EP0250559A1 - Therapie de nutrition parenterale avec acides amines - Google Patents

Therapie de nutrition parenterale avec acides amines

Info

Publication number
EP0250559A1
EP0250559A1 EP19870900533 EP87900533A EP0250559A1 EP 0250559 A1 EP0250559 A1 EP 0250559A1 EP 19870900533 EP19870900533 EP 19870900533 EP 87900533 A EP87900533 A EP 87900533A EP 0250559 A1 EP0250559 A1 EP 0250559A1
Authority
EP
European Patent Office
Prior art keywords
liter
solution
anions
mmoles
lactate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19870900533
Other languages
German (de)
English (en)
Inventor
Richard L. Veech
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP0250559A1 publication Critical patent/EP0250559A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof

Definitions

  • This invention lies in the field of parenteral nutrition therapy, and especially in the field of amino-acid containing solutions and methods for practicing such therapy.
  • acetate in parenteral fluids developed in the late 40's and early 50's following reports that "acetate could serve as an alternative source of fixed base such as bicarbonate" (Mudge GH, Manning JA, Gilman A. Sodium acetate as a source of fixed base. Proc Soc Exptl Biol Med 71:136-138, 1949; Fox CL, Winfield JM, Slobody LB, Swindler CM, Lattimer JK. Electrolyte solution approximating plasma concentrations with increased potassium for routine fluid and electrolyte replacement. J Am Med Asso 148: 827-833, 1952) .
  • Acetate was used in parenteral fluids for four major reasons, the first being low cost, and the second, ignorance of its toxic effects. The third was an attempt to avoid hyperchloremic acidosis. Amino acid solutions which included amino acids as their chloride salts lead to
  • acetate was included in the amino acid mixtures, particularly those containing sulfur, was to avoid a metabolic acidosis.
  • an alkalizing agent was administered, which, at the time, was thought to be harmless. This has now been proven not to have been the case.
  • the improvement here consists in substituting for acetate other anionic metabolites which may accomplish this function in a non-harmful manner.
  • Another adverse consequence of the use of acetate in parenteral nutrition fluids is the lowering of the phosphorylation potential which occurs in tissues exposed to high levels of acetate (Veech, RL et al, 1986) . This inevitably results in an increased 0 2 demand for any organ to do a comparable amount of work. In short, this decreases the metabolic efficiency of the organism because less energy is released from each ATP utilized.
  • Adenosine is a potent vasodilator. Given the well known occurrence of hypotension (Graefe U et al, Less dialysis induced morbidity and vascular instability with bicarbonate in dialysate.
  • the prior art amino acid formulations suffer because they are commonly derived from the amino acid composition of casein, a common milk protein, and bear little resemblance to the normal human plasma concentrations of free amino acids. Certain classes of amino acids are even missing, particularly the major plasma amino acid, glutamine, which is essential to the function of many organs, such as kidney and gut. It is further known that the plasma concentrations of amino acids are carefully regulated. It is, therefore, desirable that the prior art compositions be replaced by mixtures wherein the respective amino acid concentrations, relative one to another, resemble the plasma to which such are being added. Finally, the hormonal balance in many patients receiving such treatments favors the breakdown of protein with concurrent loss of muscle and tissue mass and the synthesis of glucose and urea. The action of hormones can be effected by control of the redox state (Sistare FD, Haynes RD, J Biol Che 260:12748-12753, 1985).
  • this invention is directed in one aspect to a new and improved class of non-hyper- chloremic, alkalinizing, compositions which prevent both metabolic acidosis and metabolic bone disease.
  • compositions comprise water having dissolved therein:
  • (C) from about 0.1 to 150 mM/L of at least one cation selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium.
  • mMoles/L has conventional reference to millimoles per liter (sometimes shown as mM/1 or the like) .
  • compositions can contain at least one os otically active nonionic water soluble nutrient, such as glucose, in a total quantity ranging from about 5 to 400 mMoles/L.
  • the solution may contain added electrolytes as defined in (C) above as accomplished in the prior art amino acid solutions (see Table 1) .
