WO2012011572A1 - Agent thérapeutique pour insuffisance cardiaque diastolique - Google Patents

Agent thérapeutique pour insuffisance cardiaque diastolique Download PDF

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Publication number
WO2012011572A1
WO2012011572A1 PCT/JP2011/066707 JP2011066707W WO2012011572A1 WO 2012011572 A1 WO2012011572 A1 WO 2012011572A1 JP 2011066707 W JP2011066707 W JP 2011066707W WO 2012011572 A1 WO2012011572 A1 WO 2012011572A1
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Prior art keywords
carnitine
heart failure
derivative
pharmaceutically acceptable
acceptable salt
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PCT/JP2011/066707
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English (en)
Japanese (ja)
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一博 山本
敏昭 真野
泰史 坂田
洋介 大森
朋義 曽我
朋仁 大谷
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国立大学法人大阪大学
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Publication of WO2012011572A1 publication Critical patent/WO2012011572A1/fr

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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
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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

Definitions

  • the present invention relates to a therapeutic agent for diastolic heart failure.
  • Heart failure is a leading cause of death in industrialized countries, including Japan, and it reduces the quality of life for patients.
  • Heart failure is categorized as systolic heart failure, in which the left ventricle expands and movement decreases (lower left ventricular ejection fraction), and diastolic heart failure, in which the left ventricle does not expand and left ventricular ejection fraction is maintained.
  • the ratio of heart failure patients is about 3: 2, and both have a poor prognosis.
  • Patent Document 1 describes a medicine containing acylcarnitine as an active ingredient for the prevention and / or treatment of a disease involving the production of inflammatory cytokines, and is one of the diseases involving the production of inflammatory cytokines. As heart failure is described. However, according to the results of a large-scale clinical trial for contractile heart failure conducted before the filing of Patent Document 1, it has been reported that suppressing inflammatory cytokines is not necessarily effective as a treatment for heart failure ( It is not scientifically supported that the invention described in Patent Document 1 is effective for heart failure.
  • Patent Document 2 describes that propionyl L-carnitine suppresses left ventricular hypertrophy in end-stage renal disease dialysis patients.
  • diastolic heart failure indicates a pathological condition in which the left ventricle does not dilate as described above, it cannot be inferred from the description in Patent Document 2 that propionyl L-carnitine is effective for diastolic heart failure. .
  • Non-Patent Document 6 describes the use of L-carnitine for the treatment of diastolic heart failure. However, there is no “foundation for diagnosing heart failure” necessary to determine whether the target patient meets the criteria as a patient with diastolic dysfunction, and how blood pressure and pulse have changed as a result of treatment. Since there is no description about it, it is undeniable that the evaluation index has simply changed due to an antihypertensive action or the like, and that the expanded function has not been changed directly. Therefore, Non-Patent Document 6 cannot be said to scientifically demonstrate that L-carcinin is effective in the treatment of diastolic heart failure.
  • JP 2006-347935 A JP-T 2009-511619
  • an object of the present invention is to provide a medicament effective for the prevention or treatment of diastolic heart failure.
  • the present invention includes the following inventions in order to solve the above problems.
  • a preventive or therapeutic drug for diastolic heart failure comprising carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a myocardial sclerosis inhibitor comprising carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a myocardial fibrosis inhibitor comprising carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a prostacyclin increasing agent comprising carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Carnitine which is an active ingredient of the present invention, is a compound synthesized in vivo and is already commercially available as a pharmaceutical product for other purposes, so it is very useful in terms of low safety concerns.
