WO2007129149A1 - Composition et procede destines au traitement du stade aigu de l'infarctus du myocarde a l'aide de cyclosporine a ou de melle4-cyclosporine - Google Patents

Composition et procede destines au traitement du stade aigu de l'infarctus du myocarde a l'aide de cyclosporine a ou de melle4-cyclosporine Download PDF

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Publication number
WO2007129149A1
WO2007129149A1 PCT/IB2007/000402 IB2007000402W WO2007129149A1 WO 2007129149 A1 WO2007129149 A1 WO 2007129149A1 IB 2007000402 W IB2007000402 W IB 2007000402W WO 2007129149 A1 WO2007129149 A1 WO 2007129149A1
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Prior art keywords
cyclosporin
reperfusion
composition
melle
myocardial infarction
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PCT/IB2007/000402
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English (en)
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Michel Ovize
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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

Definitions

  • the invention relates to a composition and a method for the treatment of acute myocardial infarction, especially in humans.
  • Acute myocardial infarction is frequent (about 1 ,000,000 cases per year in the United States of America) and remains a leading cause of cardiac death in Western countries.
  • Heart failure is an increasingly common outcome of myocardial infarction, and a frequent cause of cardiovascular morbidity and mortality, with approximately 400,000 new cases reported annually in the United States of America. Survival 5 years after the diagnosis of heart failure is poor, ranging as low as 25-35%.
  • Infarct size is a major determinant of post-infarction mortality: the largest the infarct, the worse the prognosis. Besides treatment of heart failure per se, limitation of infarct size appears the best-suited strategy to improve survival .
  • Acute myocardial infarctions are consecutive to ischemia, which are generally caused by insufficient blood circulation toward the cardiac tissues, leading to reduced oxygen supply to the myocardial tissue.
  • the treatment of acute myocardial infarction is primarily based on reperfusion of jeopardized myocardium, i .e. re-opening of the occluded coronary artery, either by thrombolysis or by percutaneous coronary intervention (PCI), in order to restore blood circulation in the myocardial tissue suffering from ischemia.
  • PCI percutaneous coronary intervention
  • this re-opening of the culprit coronary artery does salvage part of the jeopardized myocardium
  • reperfusion per se also kills a significant amount of cardiac tissue.
  • the final damage of cardiac tissue represents the addition of an irreversible damage occuring before the re-opening of the occluded coronary artery (ischemic damage), to an irreversible damage occuring just at the time of reflow (reperfusion damage).
  • the invention relates to a composition for the treatment of acute myocardial infarction, comprising Cyclosporin A or MeIIe 4 - cyclosporin as an active principle, in a pharmaceutically suitable vehicle.
  • the composition of the invention is more particularly intended to be used in humans.
  • the vehicle is then chosen so as to be suitable for such an application.
  • the invention also relates to the use of Cyclosporin A or Melle 4 -cyclosporin for the preparation of a composition for the treatment of acute myocardial infarction, and to a method for such a treatment with such a composition, said method comprising at least starting said administration before proceeding to a reperfusion process after a prolonged myocardial ischemia.
  • Cyclosporin A is a cyclic undecapeptide poly-N- methylated, of the structure (in its usual nomenclature) :
  • Abu is L- ⁇ -aminobutyric acid; Ala is L-alanin; MeBmt is N- methyl-(4R)-4-[(E)-2-butenyl]-4-methyl-L-threonin; MeLeu is N- methyl-L-leucin; MeVaI is N-methyl-L-valin; Leu is L-leucin; Sar is sarcosin ; VaI is L-Valin.
  • CsA may be prepared by known methods, such as described for example by Kobel and al ., European Journal of applied microbiology and biotechnology, 1982; 14: 237-240, or in US 4, 108,985.
  • Melle 4 -cyclosporin may be obtained by known methods, such as fermentation of the fungus Tolypocladium niveum (also designated Beauveria nivea), followed by extraction and purification.
  • the compound obtai ned is > 98% pure as determined by analytical high-pressure l iquid chromatography (Rosenwirth B and al ., Anti microbal agents and chemotherapy, 1 994;38 (8): 1763-1772).
  • a composition according to the invention contains from about 5 mg to about 6 g of Cyclosporin A, in a vehicle suitable to be administered intravenously at a dose of from 0.1 to 50 mg of Cyclosporin A per kg of body weight of a patient.
