WO2013068626A1 - Triterpènes pentacycliques à utiliser dans la prévention ou le traitement de la myocardite aiguë ou subaiguë - Google Patents

Triterpènes pentacycliques à utiliser dans la prévention ou le traitement de la myocardite aiguë ou subaiguë Download PDF

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WO2013068626A1
WO2013068626A1 PCT/ES2012/070775 ES2012070775W WO2013068626A1 WO 2013068626 A1 WO2013068626 A1 WO 2013068626A1 ES 2012070775 W ES2012070775 W ES 2012070775W WO 2013068626 A1 WO2013068626 A1 WO 2013068626A1
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disease
pentacyclic triterpene
myocarditis
pharmaceutical
acid
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PCT/ES2012/070775
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Spanish (es)
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María Luisa NIETO CALLEJO
Rubén MARTÍN MONTAÑA
José Alberto SAN ROMÁN CALVAR
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Consejo Superior De Investigaciones Científicas (Csic)
Universidad De Valladolid
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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • a pentacyclic triterpene for the preparation of a therapeutic agent for the treatment of diseases of inflammatory origin of the myocardium and especially for protection against acute or subacute myocarditis and the alterations associated with them.
  • the present invention also relates to the use of a pentacyclic triterpene for the preparation of a nutraceutical composition to prevent diseases of inflammatory origin of the myocardium and especially for protection against acute or subacute myocarditis and the alterations associated with them.
  • Myocardial abnormalities - myocarditis - together with cardiomyopathies are the main cause of heart failure in patients younger than 40 years or young athletes (Eva Laraudogoitia and Ignacio Diez. Rev Esp Cardiol. Suppl. 2006; 6:21 E-9E; Gupta S et al. Nat Clin Pract Cardiovasc Med. 2008; 5: 693-706).
  • Myocarditis is a non-ischemic inflammatory process of the heart muscle, and according to its evolution it can be acute, subacute or chronic. It should be noted that some patients recover spontaneously and completely and there are even subjects in whom the process goes unnoticed and resolves itself, without any sequela or symptom.
  • DCM dilated cardiomyopathy
  • mice susceptible to inoculation with CVB3 Kermandiasis
  • CVB3 Kermandiasis ⁇ heavy chain
  • MyHC- ⁇ cardiac myosin ⁇ heavy chain
  • Myocarditis induced by immunization with cardiac myosin or its peptide provides an experimental virus-free model.
  • This model can be developed in the Balb / c strain and is characterized by the presence of giant cells in the lesions and infiltrate of eosinophils, macrophages, CD4 + T cells, with some CD8 + and B B220 + T cells in the myocardium.
  • Th2 cytokines especially IL-4, as well as Th1, TNFoc or IL-12 cytokines, and Th17, IL-17 have a crucial role in the development of the disease.
  • low inflammation and myocardial fibrosis becomes a characteristic of the disease. This phase is associated with systolic and diastolic dysfunction.
  • the acute phase of the disease is considered to be 21 days, the subacute phase takes place between days 40 and 48, and the chronic phase between days 65 and 70.
  • the treatment of myocarditis is a great challenge, mainly due to the complex clinical characteristics of the disease, and it can be classified as symptomatic and specific.
  • Symptomatic treatment is basically supportive and is applied to patients with heart failure of any grade.
  • the specific and standardized treatment is much discussed and not yet defined.
  • the response to treatment depends on the specific cause of the disease, the severity of irreversible tissue alterations at the onset of treatment and the ability of the myocardium to compensate for these alterations. In the best case with the specific treatment, a rapid progression of the disease can be stopped, but no significant improvement in ventricular function has been achieved.
  • studies in murine experimental models support the recommendations of the treatments, and various clinical trials have been carried out with the objective of defining clinical intervention guidelines.
  • oleanolic acid is a pentacyclic triterpene from the group of oleananos present in numerous plants (Jager S, et al. Molecules 2009, 14: 2016-2031), some of them frequently used in traditional medicine in various countries.