  • this invention is directed to an improved in vivo process for accomplishing parenteral nutrition which comprises introducing intravenously into a human being a composition from the class above described preferably at a rate which is sufficient to be nutritionally effective.
  • a rate with such a composition can also be generally effective in normalizing organ function particularly when near equilibrium couples are employed as taught hereinbelow.
  • compositions from the class above described may additionally contain dissolved therein glutamine.
  • glutamine a composition from the class above described
  • the quantity of glutamine employed in any given such composition is as herein below described.
  • the glutamine containing compositions of the present invention are applicable for use in various particular parenteral fluid therapy applications.
  • concentrations and the relationship of the component concentrations to one another in such application can be varied.
  • a glutamine containing composition may result in an increase in organ protein content and/or an increase in organ functional capacity compared to compositions of the class above described.
  • a composition of this invention contains at least 5 of such nitrogen containing compounds of Table 5, more preferably at least 10, still more preferably at least 15, and most preferable all of the compounds of Table 5.
  • the relative quantities of each in relation to the other(s) thereof present follows the hierarchical listing order shown in Table 5.
  • An object of the present invention is to provide parenteral nutritional compositions which do not contain toxic levels of acetate or d,1-lactate.
  • Another object is to provide parenteral nutritional compositions which contain at least one 1-amino acid and at least one monocarboxylic anionic metabolite.
  • Another object is to provide therapeutic organic nitrogen containing fluid compositions which include near equilibrium couples which comprise either metabolite carboxylic anions or amino acids.
  • Another object is to provide a class of organic nitrogen containing parenteral nutrition fluids which, when
  • SUBSTITUTE SHEET administered, regulate and control the cellular p osphorylation state, thus normalizing and improving the efficiency of organ function in a living mammal.
  • Another object is to provide a class of mixtures of organic nitrogen containing compounds which mixtures are adopted to be employed, if desired, in multiples of the physiologic concentrations of such compounds found in normal human plasma and which mixtures are not simple compositions derived from the amino acid content of casein or other low cost hydrolyzable proteins.
  • Another object is to provide aqueous compositions containing amino acids and certain redox action carboxylic acid near equilibrium couples which are suitable for use in parenteral nutrition therapy to restore and maintain muscle and other cellular functions.
  • SUBSTITUTE SHEET of protein is impaired by obstruction, inflammatory disease or complications of antineoplastic therapy; (3) bowel rest is needed because of GI surgery or its complications, such as ileus, fistulae or anastomotic leaks; or (5) burns, trauma, infections, or other such so called hypermetabolic states exist.
  • SUBSTITUTE SHEET is further evidence to suggest that the specific concentrations and .components of the nitrogenous compounds present in the current commercial formulations are not optimized so as to promote a positive nitrogen balance and a return to physiologically normal status. For these reasons, the present and new improved formulations of parenteral amino acid supplements have been created as taught herein.
  • compositions provide less toxic and more efficacious forms of parenteral nitrogenous nutritional supplements to treat patients in negative nitrogen balance for the above listed reasons.
  • the concentration of the central amino acid transaminase pairs namely alpha ketoglutarate x gluta ate, and oxaloacetate x aspartate, or pyruvate x alanine, as well as the ketoacids of the branched chain amino acids, ketoisovaleric, and ketoisocaproic, are related to the redox state of one or another of the cellular redox states as the result of highly
  • SUBSTITUTE SHEET active transaminase systems which maintain a state of near equilibrium between the various cellular components.
  • Administration of solutions of amino acids alone, without simultaneous administration of one or another substrate couple with which that amino acid is in a state of near equilibrium results in a change of the general cellular redox state towards that state which is characteristic of the starved state.
