WO2013016598A2 - Procédés pour réduire une lésion de reperfusion en utilisant un porteur de monoxyde de carbone à base d'hémoglobine - Google Patents

Procédés pour réduire une lésion de reperfusion en utilisant un porteur de monoxyde de carbone à base d'hémoglobine Download PDF

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WO2013016598A2
WO2013016598A2 PCT/US2012/048450 US2012048450W WO2013016598A2 WO 2013016598 A2 WO2013016598 A2 WO 2013016598A2 US 2012048450 W US2012048450 W US 2012048450W WO 2013016598 A2 WO2013016598 A2 WO 2013016598A2
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malpeg
hbco
hemoglobin
carbon monoxide
reperfusion
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PCT/US2012/048450
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WO2013016598A3 (fr
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Mark Young
Kim D. Vandegriff
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Sangart, Inc.
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Publication of WO2013016598A3 publication Critical patent/WO2013016598A3/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/41Porphyrin- or corrin-ring-containing peptides
    • A61K38/42Haemoglobins; Myoglobins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol

Definitions

  • the present invention relates generally to methods for reducing reperfusion injury. Specifically, the present invention is directed to administering a hemoglobin-based carbon monoxide carrier to a subject, prior to or following surgery to reduce injury resulting from reperfusion by delivering both carbon monoxide and oxygen to ischemic tissue.
  • Ischemia is a restriction in blood supply to cells that results in damage or dysfunction of tissue. Ischemia may occur because of damage to the vessels supplying blood to the organ, such as by laceration, a blockage in the vessel, such as a blood clot, or in surgery where the supply is blocked during a procedure. In each case, cellular damage results because of the shortage of oxygen, glucose and other fuels provided by the blood.
  • ROS reactive oxygen species
  • This application relates to a method of reducing reperfusion injury in a subject suspected of having ischemic tissue comprising the steps of: administering a maleimidyl polyethylene glycol surface modified hemoglobin-carbon monoxide complex (MalPEG-HbCO); and allowing the MalPEG-HbCO to exchange CO for 0 2 such that both CO and 0 2 are delivered to the ischemic tissue.
  • MalPEG-HbCO maleimidyl polyethylene glycol surface modified hemoglobin-carbon monoxide complex
  • the MalPEG-HbCO can be administered intravenously to a subject.
  • the MalPEG-HbCO is administered intra- arterially.
  • the step of administering MalPEG-HbCO is performed by positioning a catheter in the arterial circulation supplying an organ.
  • the Mai PEG is maleimidyl- activated polyethylene glycol having an average molecular weight of about 5000 (MalPEG 5000).
  • the MalPEG-Hb has a p50 between 3 and 10 mmHg.
  • the MalPEG-Hb has a p50 between 4 and 6 mmHg.
  • Various exemplary embodiments of the present invention feature a MalPEG-HbC wherein the hemoglobin is thiolated before being surfaced modified with the MalPEG.
  • Figure 1 shows a graph depicting experimental measurements of ischemic risk area and infarct size resulting from the administration of MalPEG-HbCO (MP4CO) or MalPEG- HbO? (MP40X ), where Lactated Ringer ' s (LR) solution and preconditioning (PC) were used as controls.
  • MP4CO MalPEG-HbCO
  • MP40X MalPEG- HbO?
  • LR Lactated Ringer ' s
  • PC preconditioning
  • FIG. 2 shows a graph depicting experimental measurements of phosphorylation of extracellular signal-regulated kinase (ERK) in brain tissue resulting from the administration of cross-linked hemoglobin (acxHb), MalPEG-Hb0 2 (MP4) or MalPEG-HbCO (COMP4).
  • ERK extracellular signal-regulated kinase
  • the present invention relates generally to methods for reducing reperfusion injury. Specifically, the present invention is directed to administering a hemoglobin-based carbon monoxide carrier to a subject, prior to or following surgery, to reduce injury resulting from reperfusion by delivering both carbon monoxide and oxygen to ischemic tissue.
  • activated polyalkylene oxide or “activated PAO” as used herein refer to a PAO molecule that has at least one functional group.
