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WO2023070164A1 - Traitement d'une insuffisance cardiaque avec fraction d'éjection préservée - Google Patents

Traitement d'une insuffisance cardiaque avec fraction d'éjection préservée Download PDF

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Publication number
WO2023070164A1
WO2023070164A1 PCT/AU2022/051301 AU2022051301W WO2023070164A1 WO 2023070164 A1 WO2023070164 A1 WO 2023070164A1 AU 2022051301 W AU2022051301 W AU 2022051301W WO 2023070164 A1 WO2023070164 A1 WO 2023070164A1
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WIPO (PCT)
Prior art keywords
heart failure
pharmaceutically acceptable
ejection fraction
subject
acceptable salt
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Ceased
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PCT/AU2022/051301
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English (en)
Inventor
Ravi Krishnan
Maria VISTNES
Geir Christensen
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.)
Paradigm Biopharmaceuticals Ltd
Universitetet i Oslo
Oslo Universitetssykehus hf
Original Assignee
Paradigm Biopharmaceuticals Ltd
Universitetet i Oslo
Oslo Universitetssykehus hf
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Priority claimed from AU2021903453A external-priority patent/AU2021903453A0/en
Application filed by Paradigm Biopharmaceuticals Ltd, Universitetet i Oslo, Oslo Universitetssykehus hf filed Critical Paradigm Biopharmaceuticals Ltd
Publication of WO2023070164A1 publication Critical patent/WO2023070164A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue

