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WO1992004023A1 - Composition et procede de protection du c×ur pendant une reperfusion - Google Patents

Composition et procede de protection du c×ur pendant une reperfusion Download PDF

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Publication number
WO1992004023A1
WO1992004023A1 PCT/US1991/006545 US9106545W WO9204023A1 WO 1992004023 A1 WO1992004023 A1 WO 1992004023A1 US 9106545 W US9106545 W US 9106545W WO 9204023 A1 WO9204023 A1 WO 9204023A1
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WO
WIPO (PCT)
Prior art keywords
alanine
heart
effective amount
glutamate
animal
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Application number
PCT/US1991/006545
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English (en)
Inventor
Austin L. Shug
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Individual
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Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO1992004023A1 publication Critical patent/WO1992004023A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—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

Definitions

  • MI acute myocardial infarction
  • blood flow to the cardiac muscle becomes severely restricted if not stopped. If flow is not restored, myocardial ischemia and death ultimately result.
  • Three major objectives in treatment of MI are to restore, toward normal, the compromised blood flood and to protect the heart muscle until such blood flow is restored, and to prevent further damage during reperfusion.
  • Myocardial ischemia leads to a number of well documented sequelae, one of which is the breakdown of myocardial protein.
  • BCAA branched chain amino acids
  • Rubinstein, A., Gur, Y. "Branched Chain Amino Acids in the Protection of the Myocardium from Ischemic Damage," Israel J. Med. Sci. f Vol. 25:1, 1989; Schwalb, H.J., Freund, H.R. and Uretsky, G. , "Role of Amino Acids Acids in Myocardial Protection During Ischemia and Reperfusion," Perspectives in Clinical Nutrition, ed. J.M. Kenney and P.R. Borum, 1989, Urban & Schwarzenberg, Baltimore-Munich, pages 57-67.
  • One explanation for the observed protective effect has been that such preparations may stimulate protein synthesis and reduce the degradation of heart proteins. Id.
  • Lagendorff Non-recirculating retrograde perfusion in oxygenated Krebs Henseleit bicarbonated saline solution, containing 11 mM glucose , (KBH)
  • the heart was then perfused in a recirculating anterograde "working" mode by switching perfusate input source to the left atrial pre-load reservoir (15cm H 2 0 filling pressure) , opening the aortic output line (80cm H 2 0 after-load pressure) , and pacing at 315 beats per minute by atrial anodal stimulus for a 30 minute stabilization period at which time baseline measurements were made of various parameters including cardiac output (CO) .
  • CO cardiac output
  • NFI flow ischemia
  • reperfusion was started by reversing the sequence in NFI. Reperfusion was continued in each case for slightly more than 40 minutes. In some cases resuscitation manipulations were employed until recovery. The measurements reported below were taken at the end of 40 minutes of reperfusion.
  • the reperfusion solution was KBH.
  • alanine, or alanine plus glutamate or glutamate were added to the KBH solution in the concentrations indicated in Table 1.
  • Coronary flow was determined in a analogous fashion.
  • LVMW left ventricular minute work
  • CO cardiac output
  • MAP mean aortic pressure
  • MAP (2 x ADP) + ASP 3
  • ADP represents aortic diastolic pressure
  • ASP represents aortic systolic pressure.
  • Aortic pressures were measured using a spectromed strain gauge transducer, P23XL, with a Gilson 5/6 polygraph outfitted with a 1C-MP module.
  • Lactate was measured according to the procedure of Gutmann, H. and Wahlefeld, Methods of Enzymatic Determinations f Bergmeyer, H. (ed.) Vol. 3, Academic Press, New York, N.Y. (1974), "Lactate Determination” pp. 1464-1468.
  • Adenosine triphosphate was measured according to the method of Stanley, P.E. and Williams, S.G., "Use of the Liquid Scintillation Spectrometer for Determining Adenosine triphosphate by the Luciferase Enzyme" Analyt. Biochem. 29:381-392 (1969).
  • 1 % REC. CO. represents the % of recovery of cardiac output as compared to the control.
  • WORK represents the % of recovery of cardiac work as compared with the control.
  • treatment with the amino acids of the present invention results in a significantly lower lactate concentration when compared with the control. This finding alone is evidence of the protective effect of the treatment of the invention. Moreover, the treated hearts show a significance increase from control in ATP concentrations which is evidence of a stimulation of mitochondrial respiration and oxidative phosphorylation.
  • alanine or the combination of alanine plus glutamate to protect the heart in humans and other mammals during developing ischemia and reperfusion.
  • Medical situations where such treatment would be useful are acute MI, chronic low flow caused by coronary artery disease and open heart surgery where the heart is stopped and needs to be resuscitated.
  • alanine with a combination of alanine plus glutamate is administered to a patient, either alone or in combination with one or more drugs known to be useful in the treatment of MI.
  • alanine or alanine plus glutamate
  • glutamate may act to increase mitochondrial malate.
  • alanine may act as a substrate to increase mitochondrial pyruvate which is rapidly converted to acetyl CoA.
  • Acetyl CoA is at a rate-limiting step in the citric acid cycle and is known to decrease markedly in myocardial ischemia.
  • an increase in Acetyl CoA by conversion from alanine may be a possible mechanism by which alanine so effectively increases heart mitochondrial respiration.
  • the administration of the amino acids of the present invention can be effected orally, intraperitonally, subcutaneously, intravenously or intramuscularly.
  • the amino acids of the present invention are mixed or dissolved in any innocuous vehicle such as water or sterile saline solution or an electrolyte solution such as Krebs Heneleit Solution or in tablet or powder form containing the usual solid diluents or carriers.
  • the glutamate concentration should be sufficient to stimulate respiration but not so great as to risk the development of unwanted neurotoxic side effects. In humans, a dosage sufficient to raise the blood concentration to 1-20 mM alanine plus 0-5 mM glutamate is preferable.
  • amino acids of the invention can be co-administered with other amino acids, branched chain amino acids or with drugs that are known to be useful in the treatment of heart disease, such as drugs which display positive iontropic action or drugs with anti- arrhythmic effects. Effective amounts of the amino acids of the invention may also be co-administered with other compounds such as L-Carnitine which are believed to be useful supplements for treating heart disease.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention décrit une composition pharmaceutique et un procédé servant à protéger le c÷ur d'un animal ou d'un humain pendant l'ischémie ou la reperfusion. L'alanine amino acide, quand elle est administrée en quantité suffisante pour augmenter le niveau du sang de l'animal ou de l'humain entre 1,0 et 20,0 mM d'alanine, protégera le myocarde contre des atteintes pendant l'ischémie ou la reperfusion.
PCT/US1991/006545 1990-09-10 1991-09-09 Composition et procede de protection du c×ur pendant une reperfusion Ceased WO1992004023A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US58012790A 1990-09-10 1990-09-10
US580,127 1990-09-10

