CN1406132A - Methods of treating or inhibiting cell damage or cell death - Google Patents
Methods of treating or inhibiting cell damage or cell death Download PDFInfo
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- CN1406132A CN1406132A CN01804781A CN01804781A CN1406132A CN 1406132 A CN1406132 A CN 1406132A CN 01804781 A CN01804781 A CN 01804781A CN 01804781 A CN01804781 A CN 01804781A CN 1406132 A CN1406132 A CN 1406132A
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- antagonists
- tnf alpha
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- cell
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The present invention provides a method of treating or inhibiting cell death following an ischemic event, treating or inhibiting reperfusion injury, and reducing mortality following myocardial infarction by providing therapy with a TNF α antagonist.
Description
The present invention relates to by cell injury or cell death after the therapy processes of using the TNF alpha-2 antagonists being provided or suppressing ischemic event, the mortality rate after processing or inhibition reperfusion injury and the reduction myocardial infarction.
The minimizing of vascular bed blood flow or interruption are the reasons of many clinical events, and these incidents need to handle immediately and impaired organ or organized renewing are fully poured into.Different tissues can bear ischemic injuries in various degree.Yet if do not pour into, institute can develop into irreversible damage and necrocytosis in a organized way again.Heart tissue reduces perfusion (ischemia), can cause heart because tissue lacks oxygen and energy and lose the ability of operate as normal.Permanent damage is directly related with the persistent period that the oxygen that cardiac muscle is stood lacks.Ischemic tissue pours into again, simply refers to the restoration of blood flow of those tissues or tract.Realize dabbling again necessity by machinery or pharmacology method, accepted, particularly in the myocardial infarction Clinical Processing by medical bodies.Data show is got back to when organizing when blood flow, the degree that " reperfusion injury " can damaging tissue's treatment.
Treatment intervention as the coronary angioplasty thromboembolism treatment is directly to treat at acute myocardial ischemia.Know, the mortality rate of infraction takes place, directly depend on the degree of left ventricular dysfunction, the latter is directly related with the quantity that the cardiac muscle that also therefore loses function is blocked in formation.Such common recognition is generally arranged, stand the cardiac muscular tissue of a period of time ischemia, depend on the restoration of blood flow that in the time of determining, is used to recover cell viability and function.
Damaged tissues behind the ischemia can only recover by pouring into again.Though dabbling again way can further increase the weight of damage.Because researcher begins to recognize this point, so research work all is at mechanism of action, and the potential Therapeutic Method of the exploitation cell injury that is used to suppress relevant with reperfusion injury.A lot of cell mechanisms are considered to cause the reason of the reperfusion injury that ischemia causes.
TNF α is a kind of macrophage and the excretory cytokine of mononuclear cell, and it can cause effect widely to a lot of cell types.TNF protein by with specificity T NF receptor (TNFR) protein bound of on TNF responsive cell serous coat, expressing, excite the biological effect of pair cell.The effect that TNF α causes comprises, inhibitory action or cytotoxic effect to tumor cell line, stimulate the cytophagy/cytotoxic activity of fibroblasts proliferation and medullary cell, the adhesion molecule of inducing endothelial cell, certain enzyme is synthetic in the inhibition adipose cell, and the expression of induced tissue compatibility antigen.[referring to, United States Patent (USP) 5,610,279].TNF α also can cause short scorching effect, and this short scorching effect causes tissue injury, for example the degraded of cartilage and bone [Saklatvala, Nature 322:547 (1986); Bertolini, Nature 319:516 (1986)].TNF α is also with infection, immunologic derangement, tumor pathology, autoimmune pathology and to host's transplanting disease association.TNF α also relates to and causes the be called cachectic exhaustion syndrome relevant with cancer, and it comprises, and the progressivity that reacts on malignancy loses weight, anorexia and to the lasting erosion of thin and weak body constitution.[referring to WO 98/51344].
TNF α also is believed to be helpful in and causes ventricular function disorder, pulmonary edema and cardiomyopathy.[Torre-Amione?G，J?Am?Coll?Cardiol?27：1201-1206(1996)]。Ever-increasing evidence shows, (p75) composition in conjunction with the inflammation cascade reaction that triggers is the immediate cause [Oral that causes observed acute injury effect in cardiac muscle for TNFR, p55 by TNF and TNF receptor I and II, H., J Biol Chem.272 (8): 4836-4842 (1997); Kapadia, S., Am J.Physiol.268:H517-H525 (1995)].