  • composition according to the invention contains from about 5 mg to about 6 g of Melle 4 -cyclosporin in a vehicle suitable to be administered intravenously at a dose of from 0.1 to 50 mg of Melle 4 -cyclosporin per kg of body weight of a patient.
  • the administration is carried out at a concentration of 0.1 to 50 mg of CsA or Melle 4 -cyclosporin, per kg of body weight.
  • the administration is carried o )uutt aatt aa ccoonncceennttrraattiioonn ooff 1 mg to 50 mg of CsA or MeIIe 4 - cyclosporin per kg of body weight.
  • the administration starts at least at the time of reperfusion, after a prolonged ischemia.
  • CsA and Melle 4 -cyclosporin by binding to the mitochondrial cyclophylin D, inhibit the opening of a mega-channel (called the " mitochondrial permeability transition pore ", or mPTP), located within the inner membrane of mitochondria.
  • This pore which is in a closed state in normal conditions, opens in conditions of severe stress, e.g. after prolonged ischemia and reperfusion.
  • Evidence indicates that the transition pore opens at the time of reperfusion after a prolonged myocardial ischemia. Opening of the transition pore triggers various mechanisms that may kill the cell .
  • CsA or Melle 4 -cyclospo ⁇ n administered at the concentration range of the invention, i. e. 0.1 to 50 mg per kg of body weight, by blocking the opening of the transition pore at the time of reflow, limit lethal myocardial reperfusion injury, and thus the infarct size.
  • the method according to the invention is especially suitable to be carried out in humans.
  • Administration of CsA or Melle 4 -cyclosporin is carried out before re-opening of the culprit occluded coronary artery responsible for the ischemia, either by thrombolysis or by percutaneous coronary intervention, according to standard methods.
  • the object of the invention is achieved particularly efficiently when the method for the treatment of acute myocardial infarction in humans comprises administering intravenously to a patient a composition of Melle 4 -cyclosporin as an active principle in a suitable vehicle, at a concentration of 0.1 to 50 mg of MeIIe 4 - cyclosporin per kg of body weight, starting the administration before proceeding to re-opening of the culprit occluded coronary artery after a prolonged myocardial ischemia.
  • the method of the invention may also be applied for the treatment of other diseases, in particular for the treatment of ischemic stroke, which shows an analogy to AMI both in terms of the disease and of the pathophysiology.
  • the general objective of this study was to determine whether CsA and Melle 4 -cyclosporin may reduce infarct size when administered at the time of reperfusion following a prolonged ischemia.
  • LV angiography (30° RAO) was performed just before coronary angioplasty. It was used to evaluate the size of the risk region, a major determinant of infarct size, according to validated techniques .
  • the aim of the study was to determine whether CsA, administered immediately before reperfusion, could decrease infarct size in patients with ongoing acute myocardial infarction that undergo with percutaneous transluminal coronary angioplasty. Study population
  • Blood concentration of cyclosporin A was measured at 1 and 20 minutes, 3 and 12 hours after injection (RIA kit; Diasorin®). Blood pressure, serum concentrations of creatinine, potassium, bilirubine, ⁇ -glutamyl ⁇ transpeptidase ( ⁇ G ⁇ 0 and alcaline phosphatases were measured repeatedly after cyclosporin A administration.
  • infarct size was quantified by planimetry of the hyper-enhanced myocardium with the postprocessing software Argus (Siemens, Er Weg, Germany). For all slices infarct absolute mass in grams was measured according to the following formula:
  • Infarct mass (g) ⁇ (hyperenhanced area (cm 2 )) x slice thickness (cm) * myocardial specific density (1 ,05 g/cm 3 ).
  • the area under the curve of serum creatine kinase release during the first 72 hours of reperfusion was significantly reduced in the cyclosporin A group when compared to the control group, averaging 180936 ⁇ 16134 (arbitrary units) in cyclosporin A, versus 325548 ⁇ 48136 in control, which represents a 44 % reduction in infarct size (p ⁇ 0.01 ).
  • MRl area of hyper-enhancement was significantly reduced in the cyclosporin A versus control group, averaging 39 ⁇ 5 and 53 ⁇ 5 g, respectively (p ⁇ 0.05).
  • This 29% reduction in MRI area of hyper-enhancement corresponded to the 26% and 36% reduction in time-curve areas of creatine kinase and troponin I release observed in that unselected subset of patients.
  • CsA an inhibitor of mPTP
  • Protocol II incidence of ventricular fibrillation

