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WO1999004801A1 - Utilisation de glycosaminoglycanes sulfates dans le traitement de la retinopathie - Google Patents

Utilisation de glycosaminoglycanes sulfates dans le traitement de la retinopathie Download PDF

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Publication number
WO1999004801A1
WO1999004801A1 PCT/EP1998/004929 EP9804929W WO9904801A1 WO 1999004801 A1 WO1999004801 A1 WO 1999004801A1 EP 9804929 W EP9804929 W EP 9804929W WO 9904801 A1 WO9904801 A1 WO 9904801A1
Authority
WO
WIPO (PCT)
Prior art keywords
retinopathy
pharmaceutically acceptable
treating
sulfated glycosaminoglycan
use according
Prior art date
Application number
PCT/EP1998/004929
Other languages
English (en)
Inventor
Johan Wennemar Van Der Pijl
Herman Hendrik Pieter Jan Lemkes
Original Assignee
Rijks Universiteit Leiden
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 Rijks Universiteit Leiden filed Critical Rijks Universiteit Leiden
Priority to AU91604/98A priority Critical patent/AU9160498A/en
Publication of WO1999004801A1 publication Critical patent/WO1999004801A1/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

Definitions

  • the invention relates to the use of sulfated glycosaminoglycans and/or synthetic functional analogues thereof for the manufacture of a medicament for treating and preventing of retinopathy. Further the invention relates to a pharmaceutical composition for said use.
  • a severe disorder in diabetic retinopathy is so-called background retinopathy, which is caused by retinal leakage.
  • Diabetes induces a deterioration of the condition of the basement membrane of the retinal capillary blood vessels resulting in increased permeability of the capillary blood vessels, which results, in turn, in increased leakage of proteins.
  • This leads to swelling of the retina (oedema) and the formation of deposits of the proteins on the retina (hard exudates in diabetic maculopathy), which impaires the eyesight and may finally cause blindness.
  • sulfated glycosaminoglycans and/or synthetic functional analogues thereof or pharmaceutically acceptable salts thereof can be used to treat and prevent retinopathy. This is in particular successful in diabetic background retinopathy, caused by increased permeability of capillary blood vessels on the retina.
  • the use of the sulfated glycosaminoglycans and/or synthetic functional analogues thereof or pharmaceutically acceptable salts thereof according to this invention results in effective improvement of the condition of the retina of diabetes patients with background retinopathy. In particular the progression of hard exudates stops and is even reversed.
  • the use of this invention can be the only therapy used to treat to a patient, but it may also be an adjuvans treatment together with other therapies, such as focal laser therapy.
  • the class of sulfated glycosaminoglycans which can be used according to this invention comprises heparin, low molecular weight heparins (L W ⁇ s) like dalteparin (Fragmin®), enoxaparin (Clexane®) and nadroparin (Fraxiparine®), and especially sulfated glycosaminoglycans for the major part consisting of heparan sulfate, in particular those described in EP 421,508 (66 % to 95 % heparan sulfate), of which the commercially available danaparoid sodium (danaparoid; Orgaran®, N.V.
  • the sulfated glycosaminoglycan and/or a synthetic functional analogue thereof or a pharmaceutically acceptable salt thereof may be administered enterally (e.g. orally or topically) or parenterally (e.g. via the subcutaneous or intravenous route).
  • the active agent is administered as a subcutaneous injection to the mammal undergoing treatment.
  • the mammal is a human.
  • the dosage is 0,001-10 mg per kg body weight per treatment. More preferably, the active agent is administered at doses of between 1 mg and 150 mg, and most preferably between 30 mg and 100 mg, per patient per treatment.
  • the active agent may be used alone or in combination with other therapeutic agents and may be presented as a pharmaceutical composition.
  • the present invention further provides a pharmaceutical composition for treating and preventing of retinopathy comprising said active agent together with pharmaceutically acceptable auxiliaries and optionally other therapeutic agents.
  • the term "acceptable" means being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • Compositions include e.g. those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, transdermal, transmucosal, local, or rectal administration, and the like, all in unit dosage forms for administration.
  • the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like.
  • the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use.
  • sterile liquid carrier e.g. water
  • the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
  • the active agent can be applied as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
  • solid dosage units For making solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. Suitable carriers with which the active agent of the invention can be administered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotone saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.
  • the invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.
  • a pharmaceutical composition as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.
  • Danaparoid sodium as a representative compound for use according to the present invention, has been subject to a pilot clinical study in 9 patients with diabetes mellitus.
  • Danaparoid sodium is a mixture of sulfated glycosaminoglycans, consisting of 84% heparan sulfate, 12% dermatan sulfate and 4% chondroitin sulfate isolated from digested porcine intestinal mucosa. It has an average molecular weight of 4000-7000 d, and a specific anti-Xa activity of 1 1.0-17.0 U/mg. The elimination half-life of anti-Xa activity is ⁇ 25 h.
  • danaparoid sodium formulation used is a sterile aqueous solution containing danaparoid sodium (1250 anti Xa units per ml), sodium sulfite (1.5 mg/ml), sodium chloride to isotonic and hydrochloric acid to pH 7.0. In this study 0.6 ml ampoules were used.
  • the study was designed as a phase II, randomized, double blind, placebo controlled, crossover study evaluating putative effects of danaparoid sodium on the rate of proteinuria in insulin dependent diabetic mellitus (IDDM) patients (J.Am.Soc.Nephrol. 8, 456-62, 1997).
  • IDDM insulin dependent diabetic mellitus
  • IQR interquartile range
  • Mean arterial blood pressure was 105 mrnHg (median) (IQR 100-107); the use of angiotensin I converting enzyme inhibitors and other anti hypertensive medications was on a stable dosage at least 6 weeks prior to the start of the study and remained unchanged. Median HbAlc was 8.3% (IQR 7.7-9.8%). Six out of 9 patients had undergone pattern photocoagulation previously because of proliferative retinopathy. The other 3 patients had stable background retinopathy. At baseline, in 7 patients hard exudates were present in both eyes.
  • the patients were randomly assigned to one of the treatment orders: 750 anti-Xa units danaparoid sodium (0.6 ml), subcutaneously administered once daily for 6 weeks; a wash-out period of 4 weeks, followed by 6 weeks placebo (saline with sulfite) or the same scheme in the opposite direction.
  • Fundus photography was performed at inclusion and at the end of the study. Seven field, red- free photographs of both eyes were obtained after mydriasis with a Zeiss camera. No bleeding complications were observed.
  • To evaluate the course of signs of retinal leakage a 45° photograph centered around the fovea was projected and all hard exudates were traced. Photographs were studied anonymous, masked for pre- or post-treatment assessment. Hard exudates were semi-quantitatively graded, ranging from 1+ (only minimal) to 5+ (extensive circinate).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un glycosaminoglycane sulfaté et/ou de son analogue synthétique fonctionnel ou de son sel pharmaceutiquement acceptable dans la fabrication d'un médicament destiné au traitement ou à la prévention de la rétinopathie diabétique de fond.
PCT/EP1998/004929 1997-07-28 1998-07-23 Utilisation de glycosaminoglycanes sulfates dans le traitement de la retinopathie WO1999004801A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU91604/98A AU9160498A (en) 1997-07-28 1998-07-23 Use of sulfated glycosaminoglycans for treating of retinopathy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP97202362 1997-07-28
NL97202362.6 1997-07-28