Shown that the inflammatory cytokine that comprises TNF is to discharge [Meldrum immediately by the myocyte after ischemia takes place, D.R., J Mol Cell Cardiol.30:1683-1689 (1998)], and think that it participates in the expression of adhesion molecule, these adhesion molecules help neutrophilic granulocyte to exosmose.The sphingomyelinase approach can discharge by TNF and activate, and is considered to the important signal pipeline of cytokine [Kim et al.J Biol Chem 266:484-489 (1991); Dressler et al., Science 255:1715-1718 (1992); Yang et al.J Biol Chem 268:20520-20523 (1993)].This approach is proved to be and is present in the myocardial cell.[Oral?et?al.，J?Biol?Chem?272：4836-4842(1997)]。Sphingomyelinase can be activated by TNF, and will be degraded to ceramide with membrane-bound sphingomyelins.Endogenous ceramide enzyme catalysis ceramide synthesizes sphingol.Proved that ceramide and sphingol all have second message,second messenger's characteristic.Shown that sphingol can the inductive sarcoplasmic reticulum calcium of calcium discharges and the ability that directly suppresses L-type calcium current suppresses cardiac function by reducing.Cain etc. [Crit CareMed.27 (7): 1309-1318 (1999)] use the activated people atrium girder that is suspended in the organ bath, and have write down the expansion power that tissue produces.TNF-α, the IL-1 β or the TNF-α+IL-1 β that add concentration graded, and evaluation function.In addition, before TNF-α or IL-1 β, tissue is exposed to N-Oleoyl monoethanolamide (NOE).TNF-α and IL-1 β suppress the function of people's cardiac muscle in concentration dependence mode.By NOE myocardium sphingol is suppressed, eliminated the myocardium inhibitory action of TNF-α or IL-1 β.Researcher has summed up TNF-α and IL-1 β can respectively and work in coordination with inhibition people cardiac muscle function.Sphingol may participate in causing the TNF-α and the IL-1 signal beta of people's cardiac muscle function inhibition.
Cell injury also is proved to be and is present in its hetero-organization.Sphingol and metabolite and C2, C8 or the C16 ceramide exists or non-existent situation under bring out kidney proximal tubule (HK-2) cell 0-20 hour.Sphingol (＞or=10 micromoles every liter) and the ceramide (C2 and C8) selected be not when having dna ladder or apoptotic form to change, and the cytotoxicity of all inducing concentration fast to rely on shows it is a kind of downright bad form of cell death.Researcher can reappear this result in human foreskin fibroblast, show this extensively relevant with acute cell injury and restoring area [Iwata et al., PANS 92 (19): 8970-8974 (1995)].
ENBREL (etanercept; P75TNFR:Fc) be a kind of dimer fusion protein matter, partly form by the extracellular ligand conjugated protein and the connected human IgG1 Fc of people's 75 kilodaltons (p75) Tumor Necrosis Factor Receptors (TNFR).Etanercept is a kind of TNF alpha-2 antagonists of selling in the market that is used for the treatment of rheumatoid arthritis, and the clinical trial [Bozkurt B, JACC (Suppl) 184-185A (1999) that are carrying out the chronic heart failure treatment; Deswal A, Circulation (suppl) 96 (8): I-323 (1997)].
WO 98/51344 discloses in conjunction with the VEGF antagonist and has used the treatment of TNF alpha-2 antagonists or prevent TNF-disease mediated, comprises rheumatoid arthritis, clone disease and the acute and chronic immune disease relevant with transplanting.
Detailed Description Of The Invention
The cell injury after the invention provides a kind of processing or suppressing ischemic event or the method for cell death, this method comprises provides the TNF of effective dose alpha-2 antagonists.More specifically, the invention provides by the TNF alpha-2 antagonists of effective dose is provided, handle or suppress because myocardial infarction, myocardial ischemia, retinal ischemia, retina medium-sized artery are blocked, peripheral arterial occlusion (for example, thromboembolism), of short duration ischemic episode (for example, cerebral ischemia attack), Ischemic Stroke, ischemic the obstruction of artery cell injury or the cell death that cause, and handle and suppress because a kind of method of the reperfusion injury that chilblain, artery thrombosis and obstruction and crush injury cause.A kind of method by mortality rate after providing effective dose TNF alpha-2 antagonists with the reduction myocardial infarction also is provided in the present invention.A kind of method by heart and injury after providing effective dose TNF alpha-2 antagonists with inhibition heart ischemia incident is provided in addition in the present invention.The present invention further provides a kind of by providing effective dose TNF alpha-2 antagonists to handle or to suppress the method for reperfusion injury.
Term used in the present invention provides effective dose TNF alpha-2 antagonists, is meant or directly gives this antagonist, perhaps gives to form in vivo prodrug, derivant or the analog of effective dose TNF alpha-2 antagonists.
