WO2012139148A1 - Composition d'antioxydants pour la préservation de tissus et d'organes - Google Patents

Composition d'antioxydants pour la préservation de tissus et d'organes Download PDF

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Publication number
WO2012139148A1
WO2012139148A1 PCT/AT2012/050049 AT2012050049W WO2012139148A1 WO 2012139148 A1 WO2012139148 A1 WO 2012139148A1 AT 2012050049 W AT2012050049 W AT 2012050049W WO 2012139148 A1 WO2012139148 A1 WO 2012139148A1
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composition according
antioxidant composition
acetyl
group
karal
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Inventor
Michaela SCHWARZ
Joachim Greilberger
Robson Santos
Mariana LAMACIE
Reinhold WINTERSTEIGER
Peter Moser
Christian Bücherl-Harrer
Ernst Kager
Millan RUBEN DARIO SINISTERRA
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Cyl Pharmazeutika - Cyl GmbH
Medizinische Universitaet Graz
Karl Franzens Universitaet Graz
UNIVERSIDADE FEDERAL DE MINAS GERAIS INSTITUICAO DE ENSINO E PESQUISA
Original Assignee
Cyl Pharmazeutika - Cyl GmbH
Medizinische Universitaet Graz
Karl Franzens Universitaet Graz
UNIVERSIDADE FEDERAL DE MINAS GERAIS INSTITUICAO DE ENSINO E PESQUISA
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/10—Preservation of living parts
    • A01N1/12—Chemical aspects of preservation
    • A01N1/122—Preservation or perfusion media
    • A01N1/126—Physiologically active agents, e.g. antioxidants or nutrients
    • 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
    • A61K31/11—Aldehydes
    • 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
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • 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
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/085—Angiotensins

Definitions

  • the present invention relates to a new antioxidant solution able to preserve the cardiac function during warm (coronary occlusion) and prolonged cold (cardioplegy and 6 hour storage) ischemia.
  • Ischemia/ reperfusion injury plays an important role in the cardiological as well the surgical field, (stenting, myocardial infarction, vascular as well as cardiac surgery.) Furthermore it plays a major role in the field of transplantation on post transplant organ function and patients'survival.
  • Heart transplantation has emerged as the most effective therapy for end- stage heart failure. Because of the increasing divergence between the availability and the demand of organs, special interest has to be drawn to optimize the long-term success of each transplant. Various risk factors, antigen- dependent as well as antigen -independent, have been identified to be responsible for initial and late graft performance, thus influencing patients' post transplant life quality and expectancy. (Large SR. Is there a crisis in cardiac transplantation? The Lancet, 2002; 359 (9308): 803-804; Wilhelm MJ, Pratschke J, Laskowski I, Tilney NL. Ischemia and reperfusion injury Transplantation Reviews, 2003;17 (3): 140-157).
  • RONS do not only cause acute events like stunning, infarction or potentially lethal arrhythmias; they are also present in the chronically failing heart.
  • Giodarno FJ Oxygen, oxidative stress, hypoxia and heart failure. Journal of Clinical Investigation 2005;115(3):500-508).
  • GCAD graft coronary artery disease
  • N02- has the potential to act as an endogenous store of NO especially liberated during ischemia, when the generation of NO from L-arginine by NOS enzymes is impaired.
  • an inactivation of ONOO- also prevents the nitration on amino acids like L-arginine forming nitro-L-arginine known as a potential inhibitor of NOS activity formed easily during ischemia/ reperfusion.
  • oxidative stress plays an important role within the surgical stress response leading to an impairment of the NO regulating system. Especially during transplantations, where prolonged episodes of I/R are present, the reduction of eNOS activity is aggravated. Modulation of oxidative stress by administration of antioxidants has been shown to reduce morbidity and mortality in various patient populations (Humphrey CD, Pittman FE. A simple methylene blue-azure II basic fuchsin stain for epoxi- embedded tissue sections. Stain Technology 1974; 42:9-14).
  • Karal® is a new antioxidant infusion solution consisting of a-ketoglutaric acid (aKG), 5 hydroxy-methyl-furfural (5 HMF), trace amounts of N-Acetyl-Selenium-L-Methionine and N-Acetyl-L-Methionine.