  • a functional group is a reactive moiety that interacts with free amines, sulfhydryls or carboxyl groups on a molecule forming a covalent bond.
  • maleimide is a functional group that interacts with free sulfhydryls
  • succinimide is a functional group that interacts with free amines.
  • One type of activated polyalkylene oxide is polyethylene glycol (PEG) with a single maleimide group at one terminus ( Mai PEG- Hb).
  • donor or “donor patient” as used herein refer to an animal (human or non-human) from whom an organ or tissue can be obtained for the purposes of transplantation to a recipient patient.
  • recipient or “"recipient patient” refer to an animal (human or non- human) into which an organ or tissue is transplanted.
  • Hb hemoglobin
  • l ib by itself refers both to native unmodified Hb as well as modified Hb.
  • Each molecule o Hb contains 4 subunits, 2 a-chain subunits and 2 ⁇ -chain subunits that are arranged in a tetrameric structure.
  • Each subunit also contains one heme group, which is the iron-containing center that binds ligands like 0 2 , NO and CO.
  • MalPEG-Hb as used herein refers to Hb bound to maleimidyl-activated PEG.
  • the conjugation is performed by reacting MalPEG with surface thiol groups and to lesser extent amino groups of Hb.
  • These thiol groups may be present in the native amino acid sequence of Hb or they may be introduced by modifying free amines in the native sequence with a thiolating reagent, such as iminothiolane.
  • metalhemoglobin or "metHb” as used herein refer to an oxidized form of Hb that contains iron in the ferric state and cannot function as an oxygen carrier.
  • methoxy-PEG or "mPEG” as used herein refer to PEG wherein the hydrogen of the hydroxyl terminus is replaced with a methyl (-C3 ⁇ 4) group.
  • Hb hemoglobin' * or "modi fied Hb" as used herein refer to, but are not limited to, Hb that has been altered so thai it is no longer in the "native" state.
  • Native Hb may be chemically modified, such as by inter- or intra-moiecular crosslinking or by preparing a modified I lb utilizing recombinant techniques known in the art.
  • on average '* refers to the sum of a set of numbers divided by the number of members in the set.
  • the average of the set of numbers 8, 10, 7, 7, 8 can be calculated as the sum of the numbers (40) divided by the number of members in the set (5) giving the average of the numbers in the set as 8.
  • organs refer to any anatomical part or tissue having a specific function in an animal. This also includes a portion of an organ, e.g., a lobe of a lung. Such organs include, but are not limited to, the kidney, liver, heart, intestine, pancreas, and lung.
  • perfluorocarbons refers to inert synthetic molecules that consist entirely fluorine and carbon atoms. Perfluorocarbons emulsions dissolve many times more oxygen than equivalent amounts of plasma or water and are potential substitutes for blood.
  • PEG polyethylene glycol
  • H(OCH 2 CH 2 ) n OH also known as (a-Hydro-co-hydroxypoly-( oxy- 1 , 2- ethanediyl), where "n" is greater than or equal to 4.
  • Any PEG formulation, substituted or unsubstituted, is encompassed by this term.
  • PEGs are commercially available in a number of formulations (e.g., CarbowaxTM (Dow Chemical, Midland, MI) and Poly-G® (Arch Chemicals. Norwalk, CT)).
  • PEG-Hb conjugate or ' “PEG-Hb” as used herein refer to Hb that has molecules of PEG covalently bound to its surface.
  • the term "reper fusion injury” as used herein refers to damage to all or part of a tissue, organ or organ system caused by the resumption of normal blood flow following a cessation or diminishment of blood flow, such as ischemia. This will include injury acquired both during the ischemic episode and in response to the reperfusion.
  • stroma-free hemoglobin or "SFH” as used herein refer to Hb from which all red blood cell membranes have been removed.
  • the term "surgery” as used herein refers to any invasive or non-invasive medical procedure performed on a patient, organ or tissue, including any surgical operation or medical intervention that involves a partial or complete blood flow occlusion and/or blood loss.
  • MalPEG refers to the percentage of MalPEG having an active maleimide ring able to react with free sulfhydryls and amines on Hb.