Term TNF alpha-2 antagonists has explication in WO 98/51344, be defined as in vivo to reduce, block, suppress, eliminate or disturb the TNF alpha active.For example, suitable TNF alpha-2 antagonists can be in conjunction with TNF α, and comprises anti-TNF alpha antibody, its Fab, and the derivant of acceptor molecule and specific bond TNF α.Suitable TNF alpha-2 antagonists also can stop or suppress the synthetic and/or TNF α release of TNF α, and comprise such chemical compound, for example neurosedyn, tenidap, and phosphodiesterase inhibitor, for example, but be not limited to pentoxifylline and rolipram.Can stop or suppress the suitable TNF alpha-2 antagonists that TNF α is synthetic and/or TNF α discharges, (for example also comprise A2b adenosine receptor enhancer and A2b adenosine receptor agonist, 51-(N-cyclopropyl)-Carboxylamide adenosine, 51-N-ethyl Carboxylamide adenosine, cyclohexyladenosine and R-N6-phenyl-2-propyl group adenosine) referring to, for example, Jancobson, GB 2 289218A.Suitable TNF alpha-2 antagonists also can stop or suppress the conduction of TNF α receptor signal, comprises mitogen activator protein (MAP) inhibitors of kinases.Other suitable TNF alpha-2 antagonists comprise reduction, blocking-up, inhibition, eliminate or disturb the reagent of film TNF α shearing, for example, but are not limited to inhibitors of metalloproteinase; Reduce, block, suppress, eliminate or disturb the reagent of TNF alpha active, for example, but be not limited to Angiotensin-Converting (ACE) inhibitor, for example captopril, enalapril and lisinopril; And reduction, blocking-up, inhibition, elimination or interference TNF α generation and/or synthetic dose of examination, for example, but be not limited to map kinase inhibitor.
TNF alpha-2 antagonists preferred combination TNF α.Preferred TNF α acceptor molecule is a kind of TNF α receptor fragments/domain-immunoglobulin fusion proteins.More preferably, this fusion rotein comprises one section TNFR fragment and human immunoglobulin heavy chain's some or all of constant region.
Particularly preferred TNF alpha-2 antagonists is etanercept (p75TNFR:Fc), it is a kind of dimer fusion protein matter, extracellular ligand conjugated protein and connected human IgG1 Fc by people's 75 kilodaltons (p75) Tumor Necrosis Factor Receptors (TNFR) partly form.The commercial distribution title of Etanercept is ENBREL, is permitted for the treatment rheumatoid arthritis at present.Etanercept can be according to United States Patent (USP) 5,605,690,5,478,925, the method preparation of describing among EP 464533 and the EP 670730, and these patents are hereby incorporated by.
Another kind of preferred TNF alpha-2 antagonists is called p55TNFR:Fc, it is a kind of dimer fusion protein matter, partly is connected with connected human IgG1 Fc by the extracellular ligand conjugated protein of people's 55 kilodaltons (p55) Tumor Necrosis Factor Receptors (TNFR).The preparation of p55TNFR:Fc is disclosed in United States Patent (USP) 5,610, and in 279, this patent is received for referencial use herein.
The cell injury behind processing of TNF alpha-2 antagonists or the inhibition ischemic event or the ability of cell death, and the ability of handling or suppress reperfusion injury obtain assessment in two individual internal standard pharmacology test processes.First process of the test has been assessed the influence to cardiac function of TNF and sphingol, and second process of the test assessed main coronary occlusion survival rate after the perfusion again after 30 minutes.In second process of the test, Etanercept is evaluated as representational TNF alpha-2 antagonists, this test simulation acute myocardial infarction.Also carried out an individual outer standard pharmacology test process, with the heart inhibitory action of assessment sphingol to the myocyte.Step of using and the result who obtains are described below.
Step
Operation is preparedWith pentobarbital sodium (50 mg/kg I.P.) anesthesia body weight is the male Sprague-Dawley rat of 505 ± 5g.Tracheal intubation is sewn onto certain position, with small animal respirator (Harvard Apparatus, Model 683, South Natick MA) connects, and is set to breaths/min 100 times, tidal volume is that 2-3mL/ breathes.Keep body temperature with the heating cushion with circulating hot water (K-model 100, Baxter Laboratories).Carry out left breast otomy, expose heart, remove pericardium.Use the saline polyethylene catheter that fills that connects vessel catheter (20 Gauge) to measure left ventricular pressure, this vessel catheter passes the apex of the heart, and links to each other with a P23 ID Statham/Gould pressure transmitter.Arteriotony is monitored by the saline polyethylene catheter (PE 50) that fills that inserts left neck artery.Right jugular vein also sleeve pipe inserts polyethylene catheter (PE 50), is used for the intravenous drug perfusion and replenishes volume (0.9%NaCl).Hypodermic needle places extremity, is used for electrocardiographic recorder.All data output all is recorded in has Po-Ne-Mah data-acquisition system (Valley View, OH) Gould Model 6600 (Valley View, OH) serial monitor, be presented on the physiology platform CRS800W/CRS400W monitor (GeneralScanning Inc., Bedford MA).
In first process of the test, surgical procedure rat (open breast, but do not block), and give TNF, sphingomyelins or sphingol by low speed venoclysis (per 5 minutes 0.1mg/kg).Every animal was observed 15 minutes continuously, carried out the administration second time then, low speed venoclysis (per 5 minutes 0.3mg/kg), and every animal was observed 15 minutes again.
