WO1997040849A1 - Procede de traitement ou de prevention des lesions lors d'une reperfusion au cours d'une ischemie - Google Patents

Procede de traitement ou de prevention des lesions lors d'une reperfusion au cours d'une ischemie Download PDF

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Publication number
WO1997040849A1
WO1997040849A1 PCT/US1997/006809 US9706809W WO9740849A1 WO 1997040849 A1 WO1997040849 A1 WO 1997040849A1 US 9706809 W US9706809 W US 9706809W WO 9740849 A1 WO9740849 A1 WO 9740849A1
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Prior art keywords
ischemia
reperfusion injury
injury
repair
reperfusion
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PCT/US1997/006809
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English (en)
Inventor
James M. Seeger
Timothy R. S. Harward
Satwant K. Narula
Lyle L. Moldawer
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Schering Corporation
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Publication date
Application filed by Schering Corporation filed Critical Schering Corporation
Priority to AU27405/97A priority Critical patent/AU721943B2/en
Priority to KR1019980708806A priority patent/KR20000065178A/ko
Priority to BR9709752A priority patent/BR9709752A/pt
Priority to IL12665797A priority patent/IL126657A0/xx
Priority to JP9539013A priority patent/JP2000509073A/ja
Priority to NZ332412A priority patent/NZ332412A/xx
Priority to EP97921343A priority patent/EP0906117A1/fr
Publication of WO1997040849A1 publication Critical patent/WO1997040849A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2066—IL-10
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Ischemia-reperfusion injury frequently occurs when the flow of blood to a region of the body is temporarily halted (ischemia) and then re-established (reperfusion). Ischemia-reperfusion injury can occur during certain surgical procedures, such as repair of aortic aneurysms and organ transplantation.
  • Clinically ischemia-reperfusion injury may be manifested by such complications as pulmonary dysfunction, including adult respiratory distress syndrome, renal dysfunction, consumptive coagulopathies including thrombocytopenia, fibrin deposition into the microvasculature and disseminated intravascular coagulopathy, transient and permanent spinal cord injury, cardiac arrhythmias and acute ischemic events, hepatic dysfunction including acute hepatoceUular damage and necrosis, gastrointestinal dysfunction including hemorrhage and/or infarction and multisystem organ dysfunction (MSOD) or acute systemic inflammatory response syndromes (SIRS).
  • the injury may occur in the parts of the body to which the blood supply was interrupted, or it can occur in parts fully supplied with blood during the period of ischemia.
  • WO 96/01318 relates to polypeptides other than interleukin -10 (IL-10) allegedly having one or more properties similar to those of IL-10.
  • IL-10 interleukin -10
  • tissue damage as a result of "hypoxia/ischemia (infarction: reperfusion)", “ischemia”, “reperfusion injury”, and “reperfusion syndrome”.
  • the non-IL-10 proteins would actually work for treating all of the diseases in the long list.
  • the present invention comprises a method for treating ischemia- reperfusion injury comprising administering to a patient in need of such treatment an effective amount of IL-10.
  • Another aspect of this invention comprises a method for preventing ischemia-reperfusion injury in a patient about to undergo a procedure capable of causing ischemia-reperfusion injury or to a patient who has already undergone such procedure in which ischemia-reperfusion injury has not yet occurred comprising administering to the patient an effective amount of IL-10.
  • Preferred applications of this invention are preventing ischemia reperfusion injury by administering the IL-10 in conjunction with surgical repair of the thoracic or suprarenal aorta due to aneurysmal disease, but also in conjunction with those surgical procedures that induce or require transient occlusion or bypass of the visceral blood supply via the hepatic, renal and/or enteric arteries secondary to major organ transplant, including liver, kidney, small intestine, and pancreas as well as surgical procedures that result in the transient reduction or prevention of blood flow to the viscera including hepatic and biliary surgical resections, total or partial pancreatectomy (Whipple procedure), total and partial gastrectomy, esophagectomy, colorectal surgery, vascular surgery for mesenteric vascular disease, or abdominal insufflation during laparoscopic surgical procedures.
  • Additional applications include blunt or penetrating trauma that results in interrruption of blood flow to the visceral organs including those arising from penetrating wounds to the abdomen resulting from gun shot wounds, stab wounds or from penetrating wounds or blunt abdominal trauma secondary to deacceleration injury and/or motor vehicle accidents.
  • Other preferred applications include diseases or procedures that result in systemic hypotension that either disrupts or decreases the flow of blood to the visceral organs, including hemorrhagic shock due to blood loss, cardiogenic shock due to myocardial infarction or cardiac failure, neurogenic shock or anaphylaxis.
  • Further applications of this invention include preventing or treating lower torso or extremity ischemia reperfusion injury by administering IL-10 in conjunction with surgical procedures that induce or require transient occlusion or bypass of the blood supply to the torso or the upper or lower extremities.
