WO2008100258A1 - Intraperitoneal administration of antithrombin iii, related compositions and methods - Google Patents
Intraperitoneal administration of antithrombin iii, related compositions and methods Download PDFInfo
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- WO2008100258A1 WO2008100258A1 PCT/US2007/003977 US2007003977W WO2008100258A1 WO 2008100258 A1 WO2008100258 A1 WO 2008100258A1 US 2007003977 W US2007003977 W US 2007003977W WO 2008100258 A1 WO2008100258 A1 WO 2008100258A1
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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
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
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- 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
Definitions
- AT is a serine protease inhibitor and inhibits multiple components of the common, intrinsic and extrinsic coagulation pathways: .thrombin, factor (F) IXa, FXa and FXIa [4,9,10]. AT also functions with heparin and tissue factor (TF) pathway inhibitor to inactivate the TF- FVIIa complex [H]. AT reduces the inflammatory response through interaction with endothelium to produce prostacyclin, thereby reducing neutrophil activation and cytokine production [12—14]. AT precludes generalized microvascular thrombosis, preventing bacteria in the tissues from reaching the systemic circulation via the capillaries.
- TF tissue factor pathway inhibitor
- Severe intra-abdominal infections such as peritonitis and sepsis, result in activation of coagulation and inflammatory cascades systemically and even in extraperitoneal organs, with the lungs being the first and most frequently affected organ [8,19,20].
- Multiple studies have demonstrated distinction between infection and inflammation at the different sites of the body, suggesting that these responses are compartmentalized [19,21].
- a method for producing a systemic anticoagulant or anti-inflammatory effect in a subject comprises administering antithrombin III intraperitoneally in an amount effective to produce the systemic anticoagulant or anti-inflammatory effect in the subject.
- the effect is effective in treating the subject.
- the effect is effective for prophylaxis in the subject.
- a method for producing a pulmonary anticoagulant or anti-inflammatory effect in a subject comprising administering antithrombin III intraperitoneally in an amount effective to produce the pulmonary anticoagulant or antiinflammatory effect in the subject is provided.
- the effect is effective in treating the subject. In another embodiment, the effect is effective for prophylaxis in the subject.
- the treatment or prophylaxis can be for the treatment or prophylaxis of any of the disease, conditions or indications provided herein.
- a method of treating sepsis in a subject comprising administering antithrombin III intraperitoneally in an amount effective to treat sepsis in the subject.
- a method of preventing sepsis in a subject comprising administering antithrombin III intraperitoneally in an amount effective to prevent sepsis in the subject is provided.
- the amount effective is also effective in treating an injury local to the peritoneum in the subject.
- the amount is also effective to produce a systemic or pulmonary anticoagulant or antiinflammatory effect in the subject.
- a method of treating a subject with an injury local to the peritoneum comprises administering antithrombin III intraperitoneally in an amount effective to treat the injury is provided.
- the antithrombin III is administered by intraperitoneal injection or intraperitoneal lavage.
- the amount is also effective to treat or prevent sepsis.
- the amount is also effective to produce a systemic or pulmonary anticoagulant or anti-inflammatory effect in the subject.
- a method of treating a subject with disseminated intravascular coagulation comprises administering antithrombin III intraperitoneally in an amount effective to treat the subject-
- a method of preventing disseminated intravascular coagulation comprises administering antithrombin III intraperitoneally in an amount effective to prevent DIC in the subject.
- the subject has an injury local to the peritoneum.
- the amount effective is also effective in treating the injury local to the peritoneum, hi another embodiment, the subject has or is at risk of sepsis, hi one embodiment, the amount effective is also effective in treating or preventing sepsis. In still another embodiment, the subject does not have pancreatitis.
- the methods provided can, in one embodiment, further comprise assessing the effect of the administration in the subject.
- the effect is anticoagulation or anti-inflammation.
- anticoagulation or anti-inflammation is assessed in the subject systemically (e.g., using plasma samples).
- anticoagulation or anti-inflammation in the pulmonary compartment of the subject is assessed.
- the antithrombin III is administered by peritoneal lavage or intraperitoneal injection.
- the antithrombin III is administered at a high dose.
- the subject has sepsis. In one embodiment, the subject has severe sepsis or septic shock, In still a further embodiment, the subject has an injury local to the peritoneum. In yet a further embodiment, the subject has disseminated intravascular coagulation (DIC). In another embodiment, the subject does not have DIC. In yet another embodiment, the subject is not at risk of DIC. In still another embodiment, the subject does not have and is not at risk of DIC. In still another embodiment, the subject does not have pancreatitis.
- DIC disseminated intravascular coagulation
- the subject has an injury local to the peritoneum and has or is at risk of sepsis, hi one embodiment, the subje ⁇ t that has an injury that is local to the peritoneum and/or has or is at risk of sepsis, does not have pancreatitis and/or has or is not at risk of DIC.
