WO2004112631A1 - Formulation et procede de reduction de la deterioration des globules rouges du sang lors du stockage, notamment en ce qui concerne la diminution du niveau de 2,3 diphosphoglycerate - Google Patents

Formulation et procede de reduction de la deterioration des globules rouges du sang lors du stockage, notamment en ce qui concerne la diminution du niveau de 2,3 diphosphoglycerate Download PDF

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Publication number
WO2004112631A1
WO2004112631A1 PCT/IN2003/000226 IN0300226W WO2004112631A1 WO 2004112631 A1 WO2004112631 A1 WO 2004112631A1 IN 0300226 W IN0300226 W IN 0300226W WO 2004112631 A1 WO2004112631 A1 WO 2004112631A1
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WIPO (PCT)
Prior art keywords
rbcs
blood
solution
bag
formulation
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Application number
PCT/IN2003/000226
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English (en)
Inventor
Achutha Kurup Parameswara
Arun Peethambaran
Balagopal Chandrasekhar
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Terumo Penpol Limited
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.)
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Publication date
Application filed by Terumo Penpol Limited filed Critical Terumo Penpol Limited
Priority to PCT/IN2003/000226 priority Critical patent/WO2004112631A1/fr
Priority to AU2003250529A priority patent/AU2003250529A1/en
Publication of WO2004112631A1 publication Critical patent/WO2004112631A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/02—Blood transfusion apparatus
    • A61M1/0272—Apparatus for treatment of blood or blood constituents prior to or for conservation, e.g. freezing, drying or centrifuging
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
    • A01N1/0226—Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0236—Mechanical aspects
    • A01N1/0263—Non-refrigerated containers specially adapted for transporting or storing living parts whilst preserving, e.g. cool boxes, blood bags or "straws" for cryopreservation