Definitions

  • This invention relates to the use of pentosan polysulfate, including pharmaceutically acceptable salts and compositions thereof for the treatment of heart failure in a mammal.
  • the invention relates to the use of pentosan polysulfate, including pharmaceutically acceptable salts and compositions thereof for the treatment of heart failure with preserved ejection fraction.
  • Pentosan polysulfate is a weaker anticoagulant than heparin but has been used post-surgically and prophylactically as a thrombolytic agent.
  • PPS is used as the sodium salt (NaPPS).
  • NaPPS sodium salt
  • NaPPS is the active agent in the drug ELMIRON® which is currently prescribed for interstitial cystitis.
  • PPS chronic obstructive pulmonary disease
  • PPS has been disclosed as effective in the treatment of acute respiratory disease syndrome (ARDS). Particularly, the use of PPS in the treatment of ARDS induced by coronaviruses, such as SARS-CoV-2.
  • ARDS acute respiratory disease syndrome
  • PPS is an effective inhibitor of ADAMTS4 or AD AMTS 5. This property is useful in treating or preventing cardiac remodeling or chronic heart failure in a subject with cardiac remodeling or chronic heart failure or with a condition that may lead to cardiac remodeling or chronic heart failure.
  • Heart failure with preserved ejection fraction is a clinical syndrome in which patients have clinical features of heart failure in the presence of normal or near-normal left ventricular ejection fraction, usually defined as ejection fraction at 50% or above.
  • the left ventricle contracts and pumps normally but the muscle may be stiff or thickened. This prevents the ventricle from relaxing properly and filling up with blood all the way.
  • the ejection fraction may be normal, the heart has less blood available inside the ventricle to pump out to the rest of the body when the heart contracts.
  • Heart failure with reduced ejection is a clinical syndrome in which patients have clinical features of heart failure in the presence of reduced left ventricular ejection fraction, usually defined as ejection fraction of 40% or less.
  • the left ventricle may be enlarged and cannot contract forcefully enough to pump the right amount of blood to the rest of the body.
  • Multimorbidity is common in HFpEF with approximately 50% of patients having five or more major comorbidities.
  • Estimates of mortality of patients with HFpEF vary depending on the study design with consistently higher mortality in observational studies than clinical trial populations. At 1 year, mortality in HFpEF ranges from 20% to 29% and, by 5 years, at least half of the patients have died with published mortality estimates ranging from 53% to 74%.
  • Myocardial fibrosis is an important part of cardiac remodeling that leads to heart failure and death. Myocardial fibrosis results from increased myofibroblast activity and excessive extracellular matrix deposition. It is defined by a significant increase in the collagen volume of myocardial tissue. It is a complex process that involves all components of the myocardial tissue and can be triggered by tissue injury from myocardial ischemia (hypoxia), inflammation, and hypertensive overload. Summary
  • the present disclosure provides a method of treating heart failure with preserved ejection fraction (HFpEF) comprising administering an effective amount of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • HFpEF preserved ejection fraction
  • the present disclosure further provides a use of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of heart failure with preserved ejection fraction (HFpEF).
  • HFpEF preserved ejection fraction
  • the present disclosure still further provides a composition comprising pentosan polysulfate, or a pharmaceutically acceptable salt thereof, for the treatment of heart failure with preserved ejection fraction (HFpEF).
  • HFpEF preserved ejection fraction
  • the present disclosure still further provides a method of treating heart failure with reduced ejection fraction (HFrEF) comprising administering an effective amount of pentosan polysulfate, or pharmaceutically acceptable a salt thereof, to a subject in need thereof.
  • HFrEF reduced ejection fraction
  • the present disclosure still further provides a use of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of heart failure with reduced ejection fraction (HFrEF).
  • the present disclosure still further provides a composition comprising pentosan polysulfate, or a pharmaceutically acceptable salt thereof, for the treatment of heart failure with reduced ejection fraction (HFrEF).
  • PPS is effective in the treatment of myocardial fibrosis resulting from heart failure with preserved ejection fraction (HFpEF).
  • the present disclosure also contemplates the prophylactic treatment of an individual diagnosed with a risk of heart failure with preserved ejection fraction (HFpEF).
  • HFpEF preserved ejection fraction
  • the present disclosure provides a method of prophylactic ally treating a subject with a risk of heart failure with preserved ejection fraction (HFpEF) comprising administering an effective amount of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, to the subject.
  • HFpEF preserved ejection fraction
  • the present disclosure further provides a use of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prophylactic treatment of a subject at risk of heart failure with preserved ejection fraction (HFpEF).
  • HFpEF preserved ejection fraction
  • the present disclosure still further provides a composition comprising pentosan polysulfate, or a pharmaceutically acceptable salt thereof, for the prophylactic treatment of a subject at risk of heart failure with preserved ejection fraction (HFpEF).
  • HFpEF preserved ejection fraction
  • the present disclosure further contemplates the prophylactic treatment of an individual diagnosed with a risk of heart failure with reduced ejection fraction (HFrEF).
  • HFrEF reduced ejection fraction
  • the present disclosure provides a method of prophylactic ally treating a subject with a risk of heart failure with reduced ejection fraction (HFrEF) comprising administering an effective amount of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, to the subject.
  • the present disclosure further provides a use of pentosan polysulfate, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prophylactic treatment of a subject at risk of heart failure with reduced ejection fraction (HFrEF).
