WO2002085368A2 - Utilisation de composes antiradicalaires dans le traitement et la prevention de troubles de la microcirculation no-dependants - Google Patents

Utilisation de composes antiradicalaires dans le traitement et la prevention de troubles de la microcirculation no-dependants Download PDF

Info

Publication number
WO2002085368A2
WO2002085368A2 PCT/EP2002/004129 EP0204129W WO02085368A2 WO 2002085368 A2 WO2002085368 A2 WO 2002085368A2 EP 0204129 W EP0204129 W EP 0204129W WO 02085368 A2 WO02085368 A2 WO 02085368A2
Authority
WO
WIPO (PCT)
Prior art keywords
microcirculation disorders
disease
substance
microcirculation
treatment
Prior art date
Application number
PCT/EP2002/004129
Other languages
English (en)
Other versions
WO2002085368A3 (fr
Inventor
Wolfgang Eisert
Original Assignee
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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 Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority to EP02764059A priority Critical patent/EP1389112A2/fr
Priority to JP2002582941A priority patent/JP2004525979A/ja
Priority to CA002444370A priority patent/CA2444370A1/fr
Priority to HU0303754A priority patent/HUP0303754A3/hu
Priority to MXPA03009506A priority patent/MXPA03009506A/es
Priority to AU2002338396A priority patent/AU2002338396B2/en
Priority to IL15809102A priority patent/IL158091A0/xx
Priority to NZ529115A priority patent/NZ529115A/en
Publication of WO2002085368A2 publication Critical patent/WO2002085368A2/fr
Publication of WO2002085368A3 publication Critical patent/WO2002085368A3/fr