  • thiolation refers to a process that increases the number of sul hydryl groups on a molecule. For example, reacting a protein with 2-iminothiolane ("2- ⁇ ") converts free amines on the surface of a protein to sulfhydryl groups.
  • 2-iminothiolane 2-iminothiolane
  • transplantation refers to the process of transferring an organ or tissue from one patient into another.
  • transformation is defined in the art as the transfer of living tissues or cells from a donor to a recipient, with the intention of maintaining the functional integrity of the transplanted tissue or cells in the recipient (see, e.g., The Merck Manual, Berkow, Fletcher, and Beers, Eds., Merck Research Laboratories, Rahway, N.J., 1992).
  • CO Carbon monoxide
  • ppm parts per million
  • CO is produced naturally in the body by the enzyme, hemeoxygenase, which catalyzes the metabolism of heme to the products CO, biliverdin and free iron.
  • the CO released by this metabolism is thought to have important cell signaling properties which might he amplified by exogenous administration of CO.
  • Inhaled CO is potentially toxic at levels of prolonged exposure greater than 100 ppm. This is because CO binds to Hb in circulation to form carbox y he mo lob i n , which prevents the hemoglobin from carrying oxygen. This causes an overall reduction in the oxygen-carrying capacity of the blood and leads to hypoxia. Symptoms of low level exposure may include, for example, headaches, vertigo and flu-like symptoms. High levels of exposure can be toxic to the central nervous system and the heart, and can even cause death.
  • PAO-Hbs are effective CO carriers. ⁇ See Vandegriff, K., et al, 2008, Br. Journal of Pharmacol. 254: 1649- 1661.) Specifically, MalPEG-Hb conjugates to which CO is bound have overall CO equilibrium constants similar to that of unmodi fied Hb.
  • the surface modified Hb has a molecular weight of greater than 64,000 Da.
  • the Hb utilized in the present methods is not limited by its source and can be derived from humans or animals, or from recombinant techniques. It may be either native (unmodified) or modified, or recombinantly engineered. Human a- and ⁇ -globin genes have both been cloned and sequenced (Liebhaber, S.A. et al, PNAS 1980, 77:7054-7058; Marotta, C.A. et al., J. Biol. Chem. 1977, 353: 5040-5053 ( ⁇ -globin cDNA)).
  • Hb is stroma free and endotoxin free.
  • suitable polyalkylene oxide polymers include, polyethylene oxide (-(CH 2 O F 0) n -), polypropylene oxide (-(CH(CH 3 )CH 2 0) n -) and a polyethylene/polypropylene oxide copolymer (-(CH 2 O F 0) n -(CH(CH 3 )CH 2 0) n -).
  • polyethylene oxide -(CH 2 O F 0) n -
  • polypropylene oxide -(CH(CH 3 )CH 2 0) n -
  • a polyethylene/polypropylene oxide copolymer -(CH 2 O F 0) n -(CH(CH 3 )CH 2 0) n -.
  • Other straight, branched chain and optionally substituted synthetic polymers that would be suitable in the practice of the present invention are well known in the medical field.
  • PEG polystyrene glycol
  • PEG-200 has an average molecular weight of 200 Da and may have a molecular weight range of 1 0-2 10 Da.
  • Amines can also be indirectly thiolated by reaction with succinimidyl
  • acetylthioacetate followed by removal of the acetyl group with 50 mM hydroxylamine, or hydrazine, at near-neutral pH.
  • 2-iminothiolane (2-IT) can be used to convert free amine groups into thiol groups.
  • the thiolation reaction is carried out at a pH of between 7 to 9, which is below the pH at which the 2-IT hydrolyzes significantly before the reaction is completed and also below the pKa of lysine to optimize the extent of the reaction.
  • the CO carrier is a MalPEG-Hb conjugate, in which case the MalPEG-Hb conjugate may have an oxygen affinity greater than whole blood, and more specifically, twice or even thrice that of whole blood. Stated differently, the MalPEG-Hb may have an oxygen affinity greater than that of stroma free hemoglobin (SFH), when measured under the same conditions. This means that the PEG-Hb conjugate will generally have a P50 less than 10 millimeters of mercury (mmHg), but greater than 3 mmHg. In one embodiment, the MalPEG-Hb conjugate, when the ligand is O?, will have a p50 between 4 and 6 mmHg.
