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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
  • A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • 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

• This invention relates to treating or inhibiting cellular injury or cell death following an ischemic event, treating or inhibiting reperfusion injury, and reducing mortality following a myocardial infarction by providing therapy with a TNF ⁇ antagonist.
• Therapeutic interventions such as coronary angioplasty and thrombolytic therapy are directed toward the treatment of acute myocardial ischemia. It is well recognized that mortality among patients who are experiencing a myocardial infarction is dependent upon the extent of left ventricular dysfunction, which, in turn is directly related to the amount of myocardium that becomes infarcted and thus nonfunctional. There is general agreement that myocardial tissue subjected to an ischemic interval is dependent upon the restoration of blood flow within a defined period for cellular viability and function to be restored. Compromised tissue following ischemia can only be recovered by reperfusing it Though the act of reperfusion can extend injury further. As investigators began to recognize this, studies were directed to explore the mechanisms responsible, as well as to develop potential therapies to suppress cellular damage associated with reperfusion injury A number of cellular mechanisms are believed to be responsible for ischemia-induced reperfusion injury.
• TNF ⁇ is a cytokine secreted by macrophages and monocytes w hich causes a wide va ⁇ ety of effects on a number of cell types.
• TNF proteins initiate their biological effect on cells by binding to specific TNF receptor (TNFR) proteins expressed on the plasma membrane of a TNF responsive cell.
• TNFR TNF receptor
• the effects caused b ⁇ TNF ⁇ include inhibitory or cytotoxic effects on tumor cell lines, stimulation of the proliferation of fibroblasts and the phaogcytic/cytotoxic activity of myeloid cells, induction of adhesion molecules in endothehal cells, inhibition of the synthesis of specific enzymes in adipocytes, and induction of the expression of histocompatibiht ⁇ antigens [see, US Patent 5,610,279].
• TNF ⁇ also causes pro-inflammatory actions which result in tissue injury, such as degradation of cartilage and bone [Saklatvala. Nature 322: 547 (1986); Bertolim, Nature 319: 516 (1986)].
• TNF ⁇ is also associated with infections, immune disorders, neoplastic pathologies, autoimmune pathologies. and graft vs. host disease.
• TNF ⁇ is also implicated in causing a wasting syndrome known as cachexia associated with cancer, which includes progressive weight loss, anorexia, and persistent erosion of lean body mass in response to malignant growth [see WO 98/51344].
• TNF ⁇ is also believed to cont ⁇ bute to the induction of ventricular dysfunction, pulmonary edema, and cardiomyopathy.
• TNFR TNF receptor I and II
• Inflammatory cytokines including TNF have been shown to be released the myocytes immediately after the onset of ischemia [Meldrum, D.R , J Mol Cell Cardiol 30.1683-1689 (1998)] and are believed to be involved in the expiession of adhesion molecules that aie instrumental in neutrophil extravasation
• the sphingomyehnase pathway can be initiated by the release of TNF, and is considered the predominant signaling pathway of the cytokine [Kim et al., J Biol Chem 266: 484- 489 (1991); Dressier et al., Science 255: 1715-1718 (1992); Yang, et al.
• ENBREL etanercept, p75TNFR Fc
• TNFR tumor necrosis factor receptor
• WO 98/51344 discloses the use of a TNF ⁇ antagonist in combination with a VEGF antagonist for the treatment or prevention of TNF-mediated diseases including rheumatoid arthritis, Crohn's disease, and acute and chronic immune diseases associated with transplantation
• This invention provides a method of treating or inhibiting cellular injury or cell death following an ischemic event which comp ⁇ ses providing an effective amount of a TNF ⁇ antagonist More particularly, this invention provides a method of treating or inhibiting cellular injury or cell death resulting from myocardial infarction, myocardial ischemia, retinal ischemia, central retinal occlusion, pe ⁇ pheral arterial occlusion (l e , an embolism), transient ischemic attacks (I e , ceberal ischemic attacks), ischemic stroke, ischemic arterial obstruction, reperfusion injury resulting from frostbite, arterial thiombosis and occlusion, and crush injury by providing an effective amount of a TNF ⁇ antagonist
• This invention also provides a method of reducing mortality following myocardial infarction by providing an effective amount of a TNF ⁇ antagonist
• This invention additionally provides a method of inhibiting cardiac damage following a cardiac ischemic event by providing an effective amount of a TNF ⁇ antagonist
• This invention
• the term providing an effective amount of a TNF ⁇ antagonist means either directly administe ⁇ ng such antagonist, or administe ⁇ ng a prodrug, derivative, or analog which will form an effective amount of the antagonist within the body
• TNF ⁇ antagonist has been well defined m WO 98/51344, and is defined as decreases, blocks, inhibits, abrogates or interferes with TNF ⁇ activity in vivo.
