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WO1996003139A1 - Utilisation de l'oxyde nitrique ou de ses produits d'addition pour la conservation des plaquettes - Google Patents

Utilisation de l'oxyde nitrique ou de ses produits d'addition pour la conservation des plaquettes Download PDF

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Publication number
WO1996003139A1
WO1996003139A1 PCT/US1995/009287 US9509287W WO9603139A1 WO 1996003139 A1 WO1996003139 A1 WO 1996003139A1 US 9509287 W US9509287 W US 9509287W WO 9603139 A1 WO9603139 A1 WO 9603139A1
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Prior art keywords
platelets
nitroso
nitric oxide
group
proline
Prior art date
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PCT/US1995/009287
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English (en)
Inventor
Jonathan Stamler
Stuart Lind
Original Assignee
Duke University
Brigham And Women's Hospital
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Publication date
Application filed by Duke University, Brigham And Women's Hospital filed Critical Duke University
Priority to AU31987/95A priority Critical patent/AU3198795A/en
Publication of WO1996003139A1 publication Critical patent/WO1996003139A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • 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
    • A01N1/10—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
    • A01N1/10—Preservation of living parts
    • A01N1/12—Chemical aspects of preservation
    • A01N1/122—Preservation or perfusion media
    • A01N1/125—Freeze protecting agents, e.g. cryoprotectants or osmolarity regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/19—Platelets; Megacaryocytes