  • mmHg millimeters of mercury
  • SFH has a p50 of approximately 1 5 mmHg at 37° C, pH 7.4. whereas the p50 for wh le blood is approximately 28 mmHg under the same conditions. It was suggested that increasing oxygen affinity of a hemoglobin-based oxygen carrier ("HBOC"), and thereby lowering the p50, could enhance delivery of oxygen to tissues, but that an oxygen affinity lower than that of SFH would not be acceptable. See Winslow, R.M. et al, in "Advances in Blood Substitutes” ( 1997), Birkauser, eds. Boston, Mass., at page 167, and U.S. Pat. No. 6,054,427.
  • HBOC hemoglobin-based oxygen carrier
  • the HbCO complex of the present invention is formulated in an aqueous diluent that is suitable for administration to a subject prior to or following surgery.
  • concentration of the oxygen carrier in the diluent may vary according to the application, it does not usually exceed a concentration of 10 g/dl of Hb. More specifically, the concentration is usually between 0.1 and 8 g/dl Hb.
  • Suitable aqueous diluents include, inter alia, aqueous solutions of proteins, glycoproteins, polysaccharides, and other col loids. It is not intended that these embodiments be limited to any particular diluent. Consequently, diluents may encompass aqueous cell-free solutions of albumin, other colloids, or other non-oxygen carrying components.
  • the solution properties of a PEG-Hb conjugate are influenced by the strong interaction between PEG chains and solvent water molecules. This is believed to be an important attribute for an HBOC for two reasons: 1) higher viscosity decreases the diffusion constant of the PEG-Hb molecule, and 2) higher viscosity increases the shear stress of the solution flowing against the endothelial wall, eliciting the release of vasodilators to counteract vasoconstriction.
  • the formulation of PEG-Hb in the aqueous diluent usually has a viscosity of at least 2 centipoise (cP). More specifical ly, between 2 and 4 cP, and particularly around 2.5 cP. In other embodiments, the viscosity of the aqueous solution may be 6 cP or greater, but is usually not more than 8 cP.
  • Reperfusion injury can occur in a number of ways.
  • the injury may be enzymatic (e.g. thrombolysis), mechanical (e.g. angioplasty, stenting, or embolectomy), or the result of bypass grafting.
  • reperfusion injury results from reinitiating the blood supply, it can occur in any event where such perfusion is necessary. Consequently, injury can result in organ preservation, organ transplantation, and treatment of conditions such as myocardial infarct, pulmonary hypertension, stroke as well as diseases such as malaria and multiple sclerosis.
  • Injury can be determined by direct measurement of organ function (e.g. renal function, myocardial ejection, and cognition), the presence or absence of biomarkers (e.g. cardiac enzymes), imaging methods (e.g. MRI, MR A. PET scan) or clinical signs (e.g. length of hospital stay, ventilator days, etc.).
  • Reperfusion injury can be reduced using the methods of the present invention by administering HbCO directly into the affected artery undergoing reperfusion or intravenously to expose the entire circulation.
  • HbCO is administered intravenously prior to and continuing after reperfusion (i.e. loading the peripheral circulation ).
  • HbCO is infused up to 1 20 minutes following reperfusion and continuing intravenously for 24-48 hours.
  • HbCO is administered intravenously and/or intra-arterially prior to the reperfusion event and continuing for 2 to 24 hours after the event.
  • a functional evaluation is performed to determine if the treatment has achieved the desired effect. For example, if a patient has had an embolic stroke and is a candidate for thrombolysis in a cerebral artery, treatment could begin with administration of HbCO immediately by intravenous infusion. This initial administration is then followed by direct intra-cerebral artery infusion after clot lysis has been confirmed. After treatment, the patient is given a series of cognitive tests to determine the extent of damage.
  • HbCO intravenously during the surgical preparation.
  • the patient is administered HbCO intra-arterially through the coronary artery immediately before or at the time of stent placement.
  • the patient is given a cardiac function evaluation to determine the extent of damage.
