[go: up one dir, main page]

WO2004110479A1 - Agent renfermant de la lyase de hyaluronate pour le traitement d'infarctus du myocarde aigu ou de ses symptomes, ainsi que pour le traitement de myocardite et de myocardischemie post-infarctionnelle - Google Patents

Agent renfermant de la lyase de hyaluronate pour le traitement d'infarctus du myocarde aigu ou de ses symptomes, ainsi que pour le traitement de myocardite et de myocardischemie post-infarctionnelle Download PDF

Info

Publication number
WO2004110479A1
WO2004110479A1 PCT/DE2003/001789 DE0301789W WO2004110479A1 WO 2004110479 A1 WO2004110479 A1 WO 2004110479A1 DE 0301789 W DE0301789 W DE 0301789W WO 2004110479 A1 WO2004110479 A1 WO 2004110479A1
Authority
WO
WIPO (PCT)
Prior art keywords
hyaluronate lyase
composition according
enzyme
hyaluronate
treatment
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
PCT/DE2003/001789
Other languages
German (de)
English (en)
Inventor
Michael Wolfram
Jörg-Hermann Ozegowski
Peter-Jürgen Müller
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.)
Hans-Knoll-Institut fur Naturstoff-Forschung Ev
Friedrich Schiller Universtaet Jena FSU
Leibniz Institut fuer Naturstoff Forschung und Infektionsbiol eVi
Original Assignee
Hans-Knoll-Institut fur Naturstoff-Forschung Ev
Friedrich Schiller Universtaet Jena FSU
Leibniz Institut fuer Naturstoff Forschung und Infektionsbiol eVi
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 Hans-Knoll-Institut fur Naturstoff-Forschung Ev, Friedrich Schiller Universtaet Jena FSU, Leibniz Institut fuer Naturstoff Forschung und Infektionsbiol eVi filed Critical Hans-Knoll-Institut fur Naturstoff-Forschung Ev
Priority to PCT/DE2003/001789 priority Critical patent/WO2004110479A1/fr
Priority to AU2003239763A priority patent/AU2003239763A1/en
Publication of WO2004110479A1 publication Critical patent/WO2004110479A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/51—Lyases (4)

