromboplastin time (APTT) (Kleiner Gerinnungsstatus, Behringwerke Marburg) and via the inhibition of the coagulation factor Xa (Throm.
Res. 10 (1977), 399) in human plasma. The comparative substance used was heparin Na.
An important factor in the pathogenesis of arteriosclerotic vascular changes is the migration and proliferation of smooth muscle cells (SMC). Apart from the known anticoagulant property, natural heparins are also capable of inhibiting the proliferation and migration of vascular SMC and thus counteracting atherogenesis Clowes and M.J. Karnovsky, Nature, 265 (1977), 625).
SIn the case of the novel substances, this inhibition of proliferation and of migration is the principal aspect of the action (Table The anticoagulant action, which is undesirable in connection with the antiatherogenic action, is substantially weaker. The compounds therefore have a selective antiatherogenic action. On the basis of the action of the heparin used for comparison, the anticoagulant action is 12-24 times (APTT) or 530-1,550 times (anti-Xa activity) weaker than that of the comparison 2 r< i ii 7 3 O.Z. 0480/01027 substance, the antiproliferative activity in SMC being greater (substances 11 and 12) or about tfe ame (substances 16 and 17 .aS U(ka.e- c Like heparin Na, the novel substances have no effect on the proliferation of arterial endotheLium cells, or possess a proliferation-stimulating component and are therefore superior to heparin Na (substances 16 and 17).
The migration of EC is inhibited to a lesser extent by the novel compounds than by heparin Na. An exception is substance 16, which increases not only the proliferation (see above) but also the migration of the
EC.
Substances 16 and 17 increase proliferation and migration and therefore promote the formation of new vessels and the repair of endothelium damage or endothelialization after surgical replacement of vessels.
TABLE I Substance Antiatherogenic action Inhibition of coagulation O 00 00 0 pOl 0 *0 0C 0*1 1 S tOO 0 0 1 0 i Change in Change in APTT 3 Anti-Xa proliferation migration activity I IU/mg IU/mg
SMC
1
EC
2 SMC EC Substance 11 40 0 40 10 10 0.11 Substance 12 40 0 40 13 14 0.30 Substance 16 30 20 30 25 8.6 0.16 Substance 17 30 40 30 40 6.6 0.16 Natural heparin 28 0 40 45 160 160 e rirctr r c r rt ;r c r I:1 1) SMC smooth muscle cell 2EC endothelium cell 3APTT activated partial thromboplastin time The dextran sulfates are preferably administered parenterally, usually in amounts of from about 3 to 30 mg per patient per day.
io i 4 O.Z. 0480/01027 Preparation of polysulfated dextrans To pre-pare the Low moLecuLar weight polysuLfated dextrans, dextran 1 (moLecuLar weight 1,000 daLton), dextran 2 (moLecuLar weight 2,000 dalton), dextran 4 (moLecular weight 4,000 dalton), dextran 8 (molecular weight 6,000-8,000 daLton) and dextran 15 (molecular weight 12,000-15,000 daLton) were used as starting substances.
EXAMPLE 1 PolysuLfation of dextran 1 20 g of dextran 1 were suspended in 500 mL of 1:1 pyridine/dimethylformamide at 55 0 C while nitrogen was passed in. Different amounts (from 5 to 60 ml) of chLorosulfonic acid were added dropwise to 300 mL of pyridine at 85 0 C while stirring. After stirring had been carried out for a short time, the pyridine/chlorosulfonic acid mixture was introduced into the initially taken dextran suspension, and stirring was continued for 30 minutes at t ,t 75 0 C. The mixture was then cooled to 25 0 C in an ice bath.
#Ito The resulting oily precipitate was washed several times with pyridine/dimethylformamide. This precipitate was dissolved in 100.0 mL of 0.5% strength sodium chloride solution and precipitated with 6 times its volume of ethanol. The sediment was dissolved in distilled water and freed from adhering traces of pyridine by passing the solution over a cation exchanger (type DOWEX® MSC-1).
The cation-free dextran sulfate solution was then brought to pH 7 with 10 N NaOH and again precipitated with 6 times its volume of methanoL. The sediment was taken up in distilled water, the solution was filtered and the product was freeze-dried.
The degree of sulfation of the resulting products varies greatly as a function of the amount of chLorosuLfonic acid used. The Table below gives an overview of the products obtained.
ii-i Substance no.
Dextran used 5 Amount of chlorosuLfonic acid used (ml) per 20 g of dextran O.Z. 0480/01027 SuLfur content M of the product (daLton) 1 2 3 4 6 7 8
)O
tpr Dextran Dextran Dextran Dextran Dextran Dextran Dextran Dextran Dextran Dextran Dextran Dextran Dextran Dextran Dextran Dextran Dextran Dextran Dextran 4.5 7.8 13.1 16.8 19.7 7.2 14.1 18.1 5.2 9.8 14.1 16.5 7.8 14.8 17.4 7.6 9.4 15.2 18.4 2,400 2,800 3,600 4,200 4,400 4,800 5,100 7,700 8,500 9,400 15,800 9,000 16,200 19,100 1,400 1,800 2,400 2,600 3,100 16 17 18 19 PHARMACEUTICAL EXAMPLE g of dextran 2 (suLfur content were dissolved in 5,000 ml of water with the addition of NaCL, and the solution was brought to pH 6.0 with 0.1 N NaOH so that a blood-isotonic solution was formed. 5 mL portions of this solution were introduced into ampoules and sterilized.