  • aKG an intermediate of the citric cycle, is located in the cytosol and the inner mitochondrial membrane and important for several mechanisms including (i) the transamination of NH4+, (ii) the oxidative decarboxylation to succinyl-CoA, C02 and NADH+H+ which itself transfer its reduction equivalent to ubichinon necessary for ATP production, (iii) the gluconeogensis of lactate and (iv) scavenging hydrogen peroxide (H202). It is assumed, that aKG also may interact with peroxynitrite (ONOO-) (Halliwell B. and Gutteridge J. Free Radicals in Biology and Medicine, Third Edition, 1999, Oxford Press).
  • ONOO- peroxynitrite
  • Nitrated or oxidized forms of arginine by ONOO- are able to inhibit NO ' production by blocking NOS. Furthermore, a direct modification of NO- synthase (NOS) by ONOO- results in an overproduction of superoxide anion radicals (02-*) which itself reacts with NO ' forming ONOO- (Sun J, Druhan LJ, Zweier JL. Dose-dependent Effects of Reactive Oxygen and Nitrogen Species on the Function of Neuronal Nitric Oxide Synthase. Arch Biochem Biophys. 2008; 471:126-33).
  • 5-HMF was recently reported as an in vitro acting antioxidant which results in a reduced protein oxidation by free radicals (e.g. H202 ) or RONS (e.g. ONOO-). Furthermore, 5-HMF inhibited myeloperoxidase activity and increased the expression of glutathione enzymes and superoxide dismutase (Li YX, Yong L, Zhong-Ji Q, Moon-Moo K, Se-Kwon K. In Vitro Antioxidant Activity of 5-HMF Isolated from Marine Red Alga Laurencia undulate in Free Radical Mediated Oxidative Systems. J. Microbiol Biotechnol. 2009;19(11):1319-1327).
  • Adequate intake (plasma level of 70-90 ⁇ g/l) of the essential trace mineral selenium is required for optimal activity of endogenous antioxidant enzymes like glutathione- peroxidases or thioredoxin- reductases.
  • Endogenous antioxidant enzymes like glutathione- peroxidases or thioredoxin- reductases.
  • Enhanced oxidative stress due to selenium -deficiency has been correlated to heart failure.
  • Angiotensin (1-7) [Ang. (1-7)] an active biological product of the renin- angiotensin system (Santos RA, Ferreira AJ, Pinheiro SV, Sampaio WO, Touyz R, Campagnole-Santos MJ. Expert Opinion on Investigational Drugs, 2005; 14: 1019-1031).
  • Ang. (1-7) an active biological product of the renin- angiotensin system
  • Several experimental studies showed its antiarrhythmic, ameliorating post-ischemic contractile function, antiproliferative and vasodilatative effects (Ferreira AJ, Santos RAS, Almeida AP.
  • Angiotensin (1-7) Cardioprotective effect in myocardial ischemia/ reperfusion. Hypertension, 2001; 38 (2): 665- 668; Ferreira AJ, Santos RAS, Almeida AP. Angiotensin (1-7) improves the post-ischemic function in isolated perfused rat hearts. Brazilian Journal of Medical and Biological Research, 2002; 35: 1083-1090;Tallant EA, Diz DI, Ferrario CM. Antiproliferative actions of angiotensin (1-7) in vascular smooth muscle. Hypertension,1999; 34: 950-957; Sampaio WO, Santos RAS, Faria-Silva R, Machado LT, Schiffrin EL, Touyz RM. Angiotensin-(l-7) through receptor Mas mediates endothelial Nitric Oxide synthase activation via Akt-dependent pathways. Hypertension, 200749: 185-192).
  • Ang. (1-7) has been tested in clinical studies and shown to be effective and safe within the human being-at least until the maximum daily dose of 100 ng/ kg ( Ueda S, Maemoto SM, Wada A, Ishii M, Brosnihan KB, Umemura S.
  • Angiotensin-(l-7) potentiates bradykinin- induced vasodilatation in man. Journal of Hypertension, 2001; 19(ll):2001-2009; Sasaki S, Higashi Y, Nakagawa K, Matsuura H, Kajiyama G, Oshima T. Effects of angiotensin-(l-7) on forearm circulation in normotensive subjects and patients with essential hypertension.
  • selenium-compound such as seleniummethionine, seleniumcysteine or selenite
  • At least one Mas receptor agonist such as angiotensines.
  • the term "at least one" as used herein means that either one or more than one of each of the aforementioned components may be present in the composition.
  • the antioxidant composition comprises a combination of
  • Mas receptor agonist such as angiotensines.
  • the carbonic acid is selected from the group of a-ketoglutarate, iso- citrate, or a pharmaceutically acceptable salt thereof.