  • This application is particularly relevant to the practice of vascular surgery that encompasses controlled periods of visceral, torso, and extremity ischemia followed by reperfusion.
  • Procedures which involve such ischemia-reperfusion include but are not limited to repair of abdominal aortic aneurysms, aortic femoral, popliteal or tibial bypass for claudication or limb threatening ischemia, repair of popliteal or femoral aneurysms, bypass, thrombectomy or embolectomy for acute limb ischemia, or vascular trauma.
  • Administration of IL-10 may improve limb salvage and survival after significant torso or extremity ischemia.
  • the amount of IL-10 to be administered is preferably between 0.1 to 500 ⁇ g/kg of body weight, more preferably 1 to 50 ⁇ g/kg.
  • the IL-10 may be of human or viral origin produced biologically from mammalian cellular sources or by recombinant DNA technology. Administration preferably takes place by intravenous, intramuscular or subcutaneous injection. The IL-10 is preferably administered from one to zero hours before the blood flow is reestablished.
  • the IL-10 is preferably given either as a single bolus injection one to zero hours before the ischemic event or as a continuous intravenous injection beginning one to zero hours before the ischemic event and extending during the perioperative period and continuing for at least eight hours after restoration of visceral blood flow.
  • the IL-10 would be preferably given either as a single bolus injection prior to or simultaneously with restoration of normal visceral blood flow or as a continuous intravenous injection prior to or simultaneously with restoration of normal visceral blood flow and extending for at least eight hours after restoration of visceral blood flow.
  • the IL-10 would be preferably given either as a single bolus injection prior to or simultaneously with restoration of normal blood flow or as a continuous intravenous injection prior to or simultaneously with restoration of normal blood flow and extending for at least eight hours after restoration of blood flow.
  • the IL-10 may be administered by gene therapy or transfer using either liposomes and mammalian expression plasmids, mechanical delivery systems (gene gun) of viral transfection schemes, including but not limited to adenovirus, adeno-associated virus, retrovirus or he ⁇ es simplex virus constructs.
  • Figures 1(a), 1(b) and 1(c) illustrate the plasma TNF- ⁇ , IL-1 ⁇ and IL-8 concentrations, respectively, following thoracoabdominal and infrarenal aortic aneurysm repair.
  • Figures 2(a), 2(b) and 2(c) illustrate the plasma IL-6, changes in plasma p55 concentrations, and changes in plasma p75 concentrations, respectively, following thoracoabdominal and infrarenal aortic aneurysm repair.
  • Figure 3 illustrates the changes in lung myeloperoxidase levels (neutrophil infiltration) in mice following supraceiiac aortic cross clamp and treatment with inhibitors of TNF and IL-1.
  • Figure 4 illustrates the changes in lung permeability ( 125 l-albumin leakage) in mice following supraceiiac aortic cross clamp and treatment with inhibitors of TNF and IL-1.
  • Figure 5 which illustrates the appearance of IL-10 in the circulation of mice following supraceiiac aortic cross clamp used, shows plasma IL-10 concentrations in mice following supraceiiac aortic cross-clamping and treatment with recombinant human IL-10.
  • Figure 6 illustrates the changes in lung myeloperoxidase levels (neutrophil infiltration) in mice following supraceiiac aortic cross clamp and treatment with recombinant human IL-10.
  • interleukin-10 or "IL-10” is defined as a protein which (a) has an amino acid sequence of mature IL-10 (e.g., lacking a secretory leader sequence) as disclosed in U.S. Patent No. 5,231 ,012 and (b) has biological activity that is common to native IL-10. Also included are muteins and other analogs, including the Epstein-Barr Virus protein BCRF1 (viral IL-10), which retain the biological activity of IL-10.
  • BCRF1 Epstein-Barr Virus protein
  • IL-10 suitable for use in the invention can be obtained from culture medium conditioned by activated cells secreting the protein, and purified by standard methods. Additionally, the IL-10, or active fragments thereof, can be chemically synthesized using standard techniques known in the art. See Merrifield, Science 233:341 (1986) and Atherton er al., Solid Phase Peptide Synthesis: A Practical Approach, 1989, 1. R.L. Press, Oxford. See also U.S. Patent No. 5,231 ,012.
  • the protein or polypeptide is obtained by recombinant techniques using isolated nucleic acid encoding the IL-10 polypeptide.
  • General methods of molecular biology are described, e.g., by Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor, New York, 2d ed., 1989, and by Ausubel et al., (eds.) Current Protocols in Molecular Biology, Green/Woley, New York (1987 and periodic supplements).
  • the appropriate sequences can be obtained using standard techniques from either genomic or cDNA libraries. Polymerase chain reaction (PCR) techniques can be used. See, e.g., PCR
  • Libraries are constructed from nucleic acid extracted from appropriate cells. See, e.g., U.S. Patent No. 5,231,012, which discloses recombinant methods for making IL-10.