Definitions

  • Nitric Oxide or Nitric Oxide Adducts to Preserve Platelets
  • This invention relates to preserving platelets. More particularly, this invention relates to preserving platelets by contacting platelets in vitro with nitric oxide, or a compound which is capable of donating, releasing, or transferring nitric oxide.
  • Platelet transfusions are used by physicians and hospitals for a large number of uses, such as, for example, the treatment of thrombocytopenia.
  • Platelet concentrates are prepared from units of red blood cells. In general, from 4 to 10 platelet concentrates are pooled together for administration to patients. Two centrifugation steps are used in platelet concentrate preparation. In the first step, whole blood (in an amount of about 450 ml ⁇ 45 ml) is subjected to a "light spin" (e.g., about 2,000 xg for 5 minutes), after which a supernatant fluid, sometimes referred to as platelet-rich plasma, is removed. This supernatant then is subjected to a "heavy spin” (e.g., about 5,000 xg for 5 minutes) which pellets the platelets. The plasma then is discarded, except for 30-50 ml, which contain the platelets.
  • a light spin e.g., about 2,000 xg for 5 minutes
  • a supernatant fluid sometimes referred to as platelet-rich plasma
  • the platelet bag is left stationary for a period of time of about 1 hour, and the platelets then are resuspended, either by manual manipulation or by placing the bag on a rotator for about 2 hours.
  • Activation of platelets (as measured by expression of P- selectin (GMP-140 or CD62) has been noted immediately after collection and after blood bank storage. (Pijnheer, et al . , Transfusion. Vol. 30, pgs. 634-638 (1990); Rinder et al . , Transfusion. Vol. 31, pgs. 409-414 (1991)).
  • Single donor platelets are collected from individuals whose blood is subjected to platelet pheresis.
  • the blood is passed through a revolving bowl, and only platelet-rich plasma is removed from the donor. Activation of platelets
  • platelets Activation of the platelets, however, eventually renders the platelets inactive and, therefore, in general, platelets, whether such platelets are contained in platelet concentrates or are single donor platelets, in general are discarded after 4 to 5 days.
  • a method of preserving platelets comprises contacting the platelets with an effective amount of nitric oxide.
  • nitric oxide or a nitric oxide adduct inhibits, prevents, or retards the activation of platelets.
  • the nitric oxide may inhibit the activation of platelets through increasing intracellular levels of cyclic GMP.
  • the treatment of the platelets with nitric oxide encompasses the use of gaseous nitric oxide and/or the use of a compound which is capable of delivering nitric oxide.
  • nitric oxide generally refers to the reactive forms of nitric oxide, in particular (1) uncharged nitric oxide (NO') (Gaseous nitric oxide is an uncharged form of nitric oxide) ; (2) negatively charged nitric oxide or NO " (nitroxyl) and positively charged nitric oxide, or (3) NO + (nitrosonium) .
  • NO' uncharged nitric oxide
  • NO + nitrogen +
  • the reactive form of nitric oxide is provided by gaseous nitric oxide.
  • the reactive form of nitric oxide is provided by a compound which delivers nitric oxide.
  • Compounds which deliver nitric oxide include, but are not limtied to, S-nitrosothiol ⁇ , S-nitroso amino acids, S- nitroso-polypeptides, and nitrosoamines.
  • nitric oxide and compounds that release nitric oxide or otherwise directly or indirectly deliver or transfer nitric oxide to a site of its activity, such as on a cell membrane.
  • nitric oxide encompasses uncharged nitric oxide(NO*) and charged nitric oxide species, particularly including nitrosonium ion(NO + ) and nitroxyl ion(NO ⁇ ) .
  • nitric oxide releasing, delivering, or transferring compounds having the structure X-NO wherein X is a nitric oxide releasing, delivering, or transferring moiety, include any and all such compounds which provide nitric oxide to its intended site of action in a form active for their intended purpose.
  • NO adducts encompasses any of such nitric oxide releasing, delivering or transferring compounds.
  • One group of such NO adducts is the S-nitrosothiols, which are compounds that include at least one -S-NO group.
  • Such compounds include S- nitroso-polypeptides (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof) ; S- nitrosylated amino acids(including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof) ; S-nitrosated sugars, S-nitrosated- modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides) ; and an S- nitrosated hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon; S-nitroso hydrocarbons having one or more substituent groups in addition to the S-nitroso group; and heterocyclic compounds.
  • polypeptide includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof
  • S- nitrosylated amino acids including natural and
  • S-nitroso amino acids where the nitroso group is linked to a sulfur group of a sulfur-containing amino acid or derivative thereof.
  • such compounds include the following: S-nitroso-N-acetylcy ⁇ teine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine and S-nitroso- glutathione.
  • Suitable S-nitrosylated proteins include thiol- containing proteins(where the NO group is attached to one or more sulfur groups on an amino acid or amino acid derivative thereof) from various functional classes including enzymes, such as tissue-type plasminogen activator(TPA) and cathepsin B; transport proteins, such as lipoproteins, heme proteins such as hemoglobin and serum albumin; and biologically protective proteins, such as the immunoglobulins and the cytokines.
  • TPA tissue-type plasminogen activator
  • cathepsin B cathepsin B
  • transport proteins such as lipoproteins, heme proteins such as hemoglobin and serum albumin
  • biologically protective proteins such as the immunoglobulins and the cytokines.
  • S-nitrosothiols include those having the structures:
  • x equals 2 to 20 and Y is selected from the group consisting of fluoro, ⁇ -Cg alkoxy, cyano, carboxamido, C 3 -C 6 cycloalkyl, aralkoxy, C 2 -C 6 alkylsulfinyl, arylthio, ⁇ Cg alkylamino, C -C 15 dialkylamino, hydroxy, carbamoyl, C 1 -C 8 N- alkylcarbamoyl, C 2 -C 15 N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl; wherein aryl includes benzyl, naphthyl, and anthracenyl groups.
  • S-nitrosothiols that are S-nitroso- angiotensin converting enzyme inhibitors (hereinafter referred to as S-nitroso-ACE inhibitors) are described in Loscalzo, U.S. Patent No. 5,002,964 (1991) and Loscalzo et al . , U.S. Patent No. 5,025,001 (1991) both of which are incorporated in their entirety by reference.
  • S-nitroso-ACE inhibitors include compounds having structure (l) : R 2
  • R is hydroxy, NH 2 , NHR 4 , NR 4 R 5 , or C 1 -C 7 alkoxy, wherein R 4 and R 5 are ⁇ - ⁇ alkyl, or phenyl, or C 1 -C 4 alkyl substituted by phenyl;
  • R 1 is hydrogen, C 1 -C 7 alkyl, or C 1 -C 7 alkyl substituted by phenyl, amino, guanidino, NHR 6 , NR 6 R 7 , wherein R 6 and R 7 are methyl or C 1 -C 4 alkanoyl;
  • R 2 is hydrogen, hydroxy, C 1 -C 4 alkoxy, phenoxy, or
  • R 3 is hydrogen, C ⁇ -C 4 or C 1 -C 7 alkyl substituted by phenyl; m is l to 3; and n is 0 to 2.
  • S-nitroso-ACE inhibitors include N- acetyl-S-nitroso-D-cysteinyl -L-proline, N-acetyl-S-nitroso- D,L-cysteinyl-L- * proline, 1- (4-amino-2-S- nitroso) mercaptomethylbutanoyl) -L-proline, 1- [2-hexanoyl] -L- proline, 1- [5-guanidino-2- (S-nitroso)mercaptomethyl- pentanoyl] -L-proline, l-[5 -amino -2 - (S-nitroso) mercaptomethyl-pentanoyl] -4-hydroxy-L-proline, 1- [5- guanidino-2- (S-nitroso) mercaptomethyl-pentanoyl] -4-hydroxy-L- proline, l- [2-aminomethyl-3 (S-nitros
  • S-nitroso-ACE inhibitors include those having structures (2-3) :
  • X is oxygen or sulfur
  • A is 0N-S-CH 2 -CH-C;
  • R is selected from hydrogen, lower ( ⁇ -C ⁇ alkyl, benzyl, benzhydryl, and salt forming ion;
  • R ⁇ ⁇ and R 2 are independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, halo substituted lower alkyl, nitro, and S0 2 NH 2 ;
  • R 3 is hydrogen, lower alkyl, halo substituted lower alkyl, phenyl, benzyl, phenethyl, or cycloalkyl;
  • R 4 is hydrogen, lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH 2 ) ⁇ -N (lower alkyl) 2 or -(CH 2 ) g -NH 2 and q is one, two, three or four.
  • the S-nitroso-ACE inhibitors can be prepared by various methods of synthesis.
  • Acids which may be used for this purpose include aqueous sulfuric, acetic and hydrochloric acids.
  • Thiol precursors are prepared as described in the following: U.S. Pat. Nos. 4,046,889 (1977); 4,052,511; 4,053,651; 4,113,751, 4,154,840, 4129,571 (1978), and 4,154,960 (1979) to Ondetti et al .
  • Such compounds include O- nitroso-polypeptides(the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof) ; O-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof) ; O-nitrosated sugars; O-nitrosated-modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides); and an O-nitrosated hydrocarbon where the hydrocarbon can be a branched or unbranched, saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon; O-nitroso hydrocarbons having one or more substituent groups in addition to the ⁇ -nitroso group; and heterocyclic compounds.
  • NO adducts Another group of such NO adducts is the nitrites which have an -0-NO group wherein R is a protein, polypeptide, amino acid, branched or unbranched and saturated or unsaturated alkyl, aryl or a heterocyclic.
  • R is a protein, polypeptide, amino acid, branched or unbranched and saturated or unsaturated alkyl, aryl or a heterocyclic.
  • a preferred example is the nitosylated form of isosorbide.
  • Compounds in this group form S-nitrosothiol intermediates in vivo in the recipient human or other animal to be treated and can therefore include any structurally analogous precursor R-O-NO of the S-nitrosothiols described above.
  • N-nitrosoamine ⁇ which are compounds that include at least one -N-NO group.
  • Such compounds include N-nitroso-polypeptide ⁇ (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof) ; N-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures) ; N-nitrosated sugars; N-nitrosated-modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides); and an N- nitrosated hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon N-nitroso hydrocarbons having one or more substituent groups in addition to the N-nitroso group; and heterocyclic compounds.
  • C-nitroso compounds that include at least one -C-NO group.
  • Such compounds include C-nitroso-polypeptides (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof) ; C-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomer ⁇ and racemic mixtures) ; C-nitrosated sugars,- C-nitrosated-modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides) , • and a C-nitrosated hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon; C-nitroso hydrocarbons having one or more substituent groups in addition to the C-nitroso group; and heterocyclic compounds.
  • polypeptides include proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof
  • amino acids including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof
  • sugars modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides)
  • hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon,- hydrocarbons having one or more substituent groups; and heterocyclic compounds.
  • a preferred example is nitroglycerin.
  • R includes polypeptides (the term "polypeptide” includes protein ⁇ and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof) ,- amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof) ,- sugars,- modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides) ,- and a hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon,- hydrocarbons having one or more substituent groups in addition to the A-nitroso group; and heterocyclic compounds.
  • A is S, 0, or N, n and x are each integers independently selected from 1, 2 and 3, and M is a metal, preferably a transition metal.
  • Preferred metals include iron, copper, manganese, cobalt, selenium and luthidium. Also contemplated are N-nitrosylated metal centers such as nitroprusside.
