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WO1988006037A1 - Utilisation de sulfate de dextrane pour produire des medicaments therapeutiques et prophylactiques contre les vaso-constrictions et les vaso-occlusions - Google Patents

Utilisation de sulfate de dextrane pour produire des medicaments therapeutiques et prophylactiques contre les vaso-constrictions et les vaso-occlusions Download PDF

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Publication number
WO1988006037A1
WO1988006037A1 PCT/EP1988/000082 EP8800082W WO8806037A1 WO 1988006037 A1 WO1988006037 A1 WO 1988006037A1 EP 8800082 W EP8800082 W EP 8800082W WO 8806037 A1 WO8806037 A1 WO 8806037A1
Authority
WO
WIPO (PCT)
Prior art keywords
dextran sulfate
dextran
prophylaxis
treatment
sodium salt
Prior art date
Application number
PCT/EP1988/000082
Other languages
German (de)
English (en)
Inventor
Elke Seewaldt
Original Assignee
Dr. Karl Thomae 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 Dr. Karl Thomae Gmbh filed Critical Dr. Karl Thomae Gmbh
Publication of WO1988006037A1 publication Critical patent/WO1988006037A1/fr

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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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • dextran sulfate for the manufacture of a medicament for the treatment and prophylaxis of vasoconstrictions and vascular occlusions
  • high-molecular dextran or heparin and various combinations such as acetylsalicylic acid / dipyridamole, dextran / warfarin, etc. are administered today.
  • high-molecular dextran e.g. Dextran
  • extract 40,000 is also referred to as low molecular weight in the literature, in contrast to high-molecular dextran 60,000), the viscosity-reducing property and the anti-aggregating effect on erythrocytes and platelets in the foreground.
  • a vascular occlusion after vascular surgery is a multifactorial process which, according to current knowledge, focuses on the formation of a neointimal hyperplasia in addition to thrombus formation (see, for example, Drug Development Research _6, 167-176 (1985), Progress in
  • the hyperplasia is caused by damage to the endothelium (stretching), the subsequent adherence of platelets to the subendothelial matrix, the release of a growth factor for smooth muscle cells from the platelets and the proliferation of the smooth muscle cells caused thereby.
  • a substance that inhibits the growth of smooth muscle cells would have to inhibit both the formation of atherosclerotic plaques and the narrowing of the vascular lumen by intimal thickening after vascular surgery.
  • non-toxic dextran sulfate in particular its salt with a physiologically compatible base such as its sodium salt, largely inhibits hyperplasia.
  • dextran sulfate here means dextrans in which the 3 free hydroxy groups per glucose unit are partially or completely replaced by hydroxysulfonyloxy radicals.
  • the sulfur content is 13.2%
  • a degree of substitution of 2 with 19.9%
  • a degree of substitution of 3 with 23.9% each based on the free sulfonic acid.
  • preferred dextran sulfates are their physiologically tolerable salts, in particular their alkali salts such as the sodium salt.
  • alkali salts such as the sodium salt.
  • a degree of substitution of 1 has a sulfur content of. approx.12.1%, - 3 -
  • Preferred sodium salts of the dextran sulfates are those which have at least a sulfur content of 10%, but those sodium salts which have a sulfur content of 11.9% to 20%, preferably 12 to 19.5%, are particularly preferred. , exhibit.
  • x The sulfur content was determined by titration as sulfate after Schöninger combustion. Furthermore, those dextran sulfates with a molecular weight of up to 15,000 are preferred according to the invention, in particular those with a molecular weight between 1,000 and 10,000, but those with a molecular weight between 2,500 and 5,500 are particularly preferred.
  • dextran sulfates used according to the invention are known from the literature or can be obtained by processes known from the literature by chlorosulfonation of dextrans (see US Pat. No. 2,715,091) or by cleavage and simultaneous sulfonation of cellulose (see AU-A-83.22856).
  • SMC Smooth muscle cells
  • EC endothelial cells
  • the cells are sown in a specific density (approx. 3x10 "2 cells / 25 cm) onto Roux 25 plates coated with gelatin. After the cells have adhered (after 4 1/2 hours) the medium is changed and the substance is added. The determination of the cell count at this point in time represents the initial value for the assessment of the substance effect. On the 4th day, the medium is changed again (with substance addition) and on the 6th day (EC may not be confluent, Since cell contact inhibits growth), the cells are detached enzymatically and the cell number is determined again with the cell counter. The mean value is determined from 3 culture dishes (4 counts per dish).