  • HFrEF reduced ejection fraction
  • the present disclosure still further provides a composition comprising pentosan polysulfate, or a pharmaceutically acceptable salt thereof, for the prophylactic treatment of a subject at risk of heart failure with reduced ejection fraction (HFrEF).
  • HFrEF reduced ejection fraction
  • Figure 2 shows echocardiographic measurements for diastolic dysfunction and increased filling pressures as a ratio of peak mitral inflow velocity (E) to mitral tissue velocity (e') (E/e').
  • the term “about” refers to a range of ⁇ 10% of the specified value or a range associated with the experimental error known to the skilled addressee in measuring the specified value, whichever is the greater.
  • acceptable excipient includes excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are physiologically compatible and are not deleterious to PPS or a compound as described herein or use thereof.
  • excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are physiologically compatible and are not deleterious to PPS or a compound as described herein or use thereof.
  • solvents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are physiologically compatible and are not deleterious to PPS or a compound as described herein or use thereof.
  • the use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art. For example as taught
  • acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoro acetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; amino acid salts such as arginate, asparaginate, glutamate and the like; metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, discyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like.
  • inorganic acid salts such as hydrochloride,
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with
  • administering should be understood to mean providing PPS, or a pharmaceutically acceptable salt thereof, to the individual in need of treatment.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
  • This disclosure is directed to treatment of human subjects.
  • the treatment of a “human subject” may also be referred to as the treatment of a “patient” or an “individual”.
  • a human subject may be one who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, is treated for a condition, or who has been diagnosed with a condition to be treated or who is suspected of having a condition to be treated.
  • the terms “treating”, “treat” or “treatment” and variations thereof refer to clinical intervention designed to alter the natural course of the subject during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. A subject is successfully “treated”, for example, if one or more of the above treatment outcomes is achieved.
  • the terms “treating”, “treat” or “treatment” and variations thereof encompass “preventing”, “prevent” or “prevention” which would be understood to refer to clinical intervention designed to avert the development of a course of clinical pathology.
  • an “effective amount” encompasses a “therapeutically effective” amount which refers to at least the minimum concentration or amount required to effect a measurable improvement of a particular disease.
  • An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the PPS to elicit a desired response in the individual.
  • An effective amount is also one in which any toxic or detrimental effects of the PPS are outweighed by the therapeutically beneficial effects.
  • An “effective amount” also encompasses a “prophylactically effective” amount which refers to the amount of drug or the rate of drug administration needed to produce the desired preventive result.
  • the PPS is selected from the group consisting of: the sodium salt of pentosan polysulfate (NaPPS), the magnesium salt of pentosan polysulfate (MgPPS), the calcium salt of pentosan polysulfate (CaPPS), and the zinc salt of pentosan polysulfate (ZnPPS).
  • the pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS).
  • NaPPS is manufactured to the specifications lodged with the US FDA and European Community EMEA by Bene-PharmaChem GmbH & Co KG, Geretsried, Germany.
  • compositions include those formulated for delivery by injection, oral route (including tablets and capsules containing gastro-intestinal drug absorption extenders and enhancers), intravenous, respiratory and the like.
  • PPS is co- administered with a coxib as disclosed in PCT/AU2019/050119, the contents of which are included by way of cross-reference.
  • PPS may be co -administered with cardiovascular drugs such as Angiotension Receptor Blockers (ARB); ACEI (angiotensin-converting-enzyme inhibitors) and beta blockers as well as anti-diabetic drugs such as SGLT2 inhibitors.
  • cardiovascular drugs such as Angiotension Receptor Blockers (ARB); ACEI (angiotensin-converting-enzyme inhibitors) and beta blockers as well as anti-diabetic drugs such as SGLT2 inhibitors.
  • the treatment may be by administering through intra-muscular (M) or subcutaneous (SC) routes, intravenously (IV), intra-articularly (IA), peri-articularly, topically, via suppositories or orally.
  • the treatment may also be by administering through a respiratory route.
  • the respiratory route may be an intra-nasal route; an intratracheal or endo-tracheal route.
  • the respiratory route may be a pulmonary route. Administration through the pulmonary route may be achieved using a nebulizer, metered-dose inhaler or dry-power inhaler.
  • the present disclosure contemplates the methods, the compositions or the uses as described above, wherein the treatment is by administering an injection.
  • the injection is, for example, an intra-muscular (IM) injection or subcutaneous (SC) injection.
  • the treatment is by administering a subcutaneous (SC) injection.
  • SC injection is a slow subcutaneous (SC) injection.
  • the treatment is by administering PPS, or the pharmaceutically acceptable salt thereof, to the subject in an effective amount of about 0.1 mg/kg to about 4 mg/kg of the subject per dose.
  • the treatment is, for example, by administering the PPS or the pharmaceutically acceptable salt thereof to the mammal in an effective amount of about 1.5 mg/kg of the subject per dose.
  • the effective amount is about 0.75 to about 1.5 mg/kg of the subject per dose.
  • the effective amount is about 0.75 to about 1.0 mg/kg of the subject per dose.