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition destinée au traitement du stade aigu de l'infarctus du myocarde, comprenant en tant que matière active de la cyclosporine A ou de la Melle4-cyclosporine dans un véhicule pharmaceutiquement approprié. L'invention concerne également un procédé de traitement du stade aigu de l'infarctus du myocarde par l'administration à un patient de ladite composition de cyclosporine A ou de Melle4-cyclosporine, en commençant au moins ladite administration avant de poursuivre par une reperfusion après une ischémie myocardiale. Une composition préférée contient de 5 mg à 6 g de matière active dans un véhicule pharmaceutiquement approprié à administrer par voie intraveineuse à une dose de 0,1 à 50 mg par kg de poids corporel d'un patient humain.
PCT/IB2007/000402 2006-05-04 2007-02-20 Composition et procede destines au traitement du stade aigu de l'infarctus du myocarde a l'aide de cyclosporine a ou de melle4-cyclosporine Ceased WO2007129149A1 (fr)

Priority Applications (1)

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EP07733898A EP2023948A1 (fr) 2006-05-04 2007-02-20 Composition et procede destines au traitement du stade aigu de l'infarctus du myocarde a l'aide de cyclosporine a ou de melle4-cyclosporine

Applications Claiming Priority (2)

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US41712706A 2006-05-04 2006-05-04
US11/417,127 2006-05-04

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WO2007129149A1 true WO2007129149A1 (fr) 2007-11-15

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150157610A1 (en) * 2012-05-23 2015-06-11 Osaka University Pharmaceutical composition for treating inflammatory disease
US20200376074A1 (en) * 2010-03-15 2020-12-03 Stealth Bio Therapeutics Corp Combination therapies using cyclosporine and aromatic cationic peptides
CN112168952A (zh) * 2020-10-27 2021-01-05 成都市妇女儿童中心医院 水凝胶搭载环孢素a在制备治疗心肌缺血再灌注损伤的药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19711795A1 (de) * 1997-03-21 1998-09-24 Apogepha Arzneimittel Gmbh Verwendung von Cyclosporin als Arzneimittel zur Behandlung von Myokardinfarkten und deren Folgen
WO2002026245A2 (fr) * 2000-09-29 2002-04-04 Zhong Z Robert Methodes de traitement de reactions inflammatoires et immunitaires et compositions associees
WO2006072639A1 (fr) * 2005-01-10 2006-07-13 Debiopharm S.A. Utilisation d’un undecapeptide cyclique pour la preparation d’un médicament administrable lors de situations ischemiques myocardiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19711795A1 (de) * 1997-03-21 1998-09-24 Apogepha Arzneimittel Gmbh Verwendung von Cyclosporin als Arzneimittel zur Behandlung von Myokardinfarkten und deren Folgen
WO2002026245A2 (fr) * 2000-09-29 2002-04-04 Zhong Z Robert Methodes de traitement de reactions inflammatoires et immunitaires et compositions associees
WO2006072639A1 (fr) * 2005-01-10 2006-07-13 Debiopharm S.A. Utilisation d’un undecapeptide cyclique pour la preparation d’un médicament administrable lors de situations ischemiques myocardiques

Non-Patent Citations (14)