- the subject has not been and/or is not being treated with heparin.
- the subject has been treated with heparin or is being treated with heparin.
- the antithrombin III is plasma-derived antithrombin III. In another embodiment, the antithrombin III is recombinant antithrombin III. In still another embodiment, the antithrombin III is antithrombin III that is milk-derived (e.g., transgenically produced in the milk of a non-human mammal). The non-human mammal, in one embodiment, is a goat.
- the subject is human.
- the methods provided can further comprise administering another therapeutic agent to the subject.
- the other therapeutic agent is an agent for treating sepsis, DIC, peritonitis or ovarian cancer.
- the other therapeutic agent is for treating a gastrointestinal injury or infection.
- the other therapeutic agent is for treating an injury local to the peritoneum.
- the other therapeutic agent is an anticoagulant.
- the other therapeutic agent is an anti-inflammatory agent.
- the other therapeutic agent can be administered concomitantly with, subsequent to or prior to the administration of antithrombin III.
- the other therapeutic agent is administered locally.
- the other therapeutic agent is administered intraperitoneally.
- the other therapeutic agent is administered by a mode other than intraperitoneally.
- the other therapeutic agent is administered intravenously, parenterally, intramuscularly, intracavity or subcutaneously.
- the administration is by inhalation.
- the administration is intranasal, oral or sublingual.
- compositions comprising antithrombin III are provided.
- the antithrombin III is formulated for intraperitoneal administration.
- the composition is formulated for administration by intraperitoneal lavage.
- the composition is formulated for administration by intraperitoneal injection.
- compositions of antithrombin III further comprise another therapeutic agent.
- the other therapeutic agent is an agent for treating sepsis, DIC, peritonitis or ovarian cancer.
- the other therapeutic agent is for treating a gastrointestinal injury or infection.
- the other therapeutic agent is for treating an injury local to the peritoneum.
- the other therapeutic agent is an anticoagulant.
- the other therapeutic agent is an anti-inflammatory agent.
- compositions comprising another therapeutic agent can also be formulated for administration by intraperitoneal administration.
- compositions comprising other therapeutic agents e.g., without antithrombin
- Fig. 1 depicts the time line of the experiment with surgical treatment and lavage intervention.
- Fig. 2 shows the increased abdominal and reduced pulmonary clotting times after antithrombin (AT) lavage.
- Fig.3 shows that abdominal thxombin-anti-thrombin complexes (TAT) were reduced after AT lavage.
- P,-values represent differences between CLP-saline and CLP-AT (ANOVA).
- Fig. 4 provides fibrin degradation product D-dimer levels, measured in peritoneal lavage fluid (PLF), plasma and lungs, are reduced after AT lavage.
- Dotted line represents sham group. Values are expressed as means ⁇ SEM. P-values represent differences between CLP-saline and CLP-AT (ANOVA).
- Fig. 5 shows that AT lavage decreased abdominal and pulmonary cytokine and cellular inflammatory responses.
- Abdominal and pulmonary concentrations of interleukin-6 (IL-6; Fig. 5A and Fig.5D, respectively) and keratinocyte-derived chemokine (KC; Fig.5B and Fig. 5E, respectively) were measured to assess pro-inflammatory cytokine responses.
- Leukocyte count in peritoneal lavage fluid (Fig. 5C) and myeloperoxidase activity (MPO; Fig. 5F) assessed cellular response.
- FIG. 6 shows the results of the histological and immunostaining of peritoneum.
- Slices of peritoneum of CLP-AT (Fig. 6 A and Fig. 6B), CLP-saline (Fig. 6C and Fig. 6D) and sham mice (Fig. 6E and Fig. 6F) were stained with hematoxillin-eosin (upper panel), and fibrin depositions were stained immunohistochemically (lower panel).
- CLP-AT mice had less inflammatory cells and thickened peritoneal layer (Fig. 6A) compared to CLP- saline (Fig. 6C).
- Fig. 7 provides Kaplan-Meier curves of sham, CLP-saline and CLP-AT groups. 100% survival rate in sham animals (-— ), 62% survival in CLP-saline animals ( — ), 83% survival in CLP-AT ( — ). P ⁇ 0.03 CLP-saline vs. CLP- ⁇ AT (cumulative survival, LogRank).
- Inflammation was assessed by keratinocyte-derived chemokine (KC), interleukin-l ⁇ (IL-I ⁇ ), IL-6, tumor necrosis factor-alpha (TNF- ⁇ ). leukocyte count, myeloperoxidase and bacterial load. rhAT lavage was found to prolong abdominal clotting times and reduced D-dimers and TAT levels, indicating inhibited abdominal coagulation. Further, pulmonary clotting time and D-dimers decreased towards normal. Abdominal fibrinolysis was also reduced after rhAT lavage, as were abdominal IL- 1 ⁇ , KC, leukocytes and bacterial load.