In second process of the test, the rat master coronary artery that carries out coronary occlusion is fixed, and use the 5-0 stitching to block near the starting point place, sews up by under the blood vessel, can be by tightening a bit of ischemia of starting of PE pipe (PE 20).Recover perfusion again by removing PE pipe small fragment.
Determine the infraction sizeTake out heart, be cut into 5 to 6 crown sections, be immersed in 1% chlorinated triphenyl tetrazole (TTC) middle 10-15 minute.The section of taking-up heart is blotted, and traces on acetate paper.Infarct area with the clear boundary of canescence, is bolarious and do not block cardiac muscle at ischemic region.Determine the area of all sections with planimetric method, infarct area is represented with the percentage ratio of left ventricle.
The mensuration of TNF in the rat blood serumNeed not any anticoagulant, collect blood sample with syringe, place Microtainer serum separator tube (Becton Dickinson) rapidly, centrifugal 6 minutes of 2000g.Take out serum, freezing immediately, be stored in-20 ℃ until analyzing.To every rat, by enzyme-linked immunosorbent assay (ELISA), use Factor-Test-X (Genzyme Inc, Cambridge, MA., Cat #80-3905-01) according to manufacturer's explanation, be determined at the serum TNF concentration that preselected time point is collected.In brief, 1: 2 dilution 100 μ L serum adds double to the microtitration plate of 96-hole in 0.1% bovine serum albumin/phosphate buffer.Concentration by rat TNF standard is mapped to its absorbance, obtains standard curve.The analysis of manufacturer and our breadboard affirmation show that this analysis can be measured free TNF and in conjunction with the TNF (data not shown) of etanercept.The measuring limit of this analysis is 10pg/mL.In addition, manufacturer has determined that this ELISA is a high special for rat TNF.Rat INF-γ, GRO-β/MIP-2, GRO/KC and interleukin IL-1 β, IL-2 and IL-4, and mice LIF, SCF, GM-CSF and interleukin IL-1 α, IL-3, IL-5, IL-7 and IL-10 reach 10 in concentration
6During pg/mL, not producing can detected cross reaction.
The separation of ventricular muscle cellUse Sliver, et al., the improved Langendorff method for filling of listing in (13) separates ventricular muscle cell.In brief, anaesthetize the cat of any sex of body weight 2-4kg with pentobarbital sodium (40mg/kg I.P.).When anesthesia, cut breastbone, excise heart rapidly, immerse 4 ℃ no Ca
++Krebs-Henseleit buffer (KHB), be used for the aorta sleeve pipe and insert.KHB has following component (mM): 130 NaCl, 4.8KCl, 1.2MgSO
4, 1.2 NaH
2PO
4, 25 NaHCO
3, 12.5 glucoses.Use 95%O
2/ 5%CO
2PH value of solution is 7.35-7.40 during the admixture of gas balance.Solution is active ventilation in whole process.Insert telescopic heart and cleaned 2-4 minute with KHB, then with containing 0.7mg/mL II Collagen Type VI enzyme (197 units/mg at 37 ℃; Worthington; Freehold, NJ USA) KHB perfusion 12-15 minute.Ventricular organization and the atrium of digestion cutd open leave, chopping is with the nylon sieve filtration in 200 μ m holes.The centrifugal 1-2 of filter liquor 50xg minute, the isolated cells pellet resuspended was in fresh KHB.Back one step is carried out 3 times.When repeating for the third time, pellet resuspended is in containing 2% bovine serum albumin and 100 μ MCa
++KHB in.The cell suspending liquid that obtains is divided into 2 five equilibriums.A use Tyrode ' s solution (composition is as follows) dilution in 1: 1, place room temperature (19-25 ℃), be used for cell record in 12 hours in separation.Second five equilibrium is used to the cell that tiles, and is used for later record, and is dispersed to DMEM/F-12 culture medium (BioWhittaker, Walkersville, MD, USA) 1: 1 mixture, this culture media supplemented streptomycin sulfate (200 μ g/mL) and penicillin-G sodium salt (200 units/mL).The cell of tiling is kept room temperature in incubator (pH=7.2).The suspension culture base was changed once in per two days.
Myocyte's electrophysiological recordingAt 36-37 ℃,, carry out patch-clamp electric current and voltage record (14) with broken whole cellularity diaphragm.For L-type Ca
2+Improved Tyrode ' the s solution soaking of the research of electric current, cell, this solution contains (mM): 157TEA-Cl, 5 CaCl
2, 0.5 MgC1
2With 10 HEPES.Solution contains (mM) in the electrode: 10L-glutamic acid, 20 CsCl, 10 EGTA, 1 MgCl
2, 1 CaCl
2, 20 HEPES and 5 ATP-Mg
2+Regulate pH with CsOH.In all researchs, the electrode resistance that records is 2-3.5M Ω.Before forming sealing, in immersion, regulate the zero point of reference current potential.Use is connected with the Axon Instruments 200B amplifier (Axon Instruments, CulverCity, CA USA) that DigiData 1200 DA/AD obtain system and carries out record.Depolarization voltage gradient (length 1 second) excited ion stream by from-30 to+60 mV increases with 10-mV, keeps current potential and is-40mV frequency 1Hz.By injecting main instantaneous depolarization current pulse, cause action potential with the 1Hz frequency.The software that uses during data are obtained and analyzed be pClamp v.6.04 with Originv 5.0 (MicrocalSoftware, Northampton, MA).