Definitions

  • TITLE - A FORMULATION AND A PROCESS FOR REDUCING THE DETORIORATION OF RBCs OF BLOOD DURING STORAGE WITH PARTICULAR REFERENCE TO DECREASE IN THE LEVEL OF 2,3 DIPHOSPHOGLYCERATE
  • This Invention relates to a formulation and a process for reducing the deterioration of RBCs during storage, particularly the decrease Jn the level of 2, 3DPG.
  • Blood is usually collected in a triple Bag and stored in certain anticoagulant preservative solutions like ACD (acid-citrate-dextrose), CPD (citrate-phosphate- dextrose) and CPDA (dtrate-phosphate-dextrose-adenine).
  • ACD acid-citrate-dextrose
  • CPD citrate-phosphate- dextrose
  • CPDA dtrate-phosphate-dextrose-adenine
  • An ACD solution may contain
  • Trisodium citrate (dihydrate) 22.0g Citric acid (anhydrous) 8.0g Dextrose (monohydrate) 24.6g Distilled Water to make up to 1 litre
  • a CPD solution may contain
  • a CPDA solution may contain -
  • Citric add (anhydrous) - 2.99g Sodium dihydrogen phosphate
  • a triple blood Bag system with a Primary Bag and two Satellite Bags is used for the collection of whole blood and separation of RBCs.
  • the Primary Bag (Bag A) contains the anticoagulant solution, which is usually CPD.
  • One of the Satellite Bags (Bag B) contains the preservative solution for RBCs, which is usually SAGM having the following composition.
  • the other Satellite Bag(Bag C) is empty, i.e. it does not contain any solution.
  • Blood for the donor is collected in the Primary Bag (Bag A) containing CPD solution and transferred immediately to 4 ⁇ 1° C RBCs are separated by centrlfuging at 270Qrpm for 12 minutes at 4 ⁇ 1° C.
  • the RBCs sediment to the bottom and by using a plasma expresser, the plasma is transferred to the second empty Satellite Bag (Bag C).
  • the SAGM solution from the first Satellite Bag (Bag B) is transferred to the Primary Bag (Bag A) containing RBCs.
  • the RBCs are gently mixed with the SAGM solution, kept in a Wood bank refrigerator and maintained at 4 ⁇ lo c.
  • the plastic Bags normally used for the collection and storage may be PVC Bags which use di-(2-ethyi hexyl) phthalate (D&IP), tri-(2-ethyl hexyl) trim ⁇ llltate (TEHTM) or butyl-n-tri-hexyl citrate (BTHC) as the plasticfeer or non-PVC Bags like polyolefin.
  • D&IP di-(2-ethyi hexyl) phthalate
  • THCTM tri-(2-ethyl hexyl) trim ⁇ llltate
  • BTHC butyl-n-tri-hexyl citrate
  • the increase in hemolysis is believed to be due to the damage to the red ceil membrane caused by lipid peroxidation.
  • hemoglobin in the storage medium may cause renal failure and other complications when solution containing high levels of hemoglobin Is transfused. Increased levels of potassium in the storage medium may cause hyperkaiemia which may result in cardiac complications.
  • D&IP plasticized PVC Bags Another deleterious effect of storage when D&IP plasticized PVC Bags are used, is an increase in the amount of D&IP solubilized in the SAGM containing RBCs, which may cause toxic problems In recipients of RBC transfusion.
  • D&IP has been reported to be toxic particularly to the liver and reproductive organs and is also carcinogenic. Further we have found that D&IP at low levels causes decrease in insulin and cortisol, depletion of fat soluble vitamins ( ⁇ D & E), Increase In T 3 & T 4 and more important inhibition of membrane bound Na + - * ATPase. The last observation is significant since it is now known that there is inhibition of this enzyme activity in a variety of pathologic conditions like neurodegenerative disorders, cardiovascular disease, diabetes, cancer etc.
  • the decrease in the level of ATP is not very drastic, but the level of 2,3 DPG falls to a very low level during storage.
  • the invivo restoration of 2,3 DPG depends on the level of 2,3 DPG in the RBCs transfused. If the level is very low, then it may take a long time, some time over 20hrs to restore the original level.
  • a major purpose of transfusion of RBCs is to restore oxygen supply to the tissues. This is particularly so in transfusions with compromised circulation in the heart or brain, or in massive loss of blood. This is also more particularly important in infants, since inadequate delivery of oxygen can result in development of hypoxy ischemic encephalopathy, the major cause of long term euro developmental problem in children.
  • 2,3 DPG concentration in the RBCs A major factor involved in ensuring adequate delivery of oxygen to the tissues is 2,3 DPG concentration in the RBCs.
  • 2,3 DPG has a regulatory effect on the oxygen affinity of haemoglobin and on oxygen transport invlvo. Hemoglobin binds to oxygen to form oxyhemogiobin which does not release oxygen to the tissues. 2,3 DPG binds strongly to oxyhemogiobin and this binding decreases the affinity of hemoglobin to oxygen with consequent release of oxygen to the tissues. Therefore an adequate level of 2,3 DPG in the RBCs is essential particularly in critical situations like cardiac surgery, brain surgery or in case of massive hemorrhage.
  • the red cells During storage of RBCs in SAGM, the red cells usually become depleted of 2,3 DPG after 1 - 2 weeks which causes increase in the Hb oxygen affinity with conseq uent i nadeq uate oxygen delivery to the tissues.
  • ATP level is a measure of the metabolic activity of the RBCs. Maintaining of red cell viability is relatively closely associated to the cellular concentration of ATP. Since ATP level does not fail to a level below 50% of the original level, post transfusion restoration of ATP does not take much time, as is the case with the situation in 2,3 DPG
  • ATP is produced by RBCs during glycolysis, which also produces 2,3 DPG from 1,3-diphosphoglycerate by the diphospho glycerate shunt 1,3-diphospho gly erate produced during glycolysis has two metabolic fates, one, It is converted directly to 3-phospho glycerate and continues in the glycolytic pathway to lact ⁇ te. The second one is the shunt pathway where it is converted to 2,3-diphospbo glycerate by the action of the enzyme 2 ⁇ 3-diphospho glycerate mutase. 2,3- diphospho glycerate is then acted on by 2,3-dfphospbo glycerate phosphatase to form 3-phospho glycerate which continues in the glycolytic pathway.
