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WO2010049423A1 - Effets de l'inhalation d'oxyde nitrique sur les lésions à long terme de reperfusion myocardique - Google Patents

Effets de l'inhalation d'oxyde nitrique sur les lésions à long terme de reperfusion myocardique Download PDF

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Publication number
WO2010049423A1
WO2010049423A1 PCT/EP2009/064155 EP2009064155W WO2010049423A1 WO 2010049423 A1 WO2010049423 A1 WO 2010049423A1 EP 2009064155 W EP2009064155 W EP 2009064155W WO 2010049423 A1 WO2010049423 A1 WO 2010049423A1
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reperfusion
nitric oxide
heart failure
reperfusion injury
effects
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Stefan Janssens
Xiaoshun Liu
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Life Sciences Research Partners vzw
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 methods of reducing effects of reperfusion injury after ischemic episodes, particularly in the cardiac muscle. More particularly, inhalation of gaseous nitric oxide at the time of reperfusion of the ischemic heart muscle reduces the long-term effects of reperfusion injury, such as reducing the development of long-term postinfarction (left) ventricular remodeling or heart failure.
  • the pathophysiology of reperfusion injury is complex and multi-faceted. Prolonged (>30 min) myocardial ischemia results in increased production of oxygen-derived free radicals (ROS), platelet aggregation, complement activation, neutrophil infiltration, myocardial calcium overload, and myocyte apoptosis causing extensive myocardial infarction, depressed left ventricular contractile function and cardiac arrhythmias (Wang et al. 2001 , Duilio et al. 2001 ). At the molecular and cellular level, activation of nuclear factor- ⁇ B (NF- KB) (Iwata et al. 2001 ), increased coronary expression of adhesion molecules (VCAM and ICAM) (Carden et al. 2000, Youker et al. 1994), and activation of platelets and leukocytes were shown to mediate some of the reperfusion- associated inflammatory responses.
  • ROS oxygen-derived free radicals
  • NF- KB nuclear factor- ⁇ B
  • NO is an important signal transduction molecule in a variety of cell types and regulates vasomotor tone, platelet activation, interaction of platelets and leukocytes with the vessel wall, immune and inflammatory responses, and apoptosis.
  • Impaired endogenous NO release by the injured coronary vascular endothelium contributes to several pathological processes in Ml/R injury.
  • the short half life of NO and the need for continuous intravascular infusion and subsequent systemic hypotensive side effects represent major shortcomings of such pharmacological interventions.
  • nitric oxide for inhalation may constitute a novel treatment paradigm in IR injury because of its potent interaction with activated neutrophils and its antiapoptotic and cytoprotective effects on ischemic cardiomyocytes (Liu et al. 2007). These pleiotropic effects resulted in a significant reduction in infarct size 4 h after reperfusion of an occluded coronary artery and improved microvascular blood flow. Long-term effects of such NO inhalation are, however, unknown.
  • the invention is based on the surprising observation that inhalation of gaseous nitric oxide at the time of myocardial reperfusion after an ischemic episode is translating into improved long-term clinical outcome with lesser degrees of maladaptive ventricular remodeling and reduction of heart failure or reduced risk thereof.
  • Heart failure is a condition caused by a weakened heart muscle implying that the heart needs to work harder to keep blood flowing through the body.
  • Heart failure develops following injury to the heart such as ischemic damage, damage caused by a heart attack, long-term high blood pressure, or an abnormality of one of the heart valves.
  • a functional heart failure stage classification system has been devised by the New York Heart Association (NYHA).
  • the stage or class of heart failure symptoms is assessed by the patient's ability to perform everyday activities and by the patient's quality of life.
  • Four classes are discerned in the NYHA classification: - Class I (Mild heart failure): No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath);
  • Heart failure is often not recognized until a more advanced stage of heart failure, commonly referred to as congestive heart failure, in which fluid may leak into the lungs, feet, legs, and in some cases the liver or abdominal cavity.
  • the development of heart failure is meant to be correlated to an earlier ischemic or hypoxic event.
  • Myocardial ischemia can develop e.g. as a result of a myocardial infarction or as a result of occluded coronary blood supply to the myocardium or by increased oxygen, and thus blood, demand by (a) tissue(s).