  • Dextran sulfate and dextran were dissolved in phys. NaCl solution s.c. , or orally administered once a day for 21 days.
  • the i.v. Administration was only over a period of 8 days. However, both the control animals and the treated groups were only killed after 21 days.
  • intimal hyperplasia was determined by the morphometric measurement of histological thin sections.
  • dextran sulfate and heparin show a strong growth-inhibiting effect on smooth muscle cells.
  • non-sulfated dextrans show a much weaker antiproliferative effect.
  • dextran sulfates significantly reduce intimal thickening (up to 70% inhibition).
  • Intimal hyperplasia consists largely of smooth muscle cells.
  • the lipid-lowering effect is not construed er ⁇ of dextran sulfate, but only the inhibition of smooth muscle cells.
  • the dextran sulfates used according to the invention are well tolerated, especially since they have an acute toxicity similar to that of heparin (WW Kennet et al. In Brit. J. Pharmacol. 9, 1 (1954)).
  • the LDcg be i mouse is for
  • the side effects occurring in thrombosis prophylaxis with high molecular weight dextran 40,000 should not occur when using the low molecular weight dextran sulfate.
  • the anticoagulant effect of dextran sulfate (MW 5,000) is 10-20 times less than that of heparin (Genichiro, 0. et al., In Thro b. Res. 37, 361-72 (1986)) and so on. With dextran sulfate, fewer side effects (especially the risk of bleeding) can also be expected.
  • dextran sulfates used according to the invention, they are suitable as therapeutic agents for preventing vasoconstriction and vascular occlusion, which are caused by hyperplasia of the intima.
  • the application of dextran sulfate or its salt with a physiologically compatible base is indicated for all injuries to the endothelial layer, especially since these endothelial injuries are unavoidable in all vascular reconstructions.
  • vascular reconstruction recanalization, anastosis
  • atherosclerosis-related vascular narrowing or vascular occlusions such as after bypass operations, eg after coronary artery bypass, bypass of the arteria fe oralis / vena femoralis or the arteria femoralis / arteria popli - tea, after coronary angioplasty and after carotid endarteriecto ie.
  • Other indications with endothelial damage or loss include cardiac valve surgery (repair or replacement), heart transplants, kidney transplants and arteriovenous shunts for the purpose of dialysis.
  • the dextran sulfates are expediently administered subcutaneously or intravenously. In the case of subcutaneous or intravenous administration, the daily dose required to achieve a corresponding effect in humans is between 1 and 100 mg / kg body weight, but preferably between 5 and 20 mg / kg body weight, distributed over 1 to 2 doses per day.
  • the above-mentioned dextran sulfates and their physiologically tolerable salts can be incorporated into the customary soluble pharmaceutical forms of administration such as ampoules or solutions, in particular in the form of their isotonic solutions.
  • Dextran sulfate and sorbitol are dissolved in water for injections and sterile filtered, e.g. using a sterile filter from Millipore (pore size: 0.2 ⁇ mm). It is then filled into ampoules.
  • composition Dextran sulfate (M.G.: 1,000) 1,000.00 mg
  • composition dextran sulfate (M.G.: 10,000) 500.00 mg
  • dextran sulfates and their physiologically tolerable salts in which at least 1, 3 of the 3 hydroxy groups per glucose unit are each replaced by a hydroxysulfonyloxy radical, can be incorporated as "active substance" in the examples mentioned above.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

Nouvelle utilisation de sulfate de dextrane ou de ses sels avec une base physiologiquement compatible pour traiter et prévenir des vaso-constrictions et des vaso-occlusions causées par une hyperplasie endothéliale.
PCT/EP1988/000082 1987-02-21 1988-02-04 Utilisation de sulfate de dextrane pour produire des medicaments therapeutiques et prophylactiques contre les vaso-constrictions et les vaso-occlusions WO1988006037A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19873705669 DE3705669A1 (de) 1987-02-21 1987-02-21 Verwendung von dextransulfat zur herstellung eines arzneimittels zur behandlung und prophylaxe von gefaessverengungen und gefaessverschluessen
DEP3705669.7 1987-02-21

Publications (1)

Publication Number Publication Date
WO1988006037A1 true WO1988006037A1 (fr) 1988-08-25