- KC keratinocyte-derived chemokine
- IL-I ⁇ interleukin-l ⁇
- IL-6 tumor necrosis factor-alpha
- TNF- ⁇ tumor necrosis factor-alpha
- Pulmonary TNF-Ci, KC, myeloperoxidase and histopathological injury were decreased. Survival improved from 62% (saline lavage) to 83% (rhAT lavage, P ⁇ 0.05).
- the high-dose rhAT lavage inhibits coagulation activation and reduced inflammatory responses in both abdominal and pulmonary compartments, ultimately improving survival. In addition, higher doses can be used without the risk of complications.
- antithrombin also referred to herein as antithrombin III
- intraperitoneally is intended herein to refer to administration via the peritoneal compartment (i.e., administration that results in contact with the peritoneum or the compartment that is enclosed by the peritoneum).
- administration includes intraperitoneal injection, peritoneal lavage, etc.
- Such forms of administration are well known in the art. For example, peritoneal lavage with saline is routinely performed during laparotomy for peritonitis [8].
- antithrombin can be used to produce a number of effects in a subject as well as for a number of therapeutic purposes.
- the methods and compositions provided can be used, for example, to produce a systemic or pulmonary anticoagulant or antiinflammatory effect in a subject.
- such effects are in addition to local effects and are effective in treating and/or preventing sepsis in the subject, but are not necessarily so.
- serpsis refers to the serious medical condition resulting from the immune • response to an infection.
- severe sepsis refers to sepsis with acute organ dysfunction
- septic shock refers to sepsis with refractory arterial hypotension.
- the resulting effects on coagulation can be assessed by clotting time by standard procoagulant assay or the measurement of TAT complexes, D-dimer concentrations, etc.
- Anti-inflammatory effects can be assessed by determining leukocyte count, neutrophil count (e.g., by measuring myeloperoxidsae activity) or by measuring IL-6, IL-I ⁇ , tumor necrosis factor or keratinocyte-derived chemokine (KC) concentrations, for example.
- the methods provided, therefore, can also include a step of assessing the effect in a subject.
- assessing an effect in a subject refers to determining whether or not subsequent to the administration of antithrombin, anticoagulation or anti-inflammation occurs locally, systemically or in the pulmonary compartment. In one embodiment, systemic or pulmonary anticoagulation or anti-inflammation effects are assessed. Such an assessment can be performed using one of the methods provided above or those provided in the Examples. Further methods will be known to those of ordinary skill. in the art.
- Producing anticoagulant and anti-inflammatory effects with antithrombin administration can be beneficial for treatment or prophylaxis in a subject.
- “treat”, “treating” or “treatment” refers to reducing the symptoms related to an existing disease, condition or indication provided herein; slowing or halting of the progression of the existing disease, condition or indication; curing the existing disease, condition or indication; or otherwise providing some benefit to a subject that has the existing disease, condition or indication.
- “Prophylaxis”, as used herein, refers to preventing or delaying the onset of a disease, condition or indication or reducing the risk of developing the disease, condition or indication.
- the methods and compositions provided can, therefore, be used in the treatment or prophylaxis of a number of diseases, conditions or indications.
- the methods and compositions provided can be used, for example, for the treatment or prophylaxis of sepsis, disseminated intravascular coagulation (DIC), peritonitis, ovarian cancer, or for any gastrointestinal injury or infection.
- the methods and compositions can be used for any injury that is local to the peritoneum. "Injuries local to the peritoneum” refer to any injury, such as trauma or infection, that occurs in the vicinity of the peritoneum such that intraperitoneal administration of a therapeutic agent would be expected to have some local effect.
- the treatment of any of the diseases, conditions or indications provided with antithrombin can result in the treatment of the disease or condition itself as well as the treatment or prophylaxis of sepsis. Therefore, the methods and compositions provided can, in some embodiments, be used to treat any disease or condition local to the peritoneum that can result in sepsis.
- the diseases, conditions or indications are known to those of ordinary skill in the art and/or are described, for instance, in Harrison 's Principles of Internal Medicine (McGraw Hill, Inc., New York).
- the antithrombin can be plasma-derived, recombinantly produced, transgenically produced or produced by any technique known to those of ordinary skill in the art.
- Plasma- derived and recombinantly produced antithrombin can be obtained commercially and/or obtained by methods known in the art.
- Antithrombin that is transgenically produced can be produced in the milk of a non-human mammal.
- An example of such an antithrombin is ATryn®, which can be obtained commercially from GTC Biotherapeutics, Inc. (Framingharn, MA).
- Such antithrombin can also be produced by methods known to those of skill in the art. Examples of transgenically produced antithrombin and/or methods of transgenic production can be found in U.S. Patent Nos.