  • "Low-flow or no-flow ischemia” or “demand ischemia”, respectively, are the terms used for the causes of myocardial ischemia.
  • the ST segment of an electrocardiogram (ECG) is helpful in the diagnosis of ventricular ischemia or hypoxia because under those conditions, ST segment depressions or elevations may occur.
  • ECG electrocardiogram
  • the invention therefore relates in a first aspect to methods of reducing in a mammal the development of heart failure following an acute myocardial ischemic episode, said methods comprising the step of administering to said mammal gaseous nitric oxide via inhalation.
  • said heart failure is referring to long-term heart failure such as heart failure complicating an acute ischemic period (such as by myocardial infarction) and occurring or developing at 1 week, 1 month or more after the occurrence of the ischemic or hypoxic episode.
  • a traditional clinical endpoint of heart failure is usually defined as mortality rate 1 year after the occurrence of the acute myocardial ischemic or hypoxic episode.
  • a triple endpoint may be defined including (i) cardiac death (or mortality), (ii) (re)hospitalization in case of deteriorating heart failure (e.g. in case of increase in NYHA classification, e.g. from class Il to III), and (iii) recidive/recurrent myocardial infarction.
  • said development of heart failure may be (defined as or be expressed as) an increase over time in systolic and diastolic left ventricular volume. This may or may not be further accompanied by a reduction in systolic and diastolic function.
  • said development of heart failure may be (defined as or be expressed as) an increase in circulating levels of natriuretic peptides.
  • Natriuretic peptide include atrial natriuretic peptide (ANP) (or atrial natriuretic factor (ANF), or atriopeptin), brain natriuretic peptide (BNP) and the N-terminal portion of pro-BNP (NT-pro-BNP).
  • ANP is a protein (polypeptide) hormone secreted by heart muscle cells. It is involved in the homeostatic control of body water, sodium, potassium and fat (adiposity).
  • ANP is closely related to BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), which all share the same amino acid ring.
  • a review of cardiac biomarkers is provided by Carreiro-Lewandowski (2006).
  • the invention covers methods of reducing or attenuating in a mammal the effects of reperfusion injury following an acute myocardial ischemic episode, said method comprising the step of administering to said mammal gaseous nitric oxide via inhalation.
  • said effects of reperfusion injury are long-term effects of reperfusion injury such as referring to effects of reperfusion injury or functionally detrimental effects of reperfusion injury developing or occurring at 1 week, 1 month or longer after the occurrence of the ischemic or hypoxic episode.
  • said long-term effects of reperfusion injury are irreversible effects of reperfusion injury.
  • said ischemic or hypoxic episode may be caused e.g. by coronary artery occlusion, myocardial infarction or prolonged coronary artery spasm.
  • the coronary artery occlusion may be of any etiology such as of thrombotic or thromboembolic etiology, by spasm, by extrinsic compression or by trauma.
  • the gaseous nitric oxide (NO) may be administered to the mammal in need thereof in the period coinciding with the reperfusion and ending during reperfusion or together with reperfusion.
  • it may be administered over a period starting shortly prior to start of the reperfusion (pre-reperfusion period) and ending during reperfusion or together with reperfusion.
  • the gaseous NO is administered in the period following established reperfusion.
  • the total time of NO inhalation/administration may range from approximately 5 minutes to approximately 6 hours, or from approximately 5 minutes to approximately 5 hours, or may be for approximately 4 hours.
  • said NO inhalation may be occurring during at least part of the reperfusion period, or may be occurring during a period spanning part of the pre-reperfusion period and at least part of the reperfusion period.
  • the gaseous nitric oxide may be inhaled for a period of between 5 minutes and 5 hours, for instance for a period of 4 hours.
  • Systemic levels of NO obtainable via inhalation are generally substantially higher than those obtainable via NO-donor compounds without exerting negative side effects of high NO-donor concentrations. It is generally accepted that NO inhalation is safe when inhaled in concentrations ranging between approximately 5 ppm (parts per million) and approximately 100 ppm. Any NO- concentration within this range may be applied as "therapeutically effective dose" (in conjunction with the duration of administration).
  • NO-doses ranging between approximately 5 ppm and approximately 100 ppm, or between approximately 5 ppm and approximately 80 ppm are acceptable, in particular this may be a NO-dose of approximately 80 ppm.
