WO1988005044A1 - Composes d'oxyde nitreux pour la preparation d'une composition pharmaceutique destinee a la prophylaxie et au traitement de troubles causes par des cellules ischemiques - Google Patents

Composes d'oxyde nitreux pour la preparation d'une composition pharmaceutique destinee a la prophylaxie et au traitement de troubles causes par des cellules ischemiques Download PDF

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Publication number
WO1988005044A1
WO1988005044A1 PCT/SE1987/000629 SE8700629W WO8805044A1 WO 1988005044 A1 WO1988005044 A1 WO 1988005044A1 SE 8700629 W SE8700629 W SE 8700629W WO 8805044 A1 WO8805044 A1 WO 8805044A1
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WO
WIPO (PCT)
Prior art keywords
compound
alpha
cell damage
unpaired electron
organochemical
Prior art date
Application number
PCT/SE1987/000629
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English (en)
Inventor
Ulf Anders Nilsson
Ann-Christin Märta BYLUND-FELLENIUS
Original Assignee
Pharmacia Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE8605572A external-priority patent/SE8605572D0/xx
Priority claimed from SE8701110A external-priority patent/SE8701110D0/xx
Application filed by Pharmacia Ab filed Critical Pharmacia Ab
Publication of WO1988005044A1 publication Critical patent/WO1988005044A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/24—Oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to treating and preventing ischemic cell damage in a reperfusion situation .
  • the active principle is reduced forms of stable nitroxides ( >NO ⁇ red >>NOH) and some compounds which are readily convertible thereto .
  • the compounds employed according to the invention comprise the structural element ( I ) :
  • R may be selected from among one unpaired electron, the compound in that case being a nitroxide; a cation, such as a physiologically acceptable metal ion; hydrogen, the compound in that case being a hydroxylamine derivative; or a protective group which is of the type as is known per se for hydroxyl groups and which is readily removable so that R then will be hydrogen or an unpaired electron.
  • the protective group may form an ester or ether being acyl, tetrahydropyranyl, triorganosilyl (the organo groups therof being alkyl and/or aryl groups) etc.
  • the nitroxides to which the invention is applicable are stable free radicals.
  • alpha and alpha' carbon atoms may be aromatic or aliphatic with certain substituents.
  • An aliphatic alpha carbon atom is preferably tetrasubstituted. It can be a tertiary carbon atom.
  • A is a 2- or 3-membered organic bridge containing at least one or two groups CR 5 R 6 and optionally also ether, thioether, ester, amide, ketone or other structure giving a stable ring according to the formula;
  • R 1 -R 4 may be hydrocarbon groups attached to the ring via the aliphatic or aromatic alpha carbon atoms.
  • the groups may be the same or different or may pairwise form cyclic structures (be organic bridges) and optionally contain functional groups such as ester, ether, thioether, carboxyl, amine (primary, secondary, tertiary, or quaternary), alcohol, amide etc., but at least three R 1 -R 4 being preferably lower alkyl such as C 1 -C 3 as e.g. methyl;
  • R 5 and R 6 are both preferably hydrogen although at least one of them may be selected from among the aforesaid hydrocarbon groups or contain one of the functional groups, R 5 and R 6 in CR 5 P 6 at different positions of the ring being identical or different; and
  • R has the meanings set forth above.
  • a prerequisite applying to all of the substituents R 1 to R 6 in formula (II) is that they must not adversely affect the stability of the nitroxide structure or ring structure.
  • the hydroxylamine compounds and corresponding nitroxides are convertible to one another by means of oxidation and reduction, respectively.
  • WO-A-86/01110 describes the use of hydroxylamine (H 2 NOH) as an absorption enhancer for a free radical scavanger in vivo.
  • H 2 NOH hydroxylamine
  • Chemical Abstracts 95: 215492j (1981) has been cited during the first year of the prosecution of the priority application.
  • the title and summary of this latter CA. reference are inconsistent with each other.
  • the title refers to the use of a compound different from formula I in ischemia, while the text of the abstract refers to compounds of formula I but for other uses.
  • piperidine compound in which R 1 -R 4 is N-(OR)- 2,2,6,6-tetramethyl, and R is hydrogen or an unpaired electron, and which has no other substituents is called in popular terminology TEMPOH or TEMPOo, respectively.
  • the consequence will be a distrubance of cell metabolism and i ⁇ n gradients; the ultimate effects being cell death and irreversible tissue damage.
  • lipid peroxidation Several of the metabolites accumulated in the cell during the ischemic period will function as substrates for enzymic processes resulting in the formation of superoxide radicals (when oxygen supply increases at the time of reperfusion.
  • the superoxide radical may give rise to the formation of other radicals as well which are even more reactive, such as hydroxyl radicals (OHo).
  • OHo hydroxyl radicals
  • superoxide co-operates with ferri(Fe 3+ ) ions and nucleoside phosphates to form perferryl radicals, which initiates the peroxidation of polyunsaturated fatty acids in the phospholipid layers of membranes. This sequential reaction is self-propagating and it may continue as long as polyunsaturated fatty acids are available. Lipid peroxidation thus involves the formation of several intermediate free radicals and leads to destruction of the membrane, which is vital for the structural integrity of the cell.
  • substances like SOD superoxide dismutase
  • inhibitors of xanthine oxidase e.g. allopurinol
  • scavengers in the form a lowmolecular carbohydrates methionine, histidine etc.
  • the invention comprises both the method of using the compounds in question for medical drug therapy and the use of these compounds for producing compositions for such therapy.
  • the invention provides for improvements of therapies in cases where lipid peroxidation or free radical damage is part of the pathogenic process to be treated and prevented.
  • the invention is directed to the prophylaxis and treatment of ischemic cell damage either in mammals, including humans, or in organs that have been excised from them.