  • a general reduction of all the cellular redox states, or [NA(P)D + ]/[NAD(P)H] ratios there is a breakdown of protein into amino acids and an increase in gluconeogenesis. This is precisely the situation which parenteral nutrition with amino acids is trying to reverse.
  • the same situation of reduction of cellular redox states occurs under the influence of catabolic hormones, such as glucagon, sympathomimetic agents, and steroids.
  • the present class of formulations may be used to insure that the cellular redox state of the cells in a living mammal during parenteral nutrition achieves a level characteristic of the fed state when protein synthesis generally exceeds the rate of protein breakdown.
  • cytoplasmic [NAD + ]/[NADH] is directly related to the major cellular energy level, or to the cytoplasmic phosphorylation state of [ATP]/[ADP] x [Pi] ratios through the action of the glyceraldehyde 3 phosphate dehydrogenase reaction and the 3 phosphoglycerate kinase reactions (Veech RL, Lawson JWR, Cornell NW, Krebs HA. The cytoplasmic phosphorylation potential. J Biol Chem 254:6538-6547. 1979).
  • Control of the cytoplasmic phosphorylation potential allows one to manipulate, within limits, the cellular energy level which determines the degree of efficiency at which any organ operates. It has recently been shown, for example, that the maximum rate at which isolated hepatocytes are able to convert lactate to glucose is at the physiological redox state represented when the [lactate]/[pyruvate] ratio in the
  • SUB bathing media is 10:1 (Sistare FD, Haynes RC, J Biol Chem 260:1-2748-1275.3, 1985).
  • the same paper shows that, for any class of hormone tested, whether acting through cyclic AMP, through changes on intracellular Ca 2+ , or directly on a receptor and then on nuclear synthesis such as steroids, there is a particular redox state which will allow, or not allow, as the case may be, the hormone class members to maximally express their action.
  • the physician is offered the opportunity to directly alter the redox state of the tissues during such parenteral fluid therapy so as to best achieve the result desired in a particular situation.
  • the hormonal status of the patient favors the catabolism of protein and the making of glucose. While the prevention of the secretion of catabolic hormones in such a situation cannot be prevented, by alteration of the redox state of the parenteral fluids, the effects of these hormonal changes may be modified.
  • Amino Acid and Amide Composition of Plasma, Perfused Liver, and a Representative Protein -- Values are given in mmoles/liter water.
  • the values for rat serum are taken from Lunn PG, Whitehead RG, Baker BA, Br J Nutr 36: 219-230, 1976; for normal human plasma from Guanda OM, Aoki T, Soldner H, Cahill FG. ⁇ 7 Clin Invest 57: 1403-1411, 1976.
  • Liver values from perfused rat liver containing normal amino acid levels in a perfusate composed of Krebs-Henseleit are taken from Poso AR, Mortimore GE, Proc Nat'l Acad Sci USA 81: 4270-4274, 1984.
  • Table 3 shows the amino acid composition of normal human- plasma and the amino acid composition of a normal intracellular protein, actin. It can readily be seen that the composition of plasma is very different from the amino acid composition of a protein. Plasma levels of amino acids often bear little relation to tissue concentrations. Table 2 further illustrates that the amino acid composition of plasma is approximately the same as the amino acid composition of liver for certain amino acids, such as the branched chain amino acids, valine, leucine, and isoleucine, the aromatic amino acids, phenylalanine and tyrosine, and the sulfur containing amino acid, methionine.
  • amino acids such as the branched chain amino acids, valine, leucine, and isoleucine, the aromatic amino acids, phenylalanine and tyrosine, and the sulfur containing amino acid, methionine.
  • liver/plasma gradient of other amino acids may show concentration gradients from 5 to 100 between perfusing fluid and liver.
  • concentration gradients occur in the case of glutamine.
  • glutamine the major traffic in nitrogen between the various organs is borne by alanine, glutamine, and the branched chain amino acids, leucine, isoleucine and valine.
  • tissue proteins In a 70kg normal man, the major repository of the 6 kg of nitrogen is the tissue proteins, while the free tissue amino acid pools comprise less than 1% of the total amino acids. Tissue protein is in a dynamic state with half lives ranging from less than one hour to weeks, and with the overall turnover being about 300g/day in a 70kg man.