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to a method of treatment of disorders of the microcirculation, particularly those where insufficient generation of NO seems to be the cause of the problem, using substances to scavange free radicals such as Dipyridamole or Mopidamol in doses lower than those needed to directly inhibit platelet aggregation alone or in combination with substance to increase cellular Nitric oxide (NO) production such as HMG CoA reductase inhibitors at doses below the typical dose to lower serum lipids but sufficient to still enhance eNOS in cells of the vasculature.
  • substances to scavange free radicals such as Dipyridamole or Mopidamol
  • substance to increase cellular Nitric oxide (NO) production such as HMG CoA reductase inhibitors at doses below the typical dose to lower serum lipids but sufficient to still enhance eNOS in cells of the vasculature.
  • the endothelium can provide maintenance of local perfusion of the vessels by several separate mechanisms, one being the local vasodilata- tion mediated by prostacyclin and Nitric Oxide (NO, also described in literature as EDRF) and another being the decreased interaction of blood cells with each other or the negative interaction of white blood cells or blood platelets with the cells of the vessel wall.
  • aggregation and adhesion of platelets to damaged parts of the vessel wall particularly after interven- tional therapy play an important role and have been shown to be treated with inhibitors of platelet aggregation (see WO 98/11896) .
  • the benefit of enhancing endothelial NO synthesis by HMG CoA reductase inhibitors has been described in US Patent No. 5,968,983 and WO 00/56403.
  • MI myocardial infarcts
  • mild platelet inhibitors such as Aspirin
  • Aspirin have shown only limited efficacy (published meta analysis aggree to a reduction of the incidence by 18 %) .
  • Using more potent platelet inhibitors such as various orally available inhibitors of the platelet fibrinogen receptor however have shown no improvement over the effect achieved by ASA.
  • More than 37,000 patients have been subjects in major studies on the long term benefit of chronic administration of oral fibrinogen receptor antagonists in preventing cardiovascular events. All studies have been negative, in fact the treatment arm showed a higher risk for bleeding and increased mortality.
  • Tissue perfusion is vital to the health and survival and function of any organ, particularly those organs with high oxygen and nutritive demand. Even after successful revascularisation of epicardial arteries the perfusion of the tissue, i.e. the properties of the microcirculation have been shown to significantly influence the mortality after MI at 90 days (Gibbson at all, Circulation 2000, 101:125-130), resulting in a reduction of mortality from 4.6% to 0.8%, in cases where tissue perfusion, was not reduced, i.e. microcirculation was not compromised.
  • Microcirculation disorders i.e. circulation disorders caused by microvascular dysfunction, can be caused by metabolic or oxidative stress leading to diseases where vascular dysfunction or damages are involved.
  • the present invention provides a new approach for improving microcirculation by treatment and/or prevention of such disorders of microcirculation which are caused by reduced endogenous NO production by cells otherwise needed for local prevention of vessel spasm or loss of dilatory reactivity as well as prevention of cell mediated damage.
  • the improvement of NO- dependent microvascular dysfunction is especially important in small vessels or capillary vessels where the ratio of vessel wall surface area to blood volume is high, and provides a new approach for treatment and prevention of disorders of the NO. Therefore, radical scavengers like Dipyridamole and Mopidamol alone or in combination with substance capable of increasing NO production may have therapeutic potential in a variety of diseases involving progressive dysfunction of medium and small-sized vessels.
  • disorders of the microcirculation according to the present invention are meant to be those where by metabolic or genetic influence the cells of the vasculature are no longer able to produce sufficient amount of NO, the potent local regulator of homeostasis in the vascular system.
  • Such disorders are named herein "NO-dependent microcirculation disorders”. Examples of such disorders are
  • diabetic angiopathy especially diabetic microangiopathy, e.g. diabetic gangrene, diabetic retinopathy, diabetic neuropathy, or such as hyperhomocysteinemia, homocysteinuria, pulmonary hypertension, mucoviscidosis, neuro-degenerative disease, ulcus cruris, atrophic gastritis, colitis ulcerosa, or microcirculation disorders occuring after partial resection of stomach and / or bowels, •
  • diabetic angiopathy especially diabetic microangiopathy, e.g. diabetic gangrene, diabetic retinopathy, diabetic neuropathy, or such as hyperhomocysteinemia, homocysteinuria, pulmonary hypertension, mucoviscidosis, neuro-degenerative disease, ulcus cruris, atrophic gastritis, colitis ulcerosa, or microcirculation disorders occuring after partial resection of stomach and / or bowels, •
  • microcirculation disorders caused by inflammatory reactions, such as morbus crohn, colitis ulcerosa or acute respiratory dystress syndrome (ARDS) ;
  • ARDS acute respiratory dystress syndrome
  • autoimmune diseases such as autoimmune chronic-active hepatitis (idiopathic hepatitis) , primary-biliary cirrhosis or (autoimmune associated) multiple sclerosis, •
  • peripheral microcirculation disorders such as Raynaud's disease, tinnitus or sudden loss of hearing