Publications (1)

Publication Number Publication Date
WO1999004801A1 true WO1999004801A1 (fr) 1999-02-04

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/004929 WO1999004801A1 (fr) 1997-07-28 1998-07-23 Utilisation de glycosaminoglycanes sulfates dans le traitement de la retinopathie

Country Status (2)

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AU (1) AU9160498A (fr)
WO (1) WO1999004801A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021538A3 (fr) * 1997-10-24 1999-08-05 Knoll Ag Utilisation de glycosaminoglycanes pour la fabrication de preparations pharmaceutiques en vue du traitement de maladies des yeux associees au diabete

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0244298A2 (fr) * 1986-04-17 1987-11-04 Sanofi Oligosaccharides hépariniques affinés pour les facteurs de croissance cellulaires
WO1990000058A1 (fr) * 1988-06-27 1990-01-11 Roland Reiner Glycosaminoglycane pour le traitement de la microangiopathie des diabetiques
EP0394971A1 (fr) * 1989-04-24 1990-10-31 Kabi Pharmacia Ab Inhibiteurs de croissance de cellules endothéoliales et d'angiogénèse contenant un oligosaccharide
WO1995005182A1 (fr) * 1993-08-13 1995-02-23 Glycomed Incorporated Oligosaccharides pontes et leurs derives sulfates
WO1996009828A1 (fr) * 1994-09-26 1996-04-04 Glycomed Incorporated Maltooligosaccharides fortement sulfates presentant des proprietes analogues a celles de l'heparine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0244298A2 (fr) * 1986-04-17 1987-11-04 Sanofi Oligosaccharides hépariniques affinés pour les facteurs de croissance cellulaires
WO1990000058A1 (fr) * 1988-06-27 1990-01-11 Roland Reiner Glycosaminoglycane pour le traitement de la microangiopathie des diabetiques
EP0394971A1 (fr) * 1989-04-24 1990-10-31 Kabi Pharmacia Ab Inhibiteurs de croissance de cellules endothéoliales et d'angiogénèse contenant un oligosaccharide
WO1995005182A1 (fr) * 1993-08-13 1995-02-23 Glycomed Incorporated Oligosaccharides pontes et leurs derives sulfates
WO1996009828A1 (fr) * 1994-09-26 1996-04-04 Glycomed Incorporated Maltooligosaccharides fortement sulfates presentant des proprietes analogues a celles de l'heparine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AIELLO L P ET AL: "VASCULAR ENDOTHELIAL GROWTH FACTOR IN OCULAR FLUID OF PATIENTS WITH DIABETIC RETINOPATHY AND OTHER RETINA DISORDERS", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 331, no. 22, 1 December 1994 (1994-12-01), pages 1480 - 1487, XP000574787 *
CHEMICAL ABSTRACTS, vol. 124, no. 3, 15 January 1996, Columbus, Ohio, US; abstract no. 26667b, FAVARD ET AL.: "Heparin-binding growth factors: FGF and VEGF. Physiological and pathological roles, and therapeutic implications in diabetic retinopathy." page 663; XP002054088 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021538A3 (fr) * 1997-10-24 1999-08-05 Knoll Ag Utilisation de glycosaminoglycanes pour la fabrication de preparations pharmaceutiques en vue du traitement de maladies des yeux associees au diabete

Also Published As

Publication number Publication date
AU9160498A (en) 1999-02-16

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