  • Useful gene sequences can be found, e.g., in various sequence databases, e.g., GenBank and BMPL or nucleic acid and PIR and Swiss-Prot for protein, c/o Intelligenetics, Mountain View, California, or the Genetics Computer Group, University of Wisconsin Biotechnology Center, Madison, Wisconsin.
  • Clones comprising sequences that encode human IL-10 have been deposited with the American Type Culture Collection (ATCC), Rockville, Maryland, under Accession Nos. 68191 and 68192. Identification of other clones harboring the sequences encoding IL-10 is performed by either nucleic acid hybridization or immunological detection of the encoded protein, if an expression vector is used. Oligonucleotide probes based on the deposited sequences disclosed in U.S. Patent No. 5,231 ,012 are particularly useful. Oligonucleotide probes sequences can also be prepared from conserved regions of related genes in other species. Alternatively, degenerate probes based on the amino acid sequences of IL-10 can be used.
  • Standard methods can be used to produce transformed prokaryotic, mammalian, yeast or insect cell lines which express large quantities of the polypeptide.
  • Exemplary E. coli strains suitable for both expression and cloning include W3110 (ATCC Bi, 27325), X1776 (ATCC No. 31244). X2282, and RR1 (ATCC Mp/ 31343).
  • Exemplary mammalian cell lines include COS-7 cells, mouse L cells and CHP cells. See Sambrook (1989), supra and Ausubel et al., 1987 supplements, supra.
  • Various expression vectors can be used to express DNA encoding IL-10.
  • vectors used for expression of recombinant proteins in prokaryotic or eukaryotic cells may be used.
  • Preferred vectors include the pcD vectors described by Okayama et al., Mol. Cell. Biol. 3:280 (1983); and Takebe et al., Mol. Cell. Biol. 8:466 (1988).
  • Other SV40-based mammalian expression vectors include those disclosed in Kaufman et al., Mol. Cell. Biol. 2.1304 (1982) and U.S. Patent No. 4,675,285. These SV40-based vectors are particularly useful in COS- 7 monkey cells (ATCC No. CRL 1651), as well as in other mammalian cells such as mouse L cells. See also, Pouwels et al., (1989 and supplements) Cloning Vectors: A Laboratory Manual, Elsevier, New York.
  • the IL-10 may be produced in soluble foim, such as a secreted product of transformed or transfected yeast, insect or mammalian cells.
  • the peptides can then be purified by standard procedures that are known in the art. For example, purification steps could include ammonium sulfate precipitation, ion exchange chromatography, gel filtration, electrophoresis, affinity chromatography, and the like. See Methods in Enzymology Purification Principles and Practices (Springer ⁇ Verlag, New York, 1982).
  • IL-10 may be produced in insoluble form, such as aggregates or inclusion bodies.
  • the IL-10 in such a form is purified by standard procedures that are well known in the art. Examples of purification steps include separating the inclusion bodies from disrupted host cells by centrifugation, and then solubilizing the inclusion bodies with chaotropic agent and reducing agent so that the peptide assumes a biologically active conformation. For specifics of these procedures, see, e.g. Winkler et al., Biochemistry 25:4041 (1986), Winkler etal., Bio/Technology 3:9923 (1985); Koths et al., and U.S. Patent No. 4,569,790.
  • the nucleotide sequences used to transfect the host cells can be modified using standard techniques to make IL-10 or fragments thereof with a variety of desired properties.
  • modified IL-10 can vary from the naturally-occurring sequences at the primary structure level, e.g., by amino acid, insertions, substitutions, deletions and fusions. These modifications can be used in a number of combinations to produce the final modified protein chain.
  • amino acid sequence variants can be prepared with various objectives in mind, including increasing serum half-life, facilitating purification or preparation, improving therapeutic efficacy, and lessening the severity or occurrence of side effects during therapeutic use.
  • the amino acid sequence variants are usually predetermined variants not found in nature, although others may be post ⁇ translational variants. Such variants can be used in this invention as long as they retain the biological activity of IL-10.
  • human IL-10 is used for the treatment of humans, although viral IL-10 could possibly be used. Most preferably, the IL-10 used is recombinant human IL-10.
  • the preparation of human IL-10 has been described in U.S. Patent No. 5,231,012.
  • the cloning and expression of viral IL-10 (BCRF1 protein) from Epstein-Barr virus has been disclosed by Moore ef al., Science 248:1230 (1990).
  • the IL-10 is admixed with a pharmaceutically acceptable carrier or excipient which is preferably inert.
  • a pharmaceutical carrier can be any compatible non-toxic substance suitable for delivery of the polypeptide to a patient. Preparation of such pharmaceutical compositions is known in the art; see, e.g., Remington's Pharmaceutical Sciences, and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984).
  • compositions may be ingested orally or injected into the body.
  • Formulations for oral use include compounds to protect the polypeptides from proteases which occur in the gastrointestinal tract. Injections are usually intramuscular, subcutaneous, intradermal or intravenous. Alternatively, intra- articular injection or other routes could be used in appropriate circumstances.
