EP2023948A1 - Verwendung von cyclosporin a oder melle4-cyclosporin zur behandlung von akutem myokardinfarkt - Google Patents

Verwendung von cyclosporin a oder melle4-cyclosporin zur behandlung von akutem myokardinfarkt

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Publication number
EP2023948A1
EP2023948A1 EP07733898A EP07733898A EP2023948A1 EP 2023948 A1 EP2023948 A1 EP 2023948A1 EP 07733898 A EP07733898 A EP 07733898A EP 07733898 A EP07733898 A EP 07733898A EP 2023948 A1 EP2023948 A1 EP 2023948A1
Authority
EP
European Patent Office
Prior art keywords
cyclosporin
reperfusion
composition
melle
myocardial infarction
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Withdrawn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
EP07733898A
Other languages
English (en)
French (fr)
Inventor
Michel Ovize
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.)
Hospices Civils de Lyon HCL
Original Assignee
Individual
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
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Publication of EP2023948A1 publication Critical patent/EP2023948A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—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.
  • Cyclosporin A is used on a daily basis to prevent acute cardiac graft rejection in patients that experienced heart transplantation: this currently represents its only therapeutic use. Its immunosuppressive action is due to the binding of CsA to the cytosolic cyclophilin A, that inhibits an enzyme named calcineurin , which results in blocking the transcription of early activation genes (O'Keefe and al ., Nature, 1992; 357: 692-694).
  • Melle 4 -cyclosporin is a CsA derivative, of the formula:
  • Abu is L- ⁇ -aminobutyric acid ;
  • Ala is L-alanin ;
  • MeBmt is N- methy(-(4R)-4-[(E)-2-butenyl]-4-methyl-L-threonin ;
  • MeLeu is N- methyl-L-leucin ;
  • MeIIe is N-methyl-L-isoleucin ;
  • MeVaI is N-methyl-L- valin;
  • Leu is L-leucin ;
  • Sar is sarcosin ;
  • VaI is L-Valin.
  • Melle 4 -cyclosporin the molecule is modified, as compared to CsA, at the fourth amino acid (from N-methyl-leucin to N-methyl-isoleucin: MeIIe).
  • 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).
  • CsA and Melle 4 -cyclosporin show potent anti-i nfarct properties, when administered at the ti me of reperfusion .
  • Cyclosporin A or Melle 4 -cyclospori n administered a few minutes before reperfusion, advantageously efficiently reduce infarct size of patients with ongoing myocardial infarction. They also show a beneficial effect on arrhythmias induced by ischemic insults.
  • Melle 4 -cyclosporin is particularly prefered according to the invention, because it is devoid of the immunosuppressive effect, as well as of the potential nephrotoxicity (deleterious for the kidney function) of CsA.
  • the fourth residue which is responsible for the interaction with calcineurin, is modified (from N-methyl-leucine to MeIIe), whereas the binding sites for the cyclophilins, covering residues 1 -3, 10 and 1 1 , are unchanged, resulting in prevention of calcineurin binding and retention of the ability to interact with cyclophilins (Hansson and al ., Curr. Med . Chem., 2003;10(16):1485-506).
  • Melle 4 -cyclosporin does not show the immunosuppressive effects of CsA.
  • composition of the invention may be presented in the form of a solution, a dispersion, or any other suitable pharmaceutical form.
  • 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 may be carried out intravenously, orally or by intra-coronary injection.
  • 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.
  • administration of CsA or MeIIe 4 - cyclosporin is carried out a few minutes before reperfusion. It may preferably be administered within the thirty minutes that precede reperfusion. Yet, according to conditions of first medical care, administration of CsA or Melle 4 -cyclosporin may be performed earlier, i .e. within six hours prior to reperfusion.
  • a composition of the invention may be administered together with at least one other active principle, such as anti- ischemic agents, anti-aggregants (e.g. aspirin), antithrombotic agents (e.g. heparin), angiotensin converting enzyme inhibitors, or statins.
  • active principle such as anti- ischemic agents, anti-aggregants (e.g. aspirin), antithrombotic agents (e.g. heparin), angiotensin converting enzyme inhibitors, or statins.
  • 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 invention may be applied to all cases of acute myocardial infarction, in particular to AMI related to a thrombotic occlusion of a coronary artery that occurs upon a ruptured atherosclerotic plaque.
  • the invention may also be applied to AMI related to any other cause of coronary occlusion, whatever the associated diseases and cardiovascular consequences.
  • 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.
  • CsA 50mg was dissolved by stirring in a mixture of Cremophor EL (polyethoxylated castor oil) (available from SIGMA, catalog n° C5135) (0.65g) made to a volume of 1 .0 ml in ethanol- 94%.
  • Cremophor EL polyethoxylated castor oil
  • 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.
  • Rabbits were randomly assigned to one of the following three groups. One minute before reperfusion, the rabbits received an intravenous bolus of either: vehicle (i.e. Cremophor EL) (control), CsA (10 mg/kg) as prepared in Example II, Melle 4 -cyclosporin (10 mg/kg) as prepared in Exemple I. At the end of the 4 hour reperfusion period, the animals were euthanasized and hearts were excised for further assessment of area at risk and infarct size, using the triphenyltetrazolium chloride technique.
  • vehicle i.e. Cremophor EL
  • CsA 10 mg/kg
  • Melle 4 -cyclosporin 10 mg/kg
  • infarct size averaged 60 ⁇ 6 % of the area at risk.
  • Both CsA and MeIIe -cyclosporin were able to reduce infarct size that averaged 24 ⁇ 4 % and 25 ⁇ 3 % of the area at risk (p ⁇ 0.05 versus control for both groups).
  • 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 .
  • CsA cyclosporin A
  • 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
  • LV and coronary angiography were performed using a standard Seldinger technique. Estimation of the size of the area at risk, a major determinant of infarct size, was performed by LV angiography. Coronary angioplasty was performed according to the direct stenting technique.
  • 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
  • MeIIe -cyclosporin Similar results may be obtained with MeIIe -cyclosporin, given before reperfusion to patients with ongoing AMI.
  • MeIIe -cyclosporin a CsA derivative, retains, via its interaction with the mitochondrial cyclophilin D, the ability to inhibit mPTP opening. It is also as powerful as CsA to reduce infarct size in experimental models.
  • MeIIe -cyclosporin has the advantage of lacking the immunosuppressive activity and nephrotoxicity of CsA.
  • Protocol II incidence of ventricular fibrillation