Definitions

  • the invention relates to agents containing a new active substance for the treatment of acute myocardial infarction or symptoms thereon and for the treatment of postinfarctional myocarditis and myocardial ischemia.
  • the proposed active ingredient has glucosaminoglycan-cleaving activity and is characterized mainly by preferential degradation of hyaluronic acid.
  • the glucosaminoglycans include chondroitin sulfate, dermatan sulfate and heparan sulfate. These occur in the tissues of all vertebrates.
  • Hyaluronic acid is particularly present in the intercellular matrix of the skin and cartilaginous tissue as well as in body fluids such as aqueous humor of the eyes and synovial fluid. Together with the other glucosaminoglycans, hyaluronic acid forms part of the walls of blood vessels, in particular also of atheromatous deposits or plaques on arterial inner walls.
  • Hyaluronic acid has the property of binding water to form viscous, hydrocolloid solutions or to form sparingly soluble polyelectrolyte complexes with basic proteins. It consists of glucuronic acid and acetylated glucosamine linked by ß- (l-3) -glycosidic bonds. These disaccharide units are in turn linked together by glycosidic ⁇ (1-4) bonds.
  • Hyaluronic acid is cleaved by hyaluronidases according to a hydrolytic mechanism.
  • hyaluronidases does not correctly describe three different types of hyaluronic acid-splitting enzymes (Ludowieg J: The Mechanisms of Hyaluronidases, J Biol Chem 236, pp.333-339, 1961). Once upon a time, the endohydrolases hydrolytically cleave the ⁇ - (1-4) bonds. These include the majority of hyaluronidases from higher organisms, such as bovine testes hyaluronidase. These hyaluronate glycan hydrolases (hyaluronoglucosaminidases / E.C.
  • Rinderhodenhyaluronidase has a conducive effect on collateral blood flow into the ischemic tissue (Askenazi J, Hillis LD, Diaz PE et al .: The Effects of Hyaluronidase on Coronary Blood Flow Following Coronary Artery Occlusion in the Dog. Circ Res 40, p.566- 571, 1977 / Premaratne S, Watanabe BI, LaPenna WF, et al .: Effects of hyaluronidase on reducing myocardial infarct size in a baboon model of ischemia-reperfusion injury J Surg Res 58, p.205-210, 1995).
  • Interstitial edema Due to the ability to bind water, the interstitial accumulation of hyaluronic acid contributes to the interstitial edema in the infarcted myocardial tissue. Interstitial edema is believed to affect electromechanical characteristics of the myocardium, allowing reentry phenomena due to loss of contact between muscle cells, leading to tachycardia and ventricular fibrillation. In addition, edema causes increased extracellular pressure and disturbs the microcirculation of the myocardium through altered cardiac wall compliance.
  • Bovine testicular hyaluronidase limits the cellular damage during myocardial ischemia by degradation of hyaluronic acid (Waidenstrom A, Martinussen HJ, Gerdin B et al .: Accumulation of hyaluronan and tissue edema in experimental myocardial infarction, J Clin Invest 88, pp. 1622-1628, 1991).
  • Presselt proposes the treatment of atheromatous vascular diseases of humans and animals with hyaluronate lyase of microbial origin.
  • Injection preparations for intravenous and intraarterial applications are used for the treatment of the cause of cardiac arrhythmias, atherosclerosis, cerebral infarctions, cerebral thrombosis, coronary thrombosis and cardiac infarction as a result of atheromatous plaque formation.
  • the enzyme counteracts the formation of atheromatous plaques or dissolves them on prolonged use.
  • hyaluronate lyase can be used to counteract the triggering cause of myocardial infarction, atheromatous plaque formation, which is a prerequisite for the subsequent acute occlusion of the vessel by a blood thrombus.
  • the heart attack is interpreted as a normal vascular disease whose treatment is to be understood as a therapy of atherosclerotic changes or plaque formation.
  • this presentation does not do justice to the complex pathophysiology of a heart attack and its life-threatening consequences.
  • the irreversible state is particularly pronounced when the vascular occlusion is not abolished within a few hours by therapeutic measures such as the injection of antithrombotic agents.
  • the subsequent irreversible sequelae are later associated with scarring and loss of function of the heart muscle as well as in unfavorable cases death. Because of the acute threat to life therefore a specific, especially a very fast-acting therapy for the secondary symptoms is necessary.
  • a specific therapy should limit the extent of the damage or make the damage at least partially reversible.
  • the relatively slow-acting plaque degradation in the case of secondary symptoms occurring according to the application of hyaluronate lyase proposed by Presselt (WO 00/39290) is far from sufficient for this purpose.
  • Gottlieb (US Pat. No. 3,708,575) proposes treating human vascular diseases such as cardiac arrhythmias, thromboses, cardiac and cerebral infarctions with hyaluronidase from animal testes (molar mass 120,000 D) in high dosages of 20,000 to 1,000,000 IU per injection.
  • An isotonic sterile solution of, for example, 10,000 IU / ml is injected intravenously, intraarterially or intrathecally.
  • the enzyme was obtained from bovine testes.
  • the bovine testicular hyaluronidase is erroneously referred to in the patent title as glucuronoglycosaminoglycan hyaluronate lyase, although it is clear from the description of the invention and the cited literature that it is an enzyme from bovine testes.