  • ischemic cell damage here comprises not only the damage arising during ischemia but also the damage that may arise upon reperfusion.
  • the invention in its various aspects is intended for being utilized in acute resuscitation cases, e.g. upon cardiac arrest or other conditions involving circulatory collapse, where the brain is subject to ischemia.
  • Further fields of practical application comprise various types of traumas in the central nervous system, cerebral hemorrhage, stroke, subarachnoid hemorrhage or in cases of intracranial vascular surgery where temporary occlusion of blood vessels is a necessary step.
  • the drug kit may be used also in cases of ischemic conditions of other organs such as heart, kidney, intestine, liver and skeletal muscle, in association with conditions of shock, trauma, embolisms and infarctions, and moreover also when various types of surgery are carried out such as heart surgery, vessel reconstruction, and transplantation of organs.
  • Another field of applicability may be the use as perfusion solution and preservation solution for organs in cases of for example cardioplegia or organ transplantations.
  • a therapeutically active amount of the compound comprising structure (I) may be administered in a number of different ways in accordance with the the invention. Administration thus may be parenteral, e.g. intraarterial, intravenous, subcutaneous, intramuscular etc. As a rule the compounds are administered in the form of a sterile aqueous solution buffered to a physiologically acceptable pH. The solution is prepared and injected in direct conjunction with or just before administration. The dose given should be selected in the range of from 10 -9 to 10 -2 mol per kg of body weight but may deviate from this general recommendation, depending on the particular compound and indication involved in each case. The administration may be repeated.
  • a compound comprising structure (I) it may be suitable, within the concept of the invention, to administer further drugs which will have a positive effect on the particular indication involved (so-called multifactor treatment), for example a plasma volume expander (e.g. dextran or hydroxyethyl starch), SOD, calcium blocking agents (such as nifedipine, nimodipine, verapamil, lidoflazine, flunarizine etc.), diuretics (especially osmotic diuretics), antiedemics etc.
  • a plasma volume expander e.g. dextran or hydroxyethyl starch
  • SOD e.g. dextran or hydroxyethyl starch
  • calcium blocking agents such as nifedipine, nimodipine, verapamil, lidoflazine, flunarizine etc.
  • diuretics especially osmotic diuretics
  • low-molecular scavengers for instance aliphatic or aromatic thiol or alcohol, or a low-molecular compound containing nitrogen structure such as primary amine, secondary amine or imine. See WO-A-86/00812.
  • the structure (I)- containing the active compound may be packaged in the form of a drug kit containing at least one dosage unit of the compound, if desired together with at least one. of the drugs mentioned in the preceding paragraph.
  • the dosage unit may vary, depending on such factors as the indication to be treated, the particular compound comprising the aforesaid structure (I), and the particular type of patient (child, adult). For a normal person (75 kg) the amount of the compound will be in the range of 7.5x10 -8 to 7.5x10 -1 mol.
  • the compound should be packaged in a manner such as is common practice with this type of compounds, i.e. in an ampoule under an inert atmosphere or in vacuo, so that when to be used, the compound is to be reconstituted in a suitable, physiologically acceptable buffer.
  • the nitroxides contemplated can readily be converted to the reduced form, e.g. by catalytic hydrogenation in aqueous solution with PtO, although then they must usually be used immediately or within one or a few hours, in view of the risk for air oxidation.
  • Both the radical and the corresponding reduced form can be used according to the invention, though it is often practically best, for technical reasons, to use the radical.
  • VF ventricular fibrillation
  • Hearts perfused with Krebs-Heinseleit buffer were compared with hearts perfused with the same buffer but containing 25 ⁇ M OXANOH or 25 ⁇ M OXANOo.
  • OXANOo Reduction of OXANOo: In the presence of platinum oxide hydrogen gas was bubbled through a 10 mM solution of OXANOo for 45 minutes (Dulbecco's phosphate buffer). The OXANOH thus formed was stored on ice and used within two hours.
  • the reaction mixture consisted of phosphate buffer (Dulbecco), Fe 3+ (30 ⁇ M): pyrophosphate
  • OXANOH and OXANOo were added to the reaction mixtures in concentrations ranging from 0.01 to 1.0 mM (Tables 2A and 2B). Formation of malone dialdehyde was expressed as % of that of the controls (without addition of OXANOH and OXANOo). By adding OXANOH and OXANOo to the reaction mixtures after the peroxidation reaction but before the addition of thiobarbituric acid it was possible to exclude interference of these compounds with the assay procedures.
  • OXANOH At the concentrations employed, it it improbable that OXANOH will be able to efficiently compete with other, naturally occurring radical scavengers for superoxide radicals (such as SOD). More probably, OXANOH interacts with other radicals which are involved in the lipid peroxidation process, as e.g. perferryl radicals.
  • the experiment was performed as in Example 2 except that the PMN leucocytes in this case were replaced by liver microsomes from rats (0.4 mg protein/ml, final cone; produced according to Fruster L et al., J Cell Biol 15 (1962) p. 541-56).
  • the Fe 3+ concentration was 1.7 ⁇ M
  • the pyrophosphate (ADP) concentration was 1 mM.
  • (1), (2), (3) and (4) are compounds comprising structure (I).
  • Compound (1) is N-hydroxy-2- ethyl-2,4,4-trimethyl-1,3-oxazolidine
  • (2) is 2,2,6,6- tetramethylpiperidinoxyl
  • (3) is 4-hydroxy-2,2,6,6-tetramethylpiperidinoxyl
  • (4) is 2-(2'-ethoxycarbonylethyl)- 2,4,4-trimethyl-1,3-oxazolidinoxyl.
  • Compounds (5), (6) and (7) are nitrones and do not comprise structure (I).
  • Compound 5 is alpha-phenyl-N-t-butyl-nitrone
  • (6) is 5,5-dimethyl-1- pyrroline-N-oxide
  • (7) is alpha-(4-pyridyl-N-oxide)-N-t- butyl-nitrone.
  • the nitrone group has the structure

