CA2078712A1 - Composition comprising amino acids for the prevention of hypoxic damage and a process for its preparation - Google Patents
Composition comprising amino acids for the prevention of hypoxic damage and a process for its preparationInfo
- Publication number
- CA2078712A1 CA2078712A1 CA 2078712 CA2078712A CA2078712A1 CA 2078712 A1 CA2078712 A1 CA 2078712A1 CA 2078712 CA2078712 CA 2078712 CA 2078712 A CA2078712 A CA 2078712A CA 2078712 A1 CA2078712 A1 CA 2078712A1
- Authority
- CA
- Canada
- Prior art keywords
- mmol
- alanine
- composition according
- amino acids
- amino acid
- 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.)
- Abandoned
Links
Abstract
Abstract Composition for the prevention of hypoxic damage of the liver, kidney, spleen, intestine, pancreas and other parenchymatous organs and of the skin, charac-terized in that it contains glycine and/or serine and/or alanine and a process for its preparation.
Description
~7~712 Composition comprising amino acids for the pr~vention of hypoxic damage ~ a pr~x~s for its preparation The invention relates to a composition which comprises one or more amino acids and prevents hypoxic S damage of organs and of the skin and a process ~or its preparation Oxygen undersupply, hypoxia, arises, for example, during peripheral or cerebral circulatory disorders, stroke, cardiac infarct, metabolic disorders, vascular occlusion or else during the storage of organs for transplantation.
EP 0,144,489 discloses that a combination of human chorionic gonadotropin and the natural amino acids L-glutamic acid, L-i~oleucine and ~-alanine or their salts can be used for the treatment of cerebral and 1~ peripheral circulatory and met~bolic disorders, it being indicated therein that th~ ~omponents of this combination do not have antihypoxic action per se.
DE 3~820,840 further di~closes an aqueous perfusion 501ution for the reduction of tis~ue damage after acute p~ripheral va~cular oc~lusion. The active sub~tance in this aa~e i~ the calcium ankagonist contained in the soll~tion. The amino acids aspartate and glu~amate also contained should guarant~e an adequate energy production for the cellular repair proc2~ses; they thus have a purely nutritive e~ect~
DE 3,B43,241 further describes an ~ino acid mixture of glycine, alanine, serine, threonine, valine, leucine, isoleucine and proline, which i~ used in an oxygenated medium ~or the protection of the kidneys from toxic damage, for example by cytostatic~ the effect being based on the eneryy production in the tubule cell during the early phase of kidney damage by cytostatics and thus also being of purely nutritive type.
It has now unexpectedly been found that certain amino acids or their mixtures can decrease or ~ubstantially prevent damage ari~ing due to oxygen under-supply or exclusion in certain organs and in the skin, - 2 - ~ ~7~71 ~
the protective effect not being attributable to energy production and thus not being of the nutritive type.
The invention therefore relates to a composition for the prevention of hypoxic damage of the liver, 5 kidney, spleen, intestine, pancreas and other parenchymatous organs and of the skin, characterized in that it contains glycine and/or serine and/or alanine.
On their own or co~bined, the said amino acids exhibit an excellent protective effect against damage which occurs due to oxygen undersupply or exclusion in the abovementioned organs and in the skin.
The amino acids are therefore employed on their own in a concentration of 0.1 to 50 mmol/l or a~ an amino ~cid mixture, compriRing two or three amino acids, in which the total concentration of amino acids should not exceed 50 ~mol~l.
Preferably, a total concentration of amino acid or zmino acid mixture of 2 to 40 mmol/l and particularly preferably of 10 to 30 mmol/l is u~ed.
The three amlno acids here complement one another in their protective effect~ as a re~ult of which it is not nece~sary to increase the concentrat.ion of an individual Amino acid to high values in ord~r to e~sure efective protection from hypoxic cell damage.
Preferably, the composition accord;.ng ~o the invention therefore contains a csmbination of glycine and alanine or of serina and alanine or o~ glyclne and serine or of all 3 a~ino acids.
The compo~itions according to the inv~ntion can be employed for the prevention of hypoxic damage of the liver, kidney, spleen, in estine, pancreas and other parenchymatous organ~ and for the healing of wounds ko the ~kin. The compositions are particularly suitable for the prevention of hypoxic damage of organs which do not have sufficient oxygen at their disposal duriny a transplantation or other operations.
