EP2389189A1 - Procédé de prévention et de traitement d'un dysfonctionnement diastolique au moyen d'un complexe peptide/phospholipide mimétique de l'apolipoprotéine-a1 (apoa1) - Google Patents

Procédé de prévention et de traitement d'un dysfonctionnement diastolique au moyen d'un complexe peptide/phospholipide mimétique de l'apolipoprotéine-a1 (apoa1)

Info

Publication number
EP2389189A1
EP2389189A1 EP10733186A EP10733186A EP2389189A1 EP 2389189 A1 EP2389189 A1 EP 2389189A1 EP 10733186 A EP10733186 A EP 10733186A EP 10733186 A EP10733186 A EP 10733186A EP 2389189 A1 EP2389189 A1 EP 2389189A1
Authority
EP
European Patent Office
Prior art keywords
diastolic dysfunction
subject
apoa1
mimetic peptide
controlling
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Withdrawn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
EP10733186A
Other languages
German (de)
English (en)
Other versions
EP2389189A4 (fr
Inventor
Jean-Claude Tardif
David Busseuil
Eric Rheaume
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.)
Institut de Cardiologie de Montreal
Original Assignee
Institut de Cardiologie de Montreal
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 Institut de Cardiologie de Montreal filed Critical Institut de Cardiologie de Montreal
Publication of EP2389189A1 publication Critical patent/EP2389189A1/fr
Publication of EP2389189A4 publication Critical patent/EP2389189A4/fr
Withdrawn legal-status Critical Current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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • 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