  • microcirculation disorders associated with increased cell fragmentation such as tumor diseases or thrombotic-thrombocytopenic purpura
  • nephrosclerosis prerenal hypertension
  • haemolytic-uremic syndrome (HUS) arterial hypertension
  • vascular dementia nephrosclerosis , prerenal hypertension, haemolytic-uremic syndrome (HUS) , arterial hypertension, vascular dementia,
  • the present invention provides a method for improving the blood supply of the myocardium in a person in need of such treatment, for example in a person suffering from ischemic or coronary heart disease, as well as a method for prevention of myocardial infarction or re-infarction. This in particular after successful reperfusion by mechanical or pharmacological revascularisation and in parallel or after the inhibition of acute rethrombosis / reocclusion by strong inhibitors of platelet aggregation.
  • treatment of "NO-dependent microcirculation disorders" within the present invention also includes treatment or prevention of atherosclerosis by improving perfusion through the vasa vasorum of large vessels.
  • NO-dependent disorders of the microcirculation can be approached by either increasing the local production of NO or, preferably, by combining the increase of NO with reducing the local destruction of NO.
  • Preferred is pulmonary hypertension; re-establishment of blood flow upon insufficient tissue perfusion after revascularisation of large arteries such as after acute MI or Stroke or in peripheral artery disease in addition or following acute antiplatelet therapy to prevent acute reocclusion, e.g.
  • WO 98/11896 conditions where dysfunction is caused by re-perfusion injury after revasularisation or in transplant recipient; peripheral microcirculation disorders, such as Raynaud's disease, tinnitus or sudden loss of hearing; vascular dementia, Alzheimer's disease; homocysteinuria and homocystine-induced vasculopathy; ischemic or coronary heart diseases; prevention of myocardial infarction or reinfarction; and treatment or prevention of atherosclerosis .
  • peripheral microcirculation disorders such as Raynaud's disease, tinnitus or sudden loss of hearing
  • vascular dementia Alzheimer's disease
  • homocysteinuria and homocystine-induced vasculopathy ischemic or coronary heart diseases
  • prevention of myocardial infarction or reinfarction prevention or prevention of atherosclerosis .
  • Most preferred indication to be treated according to the present invention is insufficient tissue perfusion after revascularisation of large arteries such as after acute MI or Stroke or re-establishment of blood flow in peripheral artery disease in addition or following acute antiplatelet therapy to prevent acute reocclusion; homocysteinuria and homocystine- induced vasculopathy; and vascular dementia.
  • NO-dependent microcirculation disorders can be treated according to the present invention by a method of treatment comprising a substance which scavenges free radicals.
  • Preferred is a substance that scavenges free oxy- and / or peroxi- radicals.
  • Probucol Ascorbic acid, Alpha tocopherol, Dipyridamole or Mopidamol ;
  • a said substance is applied optionally in combination with an agent capable of increasing NO production.
  • a compound capable to increase NO production according to the present invention is, for example,
  • Acetylcholine estrogen or
  • HMG CoA reductase inhibitors such as
  • CI 981 preferred is ovastatin
  • eNOS endothelial nitric oxide synthe- tase
  • the substance which scavenges free radicals is chosen as Dipyridamole or Mopidamol it is of advantage to maintain a plasma level of Dipyridamole or Mopidamol of about 0.2 to 5 ⁇ mol/L, preferably of about 0.4 to 5 ⁇ mol/L, especially of about 0.5 to 2 ⁇ mol/L or particularly of about 0.8 to 1.5 ⁇ mol/L or when combined with HMO CoA reductase inhibitors at 0.2 to 2.0 ⁇ mol/L.
  • Dipyridamole or Mopidamol can be administered orally in a daily dosage of 25 to 450 mg, preferably 50 to 240 mg, most preferred 75 to 200 mg.
  • a daily dosage of 25 to 450 mg preferably 50 to 240 mg, most preferred 75 to 200 mg.
  • it is of advantage to administer repeated doses such as a dose of 25 mg Dipyridamole retard or any other instant release formulation three or four times a day.
  • Dipyridamole could be given in a dosage of 0.5 to 5 mg/kg body weight, preferably 1 to 3.5 mg/kg body weight, during 24 hours as slow i.v. infusion (not faster than 0.2 mg/min) .
  • Dipyridamole ⁇ 2, 6-bis (diethanolamino) -4, 8-dipiperidino-pyri- mido [5, 4-d] pyrimidine ⁇ closely related substituted pyrimido- pyrimidines and their preparation have been described in e.g. U.S. Patent 3,031,450. Further related substituted pyrimido- pyrimidines and their preparation have been described in e.g. GB 1,051,218, inter alia the compound Mopidamol ⁇ 2,6-bis- (diethanolamino) -4-piperidinopyrimido [5 , 4-d] pyrimidine ⁇ . Dipyridamole was introduced as a coronary vasodilator in the early 1960s.
  • Dipyridamole appears to enhance of above-mentioned antithrom- botic mechanisms (cAMP - increase, cGMP- increase) of the vessel wall, in addition to its adenosine-sparing effects. It stimulates prostacyclin production by increasing intracellular levels of cAMP, and it enhances the strongly nitric oxide system by increasing cGMP. It further prevents local fibrin formation.
  • Dipyridamole also has antioxidant properties (Free Radic. Biol. Med. 1995; 18: 239-247) that may contribute to its antiatherosclerotic effect.
  • Low density lipo- proteins become recognized by the scavenger receptor on macro- phages, which is assumed to be the necessary step in the development of atherosclerosis (Ann. Rev. Med. 1992; 43: 219-25).
  • Dipyridamole has been found to inhibit fibrinogenesis in experimental liver fibrosis (Hepatology 1996; 24: 855-864) and to suppress oxygen radicals and proteinuria in experimental animals with aminonucleoside nephropathy (Eur. J. Clin. Invest. 1998; 28: 877-883; Renal Physiol . 1984; 7: 218-226). Inhibition of lipid peroxidation also has been observed in human nonneoplastic lung tissue (Gen. Pharmacol. 1996; 27: 855-859) .
  • the present invention provides a method of treatment of the human or non-human animal body, preferably mammalian body, for treating or preventing NO-dependent micro- circulation disorders or of disease states where such micro- circulation disorders are involved, said method comprising administering to said body an effective amount of a pharmaceutical composition comprising a substance with scavenges fre radicals, according to the invention, optionally in combination with one or more agents capable of increasing NO production.
  • a preferred aspect the present invention provides the use of a pyrimido-pyrimidine selected from Dipyridamole, Mopidamol and the pharmaceutically acceptable salts thereof, Dipyridamole being preferred, optionally in combination with one or more agents capable of increasing NO production, preferably selected form the class of HMG CoA-reductase inhibitors, for the manufacture of a pharmaceutical composition for the treatment of the human or non-human animal body, preferably mammalian body, for treating or preventing NO-dependent microcirculation disorders or of disease states where such microcirculation disorders are involved.
  • Animal models used are experimental stroke models in rats and mice as well as in non-rodent animals including non-human primates.
  • the size of tissue damage after occlusion of an artery feeding a well defined area of the brain tissue is evaluated by histology and non-invasive imaging, measuring the extent of regional perfusion and tissue damage (MRI, CT) .
  • the size of the infarcted tissue is found to be dependent on the capacity of the microcirculatory system to provide blood flow in the periphery under conditions of oxidative and metabolic stress.
  • the size of the infarcted tissue is smaller after treatment with a combination of Dipyridamole and pravastatin.
  • the same effect can be shown with other agents selected from the class of HMG CoA reductase inhibitors.
  • the testing in animal models and subsequently in clinical trials with volunteers and patients includes testing of the efficacious dose range according to good clinical practice.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Toxicology (AREA)
  • Biochemistry (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne une méthode pour traiter un corps animal humain ou non humain par rapport à des troubles de la microcirculation NO-dépendants, par exemple des troubles de la microcirculation causés par des maladies métaboliques, comme des niveaux élevés de réactions inflammatoires à homocystine-homocystéine, ou par des maladies auto-immunes, à des troubles de la microcirculation périphérique ou à des troubles de la microcirculation associés à une fragmentation cellulaire élevée. Cette méthode consiste à administrer à un corps animal humain ou non humain nécessitant un tel traitement une quantité efficace d'une composition pharmaceutique contenant une substance anti-radicaux libres, telle qu'une pyrimido-pyrimidine choisie parmi Dipyridamole, Mopidamol et les sels de ceux-ci acceptables d'un point de vue pharmaceutique. La présente invention concerne également l'utilisation de cette substance pour produire une composition pharmaceutique correspondante, éventuellement en combinaison avec un agent capable d'augmenter la production de NO.
PCT/EP2002/004129 2001-04-20 2002-04-13 Utilisation de composes antiradicalaires dans le traitement et la prevention de troubles de la microcirculation no-dependants WO2002085368A2 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP02764059A EP1389112A2 (fr) 2001-04-20 2002-04-13 Utilisation de composes antiradicalaires dans le traitement et la prevention de troubles de la microcirculation no-dependants
JP2002582941A JP2004525979A (ja) 2001-04-20 2002-04-13 Ｎｏ−依存性微小循環障害の治療及び予防のためのラジカル除去化合物の使用
CA002444370A CA2444370A1 (fr) 2001-04-20 2002-04-13 Utilisation de composes antiradicalaires dans le traitement et la prevention de troubles de la microcirculation no-dependants
HU0303754A HUP0303754A3 (en) 2001-04-20 2002-04-13 Use of radical scavenging compounds for preparation of pharmaceutical compsoition suitable for treatment and prevention of no-dependent microcirculation disorders
MXPA03009506A MXPA03009506A (es) 2001-04-20 2002-04-13 USO DE COMPUESTOS ELIMINADORES DE RADICALES PARA EL TRATAMIENTO Y PREVENCIoN DE TRASTORNOS DE LA MICRO-CIRCULACION DEPENDIENTES DE NO.
AU2002338396A AU2002338396B2 (en) 2001-04-20 2002-04-13 Use of radical scavenging compounds for treatment and prevention of no-dependent microcirculation disorders
IL15809102A IL158091A0 (en) 2001-04-20 2002-04-13 Use of radical scavenging compounds for treatment and prevention of no-dependent microcirculation disorders
NZ529115A NZ529115A (en) 2001-04-20 2002-04-13 Use of probucol, ascorbic acid, vitamin E, dipyridamole and mopidamol for treatment and prevention of NO-dependent microcirculation disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10119680A DE10119680A1 (de) 2001-04-20 2001-04-20 Verwendung von Radikalfänger-Verbindungen zur Behandlung und Verhinderung von no-abhängigen Störungen der Mikrozirkulation
DE10119680.6 2001-04-20

Publications (2)

Publication Number Publication Date
WO2002085368A2 true WO2002085368A2 (fr) 2002-10-31
WO2002085368A3 WO2002085368A3 (fr) 2003-02-20

Family

ID=7682292

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/004129 WO2002085368A2 (fr) 2001-04-20 2002-04-13 Utilisation de composes antiradicalaires dans le traitement et la prevention de troubles de la microcirculation no-dependants

Country Status (10)

Country Link
EP (1) EP1389112A2 (fr)
JP (1) JP2004525979A (fr)
AU (1) AU2002338396B2 (fr)
CA (1) CA2444370A1 (fr)
DE (1) DE10119680A1 (fr)
HU (1) HUP0303754A3 (fr)
IL (1) IL158091A0 (fr)
MX (1) MXPA03009506A (fr)
NZ (1) NZ529115A (fr)
WO (1) WO2002085368A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113244395A (zh) * 2020-02-10 2021-08-13 广州市妇女儿童医疗中心 纤维化疾病机制及其治疗药物

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2594407C (fr) * 2005-02-11 2014-06-10 Nolabs Ab Dispositif, procede et utilisation destines a traiter une neuropathie impliquant l'oxyde nitrique
MD4341C1 (ro) * 2013-11-21 2015-11-30 Ион МЕРЕУЦЭ Sirop pentru tratamentul stărilor precanceroase gastrice
WO2016119701A1 (fr) * 2015-01-28 2016-08-04 Realinn Life Science Limited Composés pour augmenter l'expression et la translocation nucléaire de pparγ et utilisation thérapeutique correspondante

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0457671A2 (fr) * 1990-05-14 1991-11-21 FIDIA S.p.A. Dipyridamide pour le traitement du système nerveux central ou périphérique
EP0543653A1 (fr) * 1991-11-21 1993-05-26 Eli Lilly And Company Dipyridamole pour le traitement de maladies prolifératives
WO1995006470A1 (fr) * 1993-08-30 1995-03-09 Merck & Co., Inc. Prevention et traitement de la maladie d'alzheimer
US5639482A (en) * 1993-11-10 1997-06-17 Crary; Ely J. Composition for control and prevention of diabetic retinopathy
WO2000067737A2 (fr) * 1999-05-07 2000-11-16 The Brigham And Women's Hospital, Inc. UTILISATION D'INHIBITEURS DE HMGCoA REDUCTASE POUR LA PREVENTION DE MALADIES DONT LA PATHOGENESE DEPEND D'UNE NEOFORMATION DE VAISSEAUX SANGUINS
EP1093814A1 (fr) * 1999-10-22 2001-04-25 Boehringer Ingelheim Pharma KG Utilisation du dipyridamole ou du mopidamol dans la fabrication d'un médicament pour le traitement et la prévention des troubles de la microcirculation dépendants de la fibrine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1711892A1 (ru) * 1989-01-06 1992-02-15 Московский медицинский стоматологический институт им.Н.А.Семашко Способ лечени диабетической ангиопатии
SU1711894A1 (ru) * 1989-08-08 1992-02-15 Детская Клиническая Больница N1 Способ лечени декомпенсированных форм стенозирующего ларинготрахеита у детей

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0457671A2 (fr) * 1990-05-14 1991-11-21 FIDIA S.p.A. Dipyridamide pour le traitement du système nerveux central ou périphérique
EP0543653A1 (fr) * 1991-11-21 1993-05-26 Eli Lilly And Company Dipyridamole pour le traitement de maladies prolifératives
WO1995006470A1 (fr) * 1993-08-30 1995-03-09 Merck & Co., Inc. Prevention et traitement de la maladie d'alzheimer
US5639482A (en) * 1993-11-10 1997-06-17 Crary; Ely J. Composition for control and prevention of diabetic retinopathy
WO2000067737A2 (fr) * 1999-05-07 2000-11-16 The Brigham And Women's Hospital, Inc. UTILISATION D'INHIBITEURS DE HMGCoA REDUCTASE POUR LA PREVENTION DE MALADIES DONT LA PATHOGENESE DEPEND D'UNE NEOFORMATION DE VAISSEAUX SANGUINS
EP1093814A1 (fr) * 1999-10-22 2001-04-25 Boehringer Ingelheim Pharma KG Utilisation du dipyridamole ou du mopidamol dans la fabrication d'un médicament pour le traitement et la prévention des troubles de la microcirculation dépendants de la fibrine