  • compositions When administered parenterally, the compositions can be formulated in a unit dosage injectable form (solution, suspension, emulsion) in association with a pharmaceutical carrier.
  • a pharmaceutical carrier such as water, saline or buffered vehicles with or without various additives and/or diluting agents.
  • suitable carriers are normal saline, Ringer's solution, dextrose solution, and Hank's solution.
  • Non-aqueous carriers such as fixed oils and ethyl oleate may also be used.
  • a preferred carrier is 5% dextrose/saline.
  • the carrier may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives.
  • the IL-10 in the composition is preferably formulated in purified form substantially free of aggregates and other proteins.
  • a suspension such as a zinc suspension, can be prepared to include the polypeptide. Such a suspension can be useful for subcutaneous (SQ) or intramuscular (IM) injection.
  • ischemia-reperfusion injury is caused, at least in part, by the release of excess amounts of proinflammatory cytokines, such as TNF- ⁇ , IL-1 , IL-6, and IL-8.
  • proinflammatory cytokines such as TNF- ⁇ , IL-1 , IL-6, and IL-8.
  • Examples 1 and 2 were performed to test this theory and the effect IL-10 has on visceral ischemia-reperfusion injury.
  • Example 3 sets forth the application of the invention to a human patient undergoing aortic aneurysm repair.
  • Example 4 was performed to demonstrate that IL-10 will attenuate the skeletal muscle and pulmonary injury after hindlimb ischemia-reperfusion in a rat model.
  • the visceral arteries were sewn onto the graft as a Carrel patch or as part of the proximal anastomosis with an extensive posterior taper to the graft.
  • coagulation products platelets and fresh frozen plasma
  • a catheter was placed in the lumbar spinal column and cerebrospinal fluid drained to maintain intrathecal pressure at 5-10 cm water.
  • Infrarenal abdominal aortic aneurysms were repaired transperitoneally using standard surgical techniques and the aorta was reconstructed using either a straight tube graft to the aortic bifurcation or a bifurcated graft to the internal/external iliac artery bifurcation.
  • Postoperative pulmonary dysfunction was defined as the need for positive- pressure mechanical ventilatory assistance for greater than 7 days while postoperative hepatic dysfunction was defined as peak lactate dehydrogenase (LDH) levels greater than 500 U/L and either serum transaminase levels (AST/ALT) greater than 200 U/L or an increase in total bilirubin levels greater than 3 mg/dl.
  • Renal dysfunction was defined as an increase in serum creatinine of 2 mg/dl or more over preoperative baseline, while a platelet count less than 50,000/mm 3 or a drop in white blood cell count below 4,500 /mm 3 indicated the presence of hematopoietic dysfunction. Patients with 2 or more organ systems meeting these criteria were designated as having multiple system organ dysfunction [MSOD].
  • Freshly thawed plasma samples were assayed for TNF- ⁇ , IL-1 , IL-6, IL-8 and TNF- ⁇ shed receptors (p55 and p75) by ELISA.
  • the sensitivity of the TNF-a, IL-1 , IL-6, IL-8, p55 and p75 assays are 14, 10, 27, 313, 14 and 17 pg/ml, respectively.
  • Pulmonary dysfunction occurred in 9 patients and placement of a temporary tracheostomy was eventually required in 4 patients. Renal dysfunction developed in 6 patients and hemodialysis was necessary in 2 of them. Hepatic dysfunction, thrombocytopenia, and leukopenia developed after thoracoabdominal aortic aneurysm repair in 5, 6, and 2 patients, respectively, and lower extremity dysfunction due to spinal cord injury occurred in 2 patients. In contrast, there were no operative deaths after infrarenal aortic aneurysm repair (Table 1). Pulmonary dysfunction occurred in only 1 patient and there was no evidence of renal, hepatic, hematopoietic or lower extremity dysfunction in any patient.
  • Plasma samples were obtained 0, 1 , 2, 4, 6-8, 24, 48, 72 hours and daily for up to seven days following thoracoabdominal or infrarenal aortic aneurysm repair. Peak concentrations are reported here. Levels of all proinflammatory cytokines were significantly higher in patients following thoracoabdominal than infrarenal aortic aneurysm repair (p ⁇ 0.05).
  • Plasma TNF- ⁇ IL-1, IL-6 and IL-8 concentrations were undetectable prior to surgery. Following surgical repair of thoracoabdominal aortic aneurysms, a monophasic TNF- ⁇ response was detected in 11 of 16 patients (69%) ( Figures 1(a), 1(b) and 1(c)). TNF- ⁇ levels peaked 4 hours after reperfusion and then gradually decreased toward baseline over the next 24 hours. IL-6 and IL-8 levels also increased in a monophasic pattern with peak levels again occurring 4 hours
  • RECTIFIED SHEET (RULE 91) ISA/EP after reperfusion in 16 (100%) and 11 (70%) patients, respectively; however, unlike the pattern seen with TNF- ⁇ , circulating IL-6 and IL-8 levels decreased to baseline within 8 hours. IL-1 was also detected in a monophasic pattern in 50% of the thoracoabdominal aortic aneurysm patients, but its peak levels occurred at 1 hour after reperfusion and IL-1 levels returned to baseline levels 4-6 hours after reperfusion.
  • p55 receptor concentrations reached a zenith at 24 hours and remained elevated for several days while p75 receptor concentrations continued to increase throughout the initial 48 hours after reperfusion.
  • MSOD multisystem organ dysfunction