  • R includes polypeptides (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof) ; amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof) ,- sugars; modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides) ; and a hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon; hydrocarbons having one or more substituent groups; and heterocyclic compounds.
  • R is preferably a nucleophilic (basic) moiety.
  • M+ is a metal cation, ⁇ uch a ⁇ , for example, a
  • thionitrates which have the structure R- (S) ⁇ -NO wherein x is an integer of at least 2.
  • R is as described above for the S-nitrosothiols.
  • Pre erred are the dithiols wherein x is 2.
  • Particularly preferred are those compounds where R is a polypeptide or hydrocarbon and a pair or pairs of thiols are sufficiently structurally proximate, i.e. vicinal, that the pair of thiols will be reduced to a disulfide.
  • Those compounds which form disulfide species release nitroxyl ion(NO " ) and uncharged nitric oxide (N0«) .
  • Those compounds where the thiol groups are not sufficient! clo ⁇ e to form disulfide bridges generally only provide nitric oxide as the NO " form but not as the uncharged NO* form.
  • the platelets are contacted with the compound (gaseous nitric oxide or a nitric oxide adduct) in an amount effective to inhibit or prevent platelet activation or aggregation.
  • the platelets are contacted with the compound in an amount of from about 10 nM to about 10 mM, preferably from about 10 nM to about 1 mM.
  • the compound may be added to platelets contained in platelet concentrates or to single donor platelets.
  • the compounds may be added to the platelets at any stage of the processing of the platelets, such as (i) during their collection via whole blood donation or apheresi ⁇ ; or (ii) during manipulations of whole blood or fractions thereof performed in the course of isolating, concentrating, or washing platelets; or (iii) during storage of platelets, whether at room temperature, in a refrigerator, or in a freezer.
  • the treatment is effected prior to treatment of the platelet concentrates.
  • an anticoagulant or anti-thrombogenic agent may be added to the platelets in combination with the nitric oxide or nitric oxide adduct.
  • anticoagulant and “anti-thrombogenic agent” as used herein mean any compound which alters platelet function or interferes with other mechanisms involved in blood clotting. Examples of such compounds include, but are not limited to, heparin, warfarin, aspirin, indomethacin, dipyridamole, sulfinpyrazone, and other non-steroidal anti-inflammatory drugs.
  • the nitric oxide or nitric-oxide adduct may be added to the platelets in combination with a physiologically acceptable carrier.
  • physiologically acceptable carriers include, but are not limited to, water, and saline solutions.
  • Such a combination also can be sterilized and may be mixed with auxiliary agents such as preservatives, stabilizers, wetting agents, salts or buffers which do not react deleteriously with the nitric oxide or nitric oxide adduct, or with the platelets, or with other blood components.
  • a method of preserving platelets comprising contacting platelets with an effective amount of cyclic GMP or a derivative or analogue thereof.
  • the cyclic GMP may be administered alone or in combination with the gaseou ⁇ nitric oxide or nitric oxide adduct hereinabove described.
  • cyclic GMP (cGMP) derivatives or analogues thereof which may be employed include, but are not limited to, dibutyl cGMP, 8-bromo-cGMP, 8- (p-chlorophenylthio) -cGMP (8-pCPT-cGMP) , and ⁇ -phenyl-1, N-etheno-cGMP (1, N-PET-cGMP) .
  • the cyclic GMP or derivative or analogue thereof may be added to the platelets at any stage during processing of the platelets, as hereinabove described with respect to nitric oxide or nitric oxide adducts.
  • the platelets are contacted with the cGMP or derivative or analogue thereof in an amount of from about 10 nM to about 10 mM, preferably from about 10 nM to about 1 mM.
  • Example 1 Whole blood was collected in CPD anticoagulant in a blood donor center. Two centrifugation steps then were used to prepare platelet concentrates. In the first step, whole blood (450 ml ⁇ 45 ml) was ⁇ ubjected to a light spin (2000xg for 5 minutes) , after which the resulting supernatant fluid (platelet rich plasma or PRP) was removed. lOO ⁇ M of nitric oxide, or S-nitroso-N-acetylcysteine, or S-nitrosoglutathione or an equivalent amount of saline (control) was added to the bags of platelet-rich plasma samples. The control sample received no nitric oxide or S-nitrosothiols. Two samples were treated with nitric oxide, one sample was treated with S-nitroso-N-acetylcysteine, one sample was treated with S- nitroso-glutathione, and one sample was a control sample.
  • the platelet-rich plasma then was subjected to a "heavy spin" (5000xg for 5 minutes), which pellets the platelets. Plasma then was expres ⁇ ed until 30 to 50 ml remained.
  • the platelet bag ⁇ were left stationary for 1 hour at room temperature. The platelets then were resuspended by gentle manual manipulation of the bag and placed on a rotator for storage. Activation of platelets was measured by expression of P-selectin (GMP-140 or CD62) using flow cytometry for 120 hours. The results are shown in Figure 1.
  • Example 2 Platelet-rich plasma was prepared as described in Example 1. NO donors in the form of S-nitroso-N- acetylcysteine or S-nitrosoglutathione or nitric oxide are added in an amount of 100 ⁇ M to 8 of the samples of the platelet-rich plasma. The samples were subjected to a heavy spin, and platelet concentrates were prepared as described in Example 1. Thirteen (13) untreated samples served as controls. After the control and treated platelet samples have been incubated for l hour at room temperature, samples were drawn for testing for expression of P-selectin (GMP-140 or CD62) as described hereinabove in Example 1.
  • P-selectin GMP-140 or CD62
  • the platelet sample ⁇ treated with NO donors exhibited a lower percentage of platelet activation at both l hour and 5 days after storage, as compared with the untreated control sample ⁇ .

