GB2037161A - Preparations containing amino acids - Google Patents
Preparations containing amino acids Download PDFInfo
- Publication number
- GB2037161A GB2037161A GB7935990A GB7935990A GB2037161A GB 2037161 A GB2037161 A GB 2037161A GB 7935990 A GB7935990 A GB 7935990A GB 7935990 A GB7935990 A GB 7935990A GB 2037161 A GB2037161 A GB 2037161A
- Authority
- GB
- United Kingdom
- Prior art keywords
- solution
- amino acids
- leucine
- isoleucine
- valine
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 150000001413 amino acids Chemical class 0.000 title description 16
- OCUSNPIJIZCRSZ-ZTZWCFDHSA-N (2s)-2-amino-3-methylbutanoic acid;(2s)-2-amino-4-methylpentanoic acid;(2s,3s)-2-amino-3-methylpentanoic acid Chemical compound CC(C)[C@H](N)C(O)=O.CC[C@H](C)[C@H](N)C(O)=O.CC(C)C[C@H](N)C(O)=O OCUSNPIJIZCRSZ-ZTZWCFDHSA-N 0.000 claims abstract description 6
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 42
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 9
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 8
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 7
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 7
- 150000005693 branched-chain amino acids Chemical class 0.000 claims description 7
- 229960000310 isoleucine Drugs 0.000 claims description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 6
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 6
- 239000008103 glucose Substances 0.000 claims description 6
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 6
- 239000004474 valine Substances 0.000 claims description 6
- 238000001990 intravenous administration Methods 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 229940102223 injectable solution Drugs 0.000 claims 1
- 208000007386 hepatic encephalopathy Diseases 0.000 abstract description 7
- 235000020776 essential amino acid Nutrition 0.000 abstract description 2
- 239000003797 essential amino acid Substances 0.000 abstract description 2
- 229940024606 amino acid Drugs 0.000 description 18
- 235000001014 amino acid Nutrition 0.000 description 18
- 229960003136 leucine Drugs 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 6
- 229960001031 glucose Drugs 0.000 description 6
- 229960004295 valine Drugs 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 4
- ULSIYEODSMZIPX-UHFFFAOYSA-N phenylethanolamine Chemical compound NCC(O)C1=CC=CC=C1 ULSIYEODSMZIPX-UHFFFAOYSA-N 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- -1 aromatic amino acids Chemical class 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 229960004452 methionine Drugs 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 229960005190 phenylalanine Drugs 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229960004799 tryptophan Drugs 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- QHGUCRYDKWKLMG-QMMMGPOBSA-N (R)-octopamine Chemical compound NC[C@H](O)C1=CC=C(O)C=C1 QHGUCRYDKWKLMG-QMMMGPOBSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 2
- 208000032274 Encephalopathy Diseases 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 208000008457 Neurologic Manifestations Diseases 0.000 description 2
- 206010060860 Neurological symptom Diseases 0.000 description 2
- QHGUCRYDKWKLMG-MRVPVSSYSA-N Octopamine Natural products NC[C@@H](O)C1=CC=C(O)C=C1 QHGUCRYDKWKLMG-MRVPVSSYSA-N 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 229960003767 alanine Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940077731 carbohydrate nutrients Drugs 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229960001576 octopamine Drugs 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 229950006768 phenylethanolamine Drugs 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 229960004441 tyrosine Drugs 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 238000006418 Brown reaction Methods 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 229930182844 L-isoleucine Natural products 0.000 description 1
- 239000004395 L-leucine Substances 0.000 description 1
- 235000019454 L-leucine Nutrition 0.000 description 1
- 229930195722 L-methionine Natural products 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- IXUZXIMQZIMPSQ-ZBRNBAAYSA-N [(4s)-4-amino-4-carboxybutyl]azanium;(2s)-2-amino-4-hydroxy-4-oxobutanoate Chemical compound OC(=O)[C@@H](N)CCC[NH3+].[O-]C(=O)[C@@H](N)CC(O)=O IXUZXIMQZIMPSQ-ZBRNBAAYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000010876 biochemical test Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 235000019577 caloric intake Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004868 gas analysis Methods 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 108010049063 ornithylaspartate Proteins 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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
Abstract
Preparations usable to treat hepatic encephalopathy, comprise an aqueous solution of branched chain essential amino acids, e.g. leucine, isoleucine and valine. The preparations are administered parenterally.