Publications (1)

Publication Number Publication Date
WO1992004023A1 true WO1992004023A1 (fr) 1992-03-19

Family

ID=24319829

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/006545 Ceased WO1992004023A1 (fr) 1990-09-10 1991-09-09 Composition et procede de protection du c×ur pendant une reperfusion

Country Status (4)

Country Link
EP (1) EP0509066A4 (fr)
AU (1) AU8513191A (fr)
CA (1) CA2068333A1 (fr)
WO (1) WO1992004023A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5656608A (en) * 1995-02-23 1997-08-12 Sandoz Nutrition Ltd. Amino acid compositions and methods of treatment using same
US6048543A (en) * 1995-06-14 2000-04-11 Novartis Nutrition Ag Amino acid compositions and use thereof in clinical nutrition
EP1475090A4 (fr) * 2002-02-14 2007-08-08 Ajinomoto Kk Medicaments pour maladies mitochondriales
US20100291228A1 (en) * 2005-08-19 2010-11-18 Shigeo Ohta Scavenger of in vivo harmful reactive oxygen species and/or free radicals
US20110300237A1 (en) * 2002-05-17 2011-12-08 De Groot Herbert Protective solutions for organs

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5824662A (en) * 1996-09-27 1998-10-20 Guilford Pharmaceuticals Inc. Treatment of global and focal ischemia using naaladase inhibitors
WO1998013046A1 (fr) 1996-09-27 1998-04-02 Guilford Pharmaceuticals Inc. Compositions de naaladase et methodes de traitement des anomalies du glutamate et de suscitation d'une activite neuronale chez l'animal

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4258037A (en) * 1976-12-02 1981-03-24 Sertog Societe D'etudes De Recherches De Travoux D'organisation Et De Gestion Therapeutic compounds for the treatment of uro-genital disorders
US4780475A (en) * 1986-02-03 1988-10-25 Cerra Frank B Preparation for the prevention of catabolism
US4987123A (en) * 1988-02-24 1991-01-22 Ajinomoto Co., Inc. Compositions useful for the treatment and/or prevention of hepatic disorders, and their pharmaceutical use

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE8704217D0 (sv) * 1987-10-29 1987-10-29 Vinnars Erik Ab Aminosyrakomposition for parenteral neringstillforsel

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4258037A (en) * 1976-12-02 1981-03-24 Sertog Societe D'etudes De Recherches De Travoux D'organisation Et De Gestion Therapeutic compounds for the treatment of uro-genital disorders
US4780475A (en) * 1986-02-03 1988-10-25 Cerra Frank B Preparation for the prevention of catabolism
US4987123A (en) * 1988-02-24 1991-01-22 Ajinomoto Co., Inc. Compositions useful for the treatment and/or prevention of hepatic disorders, and their pharmaceutical use

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Biochemistry, 2nd edition (1981); STRYER et al., pages 486-488. Note page 488, top diagram. *
G. URETZKY et al., Israel J. Med. Sci., V25, No. 1 (1989), pages 3-6. Note page 5, sentence bridging columns 1-2. *
SCHWALB et al., in John Kinney et al. (eds.), Perspectives in Clinical Nutrition (1989), pages 57-67. Note page 58, lines 27-35. *
See also references of EP0509066A4 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5656608A (en) * 1995-02-23 1997-08-12 Sandoz Nutrition Ltd. Amino acid compositions and methods of treatment using same
US6048543A (en) * 1995-06-14 2000-04-11 Novartis Nutrition Ag Amino acid compositions and use thereof in clinical nutrition
EP1475090A4 (fr) * 2002-02-14 2007-08-08 Ajinomoto Kk Medicaments pour maladies mitochondriales
US20110300237A1 (en) * 2002-05-17 2011-12-08 De Groot Herbert Protective solutions for organs
US9603354B2 (en) * 2002-05-17 2017-03-28 Dr. Franz Koehler Chemie Gmbh Protective solutions for organs
US20100291228A1 (en) * 2005-08-19 2010-11-18 Shigeo Ohta Scavenger of in vivo harmful reactive oxygen species and/or free radicals
US9050278B2 (en) 2005-08-19 2015-06-09 Shigeo Ohta Scavenger of in vivo harmful reactive oxygen species and/or free radicals

Also Published As

Publication number Publication date
EP0509066A1 (fr) 1992-10-21
AU8513191A (en) 1992-03-30
CA2068333A1 (fr) 1992-03-11
EP0509066A4 (en) 1992-11-25

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