  • the NO-dosing concentration of the inhaled NO and/or duration of NO- inhalation
  • myocardial reperfusion may be achieved by standard methods including thrombolytic therapy (with any thrombolytic agent such as tPA, uPA, streptokinase, staphylokinase, plasmin, miniplasmin, microplasmin, or any active variant thereof), percutaneous coronary intervention (PCI), or coronary bypass grafting (which is likely to be emergency coronary bypass grafting).
  • thrombolytic therapy with any thrombolytic agent such as tPA, uPA, streptokinase, staphylokinase, plasmin, miniplasmin, microplasmin, or any active variant thereof
  • PCI percutaneous coronary intervention
  • coronary bypass grafting which is likely to be emergency coronary bypass grafting.
  • any of the above-mentioned methods according to the invention may be combined with a reperfusion method such as thrombolytic therapy, percutaneous coronary intervention, or coronary bypass grafting.
  • a reperfusion method such as thrombolytic therapy, percutaneous coronary intervention, or coronary bypass grafting.
  • the reperfusion method is chosen from thrombolytic therapy, percutaneous coronary intervention, or coronary bypass grafting.
  • Any of the above-mentioned methods according to the invention may be combined with (additional) thrombolytic therapy, anticoagulant therapy or antiplatelet therapy, or with a combination of at least two thereof.
  • a method according to the invention is combined with any other therapy aiming at reducing short-term or long-term reperfusion injury.
  • Such other therapy may be the stimulation of angiogenesis by administering growth factors (as protein or via gene therapy) such as vascular endothelial growth factor (VEGF, any isoform) or placental growth factor (PIGF, any isoform), see e.g. US 6,930,089 and US 7,105,168.
  • growth factor is granulocyte colony stimulating factor (G-CSF) which is reported to have a beneficial effect by means of mobilizing bone marrow stem cells (e.g. Fukuda et al. 2002).
  • any suitable method capable of measuring a relevant heart function can be applied. Such methods include assessing ventricular function and/or ventricular architecture, measuring wall thickness in the infarct core and border zone, and/or measuring the size of the infarct zone. Any combination of any of these (i.e. at least two) can be applied. Alternatively, or in combination with the above released cardiac biomarkers can be measured to assess the stage of heart failure or the extent of reperfusion injury. Of particular interest may be the assessment of left ventricular (global and/or regional) function and/or left ventricular architecture.
  • Methods for assessing ventricular function and/or ventricular architecture, measuring wall thickness in the infarct core and border zone, and/or measuring the size of the infarct zone include single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI) with injection of contrast fluid.
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • MRI magnetic resonance imaging
  • Cardiac biomarkers include those circulating in serum (and thus having the advantage of being relatively easily amenable to determination of their concentration).
  • suitable cardiac biomarkers are those reflecting increased left ventricular hemodynamic stress, cardiomyocyte necrosis and inflammation (hsCRP, troponin, adiponectin).
  • Cardiac biomarkers of heart failure include BNP and NT-pro BNP, or ANP. An overview of cardiac biomarkers is provided by Carreiro-Lewandowksi (2006).
  • gaseous nitric oxide for treatment of any of the indications in any of the above-described methods of the invention is also covered in this invention.
  • FIGURE LEGENDS Figure 1 The experimental study protocol is schematically shown. In this prospective, randomized, placebo controlled, chronic experimental study, the effects of inhaled nitric oxide (iNO) are evaluated at baseline, during I/R, and at
  • FIG. 1 Functional analysis of left ventricle (LV) function.
  • LVEDV left ventricle
  • LVEDV end-diastolic and end-systolic volumes
  • pMI post myocardial infarction.
  • FIG. 1 Infarct size. In hearts from control pigs (panel A), the infarct zone contains mainly fibrotic scar tissue (white) while more preserved viable myocardial tissue (red) is observed in iNO pigs (panel B). Infarct sizes were calculated (panel C, as % of left ventricle).
  • Pigs were sedated using azaperone 3 mg/kg IM (Stresnil, Janssen Pharmaceutics) and anaesthetized using an IV bolus of ketamine (1 mg/kg, Anesketin, Eurovet) followed by a 10 mg/kg/h continuous infusion of 2% propofol (AstraZeneca, SA). Pigs were mechanically ventilated using a 50% oxygen gas mixture. Ventilation was adjusted to maintain physiologic PaCO 2 and pH. Continuous electrocardiographic monitoring of heart rate, rhythm, and ST-segment changes was performed.