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ID=6321529

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1988/000082 WO1988006037A1 (fr) 1987-02-21 1988-02-04 Utilisation de sulfate de dextrane pour produire des medicaments therapeutiques et prophylactiques contre les vaso-constrictions et les vaso-occlusions

Country Status (2)

Country Link
DE (1) DE3705669A1 (fr)
WO (1) WO1988006037A1 (fr)

Cited By (5)

* 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
US5484777A (en) * 1989-04-20 1996-01-16 Lange, Iii; Louis G. Pancreatic cholesterol esterase inhibitor
US5605938A (en) * 1991-05-31 1997-02-25 Gliatech, Inc. Methods and compositions for inhibition of cell invasion and fibrosis using dextran sulfate
US11291684B2 (en) 2017-05-17 2022-04-05 Tx Medic Ab Treatment of glaucoma

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1152396B (de) * 1960-01-26 1963-08-08 Bernburg Serum Werk Veb Verfahren zur Herstellung von Natriumsalzen blutgerinnungshemmender Dextranschwefelsaeureester
US3141014A (en) * 1960-03-31 1964-07-14 Meito Sangyo Kk Sodium and potassium salts of the dextran sulphuric acid ester having substantially no anticoagulant activity but having lipolytic activity and the method of preparation thereof
DE1242202B (de) * 1960-03-31 1967-06-15 Meito Sangyo Kk Verfahren zur Herstellung von antilipaemisch wirksamen Alkalisalzen von Dextranschwefelsaeureestern

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1152396B (de) * 1960-01-26 1963-08-08 Bernburg Serum Werk Veb Verfahren zur Herstellung von Natriumsalzen blutgerinnungshemmender Dextranschwefelsaeureester
US3141014A (en) * 1960-03-31 1964-07-14 Meito Sangyo Kk Sodium and potassium salts of the dextran sulphuric acid ester having substantially no anticoagulant activity but having lipolytic activity and the method of preparation thereof
DE1242202B (de) * 1960-03-31 1967-06-15 Meito Sangyo Kk Verfahren zur Herstellung von antilipaemisch wirksamen Alkalisalzen von Dextranschwefelsaeureestern

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, Band 101, Nr. 25, 17. December 1984, (Columbus, Ohio, US), C.M. Gajdusek: "Release of endothelial cell-derived growth factor (ECDGF) by heparin", siehe Seite 146 *
Chemical Abstracts, Band 105, Nr. 9, 1. September 1986, (Columbus, Ohio, US), R.J. Klebe et al.: "Regulation of cell motility, morphology, and growth by sulfated glycosaminoglycans", siehe Seite 456 *
Circulation Research, Band 47, Nr. 4, Oktober 1980, R.L. Hoover et al.: "Inhibition of rat arterial smooth muscle cell proliferation by heparin", seiten 578-583 *
Dialog Information Services, Datenbank 155: MEDLINE 66-8/Mai, Zugangsnummer 05707497, D.L. Cochran et al.: "Effect of heparin on vascular smooth muscle cells. II. Specific protein synthesis *
Dialog Information Services, Datenbank 155: MEDLINE 66-8/Mai, Zugangsnummer 05867502, W.E. Benitz et al.: "Heparin inhibits proliferation of fetal vascular smooth muscle cells in the absence of platelet-derived growth factor" *
Thromb. Res., Band 46, Nr. 6, 15. Juni 1987, Pergamon Journals Ltd, (US), R. Paul et al.: "Inhibition of vascular smooth muscle cell proliferation in culture by pentosan polysulphate and related compounds", Seiten 793-801 *

Cited By (6)

* 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
US5484777A (en) * 1989-04-20 1996-01-16 Lange, Iii; Louis G. Pancreatic cholesterol esterase inhibitor
US5605938A (en) * 1991-05-31 1997-02-25 Gliatech, Inc. Methods and compositions for inhibition of cell invasion and fibrosis using dextran sulfate
US6127348A (en) * 1991-05-31 2000-10-03 Gliatech, Inc. Methods and compositions based on inhibition of cell invasion and fibrosis by anionic polymers
US11291684B2 (en) 2017-05-17 2022-04-05 Tx Medic Ab Treatment of glaucoma

Also Published As

Publication number Publication date
DE3705669A1 (de) 1988-09-01

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