Definitions

  • the present invention relates to the general field of medical methods and compounds and is particularly concerned with a method and compound for the prevention and treatment of diastolic dysfunction.
  • Diastolic dysfunction is a condition caused by an abnormal filling of the heart during diastole. This condition can cause heart failure, pulmonary edema and many other incapacitating and possibly life-threatening consequences. There is no effective and side-effect free treatment suitable for all patients for this condition. Hence, there exists a need for a new treatment of diastolic dysfunction.
  • An object of the present invention is therefore to provide a novel treatment of diastolic dysfunction.
  • the invention provides a method for preventing of treating a diastolic dysfunction in a subject, the method comprising administering to a subject in need of preventing or treating a diastolic dysfunction a therapeutically effective amount of a reverse lipid transport agonist to prevent or treat said diastolic dysfunction.
  • a reverse lipid transport agonist is a reverse cholesterol transport agonist.
  • the diastolic dysfunction is a ventricular diastolic dysfunction, a left ventricular diastolic dysfunction, or any other diastolic dysfunction.
  • the reverse lipid transport agonist is selected from the group consisting of: an HDL, a peptide with HDL-like physiological effects, a peptide with HDL-like physiological effects complexed to a lipid, an HDL-mimetic agent, a CETP modulator, an SRB1 modulator, an LXR/RXR agonist, an ABCA1 agonist, a PPAR agonist and an Apolipoprotein A-I (APOA1) mimetic peptide/phospholipid complex.
  • administering the APOA1 mimetic peptide/phospholipid complex may include injecting the APOA1 mimetic peptide/phospholipid complex in the subject.
  • dosages in this case are of from about 1 ⁇ g to about 10 g per kg body weight of the subject, about 1 mg to about .5 g per kg body weight of the subject, and about 25 mg per kg body weight of the subject.
  • the APOA1 mimetic peptide has the sequence of SEQ ID NO: 1 found herein below, and the APOA1 mimetic peptide may be complexed with egg sphingomyelin and 1 ,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC).
  • DPPC ,2-dipalmitoyl-sn-glycero-3-phosphocholine
  • the subject is a mammal, for example a human.
  • a method of controlling a diastolic dysfunction in a subject comprising providing, in a subject in need of controlling a diastolic dysfunction, an increased amount of reverse cholesterol transport for controlling the diastolic dysfunction.
  • the invention provides a method for preventing or reversing diastolic dysfunction, the method comprising administering to a patient in need thereof a reverse lipid transport agonist.
  • the invention provides a method for controlling a diastolic dysfunction in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a reverse lipid transport agonist.
  • controlling the diastolic dysfunction may include reducing a rate of progression of the diastolic dysfunction, or reversing, at least in part, the diastolic dysfunction.
  • the invention provides the use of a reverse lipid transport agonist for controlling diastolic dysfunction in a subject.
  • the invention provides the use of a reverse lipid transport agonist for the manufacture of a pharmaceutical composition of matter for controlling diastolic dysfunction in a subject.
  • the invention provides a method of preventing or treating a diastolic dysfunction in a subject, the method comprising administering, to a subject in need of preventing or treating a diastolic dysfunction, a therapeutically effective amount of a an Apolipoprotein A-I (APOA1) mimetic peptide/phospholipid complex to prevent or treat said diastolic dysfunction.
  • APOA1 Apolipoprotein A-I
  • the method comprises the administration of a therapeutically effective amount of a compound, referred to hereinafter as compound A, that mimics biologic properties of Apolipoprotein A-I (APOA1).
  • compound A a compound that mimics biologic properties of Apolipoprotein A-I
  • APOA1 Apolipoprotein A-I
  • Compound A and other suitable compounds are described in US Patent Nos. 6,287,590, issued Sep. 11 , 2001 , and 6,506,799, issued Jan. 14, 2003, which are hereby incorporated by reference in their entirety. Indeed, it is believed that in view of current knowledge regarding the action of the compounds and molecules described in these Patents, results similar to those presented herein are obtainable with these compounds and molecules.
  • treating or “treatment” of a state, disease, disorder or condition includes:
  • the benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non-domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.
  • the pharmaceutical composition of the present invention comprises at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention.
  • the compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • compositions of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th Ed., 2003 (Lippincott Williams & Wilkins).
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container, for example, in a sachet.
  • compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • the route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intra urethra I, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • Compound A is a lipoprotein that mimics biologic properties of apolipoprotein A-I (APOA1).
  • APOA1 mimetic or agonist is described in further detail in U.S. Patent No. 6,376,464 titled “Lipid complexes of APO A-1 agonist compounds,” issued to Dasseux et al. on April 23, 2002. This document is hereby incorporated by reference in its entirety.
  • these compounds include peptides, or analogues thereof, which are capable of forming amphipathic alpha-helices in the presence of lipids and which mimic the activity of APOA1. They are therefore referred-to as APOA1 agonists.