207~7~ ~
The invention furthermore relates to a process for the preparation of a composition for the prevention o~ hypoxic damage of the liver, kidney, spleen, intestine, pancreas and other parenchymatous organs and of the skin, ~haracterized in that glycine and/or serine and/or alanine a~e dissolved or suspended in water and mixed with one or more auxiliaries.
Thereby am~o aci~s are dissolved or suspen-ded in water and mixed with suitable auxiliaries such as, for example buffers, electrolytes, glucose, preservatives, antioxidants, stabilizers, emulsifiers or salts for modifying the osmotic pressure.
For the preparation of infusion solutions and perfu-sion solutions bidestillated water~ free from pyrogens is used.
lS If necessary the pH is adju~ted to about 7,0 to 7,6, preferably to about 7,4, by customary means ~uch as, ~or exam-ple, lN sodium hydroxid or lN hydrochloric acid.
If appropriate, the compositions can be sterile filtrated, lyophili~ated or autoclaved.
The co~positions ~ccor~ing to the invention can thus be used preferably as a perfusion æol~tion, infusion solution or in topical form.
The perfusion solution in this case contains a total concentration of 0.1 mmol/l to 50 mmol/l of amino acid mi~tu~e or of an individual amino acid in conventional buffer ~uch as, for example, Krebs-~enseleit bicarbonate buffer or Dulbecco minimal medium 199.
The infusion solution contains about 10 times the amino acid concentration compared to the perfusion solution~ so 3Q that in the whole blood and thus in the orqan to be treated the same effective total concentration of amino acids is achieved.
7 ,~ 7,1 ,~
The concentration in the infusion ~olution is therefore 1 mmol/l to 500 ~nol/l of amino acid mixture or o~ an amino acid. Thi~ corre~pond~, when using 500 ml of infusion, to an effective final concentration of O.1 mmol/l up to 50 mmol/l.
The infusion solution csn further contain customary additives, such as, for example, electrolytes and glucose; the pH is adjusted to about 7 ~ 4 by customa~y means.
1~ The composition according to the invention can also be used in the form of gels or ointments, it being possible in each case for 10 to 500 ~g of the 3 amino acids to be contained in 1 g of oin~ment or gel.
Preferably, in each case 50 to 200 ~g of the 3 amino acids are contained in 1 g of ointment or gel. However, the amino acid~ can also each be employed per se or in combinations of two up to a total concentration of 500 ~g per g of ointment or gel~
A preferred composition contains, for example, 172 ~g of glycine, 52 ~g of serine and 144 ~g o~ alanine in 1 g of ointment or gel.
The gels according to the invention additionally contain cu~tomary pre~ervatives such a~, for oxample, methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate and au~tomary auxiliaries such as, ~or example, carbox~methylcellulose sodium, propylene glycol or calcium pentahydrate.
~.
The ointments according to the invention contain, in addition to the amino acids, the abovementioned customary preservatives, as well as customary auxiliaries such as, for example, white petroleum jelly~ cetyl alcohol or cholesterolO
~ 5 - 2 ~ 7~S~7 ~xam~le 1 Investigation of the protective action of the amino acids on hypoxic cell damage to rat hepatocytes in primary culture.
The liver cells to be investigated were isolated from non-fasting, ~ale Wistar rats by collagenase perfusion, as described in Biol. Chem. Hoppe-Seyler (1991) 372, pages 34 to 41.
EP 0,144,489 discloses that a combination of human chorionic gonadotropin and the natural amino acids L-glutamic acid, L-i~oleucine and ~-alanine or their salts can be used for the treatment of cerebral and 1~ peripheral circulatory and met~bolic disorders, it being indicated therein that th~ ~omponents of this combination do not have antihypoxic action per se.
DE 3~820,840 further di~closes an aqueous perfusion 501ution for the reduction of tis~ue damage after acute p~ripheral va~cular oc~lusion. The active sub~tance in this aa~e i~ the calcium ankagonist contained in the soll~tion. The amino acids aspartate and glu~amate also contained should guarant~e an adequate energy production for the cellular repair proc2~ses; they thus have a purely nutritive e~ect~
DE 3,B43,241 further describes an ~ino acid mixture of glycine, alanine, serine, threonine, valine, leucine, isoleucine and proline, which i~ used in an oxygenated medium ~or the protection of the kidneys from toxic damage, for example by cytostatic~ the effect being based on the eneryy production in the tubule cell during the early phase of kidney damage by cytostatics and thus also being of purely nutritive type.