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le composé organochimique décrit comprend l'unité structurale (I) où R est choisi dans le groupe composé (i) d'un électron non apparié (ii) d'un cation tel qu'un ion de métal physiologiquement acceptable, (iii) d'hydrogène (iv) d'un groupe protecteur qui est connu en soi pour les groupes hydroxyle et qui peut facilement être scindé, et les atomes de carbone alpha et alpha' sont substitués de sorte que, si R = un électron non apparié, le composé est un oxyde nitreux stable (radical nitroxyle stable). Ledit composé est utilisé pour la préparation d'une composition pharmaceutique destinée à la prophylaxie et au traitement de troubles causés par des cellules ischémiques. L'utilisation décrite comprend un procédé permettant d'empêcher et de traiter les troubles causés par des cellules ischémiques chez les mamifères.
PCT/SE1987/000629 1986-12-29 1987-12-22 Composes d'oxyde nitreux pour la preparation d'une composition pharmaceutique destinee a la prophylaxie et au traitement de troubles causes par des cellules ischemiques WO1988005044A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE8605572A SE8605572D0 (sv) 1986-12-29 1986-12-29 Terapeutisk indikation for kend substans
SE8605572-0 1986-12-29
SE8701110-2 1987-03-18
SE8701110A SE8701110D0 (sv) 1987-03-18 1987-03-18 Terapeutisk indikation for kend substansgrupp