Description
SPECIFICATION
Injectable pharmaceutical preparation containing amino acids
The present invention relates to an injectable pharmaceutical preparation containing amino acids which is particularly useful in curing the hepatic encephalopathy.
During severe hepatic insufficencies involving risk for the noblest nervous functions, namely in case of encephalopathies of hepatic origin, it is customary to drastically reduce or stop the alimentary intake of proteins, yet maintaining the necessary caloric intake merely by means of carbohydrates.
This unbalanced alimentary intake, although it allows the symptoms of encephalic pain to be reduced to some extent, has nevertheless the obvious drawback of progressive lowering of the proteic patrimony of the organism.
On the other hand it was recently found that during certain hepatopathies, particularly in the cirrhosis, changes of the aminoacidemic configuration in man and animals take place, which are represented by a progressive increasing of aromatic amino acids such as tryptophan, phenylalanine, tyrosine and methionine, as well as by a lessening of branched chain amino acids such as leucine, isoleucine, valine.
Such changes are found also in cephalorachidian fluid and accompanied by the appearance or increase in concentration of substances qualified as "false neurotransmitters", i.e. octopamine and phenylethanolamine.
These alterations reach highly significant values at the appearance of those neurologic symptoms which are known undertheterm of"hepatic encephalopathy".
Similar hematic, humoral and clinical patterns take place in animals, particularly in dogs, which are subjected to portacaval shunt operations. As a logic consequence of the initial remarks the administration (venoclysis) of standard solutions, that is of balanced solution with regard to the proteic intake, of amino acids both to man and animals under the above-stated conditions makes worse the neurological and biochemical pattern of the syndrome.
On the basis of above remarks concerning the aminoacidemicconfiguration of ailing subjects, it has been conceived to use solutions of amino acids in which the amount of branched-chain amino acids (leucine, isoleucine, valine) is higher than the amount of other amino acids. The administration of these selective solutions, such as those described in
US-PS 3.950.529, which are characterized by a reduced concentration of methionine and aromatic amino acids and by an increased content of branched-chain amino acids, causes a remarkable clinical and bio-humoral improvement as well as a favourable change of the electroencephalogram.
Taking advantage of the acquired knowledge and with regard to observations suggesting that the getting through the blood-brain barrier is controlled by the ratio between branched-chain and aromatic amino acids, pharmacological and clinical tests have been carried out by applicants using solutions in which said ratio was stressed in favour of branched-chain amino acids.
As a result of these tests the applicants have provided a solution to be used parenterally in which the aminoacidic portion consists of leucine, isoleucine and valine only.
The pharmaceutical preparation according to this invention substantially consists of a sterile acqueous solution wherein leucine, isoleucine and valine are dissolved in suitable amount (solution A).
In order to couple the advantages issuing from the administration of carbohydrates, to this solution of said three essential amino acids a sterile aqueous solution of glucose (solution B) is mixed at the time of use.
The maintenance of the amino acid solution and glucose solution in two separate bottles up to the
moment of use aims to avoid the Maillard's reactions, occurring on steam sterilization and storage, which would lead to the formation of brown reaction products adversely affecting the stability of the compound solution.
By carrying out the preparation of the solutions and the filling of bottles under nitrogen and suitably adjusting the pH value of the content in at least one of the two bottles, there are obtained solutions which remain practically colourless during steam sterilization and storage, have a very good and lasting stability and are suitable to be injected.
The amino acid solution A according to the present invention contains 1.30 to 1.80% (w/v) leucine, 1.00 to 1.50% isoleucine and 0.90 to 1.30% valine, more preferably about 1.57% leucine, 1.28% isoleucine and 1.15%valine (all percentages being expressed as weightlvolume ratio). At the given concentrations quite clear solutions are obtained which remain unchanged even on possible cooling down toOC.
The present invention is hereinafter described by way of some embodying examples given only for the sake of illustration and not limitation.