  • Protein synthesis obviously requires a supply of amino acids. In addition, it requires that the gradients of amino acids between extracellular fluid and cells remain normal. The latter function of the cell is the result of a variety of active, energy-requiring uptake systems, which, in turn, demand that the cellular energy state, or [ATP]/[ADP] x [Pi], and its related redox state, or [NAD + ]/[NADH] , are normal.
  • the major fate of ingested amino acids is not for the synthesis of protein, but rather to serve either as substrates for gluconeogenesis, or as precursors of acetyl CoA for combustion in the Krebs cycle. Most of the nitrogen of ingested proteins, and their hydrolyzed amino acids, .
  • the carbon skeletons end as either glucose, or as ketone bodies, being metabolized by the various transa inase reactions with glutamate, or forming one or another forms of CoA, with or without an intermediate form of an acyl carnitine.
  • a first possibility or mode for improvement is the development of alternative formulations of nitrogen compound containing parenteral nutrient formulation which avoid the use of 40 to 150 mM acetate in all current amino acid containing parenteral nutrition formulation, (Facts and Comparisons March, 1984, pp. 36a-37d, JB Lippincott, St. Louis) so as to avoid the chronic bone pain, the metabolic bone disease, and the profound disordering of calcium, phosphate and pyrophosphate homeostasis which accompany the current use of unphysiological levels of acetate in parenteral nutrition formulations.
  • At least one carboxylic metabolite or more preferably, at least one redox balanced mixture as shown in Table 2 containing the near equilibrium carboxylic acid couples 1- lactate/pyruvate, d-betahydroxybutyrate/acetoacetate., and/or bicarbonate/C0 2 are used as substitutes for acetate (see, for example, my copending US patent application Serial No. 748,232).
  • Another alternative or mode for improvement is to employ nitrogen containing parenteral nutrient solutions as provided by the present invention wherein the redox state is controllable after administration using certain amino acids themselves, along with the appropriate redox and transaminase partner, when employed in the concentration ratios found in normal healthy animals, or in designed variations of those ratios. Specific effects may be achieved, such as the modification of hormone action as described previously.
  • the normal redox partner of 1-lactate is pyruvate, but, in solution, pyruvate tends to form the inactive dimer parapyruvate. This means that it preferably should be added just prior to use, as is now preferably done with cysteine.
  • the metabolite anions used in the compositions of this invention exert a desirable alkalinizing action which avoids metabolic acidosis and thereby provides alkalinizing action as desired.
  • alphaketoglutarate is somewhat greater in solution than that of either pyruvate or acetoacetate, depending upon the conditions. Even though large gradients of each of these compounds exist across plasma membranes, and their concentrations in plasma are very low relative to their intracellular concentrations, controlled transport of all of these substrates does occur. If fluids not containing these substrates are given, then the cells alter their metabolism so as to make the infused material contain a predetermined concentration gradient. Addition, therefore, of alphaketoglutarate and NH + in an amino acid solution containing glutamate can control the redox state of the mitochondria.
  • Another example is the use of various ratios, around the physiologically normal, of [ketoglutarate]/ [glutamine] which avoid the use of free ammonia, but which generate the ammonia and the production of intracellular glutamate.
  • the glutamate-pyruvate-transaminase reaction makes it possible to control redox state in an amino acid containing parenteral solution using the ratio of [1-alanine]/[1-lactate]. This appears to be useful in situations where the limited shelf life of ketoacids, such as pyruvate, in solution, may call for premixed redox balanced solutions with a long stability. Using a combination of [1-alanine]/[1-lactate] in conditions where this solution stability is needed, and the extra ammonia resulting from the formation of pyruvate from alanine and its subsequent removal as urea, does not present a problem.
  • 1-amino acids for use in the present inventive compositions in the form of salts of at least one of the metabolite anions identified herein.