  • the present invention is related to the search for new treatments against inflammatory myocardial diseases, preferably myocarditis, and describes a new pharmacological application of oleanolic acid as an agent capable of significantly attenuating or preventing clinical signs, inflammatory and system alterations.
  • immune immuno-inflammatory alterations
  • fibrotic lesions and dystrophic calcifications associated with myocarditis.
  • the object of the invention is the pharmacological application of a pentacyclic triterpene in the therapy of myocardial diseases such as for example myocarditis
  • the invention shows the ability of natural pentacyclic triterpenes present in the olive cuticle and olive leaf, as well as in oils where these fractions have an important presence (olive pomace oil), to attenuate in a way Remarkable clinical signs of myocarditis.
  • This action is associated with a normalization of the heart size normalized by body weight, a decrease in the levels of cardiac damage markers, and a regulation of the immune and inflammatory response both at systemic and tissue level, characterized by a decrease in both the levels of pro-inflammatory cytokines as in the extravasation of immuno-inflammatory cells to the myocardium and by an increase in the levels of anti-inflammatory cytokines. It also manifests a protective effect against the formation of pathological fibrotic calcifications and accumulations. Therefore, it is an object of this invention to provide a pharmaceutical and / or nutraceutical composition with applications to treat myocarditis.
  • the present invention also relates to the use of a pentacyclic triterpene, to prevent or treat a disease that occurs with the appearance of calcium salt deposits or with fibrotic accumulation.
  • an acidic pentacyclic triterpene is described, preferably isolated from the olive, oleanolic acid (3-hydroxyolean-12-en-28-oic acid) represented by the chemical formula presented below:
  • Oleanolic acid as an effective component for the preparation of drugs or pharmaceutical compositions and nutraceutical compositions for the treatment or prevention of myocardial diseases, preferably myocarditis.
  • a pharmaceutical or nutraceutical composition useful for the treatment of an inflammatory myocardial disease is part of the invention to prevent or treat a disease that occurs with the appearance of calcium salt deposits, or to prevent or treat a disease that occurs with fibrotic accumulation, which comprises an effective amount of a pentacyclic triterpene together with at least one adjuvant and / or acceptable pharmaceutical carrier.
  • a pharmaceutical or nutraceutical composition in which the natural pentacyclic triterpene is oleanolic acid, as well as the use of the pharmaceutical composition in the treatment of a human being affected by an inflammatory myocardial disease, preferably by myocarditis, which comprises the administration of said composition that reduces the progression of the disease.
  • a first object of the present invention relates to the use of a pentacyclic triterpene in the preparation of a pharmaceutical or nutraceutical composition to prevent or treat an inflammatory myocardial disease.
  • the term "pentacyclic triterpene” includes in addition to the free form of the compound, any one of its isomers, as well as any one of its pharmaceutically and / or biologically acceptable salts. (such as sodium salt, potassium salt, calcium salt or magnesium salt, among others), solvates (variable stiochemistry complexes with suitable solvents - in which it is reacted or from those that precipitate or crystallize - include, but are not limited to water, methanol, ethanol and acetic acid and the like) and chemical derivatives or prodrugs, suitable for inclusion in a pharmaceutical or nutraceutical composition
  • isomers means both individual isomers and mixtures thereof, in particular, both individual enantiomers or diastereoisomers are understood as mixtures thereof. All of them can be obtained by conventional techniques such as separation from a mixture containing them.
  • prodrug includes any compound derived from a pentacyclic triterpene, for example, esters, including carboxylic acid esters, amino acid esters, phosphate esters, metal salt sulphonate esters, etc., carbamates, amides, etc., which, when administered to an individual, is capable of providing, directly or indirectly, said pentacyclic triterpene in said individual.
  • said derivative is a compound that increases the bioavailability of pentacyclic triterpene when administered to an individual or that enhances the release thereof in a biological compartment.