  • FIG. 3 shows OCTN2 mRNA and protein expression levels in the heart. It is a figure which shows the mRNA and protein expression level of OCTN2 in a kidney. It is a figure which shows the free carnitine excretion rate (FE) in the kidney of a control group and a non-treatment group. It is a figure which shows the measured value of [ ⁇ 3 > H] proline uptake
  • FIG. 1 It is a figure which shows the measured value of 6-keto-PGF1 ⁇ concentration in the heart. It is a figure which shows the measured value of 6-keto-PGF1 ⁇ concentration in the culture supernatant of cultured cardiac fibroblasts. It is a figure which shows the mRNA expression level of FADS1 in the heart. It is a figure which shows the mRNA expression level of FADS2 in the heart. It is a figure which shows the mRNA expression level of FADS1 in a cultured cardiac fibroblast. It is a figure which shows the mRNA expression level of FADS2 in a cultured cardiac fibroblast. It is a figure which shows the arachidonic acid (AA) density
  • FIG. 6 is a graph showing measured values of 6-keto-PGF1 ⁇ concentration in cultured cardiac fibroblasts knocked down by FADS1 or FADS2. It is a figure which shows the AA density
  • the present invention provides a preventive or therapeutic agent for diastolic heart failure containing carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a myocardial sclerosis inhibitor, a myocardial fibrosis inhibitor, and a prostacyclin-increasing agent containing carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present inventors conducted comprehensive metabolomic analysis on blood and urine samples collected from diastolic heart failure model rats (Dahl salt-sensitive rats) and control rats. As a result, it was found that L-carnitine was contained in a substance in which various changes were observed, and in the heart tissue of a diastolic heart failure model rat, it was confirmed that the carnitine concentration decreased during the heart failure stage. Accordingly, the present inventors conducted an experiment in which L-carnitine was administered to a diastolic heart failure model rat. As shown in Example 1, L-carnitine was fibrotic to the myocardium accompanied by an increase in myocardial prostacyclin concentration. Based on the suppression, it was found that the myocardial sclerosis was suppressed, and as a result, the onset of diastolic heart failure could be suppressed.
  • Carnitine or a derivative thereof is not particularly limited as long as it is carnitine, an isomer thereof, or a derivative thereof (for example, a derivative that is converted into carnitine in vivo).
  • Examples thereof include L-carnitine, DL-carnitine, acyl-L-carnitine, acetyl-L-carnitine, propionyl-L-carnitine, carnitine chloride, carnitine orotate and the like.
  • the pharmaceutically acceptable salt thereof is not particularly limited, and examples thereof include metal salts such as sodium salt and calcium salt, inorganic acid salts such as hydrochloride, carbonate and sulfate, acetate, malate and succinate.
  • organic acid salts such as Specific examples include DL-carnitine hydrochloride, L-carnitine hydrochloride, L-carnitine fumarate, L-carnitine tartrate, L-carnitine magnesium citrate, N-acetyl-L-carnitine hydrochloride, and the like.
  • Carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof used in the present invention is preferably L-carnitine, carnitine chloride, L-carnitine hydrochloride, L-carnitine fumarate, L-carnitine tartrate, acyl-L -Carnitine, acetyl-L-carnitine and propionyl-L-carnitine, more preferably L-carnitine, carnitine chloride, L-carnitine hydrochloride, L-carnitine fumarate and L-carnitine tartrate.