  • Citrate in the medium for RBC storage helps to keep intracellular pH higher since the citrate ion is not permeable.
  • This modification has been achieved by (1) Maintaining the pH of the preservative solution for RBCs at 7.6. This is made possible by autoclaving the dextrose solution separately In the second Satellite Bag C since dextrose solution at alkaline pH develops a yellow to red color on autoclaving, which is not acceptable.
  • the triple Bag with CPD solution in the Primary Bag A preservative solution containing the various ingredients to be mentioned below except dextrose in Satellite Bag B and the dextrose solution in the Satellite Bag C is now autoclaved as per the standard procedure.
  • the dextrose solution after autoclaving is transferred from the Satellite Bag C to the rest of the solution at pH 7.6 in the first Satellite Bag B. Blood is collected from the donor in the Primary Bag A
  • This formulation is effective in minimizing the deleterious effects, which occur during storage of RBCs in blood Bags.
  • a formulation for better storage and preservation of RBCs characterized in that it has a pH above 7.0, it contain nicotinic acid and ascorbic acid at optimum levels.
  • None of the preservative solutions for RBCs hitherto known has all the three factors i.e. contains nicotinic acid, ascorbic acid and has pH above 7.0, and as stated herelnabove It was an Important finding for us to see that the Incorporation of nicotinic acid and ascorbic acid and maintaining pH above 7.0 of the preservative solution considerably reduces the deterioration of RBCs during storage.
  • the concentration of ascorbic acid used in the preservative solution also may vary, and it may preferably be in the range of 3 to 5 mg/dl RBC suspension. However the optimum concentration with minimum h ⁇ motytic effect and maximum beneficial effects was found to be 4.0 mg/dl RBC suspension.
  • the pH of the preservative solution can vary form 7.0 to 8.0, but the optimum pH was found to be at 7.6.
  • a triple blood Bag system which had a Primary Bag A and two Satellite Bags B & C
  • the Primary Bag A contains CPD solution (49ml for 350ml blood Bag system and 63ml for 450ml blood Bag system).
  • Isotonic buffered saline used has the following composition :
  • nicotinic acid can be replaced by nicotinamide.
  • the Bag system containing the respective solution in the Primary Bag A and the Satellite Bags B &C is aut ⁇ aved at 15Jbs pressure for 15 minutes.
  • 2,3 DPG is essential for maintaining oxygen delivery to the tissues.
  • ATP is a measure of metabolic activity of red cells.
  • Malondialdehyde is a measure of lipid peroxidation and its higher concentration indicates higher lipid peroxidation, which is harmful.
  • Reduced glutathione is an antioxidant, which protects against the harmful effects of lipid peroxidation. The higher Its concentration, the higher is the protective effect
  • the concentration of ascorbic acid is varied for 3 to 6 mg/dl RBC suspension. Similariy the concentration of ascorbic acid is kept constant while that of nicotinic acid was varied from 5 - 8 mg/dl RBC suspension. Optimum beneficial effects are obtained when the concentration of nicotinic acid is 6.8 mg/dl RBC suspension and that of ascorbic acid 4.0 mg dl RBC suspension.
  • the modified solution is thus effective in preventing the drastic fell in 23 DPG that take place during storage of RBCs.
  • the level of 2,3 DPG is maintained almost at the same level as on the day 0.
  • PH is well maintained over 7.0.
  • Hemolysis and extent lipid peroxidation are lower.
  • ATP level is not significantly altered.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dentistry (AREA)
  • Environmental Sciences (AREA)
  • Zoology (AREA)
  • Hematology (AREA)
  • Wood Science & Technology (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Anesthesiology (AREA)
  • Vascular Medicine (AREA)
  • Mechanical Engineering (AREA)
  • Biophysics (AREA)
  • Physiology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne la solution SAGM (saline-adénine-dextrose-mannitol) qui est la plus utilisée pour conserver des globules rouges (RBC) après leur séparation du sang total. Même si la période autorisée de stockage des RBC dans la solution SAGM est de 35 jours, la qualité des cellules se détériore de manière régulière et progressive, la détérioration augmentant avec la durée du stockage. Certains des changements les plus dangereux résident dans la diminution considérable du niveau de 2,3 diphophoglycérate (essentiel pour l'apport d'oxygène aux tissus), une hémolyse accrue (qui libère Hb et K+ des RBC dans la SAGM, qui sont tous deux dangereux), et une solubilisation progressive de di-2-éthylhexylphtalate (DEHP) (le plastifiant généralement utilisé pour le sac) dans le milieu contenant des RBC, ce qui est également dangereux. Selon l'invention, cette formulation permet d'empêcher l'extension de ces changements dans les RBC lors du stockage, en particulier la diminution considérable du niveau de 2,3 DPG.
PCT/IN2003/000226 2003-06-20 2003-06-20 Formulation et procede de reduction de la deterioration des globules rouges du sang lors du stockage, notamment en ce qui concerne la diminution du niveau de 2,3 diphosphoglycerate WO2004112631A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/IN2003/000226 WO2004112631A1 (fr) 2003-06-20 2003-06-20 Formulation et procede de reduction de la deterioration des globules rouges du sang lors du stockage, notamment en ce qui concerne la diminution du niveau de 2,3 diphosphoglycerate
AU2003250529A AU2003250529A1 (en) 2003-06-20 2003-06-20 A FORMULATION AND A PROCESS FOR REDUCING THE DETERIORATION OF RBCs OF BLOOD DURING STORAGE WITH PARTICULAR REFERENCE TO DECREASE IN THE LEVEL OF 2,3 DIPHOSPHOGLYCERATE