  • the mono- or polysaccharides derivatized heterolytic aldehyde is selected from the group of 5-hydroxy-methylfurfural, dehydroascorbic acid, maltol, vanillin and furan-2-aldehyde.
  • the selenium-compound is selected from the group of seleniummethionine, seleniumcysteine and selenite.
  • the Mas receptor agonist is selected from the group consisting of angiotensines such as angiotensin (1-7) and angiotensin (1-7) analogues.
  • the carbohydrate is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides and polysaccharides. In one embodiment the carbohydrate is glucose or fructose.
  • the antioxidant composition comprises a combination of a-ketoglutarate, 5-hydroxy-methylfurfural, N-acetyl-selenium-L-methionine, N-acetyl-L-methionine, glucose and angiotensin (1-7). In one specific embodiment the antioxidant composition comprises a combination of
  • angiotensin 0.22 ng/L to 2.2 mg/L angiotensin (1-7).
  • a further feature of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising the antioxidant composition as defined above and a pharmaceutically acceptable carrier.
  • a "pharmaceutically acceptable carrier” in the meaning of the present invention can be any substance used for the preparation of pharmaceutical dosage forms and known to those skilled in the art.
  • the antioxidant composition and the pharmaceutical composition according to the invention, respectively, preferably are in the form of an aqueous solution.
  • the antioxidant composition or the pharmaceutical composition according to the invention is for treatment of conditions and diseases associated with oxidative and nitro-stress.
  • conditions and diseases associated with oxidative and nitro-stress are e.g. conditions and diseases associated with ischaemia/reperfusion, cancer as well as hormonal disorders/ imbalances relating to thyroid gland, hypothalamus and pituitary gland.
  • the antioxidant composition or the pharmaceutical composition according to the invention is used in a solution for preserving organs and tissues.
  • the antioxidant composition or the pharmaceutical composition according to the invention is used in the preparation of a perfusion solution for preserving organs and tissues during the process of transplantation.
  • the antioxidant composition or the pharmaceutical composition according to the invention is for treatment of cardiovascular diseases, preferably conditions and diseases associated with ischaemia/ reperfusion.
  • a further feature of the invention is a graft treated with an antioxidant composition or with a pharmaceutical composition according to the invention as defined above and in the claims.
  • the term "graft" as used herein refers to biological material derived from a donor, wherein the biological material is intended to be transplanted into a recipient. Both donor and recipient are preferably mammalian, most preferably human.
  • the graft is selected from the group consisting of tissue, isolated cells and an organ. The organ is preferably a heart.
  • the chemical properties inside and outside of the tissues and organs are stabilized by the antioxidant composition/ solution according to the invention and/ or reversed if pathophysiological incidents took place (e.g. before occlusion).
  • the present invention further relates to a method comprising pre-treating a graft before transplantation with an antioxidant composition or with a pharmaceutical composition according to the invention as defined above and in the claims.
  • the present invention evaluates, for the first time, the effects of a-ketoglutarate (AKG) and 5- hydroxy-methylfurfural (5-HMF) on peptides containing aromatic amino acids and arginine (e.g. Ang 1-7).
  • This protection prevents the hydroxy lation and nitration of these peptides through free radicals and RONS (e.g. peroxynitrite) during reperfusion after warm and prolonged cold ischemia and thus saves their function, preserving organs and tissues during transplantation.
  • the invention evaluates for the first time the mechanism and the efficacy of the above-mentioned antioxidant solution Karal® and Ang.
  • Angiotensin (1-7) shows vasodilatative, anti-proliferative and anti-arrhythmo genie properties. These properties are reduced during ischemia/ reperfusion. a-ketoglutarate and 5-HMF protect on one hand the nitration and therefore the function of angiotensin (1-7; specially on tyrosine and arginine) and prohibit the inactivation of NOS.
  • FIG. 2- (A,B) The effect of 5, 10 and 20% Karal®, on the coronary flow during basal, occlusion and reperfusion time. (C,D) The effect of Karal® 5% and Ang (1-7) 0.22 nmol/L on coronary flow during basal, occlusion and reperfusion time.
  • Figure 3- The effect of 5, 10 and 20% Karal®, on the systolic (A) and diastolic tension (B) during and after occlusion.
  • Figure 9 Scanning electron microscopy of the endothelial sheet of rat heart endocardium.
  • A Native rat heart, freshly excised, no cardioplegy, no reperfusion.