Publications (1)

Publication Number Publication Date
WO1988005044A1 true WO1988005044A1 (fr) 1988-07-14

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WO (1) WO1988005044A1 (fr)

Cited By (29)

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Publication number Priority date Publication date Assignee Title
US5025032A (en) * 1989-10-17 1991-06-18 Oklahoma Medical Research Foundation Phenyl butyl nitrone compositions and methods for treatment of oxidative tissue damage
US5036097A (en) * 1989-10-17 1991-07-30 Oklahoma Medical Research Foundation Phenylbutyl nitrone compositions and methods for prevention of gastric ulceration
WO1992022290A1 (fr) * 1991-06-18 1992-12-23 Oklahoma Medical Research Foundation Emploi du blocage par spin pour le traitement de maladies associees a l'oxydation des lipides et des proteines
EP0520005A1 (fr) * 1990-03-16 1992-12-30 Us Health Nitroxydes utilises comme protecteurs contre la contrainte oxydative.
EP0496796B1 (fr) * 1989-10-17 1994-08-31 Oklahoma Medical Research Foundation Procede et compositions inhibant les troubles associes aux lesions oxydatives des tissus
US5498427A (en) * 1990-11-20 1996-03-12 Pasteur Merieux Serums Et Vaccines Solutions for the perfusion, preservation and reperfusion of organs
USRE35213E (en) * 1989-10-17 1996-04-16 Oklahoma Medical Research Foundation Phenylbutyl nitrone compositions and methods for prevention of gastric ulceration
WO1996040127A1 (fr) * 1995-06-07 1996-12-19 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Nitroxydes protegeant du stress oxydatif
US5591710A (en) * 1993-08-16 1997-01-07 Hsia Jen C Compositions and methods utilizing nitroxides to avoid oxygen toxicity, particularly in stabilized, polymerized, conjugated, or encapsulated hemoglobin used as a red cell substitute
US5681845A (en) * 1989-10-17 1997-10-28 Oklahoma Medical Research Foundation DMPO spin trapping compositions and methods of use thereof
US5725839A (en) * 1993-08-16 1998-03-10 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules for ERI or MRI
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US5767089A (en) * 1993-08-16 1998-06-16 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
US5804561A (en) * 1993-08-16 1998-09-08 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
US5807831A (en) * 1993-08-16 1998-09-15 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
US5817632A (en) * 1993-08-16 1998-10-06 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
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US5840701A (en) * 1993-08-16 1998-11-24 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
US5900227A (en) * 1996-06-17 1999-05-04 Oklahoma Medical Research Foundation Multicyclic nitrone spin trapping compositions
US5912019A (en) * 1997-02-07 1999-06-15 Musc Foundation For Research Development Compounds for reducing ischemia/reperfusion injury
US6001853A (en) * 1996-01-26 1999-12-14 The United States Of America As Represented By The Department Of Health And Human Services Hydroxylamine compositions for the prevention or retardation of cataracts
US6458758B1 (en) * 1993-08-16 2002-10-01 Synzyme Technologies, Inc. Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
WO2003022246A1 (fr) * 2001-09-06 2003-03-20 Synzyme Technologies Llc Traitement des effets des especes reactives de l'oxygene
EP1620097A1 (fr) * 2003-04-25 2006-02-01 Mitos Incorporated Pretraitement preventif par antioxydants
EP1689397A2 (fr) * 2003-11-20 2006-08-16 Othera Pharmaceuticals, Inc. Amelioration de la degenerescence maculaire et d'autres maladies ophtalmiques
WO2007082916A1 (fr) * 2006-01-19 2007-07-26 Medestea Research & Production Spa Utilisation de compositions de dérivés de la n-pipéridine pour protéger des systèmes biologiques
US7589107B2 (en) 2003-05-19 2009-09-15 Othera Holding, Inc. Amelioration of vitrectomy-induced cataracts
EP2620429A1 (fr) 2007-02-22 2013-07-31 Colby Pharmaceutical Company Composés d'hydroxylamine et leurs procédés d'utilisation
US8617802B2 (en) 2005-03-11 2013-12-31 Children's Hospital Medical Center Organ transplant solutions and method for transplanting organs