The result
The hemodynamic parameter that does not block ratFollowing table has shown that the opening in the breast rat of myocardial ischemia do not taken place for sphingol, sphingomyelins and TNF, to the influence of following hemodynamic parameter: heart rate, mean blood pressure, left ventricle blood pressure (LVL) and its first derivative (+dP/dt).
The cardio-vascular parameters of measuring in the breast rat of opening of myocardial ischemia is not taking place
Group heart rate mean blood pressure LVPdev+dP/dt
Rat TNF-α
0.1mg/kg?iv(n＝5) -3±1 4±7 1±4 10±5
+
0.3mg/kg?iv -3±2 4±6 -1±3 9±8
Sphingomyelins
0.1mg/kg?iv(n＝4) 7±9 -3±17 3±11 1±13
+
0.3mg/kg?iv 8±10 2±2 4±12 6±15
Sphingol
0.3mg/kg?iv(n＝4) -4±4 -24±12 -24±8
* -33±12
*
+
1.0mg/kg?iv -18±1
* -17±19 -24±14 -32±18
*
Data are represented with meansigma methods ± standard error.Data are in medication after 15 minutes, and the percentage ratio of baseline changes before the medication relatively.* be meant that whole viewing duration compares p＜0.05 with other pretreated group.
The result of this process of the test shows, infusion sphingol (0.1+0.3mg/kg) afterwards, whole myocardial function significantly reduces: LVP reduces by 24 ± 8% from baseline ,+dP/dt reduces by 33 ± 12% from baseline.In this test method, give the TNF serum-concentration that dosage causes of rat external source administration, than the TNF C of endogenous generation behind the myocardial ischemia
MaxHigh 2 times.Yet, when not having inflammatory reaction,, suppresses very high TNF serum-concentration even if can not producing the acute cardiac function, and this inflammatory reaction is essential for exciting the sphingolipid cascade reaction.When not having the myocyte to damage, give sphingomyelins will be not can inhibit feature, because the film sphingomyelinase will can not increased by TNF concentration and activate, can not be degraded to ceramide to sphingomyelins, ceramide is foregoingly can reduce its inotropic metabolite in separating the myocyte.
Sphingol is to separating myocyte's effectIn order further to assess the effect of sphingol, isolate isolating myocyte, as of the effect of above-mentioned mensuration sphingol to calcium current to myocardial function and cell injury.Studies show that in the past, sphingol can influence action potential from the release of sarcoplasmic reticulum and produces [Yasui, et al, Am J.Physiol.270:C645-649 (1996) by reducing calcium ion; MacDonell, et al.Am J. Physiol.275:H2291-2299 (1998)].The result that above-mentioned standard pharmacology test method obtains shows, sphingol has shortened the action potential duration (APD) of isolating cat ventricular muscle cell in concentration dependence mode, and 0.25 μ M, 2.5 μ M, 25 μ M sphingols make the continued time of 95% complete repolarization (APD95) reduce by 16 ± 2%, 28 ± 2% and 39 ± 2% (n=4) respectively.APD shortens, and mainly is the result who has suppressed plateau.Externally with pipette in solution in, by using a kind of K
+Stream blocker Cs
+, suppress other K
+Stream is isolated Ca
+ 2Stream (I
Ca-L).By keeping the myocyte, and externally replace NaCl with TEA-C1 in the solution, eliminate quick Na at-40mV
+Stream (I
Na), wherein-40mV is the most of (I of prevention
Na) current potential.Be exposed to sphingol (2.5 and 25 μ M), cause I
Ca-LRemarkable blocking-up (during 25 μ M blocking-up 17 ± 7 and 75 ± 4%).The minimizing of heart action potential and interior to Ca
+ 2The minimizing of stream is considered to change relevant with the negativity muscular strength that observes directly after the whole body administration or indirectly observe after TNFR1 activates.Sphingol (25 μ M) causes that finally cardiomyocyte cell death, cell death are to lose activity definite by being exposed to the form that causes after the maximum concentration sphingol with it.(200-20,000 unit/mL) the processing myocyte does not change action potential or I with TNF
Ca+2-L
The TNF level of blocking in the rat is arrangedAs mentioned above, operation is prepared rat and is blocked coronary artery.Following table has shown the serum-concentration of opening TNF in the breast rat that myocardial ischemia is arranged.