  • a hyaluronidase with the cleavage specificity of a lyase is not detectable in animal testes. Esterase activity attributed to the enzyme also indicates hyaluronidase and not hyaluronate lyase.
  • the method used to measure specific activity refers to a protocol for the determination of hyaluronidases.
  • testicular hyaluronidases are limited because of the relatively low and rapidly decreasing effect of multiple uses as well as the increased risk of transmission of infectious material.
  • purification of hyaluronidases from tissue macerates with a naturally high proportion of foreign proteins and lipoid compounds requires a high cleaning effort, so that highly active preparations can not be produced.
  • bovine test hyaluronidase is due to marked inhibition of the enzyme by sulfated glucosaminoglycans such as heparin or heparin-like glucosaminoglycans present in the mammalian extracellular matrix.
  • the invention is therefore based on the object to find means for the aforementioned treatment, with which in particular the life-threatening consequences of myocardial infarction can be treated quickly and effectively.
  • the active substance contained in the agents should not or only to a lesser extent cited the disadvantages of testicular hyaluronidase or of hyaluronidases of animal origin and, even when it is used, do not give rise to any danger from possible infections.
  • compositions comprising microbial hyaluronate lyases or their fragments which, according to their cleavage mechanism, are used as lyases of the enzyme classification number E.C. 4.2.2.1, among other things, lead to an intensive and rapid reduction of postischemic damage to the myocardium.
  • the hyaluronate lyases used are formed in particular by the microorganism of the genus Streptococcus, in particular the serological groups B or C, preferably by the species Streptococcus agalactiae and in particular by Streptococcus equisimilis or by a recombinant microorganism during a fermentation.
  • the recombinant microorganism used is preferably a microorganism of the species E. coli, in particular the strain Escherichia coli EC 084 (HKI 0295).
  • the enzymatic active ingredient unlike testicular hyaluronidases or other hyaluronidases of animal origin, cleaves hyaluronic acid according to an elimination mechanism to form unsaturated cleavage products.
  • hyaluronidases of animal origin E.C. 3.2.1.35/36) hydrolytically cleave the hyaluronic acid upon addition of water to form saturated cleavage products.
  • the hyaluronate lyases continue to differ from animal hyaluronidases by the amino acid sequences as well as the isoelectric points (IP).
  • the invention relates to galenic formulations or compositions containing microbial hyaluronate lyase and / or the active fragments prepared therefrom for the rapid treatment of acute myocardial infarction or symptoms thereon and for the treatment of postinfarctional myocarditis and myocardial ischemia.
  • implantation of valve prostheses, pacemaker supplies or coronary angiography to avoid reperfusion syndromes as well as in pectanginous complaints and acute myocardial infarction applied.
  • the particularly rapid onset of action of the agent is achieved by the application of enzyme activities up to 1,000,000 IU / kg body weight (body weight).
  • the application of such high activities has not been suggested, u. a. also because such high enzyme activities could not be produced economically.
  • the observed effect is surprising.
  • the application of the active ingredient-containing galenic formulation in high doses is carried out according to the invention by intravenous injection or via a cardiac catheter.
  • the use of the microbial hyaluronate lyases in the proposed high doses does not indicate adverse effects on the health of experimental animals.
  • the hyaluronanase activity for prophylactic use is between 100 IU / kg body weight (KG) and 1,000,000 IU / kg body weight, preferably 1000 IU / kg body weight to 500,000 IU / kg body weight.
  • the use of these relatively high activities per dose certainly also in the context of the absence of inhibitors, leads to the rapid neutralization of the life-threatening consequences of myocardial infarction.
  • Another advantage of the proposed agent is that it can be produced in a simple manner in the high activities required for the application as decisive prerequisites for effective therapy.
  • microbial hyaluronate lyases which are an enzyme group hitherto not used to treat the life-threatening consequences of myocardial infarction, develop a rapid cardioprotective effect in the proposed high dosage by reducing the damaging effect of ischemia on the myocardial cell membranes , Ventricular fibrillation or other tachycardiac arrhythmias, which usually occur in the first few hours of the infarction as an expression of electrical instability and are significantly responsible for the high mortality, are prevented and cardiac necrosis and scarring are reduced.
  • the observed cardioprotective effects of hyaluronate lyase have not previously been described in the literature.
  • the interstitial edema that occurs during myocardial infarction increases extracellular pressure and disturbs the microcirculation of the heart muscle.
  • the parallel released enzymes accumulate in the cardiac lymph. Their volume gradually increases as a result of the infarct event.
  • ischemic tissue before myocardial necrosis can develop, a reduction in lymphatic filling can be observed.
  • This mechanism of lymphatic blockage or collapse apparently plays an essential role in the pathophysiology of myocardial infarction. Reduced lymphatic drainage causes local accumulation of potentially toxic products that can contribute to local damage.