  • the preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.
  • the pentacyclic triterpene used to make a pharmaceutical or nutraceutical composition to prevent or treat an inflammatory myocardial disease as described in this patent application may be a natural pentacyclic triterpene, present in nature, or a pentacyclic triterpene synthetic, obtained by chemical derivation from a natural pentacyclic triterpene.
  • the preparation of said synthetic pentacyclic triterpene can be carried out by conventional methods known to those skilled in the art.
  • inflammatory myocardial disease refers to a pathology that involves cardiac damage, fibrotic accumulations, has an inflammatory component and an uncontrolled immune response, and more specifically refers, by way of title.
  • myocarditis dilated cardiomyopathy, rheumatic fever, cardiac pathology of Chagas disease and collagen diseases with heart injury.
  • the present invention relates to the use of a pentacyclic triterpene in the preparation of a pharmaceutical or nutraceutical composition to prevent or treat an inflammatory myocardial disease selected from the group consisting of myocarditis, dilated cardiomyopathy, rheumatic fever, pathology cardiac disease of Chagas and collagen diseases with heart injury.
  • an inflammatory myocardial disease selected from the group consisting of myocarditis, dilated cardiomyopathy, rheumatic fever, pathology cardiac disease of Chagas and collagen diseases with heart injury.
  • the invention relates to the use of a pentacyclic triterpene in the preparation of a pharmaceutical or nutraceutical composition to prevent or treat an inflammatory myocardial disease that is myocarditis.
  • myocarditis Preferably, this disease is acute or subacute myocarditis.
  • This phase is accompanied by the presence of circulating autoantibodies against myosin and other cardiac antigens, and can lead to heart failure and death associated with DCM. .
  • a large variety of autoantibodies that react against cardiac autoantigens of the plasma membrane, cytoskeleton or internal structures have been identified in many patients with DCM (Noutsias M. et al. Eur Heart J. 2002 (suppl. I) 154- 162.).
  • DCM Deep Heart J. 2002 (suppl. I) 154- 162.
  • chronic myocarditis, interstitial fibrosis develops, replacing dead muscle fibers, and myofiber hypertrophy resulting in contractile dysfunction and ventricular dilation.
  • the present invention also relates to the use of a pentacyclic triterpene as defined in this patent application, to prevent or treat a disease that occurs with the appearance of calcium salt deposits.
  • the present invention also relates to the use of a pentacyclic triterpene as defined in this patent application, to prevent or treat a disease that occurs with fibrotic accumulation.
  • the present invention relates to the use of a pentacyclic triterpene in the preparation of a pharmaceutical or nutraceutical composition to prevent or treat an inflammatory myocardial disease, preferably acute or subacute myocarditis, a disease that occurs with the appearance of deposits of calcium salts or a disease that occurs with fibrotic accumulation, characterized in that pentacyclic triterpene is a natural compound that is selected from the group consisting of oleanolic acid, ursolic acid, betulinic acid, maslinic acid, uvaol, erythrodiol and any one of its isomers, salts, solvates or prodrugs.
  • the pentacyclic triterpene is oleanolic acid (3a-hydroxyolean-12-en-28-oic acid).
  • the present invention relates to the use of a pentacyclic triterpene in the preparation of a pharmaceutical or nutraceutical composition to prevent or treat an inflammatory myocardial disease, preferably acute or subacute myocarditis, a disease that occurs with the appearance of deposits of calcium salts or a disease that occurs with fibrotic accumulation, characterized in that pentacyclic triterpene is a natural compound belonging to the family of oleananos.
  • the pentacyclic triterpene is oleanolic acid or any one of its isomers, salts, solvates or prodrugs, it being especially preferred that the pentacyclic triterpene is oleanolic acid (3a-hydroxyolean-12-en-28-oic acid).