- antithrombin molecules as well as the methods of their production are expressly incorporated herein by reference.
- the antithrombin can also be in mutated form. Examples of such mutated versions of antithrombin are provided in EP Publication No. EPl 194033 and are expressly incorporated herein by reference.
- the antithrombin can be functional variants of any of the above examples. Such functional variants include conservatively substituted versions, analogues, mimetics as well as antithrombin molecules with altered glycosylation.
- a “conservative amino acid substitution” or “conservative substitution” refers to an amino acid substitution in which the substituted amino acid residue is of similar charge as the replaced residue and is of similar or smaller size than the replaced residue.
- Conservative substitutions of amino acids include substitutions made amongst amino acids within the following groups: (a) the small non-polar amino acids, A, M, I, L 3 and V; (b) the small polar amino acids, G, S, T and C; (c) the amido amino acids, Q and N; (d) the aromatic amino acids, F, Y and W; (e) the basic amino acids, K, R and H; and (f) the acidic amino acids, E and D.
- substitutions which are charge neutral and which replace a residue with a smaller residue may also be considered “conservative substitutions" even if the residues are in different groups (e.g., replacement of phenylalanine with the smaller isoleucine).
- conservative amino acid substitution also refers to the use of amino acid analogs.
- the antithrombin can be administered at a high dose.
- "High dose” is intended to refer to any dose that when given would be expected to increase the plasma antithrombin level to a level above that of normal plasma.
- the dose is a dose that when given intravenously would be expected to increase the plasma antithrombin level to a level above that of normal plasma.
- the dose results in or would be expected to result in a plasma level that is at least 2-, 3-, 4-, or 5-fold higher than normal plasma levels.
- the dose is at least 100 U/kg, 125 U/kg, 150 U/kg, 200 U/kg, 250 U/kg, 300 U/kg, 350 U/kg, 400 U/kg, 500 U/kg or more.
- the dose is at least 1, 2, 3, 4, 5 U/ml or more.
- the absolute amount will depend upon a variety of factors (including whether the administration is in conjunction with other methods of treatment, the number of doses and individual patient parameters including age, physical condition, size and weight) and can be determined with routine experimentation. It is preferred, generally, that a maximum dose be used, that is, the highest safe dose according to sound medical judgment.
- the methods provided can further include the administration of another therapeutic agent.
- the other therapeutic agents include any agent that would provide some benefit to a subject that has or is at risk of having any of the diseases, conditions or indications provided herein.
- the other therapeutic agent can also be used for treatment or prophylaxis.
- at risk of having refers to any subject that would be considered to have some increased probability of developing the disease, condition or indication.
- not at risk of having is intended to refer to any subject that would be considered to not have an increased probability of developing the disease, condition or indication. It is within the ordinary skill of those in the art to be able to determine whether or not a subject is at risk of having a disease, condition or indication.
- the other therapeutic agent can be, for example, activated protein C (e.g., recombinant activated protein C (rhAPC), Xigris); thrombomodulin; tissue factor pathway inhibitor (TFPI); anti-TNF receptor antibodies; antibodies that modulate the TNF signalling cascade (e.g., Remicade, Humira, MAKl 95); Enbrel; or antibodies that inhibit immune cells from crossing blood vessel walls to reach various tissues (e.g., Tysabri).
- activated protein C e.g., recombinant activated protein C (rhAPC), Xigris
- thrombomodulin e.g., recombinant activated protein C (rhAPC), Xigris
- TFPI tissue factor pathway inhibitor
- anti-TNF receptor antibodies e.g., anti-TNF receptor antibodies
- antibodies that modulate the TNF signalling cascade e.g., Remicade, Humira, MAKl 95
- Enbrel e.
- the other therapeutic agent can be an anticoagulant.
- Anticoagulants include heparin, warfarin, Coumadin, dicumarol. phenprocournon, acenocoumarol, ethyl biscoumacetate and indandione derivatives.
- the other therapeutic agent can be an anti-inflammatory agent.
- Anti-inflammatory agents include Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac ; Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; D
- anti-inflammatory agents include the following aforementioned agents: activated protein C (e.g., recombinant activated protein C (rhAPC), Xigris); thrombomodulin; tissue factor pathway inhibitor (TFPI); anti-TNF receptor antibodies; antibodies that modulate the TNF signalling cascade (e.g., Remicade, Humira, MAK 195); Enbrel; and antibodies that inhibit immune cells from crossing bloo ⁇ vessel walls to reach various tissues (e.g., Tysabri).
- activated protein C e.g., recombinant activated protein C (rhAPC), Xigris
- thrombomodulin e.g., tissue factor pathway inhibitor (TFPI); anti-TNF receptor antibodies; antibodies that modulate the TNF signalling cascade (e.g., Remicade, Humira, MAK 195); Enbrel; and antibodies that inhibit immune cells from crossing bloo ⁇ vessel walls to reach various tissues (e.g., Tysabri).