  • the agonists have as their main feature a "core" peptide composed of 15 to 29 amino acid residues, preferably 22 amino acid residues, or an analogue thereof wherein at least one amide linkage in the peptide is replaced with a substituted amide, an isostere of an amide or an amide mimetic.
  • APOA1 agonists are based, in part, on the discovery that altering certain amino acid residues in the primary sequence of the 22-mer consensus sequence disclosed in Venkatachalapathi et al., 1991 , MoI. Conformation and Biol. Interactions, Indian Acad. Sci. B: 585-596 (PVLDEFREKLNEELEALKQKLK; hereinafter "Seg rest's consensus 22-mer” or “consensus 22-mer”) that were thought to be critical for activity, yields synthetic peptides which exhibit activities that approach, or in some embodiments even exceed, the activity of native APOA1.
  • the reverse lipid transport agonist function of Compound A is hypothesized to be related to improvements in the treatment and prevention of diastolic dysfunction
  • other aspects of Compound A are also hypothesized to play a role in the beneficial effects of Compound A and related compounds.
  • the effect of the APOA1 mimetic could be through other functions of HDL-related therapies, such as decreased inflammation or improved endothelial function.
  • the phospholipid composition of the mimetic may have its importance in the antiinflammatory action.
  • Rabbits were given injections through the marginal ear vein of saline or of the APOA1 mimetic peptide (25 mg/kg) complexed with phospholipids, 3 times per week for 2 weeks. Echocardiograms were performed serially (see Echocardiography Methods), including every 3 to 4 days throughout the randomized treatment period. Two days after their last infusion, the animals underwent a final echocardiogram and were sacrificed.
  • APOA1 mimetic peptide [0054] The APOA1 mimetic peptide (Compound A) of sequence: H-Pro-Val-Leu- Asp-Leu-Phe-Arg-Glu-Leu-Leu-Asn-Glu-Leu-Leu-Glu-Ala-Leu-Lys-Gln-Lys-Leu- Lys-OH (SEQ ID NO 1) was synthesized by Polypeptide Laboratories (Torrance, CA, USA), and purity assessed by high performance liquid chromatography and mass spectral analysis was greater than 98%.
  • the peptide was complexed with egg sphingomyelin and 1 ,2-dipalmitoyl-sn-glycero-3-phosphocholine (Avanti Polar Lipids. Alabaster, AL, USA) in a 1 :1 :1 weight ratio by mixing the components in saline and performing multiple heating and cooling cycles until the solution appeared perfectly clear. Fresh solution was prepared every week under sterile conditions and kept at 4°C.
  • Transthoracic echocardiographic studies were performed at baseline, on a weekly basis starting at 8 weeks of hypercholesterolemic diet until significant AVS developed, and then after 4, 7, 10 and 14 days of APOA 1 mimetic peptide or saline control treatments. Studies were carried out with a phased-array probe 1OS (4.5 ⁇ 11.5 Megahertz) and a Vivid 7 Dimension system (GE Healthcare Ultrasound, Horten, Norway). Intra-muscular injections of ketamine (45 mg/kg) and midazolam (0.75 mg/kg) were used for sedation.
  • LV M-mode spectrum was obtained in parasternal long- axis view to measure LV diameters at both end cardiac diastole (LVDd) and systole (LVDs).
  • LV fractional shortening was calculated as (LVDd - LVDs) / LVDd x 100%.
  • Teicholz method was employed to calculate LV volumes and LV ejection fraction (EF).
  • Pulsed wave Doppler was used to evaluate transmitral flow (TMF) and pulmonary venous flow (PVF) in apical 4-chamber view. TMF was used to measure the peak velocities during early filling (E) and atrial filling (A) and to calculate the E/A ratio.
  • PVF systolic flow
  • D diastolic flow
  • Ad reversed atrial flow
  • LV basal lateral peak systolic velocities (Sm) and mitral annulus velocities during early filling (Em) and atrial filling (Am) were derived by tissue Doppler imaging (TDI).
  • TDI tissue Doppler imaging
  • LVDD left ventricular diastolic dysfunction
  • LA left atrium M-mode spectrum was obtained in parasternal long-axis view at the aortic valve level and LA dimensions were measured in both end cardiac diastole and systole.
  • LA fractional shortening was calculated as (systolic dimension - diastolic dimension) / systolic dimension x 100%. The average of 3 consecutive cardiac cycles was used for each measurement.
  • Diastolic dysfunction classification was compared across groups using chi- square test. All analyses were done with SAS version 9.1 (SAS Institute Inc., Cary, NC, USA) and conducted at the 0.05 significance level.
  • Left ventricular diastolic dysfunction (DD) was attenuated by APOA1 mimetic peptide infusions (33.3% of normal DD and 66.6% of mild DD vs. 66.6% of mild DD and 33.3% of severe DD for control rabbits).
  • Infusions of an APOA1 mimetic peptide lead to reduction of left ventricular diastolic dysfunction in a hypercholesterolemic rabbit model. Treatment of diastolic dysfunction may represent a new application for HDL-based therapies.
  • HDL-based therapy such as for example one or more infusion(s) or bolus(es) of HDL or peptide (with or without lipids) with HDL-like effects, orally administered HDL-mimetic agents, and/or the administration of cholesteryl ester transfer protein (CETP) modulators, or scavenger receptor class B, member 1 (SRB1) modulators or liver X receptor (LXR)/retinoid X receptor (RXR) agonists, or ATP-binding cassette transporter-1 (ABCA1) agonists, or peroxisome proliferator- activated receptor (PPAR) agonists, among others.
  • CETP cholesteryl ester transfer protein
  • SRB1 scavenger receptor class B
  • SRB1 scavenger receptor class B
  • LXR liver X receptor
  • RXR retinoid X receptor
  • ABCA1 ATP-binding cassette transporter-1
  • PPAR peroxisome proliferator- activated receptor