  • the rapid action of the agent may also be related to the absence in the blood plasma of any natural inhibitors that inhibit hyaluronate lyase.
  • hyaluronidase is inhibited by such natural inhibitors. This property of hyaluronate lyases should be of benefit for the treatment of heart attacks, since no tissue inactivation suppresses the activity of the enzyme, thus allowing it to uninhibitedly penetrate into the tissue and exert its effect.
  • the activity of hyaluronate lyase from Streptococcus equisimilis is also hardly inhibited by another class of inhibitors, the sulfated glycosaminoglycans, such as sulfated hyaluronic acid or heparin.
  • the agents containing microbial hyaluronate lyases are used for their inventive use in the form of galenic formulations. They contain as Injection preparation, for example, an isotonic aqueous solution of a highly purified microbial Hyaluronatlyase with concentrations up to 2,000,000 IU / ml and conventional excipients in injection preparations.
  • the enzyme protein of hyaluronate lyase is advantageously used in the form of a storage-stable solid, which generally contains stabilizing additives, for example, filled in glass ampoules. The use of freeze-dried active ingredient is particularly advantageous. As stabilizing additives z.
  • sodium chloride, glucose, magnesium salts, polyvinylpyrrolidine, amino acid, albumins and their hydrolyzates or gelatin and its hydrolysates can be used.
  • the solid in physiological saline Prior to application, the solid in physiological saline is dissolved into an isotonic injection formulation.
  • the enzyme activity of an ampoule after filling with physiological saline solution is between 1000 IU / ml and 2,000,000 IU / ml.
  • a catheter enzyme-containing solutions which contain 50 IU / ml to 1,000,000 IU / ml Hyaluronatlyase and have a similar composition as the injection solutions.
  • the preparation of the microbial hyaluronate lyases used in the injection or catheter formulation can be carried out, for example, with regard to the sequence and selection of the purification steps in a manner not limiting the scope of the invention as follows. Without specifying the invention on the Hyaluronatlyase or its fragment on a particular microorganism, the invention is illustrated by the example of the enzyme from the generally available Streptococcus agalactiae.
  • Hyaluronate lyase is recovered as a highly purified enzyme for injection or the purified hyaluronate lyase is converted into a fragment with a specific protease by the following purification procedures.
  • the recombinant strain Escherichia coli EC 084 (HKI 0295) is used to produce a hyaluronate lyase substantially identical to the enzyme from Streptococcus agalactiae.
  • This strain was deposited with the DSMZ-German Collection of Microorganisms and Cell Cultures GmbH in Braunschweig according to the Budapest Treaty.
  • the preparation of the high-purity hyaluronate lyase and the highly purified fragment in a form suitable for the composition according to the invention can be carried out by way of example with regard to the order and the selection of the purification steps in a manner not limiting the scope of the invention as follows.
  • the fermentation of the microorganism, z. is carried out in a stirred fermenter under pH constant maintenance at an acidity of pH 6.5 to 7.5.
  • the lactic acid formed during the fermentation is neutralized by the addition of dilute sodium hydroxide solution.
  • the medium consists of inorganic salts, yeast hydrolyzate, optionally casein peptone or soy peptone, as well as glucose.
  • the cells are separated.
  • the cell mass is going through Microfiltration separated by filter modules with a pore size of for example 0.45 microns and discarded.
  • the culture filtrate is concentrated in an ultrafiltration apparatus and purified.
  • the exclusion limit (cut off) of the ultrafilter module is 80,000 D.
  • the result is a pre-cleaned enzyme solution, which is subjected to known purification methods.
  • the culture filtrate is concentrated in an ultrafiltration apparatus and purified.
  • the exclusion limit of the ultrafilter module is between 30 and 50 kD.
  • the result is a pre-purified enzyme solution, which must be subjected to further purification steps before it can be used as an injection preparation.
  • the purification steps and the use of pyrogen-free auxiliaries result in pyrogen-free preparation of the injection preparation.
  • the enzyme After increasing the ionic strength by adding ammonium sulfate to a saturation of 40%, the enzyme is adsorbed on phenylsepharose. Subsequently, the desorption is carried out with a neutral buffered aqueous solution containing 25% ammonium sulfate, based on 100% saturation. The solution is treated after a dialysis step to remove impurities with Q-Sepharose (Pharmacia). Subsequently, a specific adsorption to a dye, z. B. aminophenyloxamic acid. The final cleaning may be together with the determination of the molecular weight in the form of a molecular weight chromatography on Superdex (Pharmacia).
  • Streptococcus equisimilis When Streptococcus equisimilis is used as enzyme-forming agent, the remainder step is eliminated by adsorption on the dye.
  • the enzymatically active fragment is prepared by partial digestion or proteolytic partial degradation of the holoenzyme with a gap-specific protease, which cleaves the peptide bond preferentially on the C-terminal side of the aromatic amino acids.
  • the partial digestion of the holoenzyme to the fragment is carried out with immobilized or non-immobilized specific protease.
  • the highly purified enzyme or enzyme fragment show only a specific precipitation after immunization in the rabbit. Monoclonal antibodies stain all detectable bands in the blot.