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Title
ALWARDT CORY MATTHEW ET AL: "Effects of cyclosporine on hemodynamic parameters following acute myocardial infarction in mice", FASEB JOURNAL, vol. 16, no. 5, 22 March 2002 (2002-03-22), & ANNUAL MEETING OF PROFESSIONAL RESEARCH SCIENTISTS ON EXPERIMENTAL BIOLOGY; NEW ORLEANS, LOUISIANA, USA; APRIL 20-24, 2002, pages A1132, XP009087478, ISSN: 0892-6638 *
ANONYMOUS: "Ciclosporin A and Acute Myocardial Infarction", INTERNET ARTICLE, 24 November 2006 (2006-11-24), XP002444351, Retrieved from the Internet <URL:http://clinicaltrials.gov/ct/show/NCT00403728?order=1> [retrieved on 20070726] *
ARGAUD ET AL: "La mitochondrie : une cible incontournable de la cardioprotection du myocarde ischemique", REANIMATION, ELSEVIER, PARIS, FR, vol. 15, no. 2, April 2006 (2006-04-01), pages 109 - 116, XP005656571, ISSN: 1624-0693 *
ARGAUD L ET AL., JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, vol. 38, 2005, pages 367 - 374
ARGAUD L ET AL: "Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury", JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, ACADEMIC PRESS, LONDON, GB, vol. 38, no. 2, February 2005 (2005-02-01), pages 367 - 374, XP004737465, ISSN: 0022-2828 *
ARGAUD LAURENT ET AL: "Preconditioning delays Ca2+-induced mitochondrial permeability transition.", CARDIOVASCULAR RESEARCH, vol. 61, no. 1, 1 January 2004 (2004-01-01), pages 115 - 122, XP009087338, ISSN: 0008-6363 *
AU L ET AL: "2530 Ciclosporin delays calcium-induced mitochondrial permeability transition when administered at reperfusion", EUROPEAN HEART JOURNAL, THE EUROPEAN SOCIETY OF CARDIOLOGY, vol. 24, no. 5, March 2003 (2003-03-01), pages 476, XP004531324, ISSN: 0195-668X *
GOMEZ L ET AL: "Mitochondrial versus Fas/Fas ligand pathway activation following ischaemia-reperfusion", EUROPEAN HEART JOURNAL, vol. 25, no. Suppl. S, August 2004 (2004-08-01), & ESC CONGRESS 2004; MUNICH, GERMANY; AUGUST 28 -SEPTEMBER 01, 2004, pages 233, XP009087346, ISSN: 0195-668X *
JEKABSONE A ET AL: "Pre-perfusion with cyclosporin a prevents ischemia-induced apoptotic processes in myocardium", CLINICAL CHEMISTRY AND LABORATORY MEDICINE, vol. 39, no. Special Supplement, 2001, & 14TH IFCC-FESCC EUROPEAN CONGRESS OF CLINICAL CHEMISTRY AND LABORATORY MEDICINEAND 5TH CZECH NATION; PRAGUE, CZECHOSLOVAKIA; MAY 26-31, 2001, pages S354, XP009087479, ISSN: 1434-6621 *
KIN, J. CARDIOVASC. RES., vol. 62, no. 1, 2004, pages 74 - 85
LESHNOWER BRADLEY G ET AL: "Inhibition of the mitochondrial permeability transition porereduces reperfusion induced myocyte apoptosis and improves early post-MI function", CIRCULATION, vol. 112, no. 17, Suppl. S, October 2005 (2005-10-01), & 78TH ANNUAL SCIENTIFIC SESSION OF THE AMERICAN-HEART-ASSOCIATION; DALLAS, TX, USA; NOVEMBER 13 -16, 2005, pages U501 - U502, XP009087477, ISSN: 0009-7322 *
STAAT, CIRCULATION, vol. 112, 2005, pages 2143 - 2148
THIBAULT HÉLÈNE ET AL: "Acute myocardial infarction in mice: assessment of transmurality by strain rate imaging.", AMERICAN JOURNAL OF PHYSIOLOGY. HEART AND CIRCULATORY PHYSIOLOGY JUL 2007, vol. 293, no. 1, July 2007 (2007-07-01), pages H496 - H502, XP002444339, ISSN: 0363-6135 *
ZHAO, AM. J. PHYSIOL. HEART CIRC. PHYSIOL., vol. 285, no. 2, 2003, pages H579 - 88

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200376074A1 (en) * 2010-03-15 2020-12-03 Stealth Bio Therapeutics Corp Combination therapies using cyclosporine and aromatic cationic peptides
US20150157610A1 (en) * 2012-05-23 2015-06-11 Osaka University Pharmaceutical composition for treating inflammatory disease
CN112168952A (zh) * 2020-10-27 2021-01-05 成都市妇女儿童中心医院 水凝胶搭载环孢素a在制备治疗心肌缺血再灌注损伤的药物中的应用

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