• a suitable TNF ⁇ antagonist can bind TNF ⁇ and includes anti-TNF ⁇ antibodies, antigen-binding fragments thereof, and receptor molecules and de ⁇ vatives which bind specifically to TNF ⁇ .
• a suitable TNF ⁇ antagonist can also prevent or inhibit TNF ⁇ synthesis and/or TNF ⁇ release and includes compounds such as thahdomide, tenidap, and phosphodiesterase inhibitors, such as, but not limited to, pentoxifyllme and ro pram.
• a suitable TNF ⁇ antagonist that can prevent or inhibit TNF ⁇ synthesis and/or TNF ⁇ release also includes A2b adenosine receptor enhancers and A2b adenosine receptor agonists (e.g ,
• TNF ⁇ antagonist can also prevent or inhibit TNF ⁇ receptor signalling and includes mitogen activated protein (MAP) kmase inhibitors.
• MAP mitogen activated protein
• TNF ⁇ antagonists include agents which decrease, block, inhibit, abrogate or interfere with membrane TNF ⁇ cleavage, such as, but not limited to, metalloproteinase inhibitors; agents which decrease, block, inhibit, abrogate or interfere with TNF ⁇ activity, such as, but not limited to, angiotensin converting enzyme (ACE) inhibitors, such as captop ⁇ l, enalap ⁇ l and lismopnl; and agents which decrease, block, inhibit, abrogate or interfere with TNF ⁇ production and/or synthesis, such as, but not limited to, MAP kmase inhibitors
• ACE angiotensin converting enzyme
• the TNF ⁇ antagonist is a TNF receptor molecule that binds TNF ⁇ . It is more preferred that the TNF receptor molecule is a TNF receptor fragment/immunoglobu n fusion protein. It is still more preferred that the fusion protein comp ⁇ ses a fragment of TNFR and a portion or the entire constant region of a human immunoglobulin heavy chain.
• a particularly preferred TNF ⁇ antagonist is etanercept (p75TNFR:Fc), which is a dime ⁇ c fusion protein consisting of the extracellular ligand-bmdmg protein of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgGl Etanercept is commercially available as ENBREL, and is currently approved for use in treating rheumatoid arth ⁇ tis Etanercept can be prepared according to the procedures desc ⁇ bed in US Patents 5,605,690, 5,478,925 EP 464533, and EP670730, hich are hereby incorporated by reference.
• p55TNFR:Fc Another preferred TNF ⁇ antagonist is designated as p55TNFR:Fc, which is a dime ⁇ c fusion protein consisting of the extracellular hgand-bmdmg protein of the human 55 kilodalton (p55) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgGl
• p55TNFR:Fc dime ⁇ c fusion protein consisting of the extracellular hgand-bmdmg protein of the human 55 kilodalton (p55) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgGl
• TNF ⁇ antagonists to treat or inhibit cellular injury or cell death following an ischemic event and to treat or inhibit reperfusion injury was evaluated m two m vivo standard pharmacological test procedures.
• the first test procedure evaluated the effects of TNF and sphingosine on cardiac function
• the second test procedure evaluated the survival after a 30 minute occlusion of the main coronan artery followed by reperfusion Etanercept was evaluated as a representative TNF ⁇ antagonist in the second test procedure which emulates an acute myocardial infarction.
• An m vitro standard pharmacological test procedure was also performed to evaluate the cardiodepressant effect of sphingosine on myocytes. The procedures used and results obtained are desc ⁇ bed below.
• Surgical preparation Male Sprague-Dawley rats weighing 505 ⁇ 5g were anesthetized with sodium pentobarbital (50 mg/kg I.P.). An endotracheal tube was secured in place and connected to a small-animal respirator (Harvard Apparatus. Model 683, South Natick, MA) set on 100 breaths/min, with a tidal volume of 2-3 mL/breath. Body temperature was maintained using a heating pad with circulating warm water (K-model 100, Baxter Laborato ⁇ es). A left thoracotomy was performed, the heart exposed and the pe ⁇ cardium removed.