Group excipient Etanercept
-30 minutes 0 ± 00 ± 0
0 minute 6056 ± 925 2299 ± 357
*
30 minutes 2122 ± 371 2057 ± 349
60 minutes 740 ± 153 1592 ± 258
*
90 minutes 585 ± 112 1108 ± 279
*
120 minutes 338 ± 44 721 ± 209
150 minutes 204 ± 7 580 ± 193
*
Data are represented with meansigma methods ± standard error, the pg/ml of unit.
* be meant and compare p＜005 with vehicle-treated group at identical time point.
Baseline=-30 minute,
Ischemia finishes=0 minute, perfusion=30,60 again, 90...... minute.
In this process of the test, the thoracic cavity is opened in operation, but has stable TNF α concentration, Cmax 242 ± 90pg/mL without any the rat of inductive obstruction (sham-operation animal) in entire test.These data show that angiemphraxis causes the TNF alpha levels to increase greatly, reaches the peak when ischemic period finishes.The result shows that also etanercept reacts on the huge TNF α concentration impulse of angiemphraxis when significantly reducing by 0 minute.
The TNF alpha-2 antagonists is handled the survival percentage ratio after the perfusion of myocardial ischemia/again of influencing that blocks in the rat for mortality rate having.In this test, also assess.The results are summarized in following table.
Carry out myocardial ischemia/dabbling again and open the breast rat, having and do not having etanercept (3mg/kg
Survival percentage ratio in the time of iv)
Group excipient Etanercent
-30 minutes 100 100
0 minute 100 100
30 minutes 83 100
60 minutes 66 100
90 minutes 50 89
120 minutes 33 89
*
150 minutes 17 88
*
Data are represented with survival percentage ratio.
* be meant and compare p＜0.05 with vehicle-treated group at identical time point.
Baseline=-30 minute,
Ischemia finishes=0 minute, perfusion=30,60 again, 90...... minute.
In this standard pharmacology test method, before blocking, give etanercept (3mg/kg i.v.) immediately, significantly reduce because myocardial ischemia/mortality rate that causes of perfusion again.For the somatic death rate, begin to occur different pouring into the later stage (t=90 minute) again.For example, in the time of t=90 minute, 9 rats of vehicle-treated group have 4 death, and 9 rats of the etanercept processed group of comparing have only 1 death, although difference does not reach significance,statistical (p=0.08).When pouring into 120 and 150 minutes again, the difference between etanercept and the excipient matched group, it is remarkable to have reached statistics.In observed vehicle-treated group 7 routine death, 6 examples are owing to acute pump failure and carrying out property bradycardia, and also having an animal is to die from the early stage ventricular arrhythmia afterwards of perfusion again.Two routine death of etanercept processed group all are because bradycardia and pump failure.With the infraction size that left ventricle percentage ratio is represented, be 24 ± 3% in the Etanercept group, be 26 ± 2% at the excipient matched group, show that different survival rates is not the result that infraction varies in size.These results show, handle with the TNF alpha-2 antagonists, reduced the mortality rate that the perfusion of myocardial ischemia/again causes, supposition may be owing to stoped the cascade reaction that produces sphingol from sphingomyelins, and the TNF α that this cascade reaction occurs in the response ischemia/reperfusion injury is with after TNFR1 combines.
Based on the result who obtains in above-mentioned standard pharmacology test method, the TNF alpha-2 antagonists is effective reducing after the myocardial infarction on the mortality rate.Based on the result who obtains, the TNF alpha-2 antagonists also handle or suppress ischemic event after cell injury or cell death aspect be effective.More specifically, the invention provides a kind of processing or suppress because myocardial infarction, myocardial ischemia, retinal ischemia, retina medium-sized artery are blocked, peripheral arterial occlusion (for example, thromboembolism), the cell injury that causes of the damage, artery thrombosis and the obstruction that cause of of short duration ischemic episode (for example, cerebral ischemia attack), Ischemic Stroke, ischemic obstruction of artery cold injury and crush injury or a kind of method of cell death.The present invention also is effective for handling or suppressing reperfusion injury.Handling with the TNF alpha-2 antagonists also all is being that effectively this process comprises ischemic event and perfusion more thereafter before the process or during the process, transplant operation for example, and donor organ is through ischemia after a while, and then pours into by the receptor blood supply again; Angioplasty or coronary vasodilator inner support are placed; Thrombolytic treatment; Cardiac valve replacement; And by-pass operation.
The TNF alpha-2 antagonists can be prepared separately according to the reagent combination standard method, perhaps in conjunction with one or more pharmaceutically suitable carrier administrations.That route of administration comprises is oral, intestinal medicine for external use (including, but are not limited to intravenous injection, intramuscular injection, subcutaneous injection), intranasal, intraperitoneal, rectum, intravaginal, percutaneous dosing.Route of administration is according to the character of TNF alpha-2 antagonists and medication is former thereby change.For example, when TNF alpha-2 antagonists during in the very fast degraded of enteral, the just preferred intestinal medicine for external use that uses.For handling or suppress cell injury or cell death behind the ischemic event, because the acid labile of etanercept and need begin onset fast preferably provides etanercept with intravenous injection.