- the other therapeutic agent can be an antibacterial agent.
- Antibacterial agents include Acedapsone; Acetosulfone Sodium; Alamecin; Alexidine; Amdinocillin; Amdinocillin Pivoxil; Amicycline; Amifloxacin; Amifloxacin Mesylate; Amikacin; Amikacin Sulfate; Aminosalicylic acid; Aminosalicylate sodium; Amoxicillin; Amphomycin; Ampicillin; Ampicillin Sodium; Apalcillin Sodium; Apramycin; Aspartocin; Astromicin Sulfate; Avilamycin; Avoparcin; Azithromycin; Azlocillin; Azlocillin Sodium; Bacampicillin Hydrochloride; Bacitracin; Bacitracin Methylene Disalicylate; Bacitracin Zinc; Bambermycins; Benzoylpas Calcium; Berythromycin ; Betamicin Sulfate; Biapenem; Biniramycin; Biphen
- Cefuroxhne Axetil; Cefuroxime Pivoxetil; Cefuroxime Sodium; Cephacetrile Sodium; Cephalexin; Cephalexin Hydrochloride; Cephal ⁇ glycin; Cephaloridine; Cephalothin Sodium; Cephapirin Sodium; Cephradine; Cetocycline Hydrochloride; Cetophenicol; Chloramphenicol; Chloramphenicol Palmitate; Chloramphenicol Pantothenate Complex ; Chloramphenicol Sodium Succinate; Chlorhexidine Phosphanilate; Chloroxylenol; Chlortetracycline Bisulfate; Chlortetracycline Hydrochloride; Cinoxacin; Ciprofloxacin;
- Ciprofloxacin Hydrochloride Cirolemycin ; Clarithromycin; Clinafloxacin Hydrochloride; Clindamycin; Clindamycin Hydrochloride; Clindamycin Palmitate Hydrochloride; Clindamycin Phosphate; Clofazimine ; Cloxacillin Benzathine; Cloxacillin Sodium; Cloxyquin; Colistimethate Sodium; Colistin Sulfate; Coumermycin; Coumermycin Sodium; Cyclacillin; Cycloserine; Dalfopristin; Dapsone ; Daptomycin; Demeclocycline; Demeclocycline Hydrochloride; Demecyciine; Denofungin ; Diaveridine; Dicloxacillin; Dicloxacillin Sodium; Dihydrostreptomycin Sulfate; Dipyrithione; Dirithromycin; Doxycycline; Doxycycline Calcium ; Doxycycline Fosfatex; Doxycycline Hyclate;
- the other therapeutic agent can be an antimicrobial agent.
- Antimicrobial agents include Aztreonam; Chlorhexidine Gluconate; Imidurea; Lycetamine; Nibroxane; Pirazmonam Sodium; Propionic Acid ; Pyrithione Sodium; Sanguinarium Chloride ; and Tigemonam Dicholine.
- the other therapeutic agent can be an antiviral agent.
- Antiviral agents include nucleotide analogues which include acyclovir, gancyclovir, idoxuridine, ribavirin, dideoxyinosine, dideoxycytidine and zidovudine (azidothymidine).
- the other therapeutic agent can be an anti-infective, which include Difloxacin Hydrochloride ; Lauryl Isoquinolinium Bromide; Moxalactam Disodium; Ornidazole; Pentisomicin; Sarafloxacin Hydrochloride; Protease inhibitors of HIV and other retroviruses; Integrase Inhibitors of HIV and other retroviruses; Cefaclor (Ceclor); Acyclovir (Zovirax); Norfloxacin (Noroxin); Cefoxitin (Mefoxin); Cefuroxirne axetil (Ceftin); and Ciprofloxacin (Cipro).
- Difloxacin Hydrochloride Lauryl Isoquinolinium Bromide; Moxalactam Disodium; Ornidazole; Pentisomicin; Sarafloxacin Hydrochloride; Protease inhibitors of HIV and other retroviruses; Integrase Inhibitors of HIV and other retroviruse
- the other therapeutic agent can be an anti-cancer agent.
- Anti-cancer agents include Acivicin; Aclarubicin; Acodazole Hydrochloride; Acronine; Adriamycin; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnaflde Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; Chloramb
- Mitindomide Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane; Porf ⁇ mer Sodiuim; Porf ⁇ romycin; Prednimustine; Procarbazine Hydrochloride; Puromyci ⁇ ; Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol; Safingol Hydrochloride; Semusti ⁇ e; Simtrazene; Sparfosate Sodium; Sparsomycin; Spiroger
- the other therapeutic agent can be an analgesic.