  • Peak plasma concentrations of TNF, IL-6, p55 and p75 were significantly higher in patients following thoracoabdominal aortic aneurysm repair with MSOD than in patients either following thoracoabdominal aortic aneurysm repair without MSOD or in patients following infrarenal aortic aneurysm repair.
  • results presented here demonstrate that surgical repair of thoracoabdominal aortic aneurysms which causes visceral ischemia-reperfusion injury results in a systemic proinflammatory cytokine response characterized by the appearance of TNF- ⁇ , IL-1 , IL-6 and IL-8 in the blood as early as 1 to 4 hours after release of the cross-clamp. Additionally, the presence and magnitude of this proinflammatory cytokine response is associated with the incidence of postoperative organ dysfunction after thoracoabdominal aortic aneurysm repair.
  • Ischemia and subsequent reperfusion injury of the viscera appear to be critical for the induction of this systemic proinflammatory cytokine response, because the magnitude of the proinflammatory cytokine response is 3 to 15-fold less in patients undergoing repair of the infrarenal aorta where visceral ichemia/reperfusion does not occur than following thoracoabdominal aortic repair.
  • patients having infrarenal aortic aneurysm repair, in whom visceral ischemia is avoided have a significantly lower incidence of postoperative organ dysfunction.
  • LAFBP left atrial-femoral artery bypass
  • cytokine levels were measured by ELISA.
  • Clinical data concerning postoperative pulmonary, hepatic, renal, and hematopoietic dysfunction were also prospectively collected. Patients undergoing repair of thoracoabdominal aortic aneurysms with LAFBP had shorter visceral ischemia times (1815 min. vs 45112 min.) and statistically significant reductions in circulating TNF- ⁇ , IL-10, and p75 levels (p ⁇ 0.05 by two-way ANOVA) when compared to the control group (Table 5).
  • LAFB left atrial femoral bypass
  • Peak plasma concentrations of TNF- ⁇ , IL-10 and p75 were significantly higher in patients following thoracoabdominal aortic aneurysm repair without LAFB than in patients following thoracoabdominal aortic aneurysm repair with LAFB.
  • mice have been conducted that demonstrate that pretreatment with recombinant human IL-10 can reduce distant organ injury in a clinically relevant model of acute visceral ischemia-reperfusion injury.
  • the initial goal of these studies was to develop a clinically relevant model of acute ischemia- reperfusion injury that demonstrated evidence of organ injury that was dependent upon an endogenous proinflammatory cytokine response that could be inhibited by either a TNF- ⁇ receptor construct or a monoclonal antibody against the IL-1 type I (p80) receptor (35F5, Hoffmann-LaRoche, Nutley, NJ).
  • mice C57BL/6, approx. 20 gm were anesthetized with pentobarbital. In 16 of these animals, the supraceiiac aorta was cross-clamped for 30 minutes. Six animals had their infrarenal aorta cross-clamped for 30 minutes, while another 8 animals received only anesthesia, incision and bowel mobilization without aortic cross-clamping.
  • mice subjected to supraceiiac aortic cross-clamping were subjected to supraceiiac aortic cross-clamping.
  • Visceral ischemia was induced in 90 female C57BIJ6 mice (20-22gm) by supraceiiac aortic cross-claming for 25-30 minutes.
  • Plasma IL-10 levels were measured by ELISA at 1, 2, 4 and 8 hrs after reperfusion, and lung neutrophil infiltration was determined by MPO assay at 2 hrs, as previous studies had revealed that maximal neutrophil infiltration occurred in the lung at 2 hrs.
  • Visceral ischemia-reperfusion injury associated with supraceiiac aortic cross-clamping promotes the release of IL-10, while exogenous IL-10 administration prior to aortic cross-clamping limits pulmonary injury in this model of acute visceral ischemia-reperfusion injury.
  • exogenous IL-10 may offer a novel therapeutic approach to decrease complications associated with thoracoabdominal aortic aneurysm repair and other ischemia-reperfusion injuries.
  • Hypothetical Example 3 illustrates a preferred application of the invention contemplated for treating humans.
  • EXAMPLE 3 A 58 year-old white male presents to the emergency room of a local University hospital complaining of several months of intermittent sharp epigastric and periumbilical abdominal pain, with no other significant symptoms. The patient has no history of any significant medical problems other than a history of atherosclerotic disease. On physical exam, the patient is found to have a nontender, pulsatile mid-abdominal mass, with an audible Son. Laboratory examination including hematology, biochemistries, liver function tests, urinalysis and amylase are all within normal limits. Flat and upright abdominal x-rays, as well as chest x-rays, are unremarkable.
  • An abdominal CT scan with cuts through the lower chest reveals an aortic aneurysm extending from the level of the diaphragmatic hiatus to the aortic bifurcation, 6.5 cm in largest diameter.
  • the patient is prepared for surgery.
  • One hour prior to skin incision the patient is given a single bolus administration of recombinant human IL-10 at a dose of 10 ⁇ g/kg body weight through an indwelling catheter in the median cubital vein.
  • a lumbar catheter is placed to drain cerebrospinal fluid to maintain intrathecal pressure at 5-10 cm water pressure.
  • a left flank incision is made, gaining access to the aorta via a retroperitoneal approach.