It has now unexpectedly been found that certain amino acids or their mixtures can decrease or ~ubstantially prevent damage ari~ing due to oxygen under-supply or exclusion in certain organs and in the skin, - 2 - ~ ~7~71 ~
the protective effect not being attributable to energy production and thus not being of the nutritive type.
The invention therefore relates to a composition for the prevention of hypoxic damage of the liver, 5 kidney, spleen, intestine, pancreas and other parenchymatous organs and of the skin, characterized in that it contains glycine and/or serine and/or alanine.
On their own or co~bined, the said amino acids exhibit an excellent protective effect against damage which occurs due to oxygen undersupply or exclusion in the abovementioned organs and in the skin.
The amino acids are therefore employed on their own in a concentration of 0.1 to 50 mmol/l or a~ an amino ~cid mixture, compriRing two or three amino acids, in which the total concentration of amino acids should not exceed 50 ~mol~l.
Preferably, a total concentration of amino acid or zmino acid mixture of 2 to 40 mmol/l and particularly preferably of 10 to 30 mmol/l is u~ed.
The three amlno acids here complement one another in their protective effect~ as a re~ult of which it is not nece~sary to increase the concentrat.ion of an individual Amino acid to high values in ord~r to e~sure efective protection from hypoxic cell damage.
Preferably, the composition accord;.ng ~o the invention therefore contains a csmbination of glycine and alanine or of serina and alanine or o~ glyclne and serine or of all 3 a~ino acids.
The compo~itions according to the inv~ntion can be employed for the prevention of hypoxic damage of the liver, kidney, spleen, in estine, pancreas and other parenchymatous organ~ and for the healing of wounds ko the ~kin. The compositions are particularly suitable for the prevention of hypoxic damage of organs which do not have sufficient oxygen at their disposal duriny a transplantation or other operations.
207~7~ ~
The invention furthermore relates to a process for the preparation of a composition for the prevention o~ hypoxic damage of the liver, kidney, spleen, intestine, pancreas and other parenchymatous organs and of the skin, ~haracterized in that glycine and/or serine and/or alanine a~e dissolved or suspended in water and mixed with one or more auxiliaries.
Thereby am~o aci~s are dissolved or suspen-ded in water and mixed with suitable auxiliaries such as, for example buffers, electrolytes, glucose, preservatives, antioxidants, stabilizers, emulsifiers or salts for modifying the osmotic pressure.
For the preparation of infusion solutions and perfu-sion solutions bidestillated water~ free from pyrogens is used.
lS If necessary the pH is adju~ted to about 7,0 to 7,6, preferably to about 7,4, by customary means ~uch as, ~or exam-ple, lN sodium hydroxid or lN hydrochloric acid.
If appropriate, the compositions can be sterile filtrated, lyophili~ated or autoclaved.
The co~positions ~ccor~ing to the invention can thus be used preferably as a perfusion æol~tion, infusion solution or in topical form.
The perfusion solution in this case contains a total concentration of 0.1 mmol/l to 50 mmol/l of amino acid mi~tu~e or of an individual amino acid in conventional buffer ~uch as, for example, Krebs-~enseleit bicarbonate buffer or Dulbecco minimal medium 199.
The infusion solution contains about 10 times the amino acid concentration compared to the perfusion solution~ so 3Q that in the whole blood and thus in the orqan to be treated the same effective total concentration of amino acids is achieved.
7 ,~ 7,1 ,~
The concentration in the infusion ~olution is therefore 1 mmol/l to 500 ~nol/l of amino acid mixture or o~ an amino acid. Thi~ corre~pond~, when using 500 ml of infusion, to an effective final concentration of O.1 mmol/l up to 50 mmol/l.
The infusion solution csn further contain customary additives, such as, for example, electrolytes and glucose; the pH is adjusted to about 7 ~ 4 by customa~y means.
1~ The composition according to the invention can also be used in the form of gels or ointments, it being possible in each case for 10 to 500 ~g of the 3 amino acids to be contained in 1 g of oin~ment or gel.