• a small-animal respirator Hard Apparatus. Model 683, South Natick, MA
• Left vent ⁇ cular pressure was measured using a saline-filled polyethylene catheter attached to an angiocatheter (20 Gauge) inserted through the apex of the heart and connected to a P23 ID Statham/Gould pressure transducer. Arte ⁇ al pressure was monitored via a sa ne- filled polyethylene catheter (PE 50) introduced into the left carotid artery. The ⁇ ght jugular vein was also cannulated with a polyethylene catheter (PE 50) for IV drug infusions and volume repletion (0 9% NaCl) Subcutaneous needles were positioned m the limbs for ECG recordings.
• PE 50 polyethylene catheter
• the rats were surgically prepared (open chest, but no occlusion) and were administered TNF, sphmgomyehn, or sphingosine by slow l.v. infusion (0.1 mg/kg over 5 minutes). Each animal was observed continuously for 15 minutes, whereupon a second does was administered by slow I v. infusion (0.3 mg/kg over 5 minutes) and each animal was again observed for 15 minutes.
• infarct size The heart was removed and sliced in five to six coronal sections, which were immersed in 1% t ⁇ phenyltetrazohum chlo ⁇ de (TTC) for 10-15 minutes. The heart sections were removed, blotted dry and traced onto acetate sheets. The areas of infarction were clearly demarcated by a pale appearance in the ischemic zone, and a b ⁇ ck red color of non-mfarcted myocardium. The areas of all sections were determined by planimet ⁇ c methods and farct area was expressed as a percentage of the left vent ⁇ cle.
• TTC t ⁇ phenyltetrazohum chlo ⁇ de
• Ventncular Myocvte Isolation Vent ⁇ cular myocytes were isolated using a modified Langendorff perfusion procedure outlined by Silver, et al., (13) B ⁇ efly, cats of either sex, weighing 2-4 kg were anaesthetized with pentobarbital sodium (40 mg/kg I.P.). Under anesthesia, a sternotomy was performed, the heart rapidly excised, and then immersed in Ca ++ -free Krebs-Henseleit buffer solution (KHB) at 4°C for aortic cannulation. KHB had the following composition (in mM): 130 NaCl, 4.8 KC1, 1.2 MgSO 4 , 1.2 NaH2PO4, 25 NaHCO3, 12.5 dextrose.
• KHB had the following composition (in mM): 130 NaCl, 4.8 KC1, 1.2 MgSO 4 , 1.2 NaH2PO4, 25 NaHCO3, 12.5 dextrose.
• Solution pH was 7.35-7.40 when equilibrated with 95% 0 2 /5% CO2 gas mixture.
• the solution was actively aerated throughout the procedure.
• the cannulated heart was ⁇ nsed with KHB at 37°C for 2-4 minutes followed by perfusion for 12-15 minutes with KHB containing 0.7 mg/mL Type II collagenase (197 U/mg; Worthington; Freehold, NJ USA).
• Digested vent ⁇ cular tissue was then dissected from the at ⁇ a, mmced, and filtered through a 200 ⁇ m pore nylon mesh. Filtrate was cent ⁇ fuged at 50 x g for 1-2 minutes and the separated cell pellet was resuspended in fresh KHB. The latter process was performed three times.
• the pellet was resuspended with KHB containing 2% bovine serum albumin and 100 ⁇ M Ca ++ .
• Hemodynamic Parameters in Non-Occluded Rats The following table shows the effects of sphingosine, sphingomyelin, and TNF on the following hemodynamic parameters in open chest rats in the absence of myocardial ischemia: heart rate, mean blood pressure, left ventricular blood pressure (LVL) and its first derivative (+dP/dt). Cardiovascular parameters measured in open chest rats in the absence of myocardial ischemia.
• Data are expressed as mean ⁇ sem. Data are percent change from pre-drug baseline 15 minutes after drug administration * indicates p ⁇ 0.05 vs other pretreatment groups over the entire observation pe ⁇ od.
• TNF that was administered exogenously to the rats in this test procedure resulted in serum concentrations two-fold higher than the C max of TNF generated endogenoush after myocardial ischemia.
• serum concentrations two-fold higher than the C max of TNF generated endogenoush after myocardial ischemia.