  • B Rat heart endothelial cells perfused with Karal 20% plus Angiotensin (1-7).
  • C Rat heart endothelial cells perfused with Karal 20% .
  • D Rat heart endothelial cells perfused with Angiotensin (1-7).
  • E Rat heart endothelial cells perfused with Krebs Ringer solution (control).
  • FIG. 10 Electron micrographs.
  • B Rat heart endothelial cells perfused with Karal 20% plus Angiotensin (1-7).
  • C Rat heart endothelial cells perfused with Karal 20% .
  • D Rat heart endothelial cells perfused with Angiotensin (1-7).
  • E Rat heart endothelial cells perfused with Krebs Ringer solution (control).
  • a force transducer (model TSD 104 A, Biopac) was attached through a heart clip to the apex of the ventricles to record the contractile force (tension, g) on a computer, by a data-acquisition system (Biopac System, Santa Barbara, CA).
  • a diastolic tension of 1.0 ⁇ 0.2g was applied to the hearts.
  • Electrical activity was recorded with an ECG (Nihon Kohden, Japan) with the aid of 2 cotton wicks placed directly on the surface of the right atrium and left ventricle (bipolar lead). Coronary flow was measured by collecting the perfusate over a period of 1 minute at regular intervals. The hearts were perfused for an initial 20-minute period with KRS.
  • the left anterior descending coronary artery was ligated according to the method described by Lubbe (Lubbe WF, Daries PS, Opiel LH. Ventricular arrhythmias associated with coronary antifibrillatory action of antiarrhythmic agents. Cardiovascular Research, 1978; 12: 212-220), beneath the left auricular appendage together with the adjacent veins.
  • the ligature was released after 15 minutes, and reperfusion with different KRS (above) was performed for additional 30 minutes.
  • Cardiac arrhythmias were defined as the presence of ventricular tachycardia and / or ventricular fibrillation after the ligature of the coronary artery was released.
  • arrhythmia severity index (ASI) (Bernauer W, Ernenputsch I. Antagonistic effects of alpha -adrenoceptor blocking agents on arrhythmias, enzyme release and myocardial necrosis in isolated rat hearts with coronary occlusion and reperfusion. Naunyn Schmiedebergs Archives of Pharmacology, 1988; 338: 88-95).
  • the groups receiving Karal® alone or in combination with Ang(l-7) 0.22 nmol/L presented an increase of the coronary flow compared to the control group or that with Ang (1-7) alone.
  • the increase was significantly higher using the combination Karal® 5% + Ang (1-7) 0.22 nmol/L compared to Karal® 5% alone ( Figures 2C and 2D).
  • Karal® 20% enhanced the systolic tension significantly throughout the entire experiment.
  • Karal® 5% and 10% did not improve the contractile function during and after occlusion (Figure 3A).
  • the diastolic function was preserved throughout the whole experiment using the 20% Karal® concentration.
  • Karal® 5% and 10% increased the diastolic tension during reperfusion ( Figure 3B).
  • Nitrite concentrations during basal, occlusion and reperfusion are significantly higher using 10 and 20% Karal compared to control (Krebs Ringer Solution) due to the effect that KARAL was able to convert peroxynitrite to nitrite.
  • Peroxynitrite consumption through aKG one of the main ingredients of Karal®, led to the formation of succinic acid and nitrite (NO2 ).
  • NO2- has the potential to act as an endogenous store of NO especially liberated during ischemia, when the generation of NO from L-arginine by NOS enzymes is impaired.
  • ONOO- was prepared according to Hughes and Nicklin (Hughes MN, Nicklin HG. The chemistry of pernitrites. Part I. Kinetics of decomposition of pernitrous acid. Journal of the Chemical Society, 1968, 450-452).
  • the ONOO- concentration was determined spectropho- tometrically at 302nm with a coefficient of extinction of 1670 M-lcm- .
  • Consumption of peroxynitrite was measured with luminescence technique according to Radi et al (Radi R, Consgrove TP, Beckman JS, Freeman BA. Peroxynitrite- induced luminol chemiluminescence. Biochemical Journal, 1993; 290:51-57).
  • Figure 5 shows that aral® was able to decrease the oxidative damage in a dose dependent manner: 5% of Karal® decreased the signal to 58% compared to the control signal without, 7.5% to 16%, 10% to 11%, 15% to 3%, 20% to 1% and 25% nearly to 0%
  • Figure 6 shows that Ang. (1-7) was able to react with ONOO- at very low concentration.