Preferably, in each case 50 to 200 ~g of the 3 amino acids are contained in 1 g of ointment or gel. However, the amino acid~ can also each be employed per se or in combinations of two up to a total concentration of 500 ~g per g of ointment or gel~
A preferred composition contains, for example, 172 ~g of glycine, 52 ~g of serine and 144 ~g o~ alanine in 1 g of ointment or gel.
The gels according to the invention additionally contain cu~tomary pre~ervatives such a~, for oxample, methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate and au~tomary auxiliaries such as, ~or example, carbox~methylcellulose sodium, propylene glycol or calcium pentahydrate.
~.
The ointments according to the invention contain, in addition to the amino acids, the abovementioned customary preservatives, as well as customary auxiliaries such as, for example, white petroleum jelly~ cetyl alcohol or cholesterolO
~ 5 - 2 ~ 7~S~7 ~xam~le 1 Investigation of the protective action of the amino acids on hypoxic cell damage to rat hepatocytes in primary culture.
The liver cells to be investigated were isolated from non-fasting, ~ale Wistar rats by collagenase perfusion, as described in Biol. Chem. Hoppe-Seyler (1991) 372, pages 34 to 41.
3 106 cells were ~dded per culture flask and cultured in lS Leibowitz L15 medium. To carry out he investigation, cultures 24 hours old were used. The test medium used was a nitrogen-saturated Krebs-Henseleit buffer, pH 7.4, which additionally contained 20 mmol/l of HEPES and 83 ~mol/l oi Trypan Blue. The temperature of the test arrangement was 37C. The amino acids, dissolved in 0.5 ml of incubation buffer, were added directly before the start of the hypoxic incubations. The total volume of incubation buffer was 5.5 ml. 0.5 ml of incubation buffer was also added to the controls. The cell damage was determined by absorption of Trypan Blue and by the release of lactate dehydrogenase.
The test~ showed that the rat hepatocyte~ exhibited considerable d~maqe in primary culture under hypoxic conditions even after 2 hours. After incubation for 6 h, 75 % o~ the cell~ had already lost their vitality. On addition of the amino acids, however, it was possible to detect a distinct reduction in the damage. The protective effects of the amino acids glycine, serine and alanine are shown in the following table~.
The cell damage was in this case determined by the release of lactate dehydrogenase (LDH).
The control values indicate the release of LDH without ~mino acid addition~
- 6 - 2f37~
Table 1 96 LD~ relez~se Control (~lycin~ (m~ol/l ) after (h) 0.1 0.3 1 3 10 Table 2 % LDH r~lea~ie Control Serine tmmo~
a~tex (h) 0.1 1 3 lO 3û
Table 3 96 LDEI rel~ase Co~trol Alani~e (mmol/l) after (h) l 3 1030 Table 4 2 0 I.D~ relea~3e Contr~DlAla/Gly Ala/Ser after (h~ (3/0~1 mmol~l (3/l }mnol~l) 4 65 4û 25
The test~ showed that the rat hepatocyte~ exhibited considerable d~maqe in primary culture under hypoxic conditions even after 2 hours. After incubation for 6 h, 75 % o~ the cell~ had already lost their vitality. On addition of the amino acids, however, it was possible to detect a distinct reduction in the damage. The protective effects of the amino acids glycine, serine and alanine are shown in the following table~.
The cell damage was in this case determined by the release of lactate dehydrogenase (LDH).
The control values indicate the release of LDH without ~mino acid addition~
- 6 - 2f37~
Table 1 96 LD~ relez~se Control (~lycin~ (m~ol/l ) after (h) 0.1 0.3 1 3 10 Table 2 % LDH r~lea~ie Control Serine tmmo~
a~tex (h) 0.1 1 3 lO 3û
Table 3 96 LDEI rel~ase Co~trol Alani~e (mmol/l) after (h) l 3 1030 Table 4 2 0 I.D~ relea~3e Contr~DlAla/Gly Ala/Ser after (h~ (3/0~1 mmol~l (3/l }mnol~l) 4 65 4û 25
Claims (10)
1. Composition for the prevention of hypoxic damage of the liver, kidney, spleen, intestine, pancreas and other parenchymatous organs and of the skin, charac-terized in that it contains glycine and/or serine and/or alanine.