  • administration to a human subject is by dosing in a treatment regimen once weekly.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound, such as PPS or a pharmaceutically acceptable salt thereof, employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • the specific compound such as PPS or a pharmaceutically acceptable salt thereof
  • the aim of the study was to investigate the effect of Pentosan Poly sulfate Sodium (PPS) on the development of heart failure, when administered once a week via the subcutaneous route (SC) in ZSF1 obese male rats for 15 consecutive weeks.
  • PPS Pentosan Poly sulfate Sodium
  • the ZSF1 rat model So-called 2-hit animal models for HFpEF combines increased afterload by aortic banding or hypertension, with insulin resistance through obesity or diabetes.
  • ZDF lean female Zucker diabetic fatty
  • SHHF spontaneously hypertensive heart failure
  • Group 1 Control group dosed with the vehicle (Phosphate Buffered Saline (PBS) only).
  • PBS Phosphate Buffered Saline
  • Treatments were administered by the SC route at a volume of 9.3 mg/kg once a week for 15 consecutive weeks.
  • Parameters evaluated in this study included in-life observations and measurements (including morbidity/mortality, body temperature, body weight, food consumption and echocardiographic evaluation at baseline and at week 22, 25 and 29), terminal clinical chemistry, urinalysis, coagulation and hematology, organ weights, necropsy and histopathology. On the day of necropsies, arterial blood pressure and left ventricle performance were assessed using the pres sure- volume (PV) loop procedure in all animals.
  • PV sure- volume
  • Natriuretic peptides are peptide hormones that are synthesized by the heart, brain and other organs. The release of these peptides by the heart is stimulated by atrial and ventricular distension, as well as by neurohumoral stimuli, usually in response to heart failure. The main physiological actions of natriuretic peptides is to reduce arterial pressure by decreasing blood volume and systemic vascular resistance.
  • Atrial natriuretic peptide is synthesized, stored, and released by atrial myocytes in response to atrial distension, angiotensin II stimulation, endothelin, and sympathetic stimulation (beta-adrenoceptor mediated). Therefore, elevated levels of ANP are found during hypervolemic states (elevated blood volume), such as occurs in heart failure.
  • ANP is first synthesized and stored in cardiac myocytes as prepro-ANP, which is then cleaved to pro-ANP and finally to ANP.
  • ANP is the biologically active peptide.
  • BNP Brain (B-type) natriuretic peptide (BNP) is synthesized largely by the ventricles (as well as in the brain where it was first identified). BNP is first synthesized as prepro-BNP, which is then cleaved to pro-BNP and finally to BNP. Like ANP, BNP is released by the same mechanisms that release ANP, and it has similar physiological actions. Proteolysis of pro-BNP results in BNP and the N-terminal piece of pro-BNP (NT-pro-BNP). Both BNP and NT-pro-BNP are sensitive, diagnostic markers for heart failure in patients.
  • NPs are involved in the long-term regulation of sodium and water balance, blood volume and arterial pressure. There are two major pathways of natriuretic peptide actions: 1) vasodilator effects, and 2) renal effects that lead to natriuresis and diuresis.
  • NPs directly dilate veins (increase venous compliance) and thereby decrease central venous pressure, which reduces cardiac output by decreasing ventricular preload.
  • NPs also dilate arteries, which decreases systemic vascular resistance and systemic arterial pressure. Chronic elevations of NPs appear to decrease arterial blood pressure primarily by decreasing systemic vascular resistance.
  • NPs affect the kidneys by increasing glomerular filtration rate (GFR) and filtration fraction, which produces natriuresis (increased sodium excretion) and diuresis (increased fluid excretion). These renal effects of NPs are potassium sparing unlike most diuretic drugs that are used to induce natriuresis and diuresis in patients.
  • GFR glomerular filtration rate
  • a second renal action of NPs is that they decrease renin release, thereby decreasing circulating levels of angiotensin II and aldosterone. This leads to further natriuresis and diuresis. Decreased angiotensin II also contributes to systemic vasodilation and decreased systemic vascular resistance.
  • natriuretic peptides serve as a counter-regulatory system for the renin- angiotensin-aldosterone system (RAAS).
  • RAAS renin- angiotensin-aldosterone system
  • Deficiency of circulating ANP in HF is associated with several clinical factors, such as age, gender, renal function, obesity, and atrial fibrillation (AF) (Wang et al 2018).
  • Lower serum ANP concentrations in HF may demonstrate an aspect of a deficiency in circulating ANP that contributes to difficulties in treating HF (Triposkiadis et al 2016; Chirinos et al 2018).
  • HFpEF may be associated with relatively low concentrations of ANP as well as BNP.
  • HFpEF may be a promising factor for predicting the presence of low serum ANP concentrations in patients with increased atrial pressure.
  • ANP as with BNP, represents a rational treatment target in HF.
  • PPS treated Animal Nos. 2100310, 2100306 and 2100309 showed an increase of ANP and BNP values. Compared with controls, PPS treatment showed a 4.7- to 10.1-fold increase in ANP and a 3.6-to 5.7-fold increase in BNP. The other 2 animals
  • Table 1 Analysis of ANP and BNP in the serum of ZSF-1 rats at week 29 following weekly treatments with PPS or vehicle for 15 weeks.
  • Figures 1A and IB demonstrate increased levels of the natriuretic peptides
  • Echocardiographic evaluation [0080] During the study period of 15 weeks, rats developed a progression of diastolic dysfunction and a left atrial dilatation. While the ejection fraction and fractional shortening decreased during the period, which may indicate a potential deterioration of systolic function, or reflect improvement in diastolic function. Aligned with findings from previous studies in this rat model, left ventricular hypertrophy and diastolic dysfunction were already present at week 14, and progressed during the study period.
  • Figure 2 shows echocardiographic measurements for diastolic dysfunction and increased filling pressures.
  • ratio of peak mitral inflow velocity (E) to mitral tissue velocity (e') (E/e') is shown in Figure 2.
  • the reduced E/e' ratios in the PPS treatment group compared to the vehicle group are an indication of reduced ‘stiffness’ of the ventricles.