  • the chemiluminescence signal of ONOO- with 0.8 mM Ang. (1-7) was reduced to nearly 50% compared to control signal (p ⁇ 0.001).
  • concentrations the inhibition of chemiluminescence signal increased: 63.4% at a concentration of 0.16 mM Ang. (1-7) and at least to 75% at 0.04 mM Ang. (1-7) compared to control (p ⁇ 0.001).
  • Chemiluminescence results show that Ang. (1-7), containing both amino acids L-tyrosine and L-arginine, reacts easily with ONOO-.
  • the synergistic effects of Karal® prevent the nitration of Ang. (1-7) and therefore prolong the function of Ang. (1-7) leading to a significant increase of coronary flow and systolic tension and a significant decrease of diastolic tension during warm and cold ischemia.
  • the brachiocephalic trunk was clamped 2-3 mm after its outlet from the aortic arch using a curved haemostat.
  • a second haemostat was attached between the outlet of the brachiocephalic trunk and the left carotid artery.
  • Cardioplegic solution (Celsior®, IMSTIX SANGSTADT,France) was applied via the brachiocephalic trunk using a subcutaneous needle attached to a 5ml syringe. The tip of the needle had been bent before, forming a 90° angle. Cardioplegia was performed air-free and under constant pressure (5mL /min) to avoid volume overload. Simultaneously the heart was cooled from the outside using cardioplegic solution and ice. After cardiac arrest the hearts were harvested rapidly by cutting off the AAo, the IVC 1-2 mm before its confluence with the RA, and both lungs.
  • Coronary flow was enhanced by Karal 20% alone (*p ⁇ 0,001 vs. control and °p ⁇ 0,001 vs. Ang (1-7)) and the combination of Karal 20% and Ang. (1-7) significantly (# p ⁇ 0,003 vs. Karal® + Ang (1-7), Figure 7). Systolic tension was increased using the combination of Karal 20% and Ang. (1-7) significantly (*p ⁇ 0,001 vs.control, Figure 8).
  • tissue blocks of the left ventricle were fixated in 2.5% glutaral- dehyde and 2% paraformaldehyde in 0.1 mol/L cacodylate buffer of pH 7.2 were embedded in historesin (LKB, Bromma, Sweden) and cut to obtain 4 ⁇ sections, which were stained with a mixture of methylene blue-azure II and basic fuchsin (Humphrey CD, Pittman FE. A simple methylene blue-azure II basic fuchsin stain for epoxi- embedded tissue sections. Stain Technology, 1974; 42:9-14).
  • rat hearts were fixated in a mixture of 2.5% glutaraldehyde and 2% paraformaldehyde, post-fixated in 2 % Os04, dehydrated, critical point dried and gold sputtered.
  • Representative electron micrographs were captured using a DSM 950 (Zeiss). All the groups were compared to a native, freshly excised rat heart.

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Abstract

La présente invention concerne une composition d'antioxydants, comportant une combinaison d'au moins un acide carbonique choisi parmi le groupe d'acides mono-carboniques et poly-carboniques, au moins un aldéhyde hétérolytique dérivé de mono- ou de polysaccharides, au moins un composé de sélénium tel que sélénium-méthionine, sélénium-cystéine, ou sélénite, au moins un composé choisi parmi le groupe d'acides aminés contenant du soufre, du disulfure ou du sulfhydryle tel que N-acétyl- L-méthionine et N-acétyl-L-cystéine, et des acides amino-sulfoniques tels que la taurine, au moins un glucide, et au moins un agoniste du récepteur Mas tel que des angiotensines. L'invention concerne également une composition pharmaceutique comportant une telle composition d'antioxydants et un excipient pharmaceutiquement acceptable. L'invention est particulièrement utile dans une solution pour la préservation d'organes et de tissus, notamment lors du processus de transplantation.
PCT/AT2012/050049 2011-04-15 2012-04-16 Composition d'antioxydants pour la préservation de tissus et d'organes Ceased WO2012139148A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4395755A1 (fr) * 2021-08-30 2024-07-10 CYL GmbH Composition comprenant de l'acide alpha-cétoglutarique (alpha-kg) et du 5-hydroxyméthyl-2-furfural (5-hmf) pour améliorer l'alimentation en oxygène médiée par l'hémoglobine

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DE3542309A1 (de) * 1985-11-29 1987-06-04 Cardona Federico Dr Medizinisches antioxidativum
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