2. Composition according to Claim 1, characterized in that it contains glycine and alanine.
3. Composition according to Claim 1, characterized in that it contains serine and alanine.
4. Composition according to Claim 1, characterized in that the effective total concentration of amino acids is 0.1 to 50 mmol/l, preferably 2 to 40 mmol/l and particularly preferably 10 to 30 mmol/l.
5. Composition according to Claim 1, characterized in that it is employed as an infusion solution and contains 1 mmol to 500 mmol of an amino acid or of an amino acid mixture/l of infusions
6. Composition according to Claim 1, characterized in that it is employed as a perfusion solution, having an amino acid concentration of 0.1 to 50 mmol/l, in a customary buffer..
7. Composition according to Claim 1, characterized in that it is employed as a gel or ointment, having an amino acid concentration of in each case 10 to 500 µg per amino acid per g of ointment or gel, where the total concentration of amino acids should not exceed 500 µg/g.
8. Use of a composition according to Claim 1, during transplantations, operations and for the healing of wounds to the skin.
9. Process for the preparation of a composition for the pre-vention of hypoxic damage of the liver, kidney, speen, in-testine, pancreas and other parenchymatous organs and of the skin, characterized in that glycine and/or serine and/or alanine are dissolved or suspended in water and mi-xed with one or more auxiliaries.
10. Process according to claim 9, characterized in that glycine and/or serine and/or alanine are mixed in an amount providing an effective total concentration of aminoacids of 0.1 to 50 mmol/l, preferably 2 to 40 mol/l and particulary preferably 10 to 30 mmol/l.
O.Z. 964 5.8.1992
O.Z. 964 5.8.1992
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ATA1901/91 | 1991-09-23 | ||
AT190191 | 1991-09-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2078712A1 true CA2078712A1 (en) | 1993-03-24 |
Family
ID=3523472
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA 2078712 Abandoned CA2078712A1 (en) | 1991-09-23 | 1992-09-21 | Composition comprising amino acids for the prevention of hypoxic damage and a process for its preparation |
Country Status (3)
Country | Link |
---|---|
JP (1) | JPH06183962A (en) |
CA (1) | CA2078712A1 (en) |
NO (1) | NO923682L (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997011694A1 (en) * | 1995-09-25 | 1997-04-03 | Desitin Arzneimittel Gmbh | Creatine for the protection of neural tissue |
US5656608A (en) * | 1995-02-23 | 1997-08-12 | Sandoz Nutrition Ltd. | Amino acid compositions and methods of treatment using same |
US5976559A (en) * | 1994-09-30 | 1999-11-02 | L'oreal | Compositions and methods for treating wrinkles and/or fine lines of the skin |
US6048543A (en) * | 1995-06-14 | 2000-04-11 | Novartis Nutrition Ag | Amino acid compositions and use thereof in clinical nutrition |
US7838122B2 (en) * | 2003-12-01 | 2010-11-23 | Rutgers, The State University Of New Jersey | Hydrazide compounds with angiogenic activity |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE60121913T2 (en) | 2000-01-18 | 2007-03-01 | Ajinomoto Co., Inc. | ALANIN- AND GLYCIN-CONTAINING DRUGS AGAINST HEPATITIS |
-
1992
- 1992-09-21 CA CA 2078712 patent/CA2078712A1/en not_active Abandoned
- 1992-09-22 JP JP25299492A patent/JPH06183962A/en not_active Withdrawn
- 1992-09-22 NO NO92923682A patent/NO923682L/en unknown
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5976559A (en) * | 1994-09-30 | 1999-11-02 | L'oreal | Compositions and methods for treating wrinkles and/or fine lines of the skin |
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 |
WO1997011694A1 (en) * | 1995-09-25 | 1997-04-03 | Desitin Arzneimittel Gmbh | Creatine for the protection of neural tissue |
US7838122B2 (en) * | 2003-12-01 | 2010-11-23 | Rutgers, The State University Of New Jersey | Hydrazide compounds with angiogenic activity |
Also Published As
Publication number | Publication date |
---|---|
NO923682L (en) | 1993-03-24 |
NO923682D0 (en) | 1992-09-22 |
JPH06183962A (en) | 1994-07-05 |
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