  • the parenteral aqueous solutions of the present invention preferably include, as solutes, more than one amino acid.
  • this quantitative relationship of individual amino acids one to another is preferably such as to correspond to the quantitative relationship of these same respective amino acids in normal plasma.
  • Each of the component amino acids present in such a mixture is preferably present in an amount which is in excess of the amount present in normal plasma.
  • such mixtures are preferably multiples of normal plasma levels. Leaving aside the concentration of amino acids in the portal vein, the diurnal variations in the amino acid composition of plasma in the systemic circulation are relatively small (Wurtman RJ et al. , Daily rhythms in the concentrations of various amino acids in human plasma. N En ⁇ J Med 279:171- 175, 1969) .
  • the concentrations are disordered from normal in both order and in concentration range.
  • the concentrations are, relative to the natural order: 4 glycine, 2 alanine, 13 arginine "1" , 9 leucine, 5 lysine, 3 valine, 10 methionine, 19 phenylalanine, 14 isoleucine, 6 proline, 7 threonine, 12 histidine, 13 tryptophane, 14 tyrosine, with the major amino acid in plasma, 1-glutamine being omitted altogether, as are the important redox active amino acids, 15 glutamate- and 19 aspartate-, and also, inexplicably, 8 serine, a precursor of pyruvate.
  • the intracellular amino acid levels are, therefore, importantly related both to the cytoplasmic [NAD + /[NADH] ratio, and to the mitochondrial [NAD + ]/[NADH] ratio, and also to the concentration of ammonia (Williamson DH, Lund P, Krebs HA, Biochem J 103:514-427, 1967). Giving one, but not another component, of a near-equilibrium couple must inevitably lead to a distortion of the intracellular concentrations of a number of metabolites. More importantly, distortion of the cellular redox state leads to changes in the cellular energy level or [ATP]/[ADP] x [Pi] ratio because:
  • parenteral amino acid supplements do not lead to an increased functional capacity in muscle which is desired to decrease operative mortality and morbidity in a reasonable pre-operative period of supplementation.
  • the increase in protein mass per se is not the goal to be sought in a human patient in need of parenteral nutrition therapy. Rather, an increased functional capacity is such a goal, and that will be judged using NMR and ergometry.
  • Part of the difficulty in present formulations may be due to the use of acetate in these formulations, which leads to a decrease in the phosphorylation potential, and to a severe decrease in the free [NADP + ]/[NADPH] ratio, in addition to the abnormalities in calcium and pyrophosphate metabolism discussed earlier. It has been suggested that the persistence of the muscle weakness and the failure of muscle mass to increase in patients receiving conventionally formulated parenteral amino acid supplements may, in fact, be a myopathy secondary to increased intracellular calcium content (see Russell D. et al. Nitrogen versus muscle calcium in the genesis of abnormal muscle function in malnutrition. J Paren Ent Nutr 9:415-421, 1985).
  • 1-carnitine Omitted from presently available commercial mixtures, but which may optionally and advantageously be included in the new compositions of this invention, are such nitrogen containing compounds as 1-carnitine, 1-ornithine, 1-citrulline, and the like.
  • Carnitine in addition to its well known role in the metabolism of fatty acids, is an important co-factor in the metabolism of the branched chain amino acids leucine, isoleucine and valine.
  • the serum and tissue levels of 1-carnitine are frequently found to be decreased in patients with malnutrition, alcoholic cirrhosis, certain congenital myopathies, and lipidemias, in patients on chronic he odialysis, or in patients who are eating no red meat, as is the case for those receiving nutrition totally parenterally.
  • Hyperammonemia is a common complication of the administration of the present amino acid supplements.
  • SUBSTITUTE urea cycle intermediates may, there-fore, be included with the amiro acids used in an infusable fluid composition of this invention in an attempt to avoid distortion of the normal physiological levels of intermediates that exist under natural conditions. In this way, optimum function of the urea cycle is maintained during the inevitable loss of amino acids into urea which is a natural accompaniment of the ingestion of protein.
  • the present invention provides a class of aqueous solutions adaptable for use in human parenteral nutrition therapy.