  • the holoenzyme has a specific activity of about 400,000 IU / mg and the specific activity of the fragment is between about 400,000 and 800,000 IU / mg.
  • at least one of the stabilizers for example albumin, preferably ovalbumin, and inorganic salts are added to the enzyme or fragment.
  • proteases are used for digestion, which cleave the C-terminal peptide bond of aromatic amino acids.
  • MO / 2 which is prepared from the culture filtrate of Streptomyces hygroscopicus (strain AP 40).
  • MO / 2 is a metalloenzyme with Co + "1" in the active center (DD 270 924).
  • the proteases are preferably used in purified form.
  • protease MO / 2 is purified, for example, by chromatography on phenylsepharose, DEAE-Sepharose, Q-Sepharose and Sephacryl SlOO with an enrichment factor of 20.
  • the molecular weight of the enzyme as determined by SDS gel electrophoresis and molecular weight chromatography on Sephadex G50 superfme is 14,000 to 15,000 D.
  • the enzyme hydrolyzes natural polypeptides such as casein, hemoglobin, bovine serum, albumin and ovalbumin.
  • An advantage of the use of the protease MO / 2 is that the enzyme cleaves proteins very specifically or has a very low general digestive activity towards proteins. The enzyme almost exclusively cleaves only the peptide bonds of the C-terminal residue from the aromatic amino acids. It has an esterolytic activity towards N-benzoyl-L-proline-nitroanilide and pronounced milk-precipitating properties.
  • the properties of milk precipitation which is detectable in the formation of a long-term stable casein gel, comparable to the gel which occurs in milk precipitation with the very specific lab enzyme, are further evidence of the limited activity of the protease which is very advantageous for the invention MO / 2, specifically to cleave the bonds of the holoenzyme, without leading to degradation of the fragments.
  • the protease MO / 2 is bound to suitable insoluble immobilization supports and used in this form for the cleavage of the holoenzyme.
  • the composition of the basal perfusion solution was: NaCl 118 mmol / l, KCl 4.7 mmol / l, CaCl 2 2.5 mmol / l, NaHPO 4 1.2 mmol / l, NaHCO 3 24.9 mmol / l, MgSO 4 1.6 mmol / l, glucose 5.5 mmol / l, Na pyruvate 2.0 mmol / l and Na 2 EDTA 0.5 mmol / l.
  • the hyaluronate lyase solution used was prepared as follows: One vial of hyaluronate lyase corresponding to 200,000 IU was dissolved in ice-cold distilled water (1 ml) and perfusion solution (4 ml) and immediately added to 1995 ml of tempered and fumigated perfusion solution so that the concentration was 100 IU / ml , With this solution, the heart was perfused either before or after global ischemia. After removal of the hearts they were clamped in the perfusion apparatus and perfused for 15 min with basal perfusion solution until stable action potentials were achieved.
  • LDH activity is a measure of cardiac damage due to permeability and integrity changes of cardiac cell membranes (LDH activity is proportional to the extent of cardiac damage).
  • Vl lactate dehydrogenase
  • the conditions given in Vl resulted in irreversible ventricular fibrillation from the 30 minute reperfusion. In V2 and V3 no ventricular fibrillation was observed until the 85th minute.
  • the protective effect of hyaluronate lyase was more effective in perfusion after ischemia (V3) with a perfect sinus rhythm comparable to the situation before ischemia.
  • V3 perfusion after ischemia
  • Body weight and mean weight of the isolated hearts of the control animals were not significantly different from the measurements of the dogs treated with hyaluronate lyase.
  • the mean weight of the infarcted myocardium in the control group was 11.2 ⁇ 1.8 g.
  • Hyaluronatlyase significantly reduced infarct tissue (p ⁇ 0.02) to 3.1 ⁇ 0.4 g. This confirms the cardioprotective effect of microbial hyaluronate lyase in vivo.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation de lyase de hyaluronate d'origine microbienne ou d'un plus petit fragment actif obtenu à partir de cette enzyme, ainsi que de formulations pharmaceutiques renfermant cette enzyme ou ce fragment, en particulier pour la thérapie des suites d'un infarctus du myocarde ou de ses symptômes. L'enzyme est utilisée sous forme de préparation pour injection ou de solution pour perfusion, pour la thérapie d'infarctus du myocarde et de syndromes de reperfusion, pour le traitement de douleurs d'angine de poitrine et d'infarctus du myocarde, ainsi que pour la cardio-protection sous/ et après interventions invasives, chirurgicales ou de diagnostic sur le coeur, par exemple, opérations en by-pass, implantations de prothèses valvulaires, soins lors de stimulations cardiaques ou coronarographie. Lors du traitement, la lyase de hyaluronate est injectée par voie intraveineuse ou appliquée au moyen d'un cathéter.
PCT/DE2003/001789 2003-05-27 2003-05-27 Agent renfermant de la lyase de hyaluronate pour le traitement d'infarctus du myocarde aigu ou de ses symptomes, ainsi que pour le traitement de myocardite et de myocardischemie post-infarctionnelle Ceased WO2004110479A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/DE2003/001789 WO2004110479A1 (fr) 2003-05-27 2003-05-27 Agent renfermant de la lyase de hyaluronate pour le traitement d'infarctus du myocarde aigu ou de ses symptomes, ainsi que pour le traitement de myocardite et de myocardischemie post-infarctionnelle
AU2003239763A AU2003239763A1 (en) 2003-05-27 2003-05-27 Hyaluronate lyase-containing agent for treating acute myocardial infarction or symptoms thereof and for the treatment of postinfarction myocarditis and myocardial ischaemia