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Cited By (47)

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Publication number Priority date Publication date Assignee Title
US5578617A (en) * 1989-10-17 1996-11-26 Oklahoma Medical Research Foundation Method and compositions for treating age related disorders
US5405874A (en) * 1989-10-17 1995-04-11 Oklahoma Medical Research Foundation PBN, DMPO, and POBN compositions and method of use thereof for inhibition of age-associated oxidation
US6107315A (en) * 1989-10-17 2000-08-22 Oklahoma Medical Research Foundation Method of treatment of conditions associated with oxidative tissue damage
US5025032A (en) * 1989-10-17 1991-06-18 Oklahoma Medical Research Foundation Phenyl butyl nitrone compositions and methods for treatment of oxidative tissue damage
USRE35112E (en) * 1989-10-17 1995-12-05 Oklahoma Medical Research Foundation Phenyl butyl nitrone compositions and methods for treatment of oxidative tissue damage
EP0496796B1 (fr) * 1989-10-17 1994-08-31 Oklahoma Medical Research Foundation Procede et compositions inhibant les troubles associes aux lesions oxydatives des tissus
US5036097A (en) * 1989-10-17 1991-07-30 Oklahoma Medical Research Foundation Phenylbutyl nitrone compositions and methods for prevention of gastric ulceration
US5681845A (en) * 1989-10-17 1997-10-28 Oklahoma Medical Research Foundation DMPO spin trapping compositions and methods of use thereof
USRE35213E (en) * 1989-10-17 1996-04-16 Oklahoma Medical Research Foundation Phenylbutyl nitrone compositions and methods for prevention of gastric ulceration
EP0520005A4 (en) * 1990-03-16 1993-04-21 Us Health Nitroxides as protectors against oxidative stress
US5462946A (en) * 1990-03-16 1995-10-31 The United States Of America As Represented By The Department Of Health And Human Services Nitroxides as protectors against oxidative stress
EP0520005A1 (fr) * 1990-03-16 1992-12-30 Us Health Nitroxydes utilises comme protecteurs contre la contrainte oxydative.
EP0787492A1 (fr) * 1990-03-16 1997-08-06 THE UNITED STATES OF AMERICA as represented by the Secretary UNITED STATES DEPARTMENT OF COMMERCE Utilisation de nitroxides et oxazolidines pour protection contre la radiation ionisante et le stress oxidative
US5498427A (en) * 1990-11-20 1996-03-12 Pasteur Merieux Serums Et Vaccines Solutions for the perfusion, preservation and reperfusion of organs
AU672364B2 (en) * 1991-06-18 1996-10-03 Oklahoma Medical Research Foundation Use of spin trapping for the treatment of diseases associated with oxidation of lipids and proteins
WO1992022290A1 (fr) * 1991-06-18 1992-12-23 Oklahoma Medical Research Foundation Emploi du blocage par spin pour le traitement de maladies associees a l'oxydation des lipides et des proteines
US6605619B1 (en) 1992-03-20 2003-08-12 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Nitroxides as protectors against oxidatives stress
US6458758B1 (en) * 1993-08-16 2002-10-01 Synzyme Technologies, Inc. Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
US5767089A (en) * 1993-08-16 1998-06-16 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
US5725839A (en) * 1993-08-16 1998-03-10 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules for ERI or MRI
US5789376A (en) * 1993-08-16 1998-08-04 Hsia; Jen-Chang Transfusions with stabilized hemoglobin covalently bound to a nitroxide or polymers thereof
US5804561A (en) * 1993-08-16 1998-09-08 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
US5807831A (en) * 1993-08-16 1998-09-15 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
US5817632A (en) * 1993-08-16 1998-10-06 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
US5824781A (en) * 1993-08-16 1998-10-20 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
US5840701A (en) * 1993-08-16 1998-11-24 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
US5741893A (en) * 1993-08-16 1998-04-21 Hsia; Jen-Chang Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules
US6323175B1 (en) 1993-08-16 2001-11-27 Synzyme Technologies, Inc. Compositions and methods utilizing nitroxides to avoid oxygen toxicity, particularly in stabilized, polymerized, conjugated, or encapsulated hemoglobin used as a red cell substitute
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