  • Transient ischemia over the anterior wall was induced by inflating a properly-sized balloon-mounted stent for 45 min in the proximal part of LAD coronary artery. Coronary artery occlusion was confirmed by contrast injection and by ST- segment elevation on the ECG. After 45 min, the LAD balloon was deflated, and restoration of normal coronary flow for 4h was documented by angiography.
  • control or O 2 -enriched room air containing 80 ppm NO (iNO) using the
  • INOvent® delivery system starting 40 minutes after balloon occultation. After reperfusion for 240 min, the carotid arteriotomy were repaired and the dermal layers closed using standard techniques and the pigs were allowed to recover. Dual antiplatelet therapy consisting of aspirin (300mg/day) and clopidogrel
  • Cardiac MRI (3.0 T, Siemens, Erlangen, Germany) analysis was performed at 2 days and 1 1 weeks after the acute event.
  • an 8 F introduction sheath was introduced into the left carotid artery for blood sampling, hemodynamic measurements and coronary angiography, as described above.
  • the pigs were euthanized using overdose of propofol and the hearts were excised for postmortem analysis.
  • Heart rate, mean blood pressure, LVEDP, LV pressures and maximum and minimum rates of pressure development were determined using a microtip catheter (Millar® Instruments Inc., USA) at a sampling rate of 2000/sec. Data were processed using PowerLab recording and analysis software (AD Instruments, United Kingdom). 1.4 Cardiac necrosis markers
  • CK, CPK-MB and Troponin versus time curves were plot-fitted, and area under the curve (AUC) was derived, using the method reported by Vollmer et al.
  • Cardiac MRI (3.0 T, Sonata, Siemens, Erlangen, Germany) was performed at 2 days and 1 1 weeks after AMI. All studies were done with Siemens Numaris 4 cardiac MRI software, electrocardiographic triggering, and cardiac-dedicated surface coils. Global and regional function was assessed with breath-hold cineMRI in the cardiac short axis, vertical axis, and horizontal long axis. In the cardiac short axis, the LV was completely encompassed by contiguous 6-mm thick slices. Infarct area was defined as the zone of bright signal on late-enhanced images ie, 10-20 min after injection of 0.15 mmol/kg of gadopentetate dimeglumine (Gd-DTPA), using an inversion-recovery gradient- echo technique.
  • Gd-DTPA gadopentetate dimeglumine
  • Transmural extent of late hyperenhancement was graded according to the following classification: ⁇ 50% and >50 hyperenhancement.
  • First-pass perfusion imaging was performed continuously for 1 minute obtaining 80 measurements (0.8 s temporal resolution) using a dual bolus injection of Gd-DTPA (0.0015/kg, and 0.05 at 3.5 cc/sec), using an ECG-gated steady state free precession (SSFP) imaging pulse sequence in cardiac short-axis direction.
  • Regional perfusion was calculated for segments 1 -2-7-8-13 (perfusion area of the LAD artery) and used as most reliable parameter for perfusion (Barkhausen et al. 2004, Nagel et al; 2003).
  • Myocardial transmural biopsies taken from the infarct, border, and remote zones were weighted and homogenized in 400 ⁇ l 0.5 M NaOH using a Ribolyzer (Hybaid, Ashford, UK). Samples kept on ice for 15 minutes were deproteinized with an equal volume of 10% zinc sulfate, precipitates were centrifuged at 14,000 g, and total oxidized NO species (NO x ) were determined in the supernatant using ozone-based chemiluminescence following injection in vanadium (lll)-chloride reductants in-line with the Sievers Model 280 NO analyzer (Boulder, CO). This assay method detects predominantly nitrite and nitrate in tissue (Yang et al. 2003, Lopez-Ramos et al. 2005).
  • Apoptosis will be evaluated on different sections of the peri-infarct areas following terminal dUTP nick end-labeling (TUNEL) using the in situ cell death detection kit (Roche, Belgium). TUNEL-positive nuclei from these regions will be counted in 20-25 microscopic fields, and the percentage of apoptotic nuclei will be calculated from a total number of more than 2.500 nuclei for each animal.