  • a solution of this class tends (a) to normalize muscle and other organ function, (b) to maintain normal cellular phosphorylation potential, and (c) avoid acidosis and bone pain characteristic of present formulations.
  • compositions of this invention preferably contain glutamine.
  • a glutamine-containing such composition (solution) preferably contains from about 0.03 to 120 millimoles per liter of glutamine plus at least one metabolizable nitrogen containing compound selected from among those shown in the Table 7 listing below. In Table 7
  • SUBSTITUTE SHEET the plasma amino acids are arranged in groups, each group indicating a specified (preferred) concentration range for use in the practice of this invention.
  • the respective ranges for the values of K which apply for each of the four classes of amino acids shown in Table 7 appear in Table 6 below:
  • the single member of Class I that is, 1-cysteine in Table 7 is preferably added to a solution just prior to administration.
  • the respective metabolizable nitrogen- containing compounds in each such concentration range class are as follows:
  • solutions of this invention contain nitrogen-containing positively or negatively charged metabolizable compounds which are in solution with correspondingly oppositely charged metabolites or electrolytes.
  • solutions of this invention are acetate anion free and are electrically neutral.
  • a solution of this invention also contains at least one
  • SUBSTITUTE SHEET inorganic cation selected from the group consisting of sodium, potassium, calcium, magnesium and ammonium.
  • the total quantity of such metabolic cation(s) present in a given solution ranges from about 0.1 to 150 mM/1.
  • Each such dissolved metabolized organic nitrogen containing compound (including glutamine) when present in a solution of this invention, is preferably present in a concentration range extending from about 1 to 150 mM/1, although larger and smaller concentrations can be used.
  • 1-lactate salts are prepared so that the following aqueous solution of 1-hydrolactates of 1- amino acids is formulated wherein the 1-amino acid concentrations are approximately 100 times their levels in normal plasma:
  • Example 1.1 to provide a composition of this invention.
  • aqueous solutions of this invention are prepared having the following compositions:
  • Example 1.1 Example 1.2
  • aqueous solutions of this invention are prepared having the following components:
  • Example 1.3 Example 1.4 Example 1.5
  • Example 2 The route of administration has an effect upon maximum dosage of nitrogen containing compounds and caloric supplementation.
  • SUBSTITUTE SHEET Parenteral nutrition is now characteristically given-, either through normal intravenous lines, using only slightly hypero ⁇ molar solutions, or through grossly hypertonic solutions administered through indwelling catheters placed in a deep vein. Both are unphysiologic in that the bulk of the nutrients normally provided to the body enter through the portal vein, where very large concentrations of substrates normally occur in a postprandial state (Veech RL, unpublished data) .
  • each of the formulations Examples 1.1 and 1.2 at the dose rate of 2 ml are administered to three starved Sprague Dawley male rats over one hour in combination with 3 ml of 5% dextrose in water.
  • the effects on the plasma and tissue metabolite levels and rate of protein turnover are measured following established methods, such as those described by Poso and Mortemore, 1984.
  • change in lean body and bone mass is measured.
  • Exercise tolerance and 31 NMR of their muscles at rest, and during exercise, is measured, and the animals are sacrificed.
  • the accumulation of pyrophosphate, phosphate, calcium, and other relevant electrolytes and metabolic intermediates is determined in blood, liver and skeletal muscle after freeze clamping of these organs during administration of the two different parenteral nutrition formulations.
  • the total protein content of liver and skeletal muscle on the two types of formulations is determined as is the liver, muscle and blood content of amino acids, soluble CoA's, phosphorylation potential or [ATP]/[ADP] [Pi] ratio, the redox state of the free pyridine nucleotide couples or [NAD(P) + ]/[NAD(P)H] ratios using the two formulations.
  • the 31 P NMR determinations are performed upon the rat hind limb placed in a NMR tube and pulsed by electrical stimulation. It is found that the function of skeletal muscle with the new formulations is approximately normal.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (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