• serum concentrations of TNF failed to produce acute cardiodepression in the absence of an inflammatory response. which is necessary for initiation of the sphingolipid cascade.
• myocyte injury one would not expect sphingomyelin administration to depress function since membrane sphmgomyehnases would not have been stimulated b> increased concentrations of TNF to degrade sphingomyelin to ceramide, the metabolite previously shown to decrease contractility in isolated myocytes.
• the Ca +2 current (I Ca L ) was isolated by suppressing other K + currents by using Cs + , a blocker of K + currents, in both the external and in the pipette solution.
• the fast Na + current (I Na ) was eliminated by holding the myocytes at -40 mV, a potential where (I Nj ) is largely inactivated, and by substituting NaCl with TEA-C1 in the external solution
• ⁇ indicates p ⁇ 0 05 vs the vehicle treatment group at the identical timepoint.
• Infarct size expressed as a percentage of the left vent ⁇ cle, was 24 ⁇ 3% for Etanercept and 26 ⁇ 2% for the vehicle-control group, showing that the difference of survival was not the result of unequal infarct size.
• TNF ⁇ antagonists are useful in reducing mortality following myocardial infarction. Based on the results obtained, TNF ⁇ antagonists are also useful in treating or inhibiting cellular injury or cell death following an ischemic event. More particularly, this invention provides a method of treating or inhibiting cellular injury or cell death resulting from myocardial infarction, myocardial ischemia, retinal ischemia, central retinal occlusion, peripheral arterial occlusion (i.e..
• TNF ⁇ antagonist Treatment with a TNF ⁇ antagonist will also be useful prior to or during procedures which involve ischemic events followed by reperfusion, such as transplant surgery, when the donor organ undergoes a period of ischemia, and is then reperfused by the recipients blood supply; angioplasty or coronary stent placement; thrombolytic therapy; heart valve replacement; and bypass surgery.
• TNF ⁇ antagonists may be formulated neat or may be combined with one or more pharmaceutically acceptable carriers for administration according to standard method for the formulation of pharmaceutical agents.
• Routes of administration include oral, parenteral (including, for example, intravenous, intramuscular injection. subcutaneous injection), intranasal, intraperitoneal, rectal, vaginal, and transdermal.
• the routes of administration vary with the nature of the TNF ⁇ antagonist and reason for administration. For example, where the TNF ⁇ antagonist will rapidly degrade in the gut, administration is preferably made parenterally. It is preferable to provide etanercept intravenously for the treatment or inhibition of cellular injury or cell death following an ischemic event, because of the acid labile nature of etanercept and the necessity for rapid onset of action.
• the TNF ⁇ antagonist When the TNF ⁇ antagonist is to be provided orally, it can be provided in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally m the form of ste ⁇ le mjectable solution or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium.
• Such pharmaceutical preparations may contain, for example, from about 0 05 up to about 90% of the active ingredient in combination with the earner, more usually between about 5% and 60% by weight.
• Formulation for tablet or capsule administration may include solid earners including starch, lactose, dicalcium phosphate, microcrystalhne cellulose, sucrose and kaolin, while liquid earners include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
• Adjuvants customa ⁇ ly employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavonng agents, colonng agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
• solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical forms suitable for mjectable use include sterile aqueous solutions or dispersions and stenle powders for the extemporaneous preparation of ste ⁇ le mjectable solutions or dispersions.
• the earner can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils Etanercept, for example is commercially available as a white, preservative free, lyophihzed powder for parenteral administration after reconstitution with water
• the dosage the TNF ⁇ antagonist will vary according to the nature of the TNF ⁇ antagonist, the reason for administration, and individual patient receiving therapy. For chronic therapy, it is generally recommended that treatment begin with the smallest effective dosage, with dosage adjustments being made through physician monitoring. For treatment with etanercept, projected intravenous dosage would be between 0.05 - 25 mg/kg etanercept It is contemplated that the TNF ⁇ antagonist may be administered in a single dose or over several doses in response to a particular ischemic event, or may be administered chronically to inhibit cellular damage or death in response to future ischemic events.
• a TNF ⁇ antagonist may be administered chronically to a patient suffenng from transient ischemic events, which often occur over long penods of time.
• the TNF ⁇ antagonist may be administered prophylactically in situations where it is anticipated that an ischemic event will occur (for example, pnor to a transplant procedure or angioplasty procedure).

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