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Immunology (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

L'invention porte sur un procédé de traitement d'un dysfonctionnement diastolique, chez un mammifère, qui comporte l'administration d'une quantité thérapeutiquement efficace d'un agoniste inverse de transport de lipide audit mammifère. L'agoniste idéal est un complexe peptide/phospholipide mimétique de l'apolipoprotéine-A1 (APOA1).
EP10733186A 2009-01-23 2010-01-25 Procédé de prévention et de traitement d'un dysfonctionnement diastolique au moyen d'un complexe peptide/phospholipide mimétique de l'apolipoprotéine-a1 (apoa1) Withdrawn EP2389189A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US20205109P 2009-01-23 2009-01-23
US20219109P 2009-02-05 2009-02-05
PCT/CA2010/000108 WO2010083611A1 (fr) 2009-01-23 2010-01-25 Procédé de prévention et de traitement d'un dysfonctionnement diastolique au moyen d'un complexe peptide/phospholipide mimétique de l'apolipoprotéine-a1 (apoa1)

Publications (2)

Publication Number Publication Date
EP2389189A1 true EP2389189A1 (fr) 2011-11-30
EP2389189A4 EP2389189A4 (fr) 2012-12-19

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EP10733186A Withdrawn EP2389189A4 (fr) 2009-01-23 2010-01-25 Procédé de prévention et de traitement d'un dysfonctionnement diastolique au moyen d'un complexe peptide/phospholipide mimétique de l'apolipoprotéine-a1 (apoa1)

Country Status (3)

Country Link
EP (1) EP2389189A4 (fr)
CA (1) CA2788223A1 (fr)
WO (1) WO2010083611A1 (fr)

Families Citing this family (5)

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RU2532222C2 (ru) 2009-02-16 2014-10-27 Серенис Терапьютикс Холдинг С.А, Миметики аполипопротеина а-i
WO2012012870A1 (fr) * 2010-07-28 2012-02-02 Institut De Cardiologie De Montreal Compositions pharmaceutiques pour le traitement du dysfonctionnement diastolique ventriculaire gauche comprenant un complexe de peptides/phospholipides d'apolipoprotéines
WO2012028526A2 (fr) 2010-08-30 2012-03-08 F. Hoffmann-La Roche Ag Tétranectine-apolipoprotéine a-i, particules lipidiques la contenant et son utilisation
JP6207507B2 (ja) 2011-08-25 2017-10-04 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 短縮されたテトラネクチン−アポリポプロテインａ−ｉ融合タンパク質、それを含む脂質粒子、及びその使用
US9402975B2 (en) 2011-08-31 2016-08-02 Becton, Dickinson And Company Systems and methods to increase rigidity and snag-resistance of catheter tip

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BUSSEUIL D ET AL: "Regression of aortic valve stenosis by ApoA-I mimetic peptide infusions in rabbits.", June 2008 (2008-06), BRITISH JOURNAL OF PHARMACOLOGY JUN 2008 LNKD- PUBMED:18414386, VOL. 154, NR. 4, PAGE(S) 765 - 773, XP002686476, ISSN: 0007-1188 * page 765 - page 766 * *
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See also references of WO2010083611A1 *

Also Published As

Publication number Publication date
EP2389189A4 (fr) 2012-12-19
CA2788223A1 (fr) 2010-07-29
WO2010083611A1 (fr) 2010-07-29

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