  • the preventive or therapeutic agent for diastolic heart failure, myocardial sclerosis inhibitor, myocardial fibrosis inhibitor, and prostacyclin-increasing agent of the present invention comprises the above active ingredient, a pharmaceutically acceptable carrier, and an additive as appropriate. It can be formulated. Specifically, oral agents such as tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, parenterals such as injections, infusions, suppositories, ointments, patches, etc. can do. What is necessary is just to set suitably about the mixture ratio of a carrier or an additive based on the range normally employ
  • Carriers or additives that can be blended are not particularly limited.
  • various carriers such as water, physiological saline, other aqueous solvents, aqueous or oily bases, excipients, binders, pH adjusters, disintegrants, absorption
  • Various additives such as an accelerator, a lubricant, a colorant, a corrigent, and a fragrance are included.
  • Additives that can be mixed into tablets, capsules and the like include binders such as gelatin, corn starch, tragacanth and gum arabic, excipients such as crystalline cellulose, corn starch, gelatin, alginic acid and the like. Leavening agents, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, red mono oil or cherry.
  • a liquid carrier such as fats and oils can be further contained in the above type of material.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice, such as dissolving or suspending active substances in vehicles such as water for injection, naturally occurring vegetable oils such as sesame oil, coconut oil and the like.
  • aqueous liquid for injection for example, isotonic solutions containing physiological saline, glucose and other adjuvants (for example, D-sorbitol, D-mannitol, sodium chloride, etc.) are used.
  • alcohols eg, ethanol
  • polyalcohols eg, propylene glycol, polyethylene glycol
  • nonionic surfactants eg, polysorbate 80 TM , HCO-50
  • oily liquid for example, sesame oil, soybean oil and the like are used, and they may be used in combination with solubilizing agents such as benzyl benzoate and benzyl alcohol.
  • Buffers eg, phosphate buffer, sodium acetate buffer
  • soothing agents eg, benzalkonium chloride, procaine, etc.
  • stabilizers eg, human serum albumin, polyethylene glycol, etc.
  • storage You may mix
  • the preparation thus obtained is safe and has low toxicity, for example, it is administered to humans and other mammals (eg, rats, mice, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.) By doing so, diastolic heart failure can be effectively prevented or treated.
  • prostacyclin can be increased to suppress myocardial fibrosis and to suppress myocardial sclerosis.
  • the dose varies depending on the patient's condition, symptom, administration method and the like, but in the case of oral administration, for example, generally about 0.01 g to 40 g as an active ingredient per day for a human body weight of about 60 kg, preferably Is about 0.1 to 10 g, more preferably about 0.3 to 4 g.
  • the single dose varies depending on the patient's condition, symptom, administration method, etc.
  • it is usually about 0.01 to 100 g in a human body weight of 60 kg, for example.
  • the total daily dose may be a single dose or divided doses.
  • Example 1 Suppression of diastolic dysfunction by administration of carnitine
  • 1-1 Experimental Method (1) Administration of L-carnitine to a diastolic dysfunction model (Dahl salt-sensitive rats) Male Dahl salt-sensitive rats were bred on a high salt diet (8% NaCl-containing diet) from day 1 of 6 weeks of age. This was used as a model for diastolic dysfunction (reference 1: Doi R, et al. J Hypertens 2000; 18: 111-120. Reference 11: Masuyama T, et al. J Am Coll Cardiol 2000; 36: 2333- 2338).
  • Echocardiography and cardiac catheterization SONOS 5500 were applied to 20-week-old Dahl salt-sensitive rats under general anesthesia with Ketamine HCl (50 mg / kg, intraperitoneal injection). (Netherlands) was used for echocardiography (see Reference 1). After echocardiography, a 1.5-Fr high-fidelity, manometer tipped catheter (SPR-407; Millar Instruments, USA) was inserted into the left ventricle from the right carotid artery for cardiac catheterization. In cardiac catheterization, left ventricular end-diastolic pressure, left ventricular relaxation time constant (Tau), and myocardial stiffness constant were measured (Reference 2: Yoshida J, et al. Hypertension 2004; 43: 686-691.).
  • Solute carrier family 22 organic cation transporter
  • member 5 OCTN2