Example 1 (preparation of amino acid solution)
In 600 ml water for injectable preparations which was saturated with nitrogen and heated to 80"C, 11 g leucine, 9 g isoleucine and 8 g valine were dissolved upon stirring.
The pH of the solution was adjusted to 7.5 by means of NaOH, then the volume was increased up to 700 ml by further addition of sterile water. The solution thus obtained was first filtered through asbest plates, then through a cellulose membrane having pores of 0.45 Cl and the filtrate was collected in a 11 bottle.
The solution contained in the bottle was again saturated with suitably filtered nitrogen gas and the vessel was sealed and sterilized at 121"C for 40 minutes.
Example2 (preparation of glucose solution)
In 150 ml water for injectable preparations which was saturated with nitrogen gas and heated to 800C, 200 g glucose monohydrate were dissolved under stirring, the volume was then increased up to 300 ml by a further addition of water for injectable preparations.
The obtained solution was then filtered and handled according to Example 1 by finally collecting the glucose solution in a 500 ml bottle.
The glucose solution is poured in the 1 I bottle containing the amino acid solution just prior to use.
Before the experimental use of the thus prepared amino acid solution was made, an evaluation of the toxicity was carried out. One single intravenous administration of massive doses did neither cause in rats and mice any toxic symptoms nor any immediate or belated mortality.
The administration of the solution containing the three branched-chain amino acids was effected in dog during a period of four weeks at a dose of 20 mllkgldaythrough intravenous route at a rate of five running days each week. In the course of the tests no death was observed nor any particular symptom was pointed out which could be ascribed to the treatment.
Also the various biochemical constants as measured by means of hematochemical and hematological analyses were kept within standard limits, except a slight increase of glycemia and an equally slight decrease of cholesterolemia; nevertheless it should be noted that such changes were noticed to the same extent also in control group.
Dogs of both sexes averaging 15 kg were subjected to termino-lateral portacaval shunt with a view to cause hepatic encephalopathy. After about three weeks the peculiar neurologic symptoms and biochemical changes of hepatic encephalopathy appeared, in particular an increase in plasma or aromatic amino acids tryptophan, tyrosine and phenylalanine as well as octopamine and phenylethanolamine, and of ammoniemia.
The animals thus treated were divided in two groups, one of which was subjected to a treatment with a solution according to this invention and the other to a treatment with a standard aminoacidic solution as commercially available.
A solution of this kind is for instance as follows:
Synthetic L-amino acids:
Essential Not essential
L-isoleucine 3.80 g/l L-alanine 10.00 g/l L-leucine 5.80 g/l L-glutamic acid 2.00 gll L-lysine (base) 5.44 girl Glycine 4.40 g/l L-methionine 4.80 g/l L-proline 12.00 g/l L-phenylalanine 6.88 gll L-ornithine L-aspartate 2.00 gll L-threonine 3.20 9/l L-serine 2.40 g/l
L-tryptophan 1.40 g/l Total N 12.40 gll L-valine 4.48 9/l L-malic acid 4.6 g/l Semi-essential Electrolytes::
L-arginine 9.20 9/l Na+ 35 mEqll
L-histidine 2.20 g/l .K+ 30 mEq/l Mg++ 5 mEqll Cl- 65 mEq/l
Acetate- 5 mEqll The therapeutic treatment was started three weeks afterthe shunt operation. The amino acid solution was administered intravenously in the amount of 1
I a day through 5 to 6 running days each week.
The biochemical observations in plasma were carried out prior to portacaval shunt operation, three weeks after it and at the 3rd, 6th and 21st day of the care period with amino acids. In parallel with the biochemical tests, blood gas analysis, hemoglobin and hematocrit were also evaluated; the weight of the animals was checked twice a week.
The group which was treated with standard amino acids showed an increasing deterioration of encephalopathy together with high percentage of deaths during the three weeks treatment; to these clinical symptoms made a pendant a progressive aggravation of biochemical values also.
In the group which was treated with solutions according to the present invention no deaths were observed, while the biochemical balance and the disappearance of neurogical symptoms were reached in a very short time.
For sake of comparison, tests were carried out also with other kinds of solutions always containing three amino acids but partially or totally different from the preceding ones (for instance 69 leucine, 10 9 alanine, 9 g arginine in 1000 ml). The effectiveness of such alternative solutions turned out to be poor or of no value, whereas an aggravation of the syndrome was on the contrary noticed.