Les solutions aqueuses de nutrition parentérales ci-décrites contiennent de préférence de la glutamine mélangée à d'autres composés contenant de l'azote organique. Les concentrations respectives des composés présents dans une solution donnée de ce type sont en général et de manière approximative des multiples de la concentration des mêmes composés que l'on trouve dans du plasma humain normal, et les rapports respectifs en moles entre ces divers composés dans une solution donnée de ce type sont approximativement identiques au rapport en moles des mêmes composés que l'on trouve dans du plasma humain normal. Des procédés d'utilisation de telles solutions sont également décrits.
EP19870900533 1985-12-18 1986-12-17 Therapie de nutrition parenterale avec acides amines Withdrawn EP0250559A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US81091685A 1985-12-18 1985-12-18
US810916 1985-12-18

Publications (1)

Publication Number Publication Date
EP0250559A1 true EP0250559A1 (fr) 1988-01-07

Family

ID=25205030

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19870900533 Withdrawn EP0250559A1 (fr) 1985-12-18 1986-12-17 Therapie de nutrition parenterale avec acides amines

Country Status (3)

Country Link
EP (1) EP0250559A1 (fr)
AU (1) AU6777487A (fr)
WO (1) WO1987003806A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6649746B1 (en) 1999-05-07 2003-11-18 University Of Virginia Patent Foundation Biological production of stable glutamine, poly-glutamine derivatives in transgenic organisms and their use for therapeutic purposes

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5310768A (en) * 1987-10-29 1994-05-10 Ab Erik Vinnars Method for improving the glutamine content in skeletal muscle and composition therefore
SE8704217D0 (sv) * 1987-10-29 1987-10-29 Vinnars Erik Ab Aminosyrakomposition for parenteral neringstillforsel
DE3936319C3 (de) * 1989-11-01 1997-05-07 Bartz Volker Phosphatbinder zur oralen Verabreichung
DE3940052A1 (de) * 1989-12-04 1991-06-06 Nephro Medica Pharma Dialysier- und spuelloesung zur intraperitonealen verabreichung
SE9002732D0 (sv) * 1990-08-24 1990-08-24 Kabivitrum Ab Product containing growth factor
SE9003844L (sv) * 1990-12-03 1992-06-04 Kabi Pharmacia Ab Naeringstillsats
US5206269A (en) * 1992-03-20 1993-04-27 Clintec Nutrition Co. Highly concentrated amino acid solution
US5646187A (en) * 1992-05-20 1997-07-08 Ab Erik Vinnars Use of alpha-ketoglutarate
SE9201584D0 (sv) * 1992-05-20 1992-05-20 Vinnars Erik Ab Use of alpha-ketoglutarate
US5378722A (en) * 1993-12-03 1995-01-03 Clintec Nutrition Co. Nutritional compositions for management of nitrogen metabolism
CA2183422A1 (fr) * 1994-02-24 1995-08-31 Kiyoshi Mukai Stimulateur de l'activite analgesique
DK2283834T3 (en) * 1997-03-17 2016-08-15 Btg Int Ltd Therapeutic compositions comprising ketone compounds and precursors thereof
ES2205646T3 (es) * 1999-06-26 2004-05-01 B. Braun Melsungen Ag Solucion acuosa para la nutricion parenteral.
US20020147237A1 (en) * 2001-01-31 2002-10-10 Lars Wiklund Preservation of bodily protein
DK1648952T3 (en) 2003-06-03 2018-05-28 The Us Gov As Represented By The Department Of Health And Human Services Dietary supplements and therapeutic compositions comprising (R) -3-hydroxybutyrate derivatives
TR201908522T4 (tr) 2008-01-04 2019-07-22 The Government Of The U S A As Represented By The Secretary Dept Of Health And Human Services Kan lipidi düşürücü maddeler olarak keton gövdeleri ve keton gövde esterleri.
US8642654B2 (en) 2009-04-16 2014-02-04 Isis Innovation Limited Hydroxybutyrate ester and medical use thereof
GB201002983D0 (en) 2010-02-22 2010-04-07 Tdeltas Ltd Nutritinal composition
EP3659595A1 (fr) 2012-11-05 2020-06-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Corps cétoniques destinés à protéger les tissus des lésions par rayonnement ionisant
GB201304467D0 (en) 2013-03-12 2013-04-24 Tdeltas Ltd Compound for use in protecting skin
US11566268B2 (en) 2013-03-14 2023-01-31 Government Of The Usa, As Represented By The Secretary, Department Of Health And Human Services Process for producing (R)-3-hydroxybutyl (R)-3-hydroxybutyrate
GB201314127D0 (en) * 2013-08-07 2013-09-18 Tdeltas Ltd Ketone body and ketone body ester for reducing muscle breakdown