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/DE2003/001789 WO2004110479A1 (fr) 2003-05-27 2003-05-27 Agent renfermant de la lyase de hyaluronate pour le traitement d'infarctus du myocarde aigu ou de ses symptomes, ainsi que pour le traitement de myocardite et de myocardischemie post-infarctionnelle

Publications (1)

Publication Number Publication Date
WO2004110479A1 true WO2004110479A1 (fr) 2004-12-23

Family

ID=33546407

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE2003/001789 Ceased WO2004110479A1 (fr) 2003-05-27 2003-05-27 Agent renfermant de la lyase de hyaluronate pour le traitement d'infarctus du myocarde aigu ou de ses symptomes, ainsi que pour le traitement de myocardite et de myocardischemie post-infarctionnelle

Country Status (2)

Country Link
AU (1) AU2003239763A1 (fr)
WO (1) WO2004110479A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007031417A1 (de) 2007-07-04 2009-01-08 Friedrich-Schiller-Universität Jena Hyaluronatlyase mit erhöhter Wirksamkeit, insbesondere für die Herstellung von pharmazeutischen Formulierungen und Medizinprodukten, sowie deren Verwendung
RU2543356C1 (ru) * 2014-03-03 2015-02-27 Федеральное государственное бюджетное учреждение "Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний" Сибирского отделения Российской академии медицинских наук (ФГБУ "НИИ КПССЗ" СО РАМН) Способ прогнозирования ранней постинфарктной стенокардии у пациентов с острым инфарктом миокарда с подъемом сегмента st в госпитальном периоде

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000039290A2 (fr) * 1998-12-23 2000-07-06 Id Pharma Gmbh Formulation pharmaceutique contenant un enzyme decomposant l'acide hyaluronique et d'origine microbienne
WO2000077221A1 (fr) * 1999-06-12 2000-12-21 Merck Patent Gmbh Hyaluronidase provenant de hirudinaria manillensis, procede d'isolation, de purification et de preparation par recombinaison
WO2002059289A1 (fr) * 2001-01-23 2002-08-01 Hans-Knöll-Institut für Naturstoff-Forschung e.V. Utilisation d'hyaluronatlyase microbienne pour ramollir des tissus conjonctifs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000039290A2 (fr) * 1998-12-23 2000-07-06 Id Pharma Gmbh Formulation pharmaceutique contenant un enzyme decomposant l'acide hyaluronique et d'origine microbienne
WO2000077221A1 (fr) * 1999-06-12 2000-12-21 Merck Patent Gmbh Hyaluronidase provenant de hirudinaria manillensis, procede d'isolation, de purification et de preparation par recombinaison
WO2002059289A1 (fr) * 2001-01-23 2002-08-01 Hans-Knöll-Institut für Naturstoff-Forschung e.V. Utilisation d'hyaluronatlyase microbienne pour ramollir des tissus conjonctifs