Solutions according to the present invention were subsequently employed in the symptomatic care of grave conditions of hepatic encephalopathy in humans suffering from advanced cirrhosis. Six patients which were subjected to observation and treatment were classified as pertaining to the 3rd and 4th level of hepatic encephalopathy on the ground of their clinical pattern, bio-humoral checkings and electroencephalographic control.
To these six patients the solutions were intraveneously administered at a rate of one phleboclysis each day in the course of 14-16 hours and repeated for 3-4 days. The used solutions according to this invention allowed to achieve in all of cared subjects a substantial clinical improvement which was characterized by the revival from coma and important bio-humoral and electroencephalographic changes. The favourable changes happened in some cases in a dramatically quick way even 5-6 hours afterthe beginning of phleboclysis only. The tolerance was good in each case.
Claims (5)
1. A sterile aqueous solution to be administered by intravenous route, characterized in that it is substantially an aqueous solution of essential branched-chain amino acids.
2. The solution of claim 1, characterized in that said essential branched-chain amino acids are leucine, isoleucine and valine.
3. The solution of claim 2, characterized in that the weightlvolume percentages of leucine, isoleucine and valine are in the range 1.30 to 1.80%, 1.00 to 1.50% and 0.90 to 1.30 respectively.
4. A solution according to the preceding claims, characterized in that it contains 11 g leucine, 9 g isoleucine and 8 g valine in 1000 ml.
5. The solution of claim 4, further characterized in that it is prepared by mixing just before the therapeutic use a solution of leucine, isoleucine and valine with an injectable solution of glucose.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT29414/78A IT1100677B (en) | 1978-11-03 | 1978-11-03 | INJECTABLE PHARMACEUTICAL FORMATION BASED ON AMINO ACIDS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2037161A true GB2037161A (en) | 1980-07-09 |
| GB2037161B GB2037161B (en) | 1983-06-15 |
Family
ID=11226937
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7935990A Expired GB2037161B (en) | 1978-11-03 | 1979-10-17 | Preparations containing amino acids |
Country Status (4)
| Country | Link |
|---|---|
| DE (1) | DE2944341A1 (en) |
| FR (1) | FR2440194A1 (en) |
| GB (1) | GB2037161B (en) |
| IT (1) | IT1100677B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4753804A (en) * | 1984-12-12 | 1988-06-28 | Boehringer Biochemica S.P.A. | Granular dietetic product based on amino acids and process for their preparation |
| US5017616A (en) * | 1989-11-30 | 1991-05-21 | Jeffrey Askanazi | Method for improving ventilation during sleep and treating sleep related ventilation abnormalities |
| US5140045A (en) * | 1989-11-30 | 1992-08-18 | Clintec Nutrition Co. | Method for improving ventilation during sleep and treating sleep related ventilation abnormalities of neonates |
| US5278190A (en) * | 1989-11-30 | 1994-01-11 | Clintec Nutrition Co. | Method for improving the quality of sleep and treating sleep disorders |
| US9271521B2 (en) | 2002-12-26 | 2016-03-01 | Ajinomoto Co., Inc. | Inhibitor for liver cancer onset and progress |
| DE102020002198A1 (en) | 2020-04-07 | 2021-11-04 | Christian Scharrer | COVID drug |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4438144A (en) | 1980-07-31 | 1984-03-20 | Blackburn George L | Amino acid preparation and therapy for treatment of stress and injury |
| WO2006006729A1 (en) * | 2004-07-14 | 2006-01-19 | Ajinomoto Co., Inc. | Inhibitor for the onset and progress of liver cancer to be used in hepatitis c virus-positive human liver cirrhosis patients |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3950529A (en) * | 1975-02-03 | 1976-04-13 | Massachusetts General Hospital | Amino acid formulations for patients with liver disease and method of using same |
-
1978