  • Preclinical data shows that administration of HbCO results in reduced whole body oxygen consumption, which is one mechanism by which HbCO translates into reduced reper fusion injury and preserved organ function.
  • HbCO could be administered prior to the ischemic episode and continue through the time of
  • RBCs red blood cells
  • a commercial source such as from a local Blood Bank, the New York Blood Center, or the American Red Cross. The material is obtained not more than 45 days from the time of collection. All units are screened for viral infection and subjected to nucleic acid testing prior to use. Non-leukodepleted pooled units are leukodepleted by membrane filtration to remove white blood cells. Packed RBCs are pooled into a sterile vessel and stored at 2- 15"C until further processing. The volume is noted, and Hb concentration is determined using a commercially available co-o imete , or other art-recognized method.
  • RBCs are washed with six volumes of 0.9% sodium chloride using a 0.45- ⁇ tangential flow filtration, followed by cell lysis by decreasing the concentration of salt.
  • Hb extraction is performed using the same membrane.
  • the cell wash is analyzed to verify removal of plasma components by a spectrophotometric assay for albumin.
  • the lysate is processed through a 0.16- ⁇ membrane in the cold to purify Hb.
  • the purified Hb is collected in a sterile depyrogenated vessel and then ultrafiltered to remove viruses. Additional viral-reduction steps, including solvent/detergent treatment, nanofiltration and anion Q membrane purification, may be performed. All steps in this process are carried out at between 2- 15° C.
  • Hb from lysate is exchanged into Ringer's lactate ("RL"), Ringer's acetate (“RA”) or phosphate-buffered saline (“PBS”), pH 7.4 using a 30-kD membrane.
  • the Hb is concentrated to 1 . 1 - 1 .5 mM (tetramer).
  • o RL or PBS are used for solvent exchange. This process is carried out at 2-15° C.
  • the pH of the solution prepared in RL is adjusted to 7.0- 7.6.
  • the Hb is sterile-filtered through a 0.45 or 0.2- ⁇ disposable filter capsule and stored at 4 ⁇ 2° C before the chemical modification reaction is performed.
  • Thiolated Hb is PEGylated with less than a 15-fold molar excess of Mai PEG based on 100% terminal activity over the starting Hb tetramer concentration.
  • the Hb is first allowed to equilibrate with the atmosphere to oxygenate the Hb.
  • Approximately 1 mM thiolated Hb in RL (pH 7.0-8.5), PBS or any similar buffer was combined with less than 16 mM MalPEG in the same buffer. This mixture was continuously stirred for less than 6 hours at 10+5 C°.
  • PEGylated-Hb is processed through a 70-kD membrane (i.e. a 20-volume filtration) to remove excess unreactcd reagents and Hb. This process is monitored by size-exclusion liquid chromatography at 540 nm and 280 nm. The protein concentration is diluted to 4 g/dl and the pH is adjusted to 7.3+0.3 using 1 N NaOH.
  • the final MalPEG-Hb product is sterile-filtered using a 0.2- ⁇ sterile disposable capsule and collected into a sterile depyrogenated vessel at 4+2° C.
  • PEG-Hb is diluted to 4 g/dl RL and the pH adjusted to 7.4+0.2.
  • the final PEG-Hb is sterile-filtered (0.2- ⁇ ) and aliquoted by weight into sterile glass vials.
  • the vials are sealed with sterile rubber stoppers and crimped seals in a laminar flow hood.
  • the vials are then stored at -80 C° until use.
  • the PEG-Hb is equilibrated with a desired concentration of CO in a chamber containing a prescribed concentration of CO.
  • a patient undergoing elective reperfusion e.g. coronary artery bypass graft, coronary stenting or cerebral embolectomy
  • HbCO any time prior to the procedure and for 24-168 hours following the procedure.
  • the in usion of HbCO would begin at the time of diagnosis and continue for 24- 168 hours following the procedure.
  • the volume and rate of administration is regulated to achieve CO-hemoglobin saturation of 1-30% of total hemoglobin in the blood.
  • Temperature of the solution infused is between room temperature and 38°C.
  • HbCO is administered by intravenous infusion or intra-arterial infusion via a catheter positioned in the arterial circulation supplying the organ.