When by oral when the TNF alpha-2 antagonists is provided, can provide with such form, but as tablet, capsule dispersed powders, granule, the suspension that perhaps contains for example about 0.05% to 5% suspending agent, the syrup that contains for example about 10% to 50% saccharide, and the elixir that contains for example about 20% to 50% ethanol, and similar form, when perhaps providing, for example contain in the medium approximately with sterile injectable solution or waiting to ooze that the form of the injectable suspensions of 0.05-5% suspending agent provides outward by intestinal.These pharmaceutical preparatioies can contain, for example, about 0.05% to 90% with carrier-bound active component, more frequent is about 5%～60wt%.
Prescription for tablet or capsule administration, can comprise solid carrier, comprise starch, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, sucrose and Kaolin, and liquid-carrier comprises sterilized water, Polyethylene Glycol, non-ionic surface active agent and edible oil, for example corn, Semen arachidis hypogaeae and Oleum sesami, these all are fit to the character and the required specific form of medication of active component.Also can preferably include the adjuvant that is generally used for pharmaceutical compositions, for example flavoring agent, coloring agent, antiseptic and antioxidant, for example vitamin E, ascorbic acid, BHT and BHA.
When outside the intestinal or intraperitoneal when giving the TNF alpha-2 antagonists, can be in the water that suitably mixes surfactant such as hydroxyl-propyl cellulose, the solution of these reactive compounds or suspension is used as free alkali or pharmaceutically acceptable salt prepares.Also can be in glycerol, liquid macrogol and its mixture in oil, the preparation dispersion.Under routine storage and service condition, these preparations contain antiseptic to prevent growth of microorganism.
The medicine type that is fit to injection comprises, is used for preparing aseptic aqueous solution or the dispersion and the sterilized powder of aseptic injectable solution or dispersion temporarily.In all cases, preparation must be aseptic, and must have flowability, is easy to injection.Must be stable under manufacturing and storage requirement, must can prevent microbial contaminations such as antibacterial and fungus.Carrier can be solvent or disperse medium, for example contains water, ethanol, polyol (for example, glycerol, propylene glycol and liquid macrogol), its suitable mixture and vegetable oil.The for example commercial Etanercept that provides is the freeze-dried powder that white does not contain antiseptic, rebuilds the rear intestinal medicine for external use at water.
The dosage of TNF alpha-2 antagonists, expection is according to character, the medication reason of TNF alpha-2 antagonists and different change of individual patient of receiving treatment.For long-term treatment, recommend usually to monitor adjustment dosage according to the doctor with the minimum effective dose begin treatment.With the etanercept treatment, the intravenous dosage of design can be 0.05-25mg/kg etanercept.At specific ischemic event, consideration can give TNF alpha-2 antagonists with single dosage or a plurality of dosage, perhaps at the ischemic event long-term prescription that will take place, to suppress cell injury or necrosis.For example, expection can suffer the patient TNF alpha-2 antagonists of of short duration ischemic event for a long time, and wherein of short duration ischemic event takes place in being everlasting for a long time.In addition, consideration TNF alpha-2 antagonists also can estimated preventive usage (for example, before transplant operation or the angioplasty) under the situation that ischemic event will take place.
Claims (24)
1. handle or suppress the method that cell injury in the mammal that needs takes place to have behind the ischemic event or suppress its cell death for one kind, this method comprises the TNF alpha-2 antagonists that effective dose is provided to this mammal.
2. the method for claim 1, cell injury wherein or death result from myocardial infarction, myocardial ischemia, retinal ischemia, retina medium-sized artery obstruction, peripheral arterial occlusion, of short duration ischemic episode, Ischemic Stroke, ischemic obstruction of artery, chilblain, artery thrombosis and obstruction or crush injury.
3. the method for claim 1, TNF alpha-2 antagonists wherein is a kind of TNF receptor/domain-immunoglobulin fusion proteins.
4. method as claimed in claim 3, TNF alpha-2 antagonists wherein comprises one section TNFR fragment and human immunoglobulin heavy chain's some or all of constant region.
5. method as claimed in claim 4, TNF alpha-2 antagonists wherein is etanercept.
6. method as claimed in claim 4, TNF alpha-2 antagonists wherein is p55TNFR:Fc.
7. method of handling or suppressing to have reperfusion injury in the mammal that needs, this method comprises the TNF alpha-2 antagonists that effective dose is provided to this mammal.
8. method as claimed in claim 7, damage wherein result from transplant operation, angioplasty, intracoronary stent placement, thromboembolism treatment, cardiac valve replacement or by-pass operation.
9. method as claimed in claim 7, TNF alpha-2 antagonists wherein are a kind of TNF receptor/domain-immunoglobulin fusion proteins.