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007031417A1 (de) 2007-07-04 2009-01-08 Friedrich-Schiller-Universität Jena Hyaluronatlyase mit erhöhter Wirksamkeit, insbesondere für die Herstellung von pharmazeutischen Formulierungen und Medizinprodukten, sowie deren Verwendung
RU2543356C1 (ru) * 2014-03-03 2015-02-27 Федеральное государственное бюджетное учреждение "Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний" Сибирского отделения Российской академии медицинских наук (ФГБУ "НИИ КПССЗ" СО РАМН) Способ прогнозирования ранней постинфарктной стенокардии у пациентов с острым инфарктом миокарда с подъемом сегмента st в госпитальном периоде

Also Published As

Publication number Publication date
AU2003239763A8 (en) 2005-01-04
AU2003239763A1 (en) 2005-01-04

Similar Documents

Publication Publication Date Title
DE3688710T2 (de) Isolierung und pharmazeutische Verwendung von Hyaluronidase und diese enthaltende pharmazeutische und tierärztliche Präparate.
EP0142860B1 (fr) Désulfatohirudine, son procédé de préparation et agent pharmaceutique
DE3617752C2 (fr)
DE69419907T2 (de) Verwendung von aktin-bindenden verbindungen zur herstellung eines medikaments zur verminderung der viskosität von pathalogischen schleimartigen bestandteilen der atemwege
DE3617753C2 (fr)
DE3885374T2 (de) Stabile wässerige Thrombinlösung.
DE3400413C2 (fr)
DE3689943T2 (de) Degradierte Spezies eines Gewebeplasminogenaktivators, pharmazeutische Zubereitung und Verfahren zur Herstellung derselben.
AT407706B (de) Prevention und behandlung ischemischer vorfälle und hieraus resultierender perfusionsverletzungen
CH672989A5 (fr)
DE69123099T2 (de) Vibrio-produzierte Protease enthaltende Zusammensetzungen und Verfahren zur Verwendung in Debridement und Wundheilung
EP0297294B1 (fr) Procédé de préparation d'une solution à haute activité volumique spécifique d'une protéine à activité d'activateur tissulaire du plasminogène (t-PA), solution comprenant la protéine à activité t-PA et utilisation de la solution en médecine humaine et vétérinaire
EP0746334B1 (fr) Preparation pharmaceutique contenant des activateurs du plasminogene
JP3140797B2 (ja) 安定化コンドロイチナーゼａｂｃ、その保存方法及び治療剤
EP1244462B1 (fr) Preparation pharmaceutique a base de venin d'araignee, sa preparation et son utilisation pour traiter des affections tumorales
DE60128399T2 (de) Verwendung von thrombomodulinanaloga zur regenerierung von rückenmarkverletzungen
DE69528573T2 (de) Verwendung einer Zubereitung enthaltend einen Plasminogen-Aktivator für die Verbesserung der Wundheilung
EP1056839A1 (fr) Formulation pharmaceutique contenant un enzyme decomposant l'acide hyaluronique et d'origine microbienne
WO2004110479A1 (fr) Agent renfermant de la lyase de hyaluronate pour le traitement d'infarctus du myocarde aigu ou de ses symptomes, ainsi que pour le traitement de myocardite et de myocardischemie post-infarctionnelle
DE60006519T2 (de) Glutathion-reduktase zur behandlung und prophylaxe von aids
DE10211457A1 (de) Verwendung von Hyaluronatlyase zur Behandlung von Myokardinfarkten
JPH08325161A (ja) 脊髄損傷に伴う神経障害の予防・治療剤
DE60313627T2 (de) Kardioprotektive therapien auf basis von enzymatischer eliminierung von lipidperoxiden durch allenoxid-synthase
JPH0418032A (ja) 組織プラスミノーゲンアクチベーター若しくはその誘導体を含有する血栓溶解剤
DE68908716T2 (de) Heparin enthaltende formulierungen.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AU BA BR CA CN CU DZ GE HR ID IL IN IS JP KR LT MA MK NO NZ PL RU SD SG UA US YU ZA

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP