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EP1389112A2 - 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

Info

Publication number
EP1389112A2
EP1389112A2 EP02764059A EP02764059A EP1389112A2 EP 1389112 A2 EP1389112 A2 EP 1389112A2 EP 02764059 A EP02764059 A EP 02764059A EP 02764059 A EP02764059 A EP 02764059A EP 1389112 A2 EP1389112 A2 EP 1389112A2
Authority
EP
European Patent Office
Prior art keywords
microcirculation disorders
disease
substance
microcirculation
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.)
Withdrawn
Application number
EP02764059A
Other languages
German (de)
English (en)
Inventor
Wolfgang Eisert
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.)
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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 and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1389112A2 publication Critical patent/EP1389112A2/fr
Withdrawn legal-status Critical Current

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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Neurology (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Obesity (AREA)
  • Biochemistry (AREA)
  • Endocrinology (AREA)
  • Transplantation (AREA)
  • Psychiatry (AREA)
  • Toxicology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (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.
EP02764059A 2001-04-20 2002-04-13 Utilisation de composes antiradicalaires dans le traitement et la prevention de troubles de la microcirculation no-dependants Withdrawn EP1389112A2 (fr)

Applications Claiming Priority (3)

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

Publications (1)

Publication Number Publication Date
EP1389112A2 true EP1389112A2 (fr) 2004-02-18

Family

ID=7682292

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02764059A Withdrawn 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

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)

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KR20070105331A (ko) * 2005-02-11 2007-10-30 노랩스 에이비 일산화질소를 포함하는 신경병증의 치료 장치, 방법 및용도
MD4341C1 (ro) * 2013-11-21 2015-11-30 Ион МЕРЕУЦЭ Sirop pentru tratamentul stărilor precanceroase gastrice
CN115282152A (zh) * 2015-01-28 2022-11-04 瑞采生技有限公司 用于增强PPARγ表现及核转位之化合物及其医疗用途
CN118903419A (zh) * 2020-02-10 2024-11-08 广州市妇女儿童医疗中心 Pde抑制剂或其盐在制备用于预防和/或治疗胃肠道疾病的药物中的用途

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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
IT1239064B (it) * 1990-05-14 1993-09-20 Fidia Spa Uso terapeutico del dipiridamolo
US5270047A (en) * 1991-11-21 1993-12-14 Kauffman Raymond F Local delivery of dipyridamole for the treatment of proliferative diseases
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

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* Cited by examiner, † Cited by third party
Title
See references of WO02085368A2 *

Also Published As

Publication number Publication date
DE10119680A1 (de) 2002-11-14
CA2444370A1 (fr) 2002-10-31
NZ529115A (en) 2005-08-26
HUP0303754A3 (en) 2006-02-28
HUP0303754A2 (hu) 2004-03-01
WO2002085368A2 (fr) 2002-10-31
AU2002338396B2 (en) 2007-10-18
WO2002085368A3 (fr) 2003-02-20
IL158091A0 (en) 2004-03-28
JP2004525979A (ja) 2004-08-26
MXPA03009506A (es) 2004-02-12

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