  • the diaphragm is divided circumferentially to allow exposure of the thoracic aorta.
  • the aorta is cross-clamped proximal to the cephalad aspect of the aneurysm and distal to the aortic bifurcation at the level of the proximal external iliac arteries.
  • the aorta is then reconstructed utilizing a bifurcated graft from the level of the caudal thoracic aorta to the external iliac arteries bilaterally.
  • the celiac and superior mesenteric arteries are then sewn to the graft as a Carrel patch.
  • Cross-clamp time and period of warm visceral ischemia is 42 minutes.
  • the aortic cross-clamps are thereafter removed, restoring perfusion of the viscera, pelvis, and lower extremities.
  • Three units of packed red blood cells and two units of fresh frozen plasma are infused. Incisions are then closed, and the patient is transported to the surgical intensive care unit intubated and receiving ventilatory assistance, but hemodynamically stable.
  • post-operative day 1 After an unremarkable night, the patient is extubated on post-operative day 1. On post-operative day 2, the patient is transferred out of the intensive care unit to the surgical ward. The patient has return of bowel function on post-operative day 5, and is discharged home, ambulating without difficulty, tolerating a regular diet, with his incision healing nicely, with no evidence of infection on post-operative day 7.
  • Another preferred application of this invention is administration of IL-10 to a patient one to zero hours before the patient receives a major organ transplant.
  • This invention is especially applicable to treatment of ischemia-reperfusion occurring in the visceral section of the body. Regardless of which procedure causes or is expected to cause the ischemia- reperfusion injury, the inventive method of treatment will be deemed successful if one or more of the signs or symptoms of ischemia-reperfusion injury are alleviated or fail to appear at all.
  • mice Twenty eight male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA., approx. 350 gm) were anesthetized with pentobarbital intraperitoneally (40 mg/kg, Abbott Laboratories, Chicago, IL.). In twenty of the rats, bilateral hindlimb ischemia was produced by placement of a rubber band tourniquet across the upper thigh of both lower extremities. The cessation of arterial blood flow was confirmed by the absence of a Doppler signal in the superficial femoral artery. The remaining eight rats received anesthesia alone.
  • the animals were euthanized (pentobarbitol 100 mg/kg BW IV) after 4 hours of reperfusion or at comparable times for the non-ischemic controls.
  • the soieus muscle from one hindlimb and one lung were analyzed for assessment of neutrophil infiltration.
  • Soieus muscle and pulmonary neutrophil sequestration were quantified by the tissue myeloperoxidase (MPO) levels (Warren et al., 1989, J.CIin.lnvest. 84:1873).
  • MPO tissue myeloperoxidase
  • the remaining soieus muscle and lung tissue were analyzed to quantify the capillary and/or cellular injury.
  • Skeletal muscle and lung capillary endothelial cell injury were quantified by uptake of I 125 labeled albumin (Welbourn ef al., 1991 , J. Appl. Physiol. 70:2645).
  • Skeletal muscle cellular injury was quantified by the uptake of Tc" labeled pyrophosphate (Blebea et al., 1988, J. Vase. Surg. 8:117).
  • the mean capillary permeability index (CPI) and the skeletal muscle injury index (SMII) were calculated using the following formulas:
  • CPI (I 125 muscle/muscle mass) / (I 125 blood/blood mass).
  • SMII (Tc 99 muscle/muscle mass) / (Tc 99 blood/blood mass).
  • Circulating bioactive TNF was measured using the TNF-sensitive WEHI murine fibrosarcoma cell line (Van Zeed et al., 1992, PNAS 89:4845).
  • mice The results are shown in Table 6.
  • the hindlimb l/R resulted in significant skeletal muscle injury.
  • Both the mean soieus muscle capillary permeability index (MCPI) and the mean soieus skeletal muscle injury index (SMII) after hindlimb l/R were significantly greater than the non-ischemic controls.
  • Pretreatment of the animals with recombinant human IL-10 prior to hindlimb ischemia resulted in a significantly lower skeletal muscle capillary injury that was not significantly different from the non-ischemic control.
  • Pretreatment with human IL-10 prior to ischemia also resulted in a decrease of the skeletal muscle cellular injury, although the difference did not reach significance.
  • the results are shown in Table 7.
  • the hindlimb ischemia-reperfusion also resulted in significant pulmonary vascular injury as determined by the leakage of 1125 albumin into the lungs.
  • Both the mean pulmonary capillary permeability index and the mean pulmonary neutrophil infiltration in the animals subjected to hindlimb ischemia-reperfusion were significantly greater than the non-ischemic controls.
  • Pretreatment with human recombinant IL-10 significantly reduced the lung capillary injury after hindlimb ischemia-reperfusion and the PCPI values in the pretreated animals were not different from the non-ischemic controls.
  • TNF Assay Serum was assessed for circulating TNF in 6/10 rats undergoing ischemia-reperfusion and TNF levels > 50 pg/ml were detected in 67% (4/6). In contrast, significant circulating TNF levels were found in only 30% (3/10) of the ischemic animals pretreated with human recombinant IL-10. Serum TNF levels of > 50 pg/ml were not detected in any of the non-ischemic control animals.