  • Oleanolic acid is found in nature in the form of a free acid or as an aglycone of triterpenoid saponins (Liu J., J Ethnopharmacol 1995, 49: 57-68) and has been isolated from different plant species, highlighting its presence in Olea europaea .
  • Another object of the present invention is a pharmaceutical or nutraceutical composition
  • a pharmaceutical or nutraceutical composition comprising a pentacyclic triterpene together with at least one pharmaceutically acceptable adjuvant and / or when the composition is nutraceutical, an adjuvant and / or a nutraceutically acceptable carrier, for prevent or treat an inflammatory myocardial disease, a disease that occurs with the appearance of deposits of calcium salts or a disease that occurs with fibrotic accumulation.
  • the pentacyclic triterpene comprised in the pharmaceutical or nutraceutical composition of the invention has meaning defined above in this patent application.
  • pharmaceutically acceptable carrier and / or adjuvant refers to those substances, or combination of substances, known in the pharmaceutical sector, used in the preparation of pharmaceutical forms of administration and includes adjuvants, solids or liquids, solvents, surfactants, etc.
  • the expression "vehicle and / or nutraceutical acceptable adjuvant” refers to those substances, or combination of substances, known in the nutraceutical sector, used in the preparation of pharmaceutical forms of administration and includes adjuvants, solids or liquids, solvents, surfactants, etc.
  • said pharmaceutical composition may further contain one or more therapeutic agents that, if necessary, enhance the therapeutic action of said pentacyclic triterpene compound or increase its spectrum of action.
  • the additional therapeutic agent (s) are agents for the supportive treatment of clinical symptoms of myocarditis.
  • These therapeutic agents may be, for example, an antiarrhythmic drug, an inonotropic, an anticoagulant, an angiotensin-renin-aldosterone system blocker, a calcium-antagonist beta-adrenergic blocker or a diuretic.
  • Non-limiting examples of these agents include captopril, enalapril, spironolactone, furosemide, dobutamine, dopamine, losarian, calvedilol, bisoprolol or amiodarone.
  • said nutraceutical composition may also contain one or more active ingredients that, if necessary, enhance the therapeutic action of said pentacyclic triterpene compound or increase its spectrum of action.
  • active ingredients can be for example active ingredients for the treatment of the pathogenic mechanisms of myocarditis.
  • Non-limiting examples of these active ingredients may be nutritional supplements with antioxidant and / or anti-inflammatory properties and include carotenoids, flavonoids, polyphenols, omega-3 polyunsaturated fatty acids, terpenoids, idols, fibers, folic acid , lipoic acid and lecithin.
  • the triterpene pentacyclic compound will be present in the pharmaceutical composition in a therapeutically effective amount, that is, in an amount appropriate to exert its therapeutic effect.
  • the pharmaceutical composition provided by this invention comprises between 0.01% and 99.99% by weight of a pentacyclic triterpene compound, in the form of a free compound, or one of its isomers, salts, solvates or prodrugs, and it can be presented in any pharmaceutical form of appropriate administration in function of the route of administration chosen, for example, oral, parenteral, intraperitoneal or topical.
  • the pentacyclic triterpene compound will be present in the nutraceutical composition in an amount appropriate to exert its preventive effect.
  • the nutraceutical composition provided by this invention comprises between 0.01% and 99.99% by weight of a pentacyclic triterpene compound, in the form of a free compound, or one of its isomers, salts, solvates or prodrugs, and it can be presented in any nutraceutical form of appropriate administration such as liquid solutions, suspensions or solid forms such as tablets, capsules, powder, etc.
  • the pharmaceutical or nutraceutical composition as described in this patent application is characterized in that the triterpene pentacycle is a natural compound that is selected from the group consisting of oleanolic acid, ursolic acid, betulinic acid, maslinic acid, uvaol , erythrodiol and any one of its isomers, salts, solvates or prodrug.