- Analgesics include Acetaminophen; AIfentanil Hydrochloride; Aminobenzoate Potassium; Aminobenzoate Sodium; Anidoxime; Anileridine; Anileridine Hydrochloride; Anilopam Hydrochloride; Anirolac; Antipyrine; Aspirin; Benoxaprofen; Benzydamine Hydrochloride; Bicifadine Hydrochloride; Brifentanil Hydrochloride; Bromadoline Maleate; Bromfenac Sodium; Buprenorphine Hydrochloride; Butacetin; Butixirate; Butorphanol; Buto ⁇ hanol Tartrate; Carbamazepine; Carbaspirin Calcium; Carbiphene Hydrochloride; Carfentanil Citrate; Ciprefadol Succinate; Ciramadol; Ciramadol Hydrochloride; Clonixeril; Clon
- Other therapeutic agents also include agents for treating sepsis, DIC, peritonitis or ovarian cancer.
- Agents for treating sepsis include antibiotics, vasopressors (e.g., dopamine, dobutamine, norepinephrine (noradrenaline), epinephrine (adrenaline), vasopressin, dopexamine, phenylephrine, phosphodiesteradse inhibitors, etc.), activated protein C, etc.
- vasopressors e.g., dopamine, dobutamine, norepinephrine (noradrenaline), epinephrine (adrenaline), vasopressin, dopexamine, phenylephrine, phosphodiesteradse inhibitors, etc.
- activated protein C etc.
- Agents for treating DIC include plasma or blood (e.g., by transfusion), a fibrinogen replacements and anti-thrombotics.
- Agents for treating peritonitis include antibiotics and morphine.
- Agents for treating ovarian cancer include cisplatin, carboplatin, paclitaxel, etc.
- the subject is treated with a combination of paclitaxel and a platinum- based drug.
- the subject is treated with an agent, surgery, radiation or a combination thereof.
- compositions are also provided that include other therapeutic agents.
- the compositions can also include antithrombin, in some embodiments.
- Effective amounts of the compositions provided (or combinations thereof) are administered to subjects in need of such treatment. Effective amounts are those amounts (of one or a combination of therapeutics) which will result in a desired improvement in the condition, disease or disorder or symptoms of the condition, disease or disorder. Effective amounts also include those amounts that lead to the desired endpoint. Such amounts can be determined with no more than routine experimentation.
- the effective amounts can be the high doses provided above.
- the formulations of the invention are applied in pharmaceutically acceptable solutions. Such preparations may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants and optionally other therapeutic ingredients.
- compositions of the invention may be administered per s ⁇ (neat) or in the form of a pharmaceutically acceptable salt.
- the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention.
- Such pharmacologically and pharmacjeutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic.
- pharmaceutically acceptable salts can "be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
- Suitable buffering agents include: acetic acid and a salt (1-2% W/V); citric acid and a salt (1-3% W/V); boric acid and a salt (0.5-2.5% W/V); and phosphoric acid and a salt (0.8-2% W/V).
- Suitable preservatives include benzalkonium chloride (0.003-0.03% W/V); chlorobutanol (0.3-0.9% W/V); parabens (0.01-0.25% W/V) and thimerosal (0.004-0.02% W/V).
- compositions for medical use, which comprise one or more agents together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients.
- the pharmaceutical compositions can also, in some embodiments, include one or more additional therapeutic agents.
- pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other animal.
- carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
- the components of the pharmaceutical compositions also are capable of being commingled with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
- the pharmaceutically acceptable carrier can, in some embodiments, be sterile.
- a variety of other administration routes are also available, such as, for example, for the administration of one or more therapeutic agents in addition to the antithrombin.
- the particular mode selected will depend, of course, upon the particular active agent(s) selected, the desired results, the particular condition being treated and the dosage required for therapeutic efficacy.
- the methods of this invention may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of a desired response without causing clinically unacceptable adverse effects.
- One mode of administration is the parenteral route.
- parenteral includes subcutaneous injections, intravenous, intramuscular, intraperitoneal, intrasternal injection or infusion techniques.
- Other modes of administration include oral, mucosal, rectal, vaginal, sublingual, intranasal, intratracheal, inhalation, ocular, transdermal, etc.
- the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
- Formulations for injection may be presented in unit dosage form, e.g. , in ampoules or in multi-dose containers, with an added preservative.
- the compounds provided are administered by infusion pump.
- the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the, compounds to allow for the preparation of highly concentrated solutions.
- the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
- a suitable vehicle e.g., sterile pyrogen-free water
- the compounds may also be formulated as a depot preparation.
- Such long acting formulations may/ be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
- Suitable liquid pharmaceutical preparation forms are, for example, aqueous or saline solutions, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, etc.
- the pharmaceutical compositions also include granules, (micro)capsules, syrups, emulsions, suspensions or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants or solubilizers are customarily used as described above.