  • fatty acid desaturase 1 FADS1
  • FADS2 fatty acid desaturase 2
  • TaqMan Gene Expression Assay TaqMan Gene Expression Assay (respective assay IDs are Rn00570533_m1, Rn01759794_g1, Rn00580220_m1; RT-PCR was performed using Applied Biosystems, USA. Each mRNA amount was corrected using the GAPDH mRNA amount as an internal control.
  • 6-keto-prostaglandin F1 ⁇ (6-keto-PGF1 ⁇ ) concentration measurement 6-keto-PGF1 ⁇ (stable metabolite of prostacyclin) in the culture supernatant of the heart and cultured cardiac fibroblasts was enzyme immunoassay kit. (Cat. No. 900-004; Assay Design, USA).
  • Systolic blood pressure, pulse and weight Table 1 shows the systolic blood pressure, pulse and weight at the age of 19 weeks.
  • the systolic blood pressure and pulse were significantly increased compared with the control group by administration of the 8% high NaCl diet, but in the carnitine group, the systolic blood pressure and pulse were increased by L-carnitine administration. There was no significant effect. There was no difference in body weight among the three groups.
  • FIG. 1 (a) Plasma Free Carnitine Concentration in Heart
  • FIG. 1 (b) the free carnitine concentration in the heart
  • FIGS. 1 (a) and 1 (b) the free carnitine concentrations in plasma and heart are both decreased in the untreated group (diastolic dysfunction model). Significantly increased. From these results, it was confirmed that the carnitine concentration decreased in the diastolic dysfunction model was improved by administration of L-carnitine.
  • Echocardiographic examination and cardiac catheter examination Table 2 shows the results of the echocardiographic examination and cardiac catheter examination.
  • the increase in relative wall thickness was reduced in the carnitine group compared with the untreated group.
  • the other echocardiographic indices showed no change due to L-carnitine administration, and the left ventricular diameter shortening rate was maintained in both the untreated group and the carnitine group.
  • Lung weight and left ventricular end-diastolic pressure increased significantly in the untreated group, but these increases were not observed in the carnitine group, indicating that the onset of diastolic dysfunction was prevented.
  • FIG. 2 shows Azan Mall stained images of the heart of each group of rats. The left ventricular fibrosis area was significantly increased in the untreated group, but the increase was suppressed in the carnitine group (see Table 2). L-carnitine was thought to have improved myocardial stiffness constant by inhibiting left ventricular fibrosis.
  • FIG. 3 (a) OCTN2 mRNA and protein expression levels in heart
  • FIG. 3 (b) OCTN2 mRNA and protein expression levels in kidney
  • the upper graph shows the mRNA expression level
  • the lower graph shows the protein expression level (western blotting result).
  • FE free carnitine excretion rate
  • 6-keto-PGF1 ⁇ concentration The measured value of 6-keto-PGF1 ⁇ concentration in the heart is shown in FIG. 6 (a), and the measured value of 6-keto-PGF1 ⁇ concentration in the culture supernatant of cultured cardiac fibroblasts is shown in FIG. This is shown in 6 (b).
  • the 6-keto-PGF1 ⁇ concentration in the heart was significantly increased in the carnitine group.
  • the 6-keto-PGF1 ⁇ concentration in the culture supernatant of cultured cardiac fibroblasts was significantly increased by the addition of L-carnitine. From these results, it is considered that an increase in tissue prostacyclin concentration contributes to suppression of cardiac fibrosis, and it is clear that L-carnitine acts directly on fibroblasts to promote prostacyclin production. It was.
  • FIG. 7 (a) shows the FADS1 mRNA expression level in the heart
  • FIG. 7 (b) shows the FADS2 mRNA expression level.
  • the FADS1 mRNA expression level in cultured cardiac fibroblasts is shown in FIG. 8 (a)
  • the FADS2 mRNA expression level is shown in FIG. 8 (b).
  • Prostacyclin is synthesized in vivo using AA as a precursor.
  • FADS1 and FADS2 are AA synthases. As is apparent from FIGS. 7 (a) and (b) and FIGS.
  • AA Concentration The measured value of AA concentration in the heart is shown in FIG. As is clear from FIG. 9, the AA concentration in the heart increased significantly in the carnitine group.