10. method as claimed in claim 9, TNF alpha-2 antagonists wherein comprises one section TNFR fragment and human immunoglobulin heavy chain's some or all of constant region.
11. method as claimed in claim 10, TNF alpha-2 antagonists wherein is etanercept.
12. method as claimed in claim 10, TNF alpha-2 antagonists wherein is p55TNFR:Fc.
13. a reduction has the method for the cardiac muscle of mammal infraction back mortality rate that needs, this method comprises the TNF alpha-2 antagonists that effective dose is provided to this mammal.
14. method as claimed in claim 13, TNF alpha-2 antagonists wherein are a kind of TNF receptor/domain-immunoglobulin fusion proteins.
15. method as claimed in claim 14, TNF alpha-2 antagonists wherein comprises one section TNFR fragment and human immunoglobulin heavy chain's some or all of constant region.
16. method as claimed in claim 15, TNF alpha-2 antagonists wherein is etanercept.
17. method as claimed in claim 15, TNF alpha-2 antagonists wherein is p55TNFR:Fc.
18.TNF alpha-2 antagonists is used for preventing, handling or suppress because the purposes of the medicine of cell injury that ischemic event causes or cell death in manufacturing.
19.TNF alpha-2 antagonists is used for preventing, handling or suppress the purposes of the medicine of reperfusion injury in manufacturing.
20.TNF the purposes of alpha-2 antagonists medicine of mortality rate after manufacturing is used for reducing myocardial infarction.
21. purposes as claimed in claim 18, cell injury wherein or death result from myocardial infarction, myocardial ischemia, retinal ischemia, retina medium-sized artery obstruction, peripheral arterial occlusion, of short duration ischemic episode, Ischemic Stroke, ischemic obstruction of artery, chilblain, artery thrombosis and obstruction or crush injury.
22. as each described purposes among the claim 18-21, TNF alpha-2 antagonists wherein is a kind of TNF receptor/domain-immunoglobulin fusion proteins.
23. as each described purposes among the claim 18-21, TNF alpha-2 antagonists wherein comprises one section TNFR fragment and human immunoglobulin heavy chain's some or all of constant zone.
24. as each described purposes among the claim 18-21, TNF alpha-2 antagonists wherein is etanercept.
Applications Claiming Priority (2)
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|---|---|---|---|
| US50186200A | 2000-02-10 | 2000-02-10 | |
| US09/501,862 | 2000-02-10 |
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| CN1406132A true CN1406132A (en) | 2003-03-26 |
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| EP (1) | EP1261364A1 (en) |
| JP (1) | JP2003522155A (en) |
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| AR (1) | AR033965A1 (en) |
| AU (1) | AU2001236764A1 (en) |
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| ES2311094T3 (en) * | 2002-02-27 | 2009-02-01 | Immunex Corporation | STABILIZED COMPOSITION OF TNFR-FC THAT INCLUDES ARGININA. |
| US9028822B2 (en) | 2002-06-28 | 2015-05-12 | Domantis Limited | Antagonists against TNFR1 and methods of use therefor |
| EP1909831A4 (en) | 2005-06-14 | 2013-02-20 | Amgen Inc | Self-buffering protein formulations |
| US10485869B2 (en) | 2011-10-18 | 2019-11-26 | Coherus Biosciences, Inc. | Etanercept formulations stabilized with meglumine |
| SG11201401562RA (en) | 2011-10-18 | 2014-09-26 | Coherus Biosciences Inc | Etanercept formulations stabilized with sodium chloride |
| CN104661651A (en) | 2012-07-09 | 2015-05-27 | 科荣生生物科学公司 | Etanercept formulations exhibiting marked reduction in sub-visible particles |
| ES2657377T3 (en) | 2012-09-11 | 2018-03-05 | Coherus Biosciences, Inc. | Etanercept folded correctly with high purity and excellent performance |
| JP6884858B2 (en) | 2016-10-21 | 2021-06-09 | アムジエン・インコーポレーテツド | Pharmaceutical product and its manufacturing method |
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| US7608262B2 (en) * | 1996-02-16 | 2009-10-27 | The Kennedy Institute Of Rheumatology | Methods of preventing or treating thrombosis with tumor necrosis factor antagonists |
| AR016551A1 (en) * | 1997-07-30 | 2001-07-25 | Smithkline Beecham Corp | DERIVATIVES OF 2-OXINDOL, PHARMACEUTICAL COMPOSITIONS THAT INCLUDE THEM AND THE USE OF THE SAME FOR THE MANUFACTURE OF MEDICINES |
| NL1007890C2 (en) * | 1997-12-24 | 1999-07-12 | Dutch Trading Dutra B V | Assembly of a rail system, at least one piece of cloth and a number of fastening elements for fixing the cloth to the rail system. |
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| WO2000062790A2 (en) * | 1999-04-19 | 2000-10-26 | Immunex Corporation | Soluble tumor necrosis factor receptor treatment of medical disorders |
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