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3697287A (en) * 1969-01-28 1972-10-10 Morton Norwich Products Inc Amino acid food composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8703806A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6649746B1 (en) 1999-05-07 2003-11-18 University Of Virginia Patent Foundation Biological production of stable glutamine, poly-glutamine derivatives in transgenic organisms and their use for therapeutic purposes

Also Published As

Publication number Publication date
WO1987003806A1 (fr) 1987-07-02
AU6777487A (en) 1987-07-15

Similar Documents

Publication Publication Date Title
US5719119A (en) Parenteral nutrition therapy with amino acids
EP0250559A1 (fr) Therapie de nutrition parenterale avec acides amines
US3950529A (en) Amino acid formulations for patients with liver disease and method of using same
US4434160A (en) Nutrient solution for complete parenteral feeding and for increased energy production
US4499076A (en) Elemental diets for liver diseases
US4670261A (en) Parenteral alimentation solution
ES2850998T3 (es) Mezcla de ácidos carboxílicos para tratar pacientes con insuficiencia renal
US6337094B1 (en) Aqueous solution for the parenteral nutrition
EP0182356A2 (fr) Compositions nutritives
Lund et al. Inter-tissue nitrogen fluxes
KR940002661B1 (ko) 요독증 치료용 영양보충물의 제조방법
EP1220670A1 (fr) Utilisation de la l-carnitine et de ses derives alkanoyles comme agents osmotiques dans des solutions a usage medical
JP2599593B2 (ja) 腎不全用アミノ酸輸液
JPWO2008123298A1 (ja) 癌患者用輸液製剤
CA2134380C (fr) Composition a base d'acides amines servant au traitement de la septicemie ou d'une atteinte induisant une reaction inflammatoire
JP2831043B2 (ja) ３―ヒドロキシ酪酸（β―ヒドロキシ酪酸）及びその塩からなる輸液製剤
Caldwell et al. Evaluation of a new amino acid source for use in parenteral nutrition.
JPH07330583A (ja) 遊離型グルタミン酸を含有する液状製剤
JPH0328403B2 (fr)
Jeevanandam et al. Relative nutritional efficacy of arginine and ornithine salts of α-ketoisocaproic acid in traumatized rats
EP0390887A1 (fr) Substrat energetique contenant de l'acide carboxylique hydroxy
EP0076841A1 (fr) Solution amelioree pour nutrition par voie parenterale
JP3429327B2 (ja) 癌用アミノ酸輸液剤
JP4187957B2 (ja) コリン配合輸液剤
JPH04352720A (ja) 癌患者用アミノ酸製剤

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19870921