  • Functional assessment of the ischemic/reperfused organ is performed using standard clinical techniques for evaluation of organ function. For example, recovery of myocardial function following a cardiac procedure often includes electrocardiography, echocardiography for myocardial wall motion and ejection fraction. Radionuclide scintigraphy, positron emission tomography, magnetic resonance imaging and magnetic resonance angiography are utilized to assess metabolic and vascular function.
  • evaluation of reper used kidney function following aortic crossclamping includes measurement of serum blood urea nitrogen and creatinine, determination of glomerular filtration rate and renal plasma flow, urine concentrating ability, fractional sodium excretion, and biomarkers of renal tubular damage (e.g. neutrophil gelatinase associated lipocalin, N-acetyl glucosaminidase. glutathione-S transferase and kidney injury molecule- 1). Histologic assessment of t issue biopsies may also be performed where appropriate.
  • Tissue damage can result from prolonged periods of ischemia and reperl ' usion. This damage can result from the absence of blood flow and oxygen supply during the ischemia, and also from the re-introduction of oxygen at the time of reperl ' usion.
  • strategies have emerged using pharmacologic approaches or manipulation of the blood supply to limit tissue death from i sc he mi a/ repe r fu s i on injury. The majority of these studies have been described in salvage of myocardial tissue ( Hausenloy, et ai, 2007, Heart Fail Rev .
  • the Reperl ' usion Injury Salvage Kinase (RISK) pathway describes the role of pro-survival intracellular kinase enzymes, including Akt and ER K 1/2, in conferring powerful protection against i sc he m i a repe i f us i on injury.
  • agents which confer protection via activation of the RIS K pathway include cytokines, G-protein coupled receptor agonists such as adenosine and bradykinin, opioids, volatile anesthetics, and vascular
  • MalPEG-HbCO acts to induce cardioprotection. and protection of other tissues/organs undergoin ischemia reperfusion by activation of the RISK pathway, including ERK and Akt as well as other, unspeci ied intracellular signaling pathways. This is supported by recent reports of cardioprotection in rabbits with inhaled CO mediated via the Akt pathway (Fujimoto et al , 2004, Arterioscler Thromb Vase Biol. 24( 10): 1848- 1853) and neuronal protection in culture with atmospheric CO mediated by the ERK 1/2 pathway (Dallas et al, 201 1 . FASEB J. 25(5): 1519-1530).

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Abstract

La présente invention concerne généralement des procédés pour réduire une lésion de reperfusion. Spécifiquement, la présente invention concerne l'administration d'un porteur de monoxyde de carbone à base d'hémoglobine à un sujet, avant ou après chirurgie, pour réduire une lésion résultant d'une reperfusion par administration de monoxyde de carbone et d'oxygène à un tissu ischémique.
PCT/US2012/048450 2011-07-27 2012-07-27 Procédés pour réduire une lésion de reperfusion en utilisant un porteur de monoxyde de carbone à base d'hémoglobine WO2013016598A2 (fr)

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WO2018138360A1 (fr) 2017-01-28 2018-08-02 Centro Nacional De Investigaciones Cardiovasculares Carlos Iii (F.S.P.) Substituts sanguins transportant de l'oxygène et leur utilisation en tant que véhicules d'administration
CN114377155A (zh) * 2022-01-14 2022-04-22 吴诗熳 一种造影剂、造影剂的制备方法及其应用
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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2018138360A1 (fr) 2017-01-28 2018-08-02 Centro Nacional De Investigaciones Cardiovasculares Carlos Iii (F.S.P.) Substituts sanguins transportant de l'oxygène et leur utilisation en tant que véhicules d'administration
US11504417B2 (en) 2017-07-18 2022-11-22 VirTech Bio, Inc. Blood substitutes comprising hemoglobin and methods of making
CN114377155A (zh) * 2022-01-14 2022-04-22 吴诗熳 一种造影剂、造影剂的制备方法及其应用
WO2023133928A1 (fr) * 2022-01-14 2023-07-20 吴诗熳 Agent de contraste, procédé de préparation d'agent de contraste et application d'agent de contraste

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