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
"Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. The DAMAD Study Group." DIABETES, APR 1989, 38 (4) P491-8, XP002130771 UNITED STATES *
CONNOLLY, J. P. ET AL: "Peripheral vasodilators and the management of peripheral vascular disease and Raynaud's syndrome in general practice" PHARMACOEPIDEMIOL. DRUG SAF., 1998, 7, 189-196, XP002130772 *
DATABASE MEDLINE [Online] April 1998 (1998-04) YOSHIDA W B ET AL: "Effect of alpha-tocopherol, taurine and selenium on the attenuation of ischemia/reperfusion injury of splanchnic organs." Database accession no. NLM9610832 XP002213339 & CARDIOVASCULAR SURGERY (LONDON, ENGLAND) ENGLAND APR 1998, vol. 6, no. 2, April 1998 (1998-04), pages 178-187, ISSN: 0967-2109 *
DATABASE MEDLINE [Online] April 1999 (1999-04) DENTON C P ET AL: "Probucol improves symptoms and reduces lipoprotein oxidation susceptibility in patients with Raynaud's phenomenon." Database accession no. NLM10378706 XP002213234 & RHEUMATOLOGY (OXFORD, ENGLAND) ENGLAND APR 1999, vol. 38, no. 4, April 1999 (1999-04), pages 309-315, ISSN: 1462-0324 *
DATABASE MEDLINE [Online] August 1989 (1989-08) LANGLEBEN D ET AL: "Effects of dimethylthiourea on chronic hypoxia-induced pulmonary arterial remodelling and ventricular hypertrophy in rats." Database accession no. NLM2535591 XP002213341 & CLINICAL AND INVESTIGATIVE MEDICINE. MEDECINE CLINIQUE ET EXPERIMENTALE. CANADA AUG 1989, vol. 12, no. 4, August 1989 (1989-08), pages 235-240, ISSN: 0147-958X *
DATABASE MEDLINE [Online] December 1989 (1989-12) ALI S M ET AL: "Role of plasma ascorbate in diabetic microangiopathy." Database accession no. NLM2629696 XP002213238 & BANGLADESH MEDICAL RESEARCH COUNCIL BULLETIN. BANGLADESH DEC 1989, vol. 15, no. 2, December 1989 (1989-12), pages 47-59, ISSN: 0377-9238 *
DATABASE MEDLINE [Online] December 2001 (2001-12) BERTUGLIA S ET AL: "Glucose-insulin-potassium treatment in combination with dipyridamole inhibits ischaemia-reperfusion-induced damage." Database accession no. NLM11793017 XP002213342 & DIABETOLOGIA. GERMANY DEC 2001, vol. 44, no. 12, December 2001 (2001-12), pages 2165-2170, ISSN: 0012-186X *
DATABASE MEDLINE [Online] July 1994 (1994-07) BALLMER P E ET AL: "[Antioxidant vitamins and disease--risk of a suboptimal supply]" Database accession no. NLM8073383 XP002213237 & THERAPEUTISCHE UMSCHAU. REVUE THERAPEUTIQUE. SWITZERLAND JUL 1994, vol. 51, no. 7, July 1994 (1994-07), pages 467-474, ISSN: 0040-5930 *
DATABASE MEDLINE [Online] June 1996 (1996-06) SHARMA R C ET AL: "Probucol suppresses oxidant stress in hypertensive arteries. Immunohistochemical evidence." Database accession no. NLM8783783 XP002213235 & AMERICAN JOURNAL OF HYPERTENSION: JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION. UNITED STATES JUN 1996, vol. 9, no. 6, June 1996 (1996-06), pages 577-590, ISSN: 0895-7061 *
DATABASE MEDLINE [Online] March 1993 (1993-03) ADEE A C: "Managing Raynaud's phenomenon: a practical approach." Database accession no. NLM8438681 XP002213236 & AMERICAN FAMILY PHYSICIAN. UNITED STATES MAR 1993, vol. 47, no. 4, March 1993 (1993-03), pages 823-829, ISSN: 0002-838X *
DATABASE MEDLINE [Online] November 1994 (1994-11) KEMPSKI O S: "[Neuroprotection. Models and basic principles]" Database accession no. NLM7840411 XP002213340 & DER ANAESTHESIST. GERMANY NOV 1994, vol. 43 Suppl 2, November 1994 (1994-11), pages S25-S33, ISSN: 0003-2417 *
DATABASE WPI Section Ch, Week 199252 Derwent Publications Ltd., London, GB; Class B05, AN 1992-431746 XP002213240 & SU 1 711 892 A (MOSC HEAMATOLOGY BLOOD TRANSFUSION INST), 15 February 1992 (1992-02-15) *
DATABASE WPI Section Ch, Week 199252 Derwent Publications Ltd., London, GB; Class B05, AN 1992-431748 XP002213239 & SU 1 711 894 A (KIEV CHILD CLINIC-2), 15 February 1992 (1992-02-15) *
KAISER H J ET AL: "SHORT-TERM EFFECT OF DIPYRIDAMOLE ON BLOOD FLOW VELOCITIES IN THE EXTRAOCULAR VESSELS" INTERNATIONAL OPHTHALMOLOGY,NL,NIJHOFF/JUNK, DORDRECHT, vol. 19, no. 6, 1 January 1996 (1996-01-01), pages 355-358, XP000650843 ISSN: 0165-5701 *
MARMONT AM ET AL: "Thrombotic thrombocytopenic purpura successfully treated with a combination of dipyridamole and aspirin." HAEMATOLOGICA, APR 1980, 65 (2) P222-31, XP002130770 ITALY *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113244395A (zh) * 2020-02-10 2021-08-13 广州市妇女儿童医疗中心 纤维化疾病机制及其治疗药物