  • the pentacyclic triterpene is oleanolic acid or any one of its isomers, salts, solvates or prodrug, it being especially preferred that the pentacyclic triterpene is oleanolic acid (3a-hydroxyolean-12-en-28-oic acid).
  • the pharmaceutical or nutraceutical composition as described in this patent application preferably when the pentacyclic triterpene is oleanolic acid, is characterized in that it can be used to prevent or treat acute or subacute myocarditis, since it reduces the progression of said disease. Additionally, the pharmaceutical or nutraceutical composition as described in this patent application is characterized in that it can be used to prevent or treat a disease that occurs with the appearance of calcium salt deposits, or to prevent or treat a disease that occurs with fibrotic accumulation.
  • Figure 1 Inhibition of increased heart weight (normalized against body weight) caused by the progression of the disease due to oleanolic acid, administered daily from the moment of disease induction - OA1 - until the 21st day after immunization.
  • MAE sick animals.
  • MAE OR AI sick animals treated with oleanolic acid (OA) from the moment of disease induction.
  • Figure 2 Inhibition of increased heart weight (normalized against body weight) caused during the progression of the disease due to oleanolic acid, administered daily from the moment of disease induction (A) or when myocarditis is established (from day 21 post-induction) (B) until day 21 and 65 post-immunization. Modulation of the serum levels of the BNP (C, D) peptide by the action of oleanolic acid, measured by commercial ELISA kit. C, healthy animals. C O A, healthy animals treated with OA. MAE, sick animals. MAE OR AI, sick animals treated with OA from the moment of disease induction. MAE 0 A2, sick animals treated with OA when myocarditis is established (from day 21).
  • Figure 3 Inhibition of cell infiltration, fibrotic accumulations and calcification in the myocardium due to oleanolic acid.
  • A. Images of healthy mouse heart and mouse heart with MAE in which calcifications are observed (Red arrows).
  • B. Histological study of cardiac tissue on day 65 post-immunization analyzed by staining with Eosin & Hematosilin (E&H), Alizarin Red (RA) and Sirius Red (RS).
  • E&H Eosin & Hematosilin
  • RA Alizarin Red
  • RS Sirius Red
  • MAE sick animals.
  • MAEOAI sick animals treated with OA at the time of disease induction.
  • MAE 0 A2 sick animals treated with OA with established myocarditis.
  • Figure 4 Modulation of the expression of pro-inflammatory proteins in serum (A), and cardiac tissue (B) by oleanolic acid, measured by commercial ELISA kit, on day 21 after disease induction.
  • C healthy animals.
  • OA healthy animals treated with OA.
  • MAE sick animals.
  • MAEOAI sick animals treated with OA from the moment of disease induction.
  • Figure 5 Modulation of the expression of anti-inflammatory proteins in cardiac tissue (A, B), and serum (C, D) by oleanolic acid, measured by commercial ELISA kit.
  • C healthy animals.
  • COA healthy animals treated with OA.
  • MAE sick animals.
  • MAEOAI sick animals treated with OA from the moment of disease induction.
  • MAE 0 A2 sick animals treated with OA when myocarditis is established (from day 21).
  • Figure 6 Modulation of serum cardiac anti-myosin antibodies by oleanolic acid, measured by ELISA kit.
  • C healthy animals.
  • COAI healthy animals treated with OA.
  • MAE sick animals.
  • MAEOAI sick animals treated with OA from the moment of disease induction.
  • the invention describes in one of its embodiments how oleanolic acid is not only an agent capable of significantly attenuating the clinical, immuno-inflammatory, profibrotic and calcification signs of experimental autoimmune myocarditis induced in Balb / c mice (animals of 6- 8 weeks of age), animal model of myocarditis, but significantly improves its evolution (see Example 1):
  • Example 1 Oleanolic acid improves the signs and symptoms of animals with SMA In the tests, ten animals are used per group. MAE is induced in the manner described (Pummerer CL, et al. J Clin Invest. 1996; 97: 2057-62) in Balb / c mice by administration of a peptide derived from the cardiac myosin- ⁇ heavy chain ( MyHC-a 6 and 4- 629) - Immunization is carried out with 200 ig of the MyHC-a 6 and 4- 629 peptide in Freund's complete adjuvant, which contains 5 mg / ml of Mycobacterium tuberculosis H37Ra. Mice are immunized by a subcutaneous injection of this emulsion on day 0 and 7.