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Abstract

Procédé de conservation des plaquettes consistant à les mettre en contact avec une quantité efficace d'oxyde nitrique, un composé qui libère, distribue ou transfert l'oxyde nitrique ou du cGMP ou l'un de ses dérivés ou analogues. Ces composés inhibent l'activation des plaquettes, ce qui permet de les entreposer pendant des durées plus longues et d'améliorer la qualité des plaquettes utilisées pour des transfusions.
PCT/US1995/009287 1994-07-27 1995-07-20 Utilisation de l'oxyde nitrique ou de ses produits d'addition pour la conservation des plaquettes WO1996003139A1 (fr)

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AU31987/95A AU3198795A (en) 1994-07-27 1995-07-20 Use of nitric oxide or nitric oxide adducts to preserve platelets

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6197745B1 (en) 1995-09-15 2001-03-06 Duke University Methods for producing nitrosated hemoglobins and therapeutic uses therefor
JP2002518557A (ja) * 1998-06-23 2002-06-25 デューク ユニバーシティ メディカル センター インビボでの酸化窒素送達用ポリマー
WO2002030193A3 (fr) * 2000-10-13 2002-09-12 Pike Lab Inc Solution de perfusion pour machine de perfusion destinee a la conservation d'organes et de tissus biologiques
US6627738B2 (en) 1995-09-15 2003-09-30 Duke University No-modified hemoglobins and uses therefor
US6855691B1 (en) 1995-09-15 2005-02-15 Duke University Methods for producing and using S-nitrosohemoglobins
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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6884773B1 (en) 1995-09-15 2005-04-26 Duke University Modified hemoglobins, including nitrosylhemoglobins, and uses thereof
US6911427B1 (en) 1995-09-15 2005-06-28 Duke University No-modified hemoglobins and uses therefore
US6197745B1 (en) 1995-09-15 2001-03-06 Duke University Methods for producing nitrosated hemoglobins and therapeutic uses therefor
US6627738B2 (en) 1995-09-15 2003-09-30 Duke University No-modified hemoglobins and uses therefor
US6855691B1 (en) 1995-09-15 2005-02-15 Duke University Methods for producing and using S-nitrosohemoglobins
JP2002518557A (ja) * 1998-06-23 2002-06-25 デューク ユニバーシティ メディカル センター インビボでの酸化窒素送達用ポリマー
US7745656B2 (en) 1998-06-23 2010-06-29 Duke University Stable no-delivering compounds
JP4846099B2 (ja) * 1998-06-23 2011-12-28 デューク ユニバーシティ メディカル センター インビボでの酸化窒素送達用ポリマー
WO2002030193A3 (fr) * 2000-10-13 2002-09-12 Pike Lab Inc Solution de perfusion pour machine de perfusion destinee a la conservation d'organes et de tissus biologiques
US7014990B2 (en) 2000-10-13 2006-03-21 Ben O'Mar Arrington Machine perfusion solution for organ and biological tissue preservation
US7005253B2 (en) 2000-10-13 2006-02-28 Ben O'Mar Arrington Cold storage solution for organ and biological tissue preservation
WO2004105837A3 (fr) * 2003-05-22 2005-02-17 Blood Res Center Composes et procedes d'amelioration de la recuperation et de la fonction plaquettaire
US8835104B2 (en) 2007-12-20 2014-09-16 Fenwal, Inc. Medium and methods for the storage of platelets
US10358627B2 (en) 2007-12-20 2019-07-23 Fenwal, Inc. Medium and methods for the storage of platelets
US9402866B2 (en) 2011-04-07 2016-08-02 Fenwal, Inc. Automated methods and systems for providing platelet concentrates with reduced residual plasma volumes and storage media for such platelet concentrates

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