Also Published As

Publication number Publication date
EP1389112A2 (fr) 2004-02-18
DE10119680A1 (de) 2002-11-14
HUP0303754A2 (hu) 2004-03-01
HUP0303754A3 (en) 2006-02-28
AU2002338396B2 (en) 2007-10-18
WO2002085368A3 (fr) 2003-02-20
JP2004525979A (ja) 2004-08-26
NZ529115A (en) 2005-08-26
MXPA03009506A (es) 2004-02-12
IL158091A0 (en) 2004-03-28
CA2444370A1 (fr) 2002-10-31

Similar Documents

Publication Publication Date Title
US20080113934A1 (en) Use of dipyridamole or mopidamol for treatment and prevention of fibrin-dependent microcirculation disorders
US20090192123A1 (en) Use of dipyridamole or mopidamole for treatment and prevention of thrombo-embolic diseases and disorders caused by excessive formation of Thrombin and/or by elevated expression of Thrombin receptors
US20080113949A1 (en) Use of dipyridamole in combination with acetylsalicylic acid and an angiotensin II antagonist for stroke prevention
US20080076786A1 (en) Use of radical-scavenging compounds for treatment and prevention of no-dependent microcirculation disorders
AU2002338396B2 (en) Use of radical scavenging compounds for treatment and prevention of no-dependent microcirculation disorders
AU2002338396A1 (en) Use of radical scavenging compounds for treatment and prevention of no-dependent microcirculation disorders
US20080275011A1 (en) Use of dipyridamole, acetylsalicylic acid and an angiotensin ii antagonist for treatment and prevention of vascular events
KR20050018330A (ko) 혈관장애의 치료 및 예방을 위한 디피리다몰,아세틸살리실산 및 안지오텐신 ⅱ 길항제의 용도
JP2005060359A (ja) 血管系病態の治療及び予防のためのジピリダモール、アセチルサリチル酸及びアンギオテンシンｉｉ拮抗薬の使用
MXPA03007462A (es) Uso de dipiridamol, acido acetilsalicilico y un antagonista de la angiotensina ii para el tratamiento y la prevencion de eventos vasculares.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 158091

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2002764059

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2002338396

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2444370

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2003/009506

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2002582941

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 529115

Country of ref document: NZ

WWP Wipo information: published in national office

Ref document number: 2002764059

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 529115

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 529115

Country of ref document: NZ