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  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention concerne un procédé de fabrication d'une composition pharmaceutique destinée au traitement des lésions lors d'une reperfusion au cours d'une ischémie, ce procédé consistant à mélanger un excipient acceptable sur le plan pharmacologique et une quantité suffisante d'interleukine-10.
PCT/US1997/006809 1996-05-02 1997-05-01 Procede de traitement ou de prevention des lesions lors d'une reperfusion au cours d'une ischemie WO1997040849A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU27405/97A AU721943B2 (en) 1996-05-02 1997-05-01 Method for treating or preventing ischemia-reperfusion injury
KR1019980708806A KR20000065178A (ko) 1996-05-02 1997-05-01 허혈-재관류손상을치료또는예방하는방법
BR9709752A BR9709752A (pt) 1996-05-02 1997-05-01 Processo para o tratamento ou a prevenção de dano de isquemia-reperfusão
IL12665797A IL126657A0 (en) 1996-05-02 1997-05-01 Method for treating or preventing ischemia-reperfusion injury
JP9539013A JP2000509073A (ja) 1996-05-02 1997-05-01 虚血再灌流傷害の治療または予防の方法
NZ332412A NZ332412A (en) 1996-05-02 1997-05-01 use of interleuklin-10 for treating or preventing ischemia-reperfusion injury
EP97921343A EP0906117A1 (fr) 1996-05-02 1997-05-01 Procede de traitement ou de prevention des lesions lors d'une reperfusion au cours d'une ischemie