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP07733898A 2006-05-04 2007-02-20 Verwendung von cyclosporin a oder melle4-cyclosporin zur behandlung von akutem myokardinfarkt Withdrawn EP2023948A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US41712706A 2006-05-04 2006-05-04
PCT/IB2007/000402 WO2007129149A1 (en) 2006-05-04 2007-02-20 Use of cyclosporin a or melle4-cyclosporin for the treatment of acute myocardial infarction

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EP2023948A1 true EP2023948A1 (de) 2009-02-18

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WO (1) WO2007129149A1 (de)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3375449A1 (de) * 2010-03-15 2018-09-19 Stealth Peptides International, Inc. Kombinationstherapien mit cyclosporin und aromatischen kationischen peptiden
WO2013176223A1 (ja) * 2012-05-23 2013-11-28 国立大学法人大阪大学 炎症性疾患治療用医薬組成物
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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DE19711795C2 (de) * 1997-03-21 2001-03-08 Apogepha Arzneimittel Gmbh Verwendung von Cyclosporin für die Behandlung von Myokardinfarkten und deren Folgen
ATE453402T1 (de) * 2000-09-29 2010-01-15 Viron Therapeutics Inc Verwendung von serp-1 in kombination mit einem immunosuppressor zur behandlung von arthritis
PT1853296E (pt) * 2005-01-10 2012-09-26 Debiopharm Sa Utilização de um undecapeptídeo cíclico para a preparação de um medicamento para administração em situações de miocardia isquêmica

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See references of WO2007129149A1 *

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