Claims (4)
1. A method of treatment of arteriosclerosis and/or for inducing angiogenesis comprising administering to a patient suffering therefrom or requiring such treatment a pharmaceutically effective quantity of a dextran sulfate having a molecular weight of 1,500 20,000 and a sulfur content of 0.5 to 20% by weight or its salt in adjunct with physiologically tolerable bases.
2. A method of preparation of drugs for treating arteriosclerosis and/or for inducing angiogenesis comprising combining in appropriate quantities so as to render the end product pharmaceutically effective, a dextran sulfate having a molecular weight of 1,500 20,000 and a sulfur content of to 20% by weight or its salts with physiologically tolerated basis and pharmaceutically acceptable carriers or excipients.
DATED this 16th day of January, 1990. KNOLL AG a i 4414 44 4r) 444 4 4CF
4- 5 1@ 4 4' 44: 4 4 4 4.45 444 *4 aI 4 a 4 4 WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD, HAWTHORN, VICTORIA, AUSTRALIA LCG:KS:BB(7.21)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863634392 DE3634392A1 (en) | 1986-10-09 | 1986-10-09 | USE OF POLYSULFATED LOW MOLECULAR DEXTRANSULFATES |
| DE3634392 | 1986-10-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU7945687A AU7945687A (en) | 1988-04-14 |
| AU595382B2 true AU595382B2 (en) | 1990-03-29 |
Family
ID=6311374
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU79456/87A Ceased AU595382B2 (en) | 1986-10-09 | 1987-10-08 | Use of polysulfated low molecular weight dextran sulfates |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0276370A3 (en) |
| JP (1) | JPS6396128A (en) |
| AU (1) | AU595382B2 (en) |
| DE (1) | DE3634392A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10485817B2 (en) | 2014-06-12 | 2019-11-26 | Tx Medic Ab | Use of dextran sulfate having an average molecular weight below 10000 DA for inducing angiogenesis in a subject |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5017565A (en) * | 1989-04-20 | 1991-05-21 | Lange Iii Louis G | Use of sulfated polysaccharides to inhibit pancreatic cholesterol esterase |
| US5063210A (en) * | 1989-04-20 | 1991-11-05 | Lange Iii Louis G | Use of sulfated polysaccharides to decrease cholesterol and fatty acid absorption |
| FR2651436B1 (en) * | 1989-09-05 | 1994-09-09 | Sanofi Sa | PHARMACEUTICAL COMPOSITIONS CONTAINING A SOLUBLE DEXTRAN SUBSTITUTED DERIVATIVE. |
| US5705178A (en) * | 1991-05-31 | 1998-01-06 | Gliatech, Inc. | Methods and compositions based on inhibition of cell invasion and fibrosis by anionic polymers |
| US5605938A (en) * | 1991-05-31 | 1997-02-25 | Gliatech, Inc. | Methods and compositions for inhibition of cell invasion and fibrosis using dextran sulfate |
| WO1997022347A1 (en) * | 1995-12-18 | 1997-06-26 | Stichting Sanquin Bloedvoorziening | Potentiation of complement and coagulation inhibitory properties of c1-inhibitor. |
| AU4938397A (en) * | 1996-12-24 | 1998-07-17 | Hyal Pharmaceutical Corporation | Methods of elevating amounts of hyaluronan in the human body |
| AU2002326069A1 (en) * | 2001-07-20 | 2003-02-17 | Genset S.A. | Inhibitors of plasminogen activator inhibitor for decreasing body mass |
| KR101376895B1 (en) | 2004-05-03 | 2014-03-25 | 헤르메스 바이오사이언스, 인코포레이티드 | Liposomes useful for drug delivery |
| CA3001467A1 (en) | 2015-10-16 | 2017-04-20 | Ipsen Biopharm Ltd. | Stabilizing camptothecin pharmaceutical compositions |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES343957A1 (en) * | 1967-08-09 | 1968-10-01 | Rocador Sa | Antilipaemic sulphated polysaccharide |
-
1986
- 1986-10-09 DE DE19863634392 patent/DE3634392A1/en not_active Withdrawn
-
1987
- 1987-10-02 JP JP62248189A patent/JPS6396128A/en active Pending
- 1987-10-05 EP EP87114497A patent/EP0276370A3/en not_active Withdrawn
- 1987-10-08 AU AU79456/87A patent/AU595382B2/en not_active Ceased
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10485817B2 (en) | 2014-06-12 | 2019-11-26 | Tx Medic Ab | Use of dextran sulfate having an average molecular weight below 10000 DA for inducing angiogenesis in a subject |
| US10925890B2 (en) | 2014-06-12 | 2021-02-23 | Tx Medic Ab | Use of dextran sulfate |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0276370A3 (en) | 1989-07-12 |
| EP0276370A2 (en) | 1988-08-03 |
| AU7945687A (en) | 1988-04-14 |
| JPS6396128A (en) | 1988-04-27 |
| DE3634392A1 (en) | 1988-04-14 |
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