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Abstract

L'invention concerne la carnitine, ou un de ses dérivés, ou un de leurs sels pharmaceutiquement acceptables, qui est utile en tant qu'ingrédient actif d'un agent prophylactique ou thérapeutique pour l'insuffisance cardiaque diastolique. La présente invention permet d'obtenir un agent pharmaceutique qui est efficace pour la prophylaxie ou le traitement de l'insuffisance cardiaque diastolique, pour laquelle un procédé thérapeutique efficace n'a pas encore été établi.
PCT/JP2011/066707 2010-07-23 2011-07-22 Agent thérapeutique pour insuffisance cardiaque diastolique WO2012011572A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59222412A (ja) * 1983-06-01 1984-12-14 Earth Chem Corp Ltd 心臓疾患治療薬
JPS62190190A (ja) * 1986-01-13 1987-08-20 シグマ−タウ・インダストリエ・フアルマシウテイシエ・リウニテ・ソシエタ・ペル・アチオ−ニ Ｌ−カルニチンのホスホリルアルカノ−ルアミド誘導体類およびその医薬組成物
JPS62272984A (ja) * 1986-03-14 1987-11-27 イステイトウト・グイド・ドネガニ・ソチエタ・ペル・アツイオニ Ｌ−（−）−カルニチンクロライドのバイオテクノロジ−による製造方法
JP2002518437A (ja) * 1998-06-23 2002-06-25 シグマ−タウ・ヘルスサイエンス・ソシエタ・ペル・アチオニ 骨粗鬆症および、更年期症候群による変容の予防および／または治療のための、プロピオニルｌ−カルニチンおよびゲニステインを含む組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59222412A (ja) * 1983-06-01 1984-12-14 Earth Chem Corp Ltd 心臓疾患治療薬
JPS62190190A (ja) * 1986-01-13 1987-08-20 シグマ−タウ・インダストリエ・フアルマシウテイシエ・リウニテ・ソシエタ・ペル・アチオ−ニ Ｌ−カルニチンのホスホリルアルカノ−ルアミド誘導体類およびその医薬組成物
JPS62272984A (ja) * 1986-03-14 1987-11-27 イステイトウト・グイド・ドネガニ・ソチエタ・ペル・アツイオニ Ｌ−（−）−カルニチンクロライドのバイオテクノロジ−による製造方法
JP2002518437A (ja) * 1998-06-23 2002-06-25 シグマ−タウ・ヘルスサイエンス・ソシエタ・ペル・アチオニ 骨粗鬆症および、更年期症候群による変容の予防および／または治療のための、プロピオニルｌ−カルニチンおよびゲニステインを含む組成物

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
BOEYNAEMS, J.M. ET AL.: "Palmitoyl-L-carnitine increases the release of prostacyclin from vascular endothelial cells", BIOCHEM. PHARMACOL., vol. 38, no. 19, 1989, pages 3261 - 3266, XP025541354, DOI: doi:10.1016/0006-2952(89)90623-0 *
CHAO, H.H. ET AL.: "L-carnitine attenuates angiotensin 11-induced proliferation of cardiac fibroblasts: role of NADPH oxidase inhibition and decreased sphingosine-1-phosphate generation", J. NUTRI. BIOCHEM., vol. 21, no. 7, July 2010 (2010-07-01), pages 580 - 588 *
CUI, J. ET AL.: "Effects of L-carnitine and its derivatives on postischemic cardiac function, ventricular fibrillation and necrotic and apoptotic cardiomyocyte death in isolated rat hearts", MOL. CELL. BIOCHEM., vol. 254, 2003, pages 227 - 234 *
ELLIOTT, G.R. ET AL.: "The effect of acute feeding of carnitine, acetyl carnitine and propionyl carnitine on basal and A23187- stimulated eicosanoid release from rat carrageenan-elicited peritoneal macrophages", BRI. J. NUTRI., vol. 64, 1990, pages 497 - 503 *
ILEICETO, S. ET AL.: "Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infraction: the L-carnitine ecocardiografia digitalizzata infarto miocardico(CEDIM) trial", J. AM. COLL. CARDIOL., vol. 26, no. 2, 1995, pages 380 - 387, XP002290008, DOI: doi:10.1016/0735-1097(95)80010-E *
JEEJEEBHOY, F. ET AL.: "Nutritional supplementation with myovive repletes essential cardiac myocyte nutrients and reduces left ventricular size in patients with left ventricular dysfunction", AMERICAN HEART JOURNAL, vol. 143, no. 6, 2002, pages 1092 - 1100, XP029482820, DOI: doi:10.1067/mhj.2002.121927 *
KAZUHIRO YAMAMOTO: "Kakucho Fuzen ni yoru Mansei Shinfuzen", KOKYU TO JUNKAN, vol. 50, no. 4, 2002, pages 407 - 411 *
KOBAYASHI, A. ET AL.: "Effects of L-carnitine on ventricular arrhythmias after coronary reperfusion", JPN. CIR. J., vol. 47, 1983, pages 536 - 542 *
PAULY, D.F. ET AL.: "The role of carnitine in myocardial dysfunction", AM. J. KIDNEY DISEASE, vol. 41, no. 4, 2003, pages S35 - S43 *
SERATI, A.R. ET AL.: "L-carnitine treatment in patients with mild diastolic heart failure is associated with improvement in diastolic function and symptoms", CARDIOLOGY, vol. 116, 21 January 2010 (2010-01-21), pages 178 - 182 *

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