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US64185996A 1996-05-02 1996-05-02
US08/641,859 1996-05-02

Publications (1)

Publication Number Publication Date
WO1997040849A1 true WO1997040849A1 (fr) 1997-11-06

Family

ID=24574163

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/006809 WO1997040849A1 (fr) 1996-05-02 1997-05-01 Procede de traitement ou de prevention des lesions lors d'une reperfusion au cours d'une ischemie

Country Status (9)

Country Link
EP (1) EP0906117A1 (fr)
JP (1) JP2000509073A (fr)
KR (1) KR20000065178A (fr)
AU (1) AU721943B2 (fr)
BR (1) BR9709752A (fr)
CA (1) CA2253313A1 (fr)
IL (1) IL126657A0 (fr)
NZ (1) NZ332412A (fr)
WO (1) WO1997040849A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999056783A1 (fr) * 1998-05-01 1999-11-11 Micrus Corporation Hydrogel entrant dans une therapie d'anevrismes
WO2000037096A2 (fr) * 1998-12-22 2000-06-29 Schering Corporation Traitement des infections du virus de l'hepatite c avec interleukine-10
WO2001002866A1 (fr) * 1999-02-19 2001-01-11 University Of Iowa Research Foundation Procedes de diagnostic et de therapie pour les maladies affectant la paroi arterielle
US7108982B1 (en) 1999-02-19 2006-09-19 University Of Iowa Research Foundation Diagnostics and the therapeutics for macular degeneration

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2523565A1 (fr) * 2003-04-25 2004-11-11 Mitos Incorporated Pretraitement preventif par antioxydants
KR101999538B1 (ko) 2016-10-31 2019-07-12 사회복지법인 삼성생명공익재단 담즙산을 포함하는 허혈성 재관류 손상의 예방 또는 치료용 약학적 조성물

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1996001318A1 (fr) * 1994-07-05 1996-01-18 Steeno Research Group A/S Immunomodulateurs

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1996001318A1 (fr) * 1994-07-05 1996-01-18 Steeno Research Group A/S Immunomodulateurs

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CONNOLLY, J. K. ET AL: "Cytokine gene expression and eicosanoid production in renal reperfusion injury", TRANSPLANT. PROC. (1995), 27(5), 2816-18, 1995, XP002035705 *
EPPINGER, MICHAEL J. ET AL: "Regulatory effects of interleukin - 10 on lung ischemia - reperfusion injury", J. THORAC. CARDIOVASC. SURG. (1996), 112(5), 1301-1306, 1996, XP002035707 *
HESS P ET AL: "Exogenous IL - 10 suppresses tumor necrosis factor (TNF) dependent pulmonary neutrophil infiltration in a mouse model of visceral ischemia - reperfusion injury.", 6TH INTERNATIONAL TUMOR NECROSIS FACTOR CONGRESS, RHODES, GREECE, MAY 8-12, 1996. EUROPEAN CYTOKINE NETWORK 7 (2). 1996. 294, XP002035706 *
SAWA Y ET AL: "Contribution of interleukin 10 as a regulating cytokine in myocardial reperfusion injury.", JOINT XIITH WORLD CONGRESS OF CARDIOLOGY AND THE XVITH CONGRESS OF THE EUROPEAN SOCIETY OF CARDIOLOGY, BERLIN, GERMANY, SEPTEMBER 10-14, 1994. EUROPEAN HEART JOURNAL 15 (ABSTR. SUPPL.). 1994. 471, XP002035704 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999056783A1 (fr) * 1998-05-01 1999-11-11 Micrus Corporation Hydrogel entrant dans une therapie d'anevrismes
US6113629A (en) * 1998-05-01 2000-09-05 Micrus Corporation Hydrogel for the therapeutic treatment of aneurysms
JP2002531379A (ja) * 1998-05-01 2002-09-24 マイクルス コーポレイション 動脈瘤の治療用ヒドロゲル
WO2000037096A2 (fr) * 1998-12-22 2000-06-29 Schering Corporation Traitement des infections du virus de l'hepatite c avec interleukine-10
WO2000037096A3 (fr) * 1998-12-22 2000-11-30 Schering Corp Traitement des infections du virus de l'hepatite c avec interleukine-10
US6685931B1 (en) 1998-12-22 2004-02-03 Schering Corporation Treatment of hepatitis C virus infections with interleukin-10
WO2001002866A1 (fr) * 1999-02-19 2001-01-11 University Of Iowa Research Foundation Procedes de diagnostic et de therapie pour les maladies affectant la paroi arterielle
US7108982B1 (en) 1999-02-19 2006-09-19 University Of Iowa Research Foundation Diagnostics and the therapeutics for macular degeneration

Also Published As

Publication number Publication date
EP0906117A1 (fr) 1999-04-07
CA2253313A1 (fr) 1997-11-06
JP2000509073A (ja) 2000-07-18
IL126657A0 (en) 1999-08-17
BR9709752A (pt) 1999-08-10
AU721943B2 (en) 2000-07-20
KR20000065178A (ko) 2000-11-06
NZ332412A (en) 2000-05-26
AU2740597A (en) 1997-11-19

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