- 1978-11-03 IT IT29414/78A patent/IT1100677B/en active
-
1979
- 1979-10-17 GB GB7935990A patent/GB2037161B/en not_active Expired
- 1979-10-31 FR FR7927018A patent/FR2440194A1/en active Granted
- 1979-11-02 DE DE19792944341 patent/DE2944341A1/en active Granted
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4753804A (en) * | 1984-12-12 | 1988-06-28 | Boehringer Biochemica S.P.A. | Granular dietetic product based on amino acids and process for their preparation |
| US5017616A (en) * | 1989-11-30 | 1991-05-21 | Jeffrey Askanazi | Method for improving ventilation during sleep and treating sleep related ventilation abnormalities |
| US5140045A (en) * | 1989-11-30 | 1992-08-18 | Clintec Nutrition Co. | Method for improving ventilation during sleep and treating sleep related ventilation abnormalities of neonates |
| US5278190A (en) * | 1989-11-30 | 1994-01-11 | Clintec Nutrition Co. | Method for improving the quality of sleep and treating sleep disorders |
| US9271521B2 (en) | 2002-12-26 | 2016-03-01 | Ajinomoto Co., Inc. | Inhibitor for liver cancer onset and progress |
| DE102020002198A1 (en) | 2020-04-07 | 2021-11-04 | Christian Scharrer | COVID drug |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2944341A1 (en) | 1980-05-08 |
| FR2440194A1 (en) | 1980-05-30 |
| FR2440194B3 (en) | 1981-08-14 |
| IT1100677B (en) | 1985-09-28 |
| IT7829414A0 (en) | 1978-11-03 |
| DE2944341C2 (en) | 1989-03-23 |
| GB2037161B (en) | 1983-06-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Zieve et al. | Pathogenesis of hepatic coma | |
| Fischer et al. | The role of plasma amino acids in hepatic encephalopathy | |
| Fürst et al. | Glutamine‐containing dipeptides in parenteral nutrition | |
| CA1212902A (en) | Amino acid solutions for parenteral nutrition and methods of formulation and use | |
| EP0347890B1 (en) | Amino acid nutrient compositions | |
| AU678559B2 (en) | A method of increasing creatine supply depot | |
| US7645796B2 (en) | Amino acid composition promoting collagen synthesis | |
| Maddrey et al. | Effects of keto analogues of essential amino acids in portal-systemic encephalopathy | |
| EP0176094B1 (en) | Parenteral alimentation solution | |
| AU627041B2 (en) | Improved nutritional formulation for the treatment of renal disease | |
| DE3037479C2 (en) | ||
| CN114392228A (en) | Long-lasting formulations of melatonin injections exhibiting long-term stability | |
| Claris-Appiani et al. | Lack of glomerular hemodynamic stimulation after infusion of branched-chain amino acids | |
| KR20020038809A (en) | Use of l-carnitine and its alkanoyl derivatives as osmotic agents in solutions for medical use | |
| GB2037161A (en) | Preparations containing amino acids | |
| Felber | A Survey of the Effect of Other Ammo-acids on the Absorption of L-arginine and L-lysine by the Rat Intestine | |
| Cano et al. | Branched-chain amino acids: Metabolism, physiological function, and application | |
| US6727285B1 (en) | Use of D-arginine and/or L-arginine to protect the amino groups of biological substances from damage, inactivation, or modification by toxic carbonyls and/or dicarbonyls | |
| US5290538A (en) | Nephro protective infusion solutions | |
| EP1153609A1 (en) | Amino acid-containing albumin preparations | |
| Vinnars et al. | THE NUTRITIVE EFFECT IN MAN OF NON‐ESSENTIAL AMINO ACIDS INFUSED INTRAVENOUSLY (TOGETHER WITH THE ESSENTIAL ONES) I. INDIVIDUAL NON‐ESSENTIAL AMINO ACIDS | |
| El Sayed et al. | Differential effects of amino acids on the isolated perfused rat kidney | |
| DE3414491A1 (en) | L-Amino acid mixtures for parenteral and oral use for kidney disorders | |
| WO1998051260A2 (en) | Use of d-arginine and/or l-arginine to protect the amino groups of biological substances from damage, inactivation, or modification by toxic carbonyls and/or dicarbonyls | |
| EP0408691B1 (en) | Antinephrotoxic perfusion solution |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PE20 | Patent expired after termination of 20 years |
Effective date: 19991016 |