  • 500ng / 300 ⁇ l of Bordetella Pertussis toxin are also administered intraperitoneally.
  • the administration of 50 mg / kg of oleanolic acid intraperitoneally is done once a day, beginning: 1 .- on the day of induction of the MAE (OA1), and continuing until day 21 (acute phase) or 65 (phase chronic) after the induction of the MAE, and 2.- after 21 days of induction of the MAE (OA2), when the acute or inflammatory phase has been reached, and continuing until day 65 after the induction of the MAE , when the chronic stage was reached.
  • the clinical evolution of the animals is observed daily using a registration system and compared with a group of MAE animals to which the vehicle is administered, with untreated (healthy) control animals or with (healthy) control animals that receive the same daily dose of oleanolic acid.
  • On days 21 or 65 the animals are sacrificed and the heart is weighed, normalizing the weight with the weight of the animal.
  • a Histopathological evaluation to confirm the effect of improvement of the disease status.
  • the heart weight / animal weight index of each group is represented in Figures 1 and 2.
  • BNP cerebral natriuretic peptide
  • FIG. 3 A shows a heart corresponding to a healthy mouse and a heart corresponding to a mouse with MAE for 65 days in which calcifications (red arrows) are observed.
  • the tissues corresponding to MAE animals show the massive presence of immuno-inflammatory infiltrate (H&E), as well as calcification foci (RA) and fibrotic accumulations (RS).
  • H&E immuno-inflammatory infiltrate
  • RA calcification foci
  • RS fibrotic accumulations
  • Figure 5 A and B shows that both serum and cardiac tissue of MAE animals treated with oleanolic acid, following the OA1 protocol, there is a marked increase in the expression of IL-10, compared to untreated MAE mice. This increase is observed on day 21 post-induction and is maintained (at least) until day 65. In addition, we find that in healthy animals, controls, treated with oleanolic acid, there is also a significant increase in the levels of the cytokine IL-10.
  • Figure 5 C and D show that animals with active myocarditis treated with oleanolic acid following the therapeutic OA2 protocol, experience an increase in plasma and tissue levels of IL-10 similar to that found in animals treated according to OA1 protocol , semi-prophylactic.
  • the animals have been kept in the animal faculty of the Faculty of Medicine of the University of Valladolid, in cages with a bed of chips, feeding them with a diet of special feed for laboratory animals, with a variable consumption depending on weight and age of animal, water ad libitum, constant temperature of 20-24 ° C and exposed to a light cycle of 12h / day (8.00 am - 8.00 pm) (Council of European Communities, 1986).
  • the study protocols have been approved by the Animal Research Ethics Committee of the Faculty of Medicine of the University of Valladolid.
  • MAE is induced in female and male mice of the Balb / c lineage of 6-8 weeks following the protocol described by (Pummerer Ch L, et al. J Clin Invest. 1996; 97: 2057-62). Animals receive day 0 and 7 a subcutaneous dose of a mixture of 200 g of the peptide derived from the heavy chain of myosin-cardiac (MyHC-i 4 -629 6), complete Freund 's adjuvant and 5 mg / ml M. tuberculosis H37 RA. An ip injection of 500 ng / animal of B. pertussis toxin administered twice, with an interval of 48 hours. Animals are examined daily to monitor weight loss and the onset of neurological symptoms.
  • OA1 The injection of 50 mg / kg of oleanolic acid begins on the day of immunization of the animals.
