AU595382B2 - Use of polysulfated low molecular weight dextran sulfates - Google Patents

Use of polysulfated low molecular weight dextran sulfates Download PDF

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Publication number
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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Australia
Prior art keywords
dextran
molecular weight
low molecular
weight
sulfur content
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Ceased
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AU79456/87A
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AU7945687A (en
Inventor
Eberhard Betz
Hugo Haemmerle
Dieter Herr
Claus D. Mueller
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Abbott GmbH and Co KG
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Knoll GmbH
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/14Vasoprotectives; 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)
AU79456/87A 1986-10-09 1987-10-08 Use of polysulfated low molecular weight dextran sulfates Ceased AU595382B2 (en)

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)

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AU7945687A AU7945687A (en) 1988-04-14
AU595382B2 true AU595382B2 (en) 1990-03-29

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AU79456/87A Ceased AU595382B2 (en) 1986-10-09 1987-10-08 Use of polysulfated low molecular weight dextran sulfates

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EP (1) EP0276370A3 (en)
JP (1) JPS6396128A (en)
AU (1) AU595382B2 (en)
DE (1) DE3634392A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES343957A1 (en) * 1967-08-09 1968-10-01 Rocador Sa Antilipaemic sulphated polysaccharide

Cited By (2)

* Cited by examiner, † Cited by third party
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

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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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