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Abstract

La présente invention concerne l'utilisation de polysulfate de pentosane, y compris de sels et de compositions pharmaceutiquement acceptables de celui-ci, pour le traitement d'une insuffisance cardiaque chez un mammifère. En particulier, l'invention concerne l'utilisation de polysulfate de pentosane, y compris de sels et de compositions pharmaceutiquement acceptables de celui-ci, pour le traitement d'une insuffisance cardiaque avec une fraction d'éjection préservée (HFpEF) et une insuffisance cardiaque avec une fraction d'éjection réduite (HFrEF).
PCT/AU2022/051301 2021-10-28 2022-10-28 Traitement d'une insuffisance cardiaque avec fraction d'éjection préservée Ceased WO2023070164A1 (fr)

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AU2021903453 2021-10-28
AU2021903453A AU2021903453A0 (en) 2021-10-28 Treatment of heart failure with preserved ejection fraction

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WO2023070164A1 true WO2023070164A1 (fr) 2023-05-04

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046237A1 (fr) * 1997-04-16 1998-10-22 The United States of America, represented by The Secretary, Department of Health & Human Services Methode de traitement de maladies vasculaires evolutives chroniques accompagnees de cicatrices
WO2011088418A2 (fr) * 2010-01-15 2011-07-21 Mount Sinai School Of Medicine Inhibition par le polysulfate de pentosane de l'activation de nfkb induite par le tnf-alpha
WO2015004209A1 (fr) * 2013-07-09 2015-01-15 Universitetet I Oslo Inhibiteurs d'adamts4 ou adamts5 à utiliser pour prévenir ou traiter un remodelage cardiaque ou une insuffisance cardiaque chronique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046237A1 (fr) * 1997-04-16 1998-10-22 The United States of America, represented by The Secretary, Department of Health & Human Services Methode de traitement de maladies vasculaires evolutives chroniques accompagnees de cicatrices
WO2011088418A2 (fr) * 2010-01-15 2011-07-21 Mount Sinai School Of Medicine Inhibition par le polysulfate de pentosane de l'activation de nfkb induite par le tnf-alpha
WO2015004209A1 (fr) * 2013-07-09 2015-01-15 Universitetet I Oslo Inhibiteurs d'adamts4 ou adamts5 à utiliser pour prévenir ou traiter un remodelage cardiaque ou une insuffisance cardiaque chronique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GONZÁLEZ ARANTXA, SCHELBERT ERIK B; DÍEZ JAVIER; BUTLER JAVED: "Myocardial Interstitial Fibrosis in Heart Failure Biological and Translational Perspectives", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 71, no. 15, 9 April 2018 (2018-04-09), AMSTERDAM, NL, pages 1696 - 1706, XP085376760, ISSN: 0735-1097, DOI: 10.1016/j.jacc.2018.02.021 *
MOHAMMED SELMA F. ET AL: "Coronary Microvascular Rarefaction and Myocardial Fibrosis in Heart Failure With Preserved Ejection Fraction", CIRCULATION, AMERICAN HEART ASSOCIATION, US, vol. 131, no. 6, 10 February 2015 (2015-02-10), US , pages 550 - 559, XP093068007, ISSN: 0009-7322, DOI: 10.1161/CIRCULATIONAHA.114.009625 *

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