  • Heart rate increased modestly in all groups during ischemia and reperfusion (Table 1 ).
  • LV dP/dtmax decreased and LVEDP increased 30 min after reperfusion in the control pigs, suggesting a reduction in both systolic and diastolic function (Table 1 ).
  • this progressive decline in LV function was not observed in iNO pigs, suggesting NO inhalation is safe and may have a favorable effect on LV contractile function (Table 1 ).
  • LVEDV and LVESV LV end- diastolic, end-systolic volumes
  • EF ejection fraction
  • infarct volume LVEDV and LVESV were indexed to body-surface area.
  • MRI measurements at 2d after I/R showed LV ejection fraction (LVEF) decreased similarly in control and iNO pigs (28 ⁇ 2 vs 32 ⁇ 3%, respectively).
  • LVEDV increased in control from 74 ⁇ 5 to 210 ⁇ 33 ml (P ⁇ 0.05)
  • LVEDV increased from 83 ⁇ 6 to 150 ⁇ 14 ml (P ⁇ 0.05).
  • LVEDV increased to a greater extent in control than in iNO pigs (P ⁇ 0.05).
  • LVESV increased from 53 ⁇ 3 to 147 ⁇ 23 ml in control and from 57 ⁇ 6 to 97 ⁇ 14 ml in iNO (P ⁇ 0.05).
  • LVESV increased to a greater extent in control than in iNO pigs (P ⁇ 0.05).
  • Table 2 MRI-based Analysis of Global LV Function at 2 days (baseline) and 11 weeks after m ocardial IR in ur in i s
  • G-CSF improves post-infarction heart failure by mobilizing bone marrow stem cells, but GM-CSF increases the mortality by deteriorating heart function in mice. J Card Fail 8:S191.

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Abstract

La présente invention concerne des méthodes permettant de réduire les effets des lésions de reperfusion après des épisodes ischémiques, en particulier dans le muscle cardiaque. Plus particulièrement, l'inhalation d'oxyde nitrique gazeux au moment de la reperfusion du muscle cardiaque ischémique réduit les effets à long terme des lésions de reperfusion, par exemple réduit l'apparition d'un remodelage ventriculaire (gauche) post-infarctus ou d'une insuffisance cardiaque à long terme.
PCT/EP2009/064155 2008-10-27 2009-10-27 Effets de l'inhalation d'oxyde nitrique sur les lésions à long terme de reperfusion myocardique Ceased WO2010049423A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2497489A1 (fr) * 2011-03-09 2012-09-12 CSL Behring GmbH Inhibiteur du facteur XII pour le traitement de la pénombre ischémique cérébrale et l'ischémie d'autres organes
WO2013191801A3 (fr) * 2012-06-17 2015-06-18 Astuce, Inc. Système et procédé pour améliorer le résultat d'une ischémie cérébrale
US10286047B2 (en) 2013-03-08 2019-05-14 Csl Behring Gmbh Treatment and prevention of remote ischemia-reperfusion injury

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US20070110751A1 (en) * 2005-10-25 2007-05-17 Maclellan Robb Compositions and methods for reducing infarct size

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2497489A1 (fr) * 2011-03-09 2012-09-12 CSL Behring GmbH Inhibiteur du facteur XII pour le traitement de la pénombre ischémique cérébrale et l'ischémie d'autres organes
WO2012120124A1 (fr) * 2011-03-09 2012-09-13 Csl Behring Gmbh Inhibiteurs du facteur xii pour traiter l'ischémie cérébrale silencieuse et l'ischémie d'autres organes
US9624307B2 (en) 2011-03-09 2017-04-18 The General Hospital Corporation Factor XII inhibitors for the treatment of silent brain ischemia and ischemia of other organs
US9265922B2 (en) 2012-04-16 2016-02-23 Astuce, Inc. System and method for improving outcome of cerebral ischemia
WO2013191801A3 (fr) * 2012-06-17 2015-06-18 Astuce, Inc. Système et procédé pour améliorer le résultat d'une ischémie cérébrale
US10286047B2 (en) 2013-03-08 2019-05-14 Csl Behring Gmbh Treatment and prevention of remote ischemia-reperfusion injury
US10973891B2 (en) 2013-03-08 2021-04-13 Csl Behring Gmbh Treatment and prevention of remote ischemia-reperfusion injury

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