- the pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer, Science 249:1527-1533, 1990 and Langer and Tirrell, Nature, 2004 Apr 1; 428(6982): 487-92, which are incorporated herein by reference.
- compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
- Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the compounds of the invention, increasing convenience to the subject and the physician.
- Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer based systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone; nonpolymer systems that are lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-, di -and triglycerides; hydrogel release systems; silastic systems; peptide based systems and the like. Specific examples include, but are not limited to: (a) erosional systems in which the agent is contained in a form within a matrix, found in U.S.
- a pump-based hardware delivery system can be used, some of which are adapted for implantation.
- Controlled release can also be achieved with appropriate excipient materials that are biocompatible and biodegradable.
- These polymeric materials which effect slow release may be any suitable polymeric material for generating particles, including, but not limited to, nonbioerodable/non-bi ⁇ degradable and bioerodable/biodegradable polymers. Such polymers have been described in great detail in the prior art.
- polyamides include, but are not limited to: polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof, alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose triacetate, cellulose sulfate sodium
- non-biodegradable polymers examples include ethylene vinyl acetate, poly(meth) acrylic acid, polyamides, copolymers and mixtures thereof.
- biodegradable polymers examples include synthetic polymers such as polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butic acid), poly(valeric acid), poly(caprolactone), poly(hydroxybutyrate), poly(lactide- co-glycolide) and poly(lactide-co-ca ⁇ rolactone), and natural polymers such as alginate and other polysaccharides including dextran and cellulose, collagen, chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), albumin and other hydrophilic proteins, zein and other prolamines and hydrophobic proteins, copolymers and mixtures thereof.
- synthetic polymers such as polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butic acid), poly(vale
- these materials degrade either by enzymatic hydrolysis or exposure to water in vivo, by surface or bulk erosion. Th'e foregoing materials may be used alone, as physical mixtures (blends), or as co-polymers.
- the most preferred polymers are polyesters, polyanhydrides, polystyrenes and blends thereof.
- a subject is any human or non-human vertebrate, e.g., dog, cat, horse, cow, monkey, pig, mouse, rat.
- ATryn® Recombinant human AT
- GTC Biotherapeutics Framingham, MA
- Lyophilized ATryn® was'reconstituted with sterile water for injections to a concentration of 50 mg/mL (350 U/ml) according to the manufacturer's descriptions. Further dilutions (up to 3.0 U/mL) were made with sterile saline (0.9% NaCl, Fresenius Kabi's-Hertogenbosch, the Netherlands).
- a dose-finding study with doses between 3 and 12 U/mL rhAT demonstrated that all doses reduced aerobe and anaerobe bacterial load significantly.
- Intra-abdominal leukocyte counts were reduced in the highest (12 U/mL) and lowest (3 U/mL) dose groups.
- Abdominal keratinocyte-derived chemokine (KC) concentrations were most reduced in the 3 and 6 U/mL groups, but not in the 12 U/mL group, which also showed slightly higher mortality (two of six) as compared with the 3 and 6 U/mL groups (both none of six). No signs of major bleeding could be detected at necropsy. Therefore, a dose of 3 U/mL was chosen, which is approximately 30 times greater than the recommended human i.v. dose.
- CLP cecal ligation and puncture
- mice received saline lavage (3 x 2.0 mL).
- PPF peritoneal lavage fluid
- AT activity was measured in PLF, plasma and lung homogenates (Berichrom®; Dade Behring, Deerfield, IL, USA). One unit was defined as .activity of 1 mL normal plasma pool (IU/mL). The detection limit was 0.12 IU/mL.
- Clotting time was determined in PLF and lung homogenates using a standard procoagulant assay as described elsewhere [24]. Briefly, 50 ⁇ L PLF or (diluted) lung homogenate was added to 50 ⁇ L mouse plasma (Sigma, St. Louis, MO, USA) and incubated for 2 min at 37 °C. Calcium chloride (50 ⁇ L, 25 mm) was added and clotting time was measured using a KC-10 coagulometer (Amelung GmbH, Lemego, Germany).
- Brain homogenate was used as standard positive control. The cut-off time for clotting was 500 s. TAT complexes and D-dimer concentrations were measured in plasma, PLF and lung homogenate by ELISA (Enzygno'st®; Dade Behring and Asserachrom, Diagnostica Stago, Asniere, France, respectively) according to manufacturers' descriptions (detection limits 2 ⁇ g Ll and 5 ⁇ g Ll, respectively). Fibrinolysis was assessed by active tissue-type plasminogen activator (t-PA) and active plasminogen activator inhibitor- 1 (PAI-I) ELISA according to the manufacturer's instructions. The detection limit was 0.05 ng/mL for both t-PA and PAI-I (Molecular Innovations®; Southfield, MI, USA). Assessment of Inflammatory Response and Histopathological Examination
- lung homogenates were dissolved in assay mix of a sodium-ethylenediaminetetraacetic acid buffer containing hexadecyl-trimethyl-ammonium- bromide and TMB. After incubation, H2O2 was added, and the reaction was stopped with 0.2 m glacial acetic acid. Color intensity was determined by photospectrometer at 655 urn. One unit (U) is defined as one OD change per minute. Results were expressed as units per milligram tissue (wet-weight).