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Application Number Priority Date Filing Date Title
PCT/IN2003/000226 WO2004112631A1 (fr) 2003-06-20 2003-06-20 Formulation et procede de reduction de la deterioration des globules rouges du sang lors du stockage, notamment en ce qui concerne la diminution du niveau de 2,3 diphosphoglycerate

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WO2004112631A1 true WO2004112631A1 (fr) 2004-12-29

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2503949A (en) * 2012-07-14 2014-01-15 Nobel Biocare Services Ag An agent for promoting osseointegration of implants
GB2503950A (en) * 2012-07-14 2014-01-15 Nobel Biocare Services Ag An agent for promoting osseointegration of bone substitute materials
EP2982374A1 (fr) * 2013-04-01 2016-02-10 Terumo Kabushiki Kaisha Solution de conservation de globules rouges, récipient contenant la solution de conservation, procédé de fabrication d'une solution de conservation de globules rouges et système de poches à globules rouges
US10035308B2 (en) 2012-08-03 2018-07-31 Nobel Biocare Services Ag Bone regeneration material
CN113557295A (zh) * 2019-03-15 2021-10-26 株式会社美加细胞 哺乳动物细胞的保存液

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5906915A (en) * 1990-11-07 1999-05-25 Baxter International Inc. Method for storing red cells using reduced citrate anticoagulant and a solution containing sodium, citrate, phosphate, adenine and mannitol

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5906915A (en) * 1990-11-07 1999-05-25 Baxter International Inc. Method for storing red cells using reduced citrate anticoagulant and a solution containing sodium, citrate, phosphate, adenine and mannitol

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2503949A (en) * 2012-07-14 2014-01-15 Nobel Biocare Services Ag An agent for promoting osseointegration of implants
GB2503950A (en) * 2012-07-14 2014-01-15 Nobel Biocare Services Ag An agent for promoting osseointegration of bone substitute materials
US10035308B2 (en) 2012-08-03 2018-07-31 Nobel Biocare Services Ag Bone regeneration material
EP2982374A1 (fr) * 2013-04-01 2016-02-10 Terumo Kabushiki Kaisha Solution de conservation de globules rouges, récipient contenant la solution de conservation, procédé de fabrication d'une solution de conservation de globules rouges et système de poches à globules rouges
EP2982374A4 (fr) * 2013-04-01 2017-04-26 Terumo Kabushiki Kaisha Solution de conservation de globules rouges, récipient contenant la solution de conservation, procédé de fabrication d'une solution de conservation de globules rouges et système de poches à globules rouges
CN113557295A (zh) * 2019-03-15 2021-10-26 株式会社美加细胞 哺乳动物细胞的保存液

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