  • OA2 The injection of 50 mg / kg of oleanolic acid begins in the acute phase, when myocarditis is established (approximately on day 21 post-immunization). Histological Analysis
  • Protein extracts from myocardium and serum samples were obtained from animals of the different experimental groups, sacrificed at 21 or 65 days after immunization.
  • the tissue was homogenized in a solution: 0.4 M NaCI, 0.05% Tween 20, 0.5% BSA, 0.1 mM Phenyl methyl sulfonyl fluoride, 0.1 mM benzetonium chloride, 10 mM EDTA and 20 Kl aprotinin (100 mg of tissue / ml).
  • the homogenate was centrifuged at 10,000 rpm for 10 min at 4 ° C and in the supernatants the concentration of IL-10, IL-17 and TNFa was determined by a commercial ELISA kit.
  • the BNP concentration was determined exclusively in serum samples.
  • the concentration of the cytokines is determined by extrapolation of a standard curve and expressed as pg / mg of total protein.
  • Serum from the animals of different groups was collected on day 21 post - immunization and antibody levels were determined against the peptide derived from the heavy chain of myosin- ⁇ heart (MyHC-i 4 -629 6) using the technique from ELISA. Thus a 96 - well plate was incubated with 0.5 g / well of peptide MyHC-6 i 4 -629 in PBS at 4 ° C overnight.

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Abstract

La présente invention porte sur l'utilisation d'un triterpène pentacyclique dans l'élaboration d'une composition pharmaceutique ou neutracétique pour prévenir ou traiter une maladie inflammatoire du myocarde, de préférence la myocardite aiguë ou subaiguë, pour prévenir ou traiter une maladie qui est accompagnée de l'apparition de dépôts de sels de calcium, pour prévenir ou traiter une maladie accompagnée d'une accumulation de fibres. De préférence, ledit triterpène pentacyclique est l'acide oléanolique. Ainsi, l'invention porte sur une composition pharmaceutique ou neutracétique qui comprend un triterpène ainsi qu'au moins un adjuvant et/ou excipient pharmaceutiquement acceptable ou bien sur une composition neutracétique qui comprend un adjuvant et/ou excipient neutracétiquement acceptable, pour traiter ou prévenir une maladie inflammatoire du myocarde, de préférence la myocardite aiguë ou subaiguë, pour prévenir ou traiter une maladie qui est accompagnée de l'apparition de dépôts de sels de calcium, pour prévenir ou traiter une maladie accompagnée d'une accumulation de fibres. De préférence, ledit triterpène pentacyclique est l'acide oléanolique.
PCT/ES2012/070775 2011-11-10 2012-11-08 Triterpènes pentacycliques à utiliser dans la prévention ou le traitement de la myocardite aiguë ou subaiguë WO2013068626A1 (fr)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2007126221A1 (fr) * 2006-05-03 2007-11-08 Rnl Bio Co., Ltd Composition comprenant de l'acide ursolique et de l'acide oléanolique destinée à améliorer un traitement contre l'arthrite
US20100048911A1 (en) * 2008-04-18 2010-02-25 Xin Jiang Antioxidant inflammation modulators: novel derivatives of oleanolic acid

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2007126221A1 (fr) * 2006-05-03 2007-11-08 Rnl Bio Co., Ltd Composition comprenant de l'acide ursolique et de l'acide oléanolique destinée à améliorer un traitement contre l'arthrite
US20100048911A1 (en) * 2008-04-18 2010-02-25 Xin Jiang Antioxidant inflammation modulators: novel derivatives of oleanolic acid

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Title
MARTIN, R. ET AL.: "Beneficial actions of the natural triterpene oleanolic acid in an experimental model of myocarditis: a potential therapeutic role", EUROPEAN HEART JOURNAL, vol. 33, 2012, MUNCHEN, GERMANY, pages 48, ISSN: 0195-668X, Retrieved from the Internet <URL:http://spo.escardio.org/SessionDetails.aspx?id=270149> [retrieved on 20130128] *

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