- Interleukin (IL)-I ⁇ , IL-6, tumor necrosis factor- ⁇ (TNF- ⁇ ) and KC concentrations were measured in PLF, plasma and lung homogenates by multiplex system (R&D Systems, Abingdon, UK) according to the manufacturer's descriptions (detection limits 1.2, 9.0, 6.0 and 12 pg/mL, respectively).
- liver, lung and peritoneum were immediately fixed in 4% buffered formaldehyde after collection, and routinely processed for hematoxylin and eosin (H&E) staining in paraffin sections. Sections of all organs were blindly scored by two independent observers. The liver was scored for thrombus formation, steatosis, portal inflammation, parenchymal inflammation and necrosis. The lung was scored for pleuritis, thrombus formation, edema, thickened septa and inflammation. The peritoneum was evaluated for inflammation and fibrin depositions.
- H&E hematoxylin and eosin
- Each parameter was graded on a scale of 0-4, with 0 meaning 'absent', 1 meaning 'occasional', 2 meaning 'mild', 3 meaning 'moderate' and 4 meaning 'severe'.
- the total organ injury score was expressed as the sum of scores for all parameters per organ [25,26].
- Aerobe and anaerobe colony forming unit (CFU) counts were determined in PLF. Serial log dilutions, using sterile saline, were plated on blood— agar plates and incubated at 37 °C. For anaerobe cultures, a GasPack® (BBL 3 Kansas City, MO) was used. CFUs were counted after 1 day (aerobic conditions) and 2 days (anaerobic conditions). Quantitative cultures are expressed as CFU per milliliter PLF. Data Analysis
- abdominal t-PA concentrations were between 0.07 and 0.38 ng/mL
- plasma t-PA concentrations were between 0.25 and 1.4 ng/mL
- pulmonary t-PA concentrations were between 3.6 and 64.5 ng/mL.
- rhAT-treated animals had increasing pulmonary t-PA levels
- saline controls had decreasing t-PA levels (P ⁇ 0.01 rhAT vs. saline).
- t-PA concentration was 0.1 ng/mL in the abdominal compartment and 0.4 ng/mL in the systemic (plasma) compartment.
- D-dimer levels reflecting both fibrin formation and degradation, were elevated after CLP at all time points in all groups in all compartments (P ⁇ 0.01 vs. sham).
- animals in the AT group had significantly reduced D-dimer concentrations in plasma and lungs as compared with saline-treated mice (P ⁇ 0.05 and P ⁇ 0.01, respectively, Fig. 4).
- PLF the difference in D-dimer levels between CLP-AT and CLP-saline failed to reach statistical significance because, after a nadir at 72 h, levels of D-dimer started to rise again in the AT group.
- cytokine production was increased after CLP and peritoneal lavage compared with sham-operated controls, which had very low or undetectable cytokine levels (P ⁇ 0.01).
- Intra-abdominal TNF- ⁇ production was not affected by rhAT lavage.
- IL-6 production was significantly reduced from 1620 ⁇ 297 pg/mL to 580 ⁇ 192 pg/mL (P ⁇ 0.05 vs. saline lavage) and KC production from 1390 ⁇ 80 pg/mL to 11.3 ⁇ 11.2 pg/mL (P ⁇ 0.05).
- pulmonary IL-6 concentrations were not affected by rhAT lavage, KC concentrations were decreased after rhAT lavage (P ⁇ 0.05, Fig. 5D ⁇ E).
- Pulmonary TNF- ⁇ was also reduced toy rhAT lavage from 1510 ⁇ 929 pg/mL to 545 ⁇ 312 pg/mL, but not IL- ⁇ .
- Leukocyte counts in PLF and MPO activity in the lungs were measured, to assess influx of intra-abdominal inflammatory cells and pulmonary neutrophils, respectively (Fig. 5C,F).
- Intra-abdominal leukocyte counts were elevated in both CLP groups as compared with sham (P ⁇ 0.01)! rriAT lavage significantly reduced intra-abdominal leukocyte counts, especially after 48 h and onward (P ⁇ 0.01 vs. CLP -saline). Similar responses were observed in the lungs.
- Elevated MPO activity indicating elevated neutrophil counts, was demonstrated in both CLP groups (P ⁇ 0.01 vs. sham). Again, rhAT lavage reduced pulmonary MPO activity as compared with saline lavage (P ⁇ 0.05).
- Aerobe and anaerobe bacteria were counted in the abdominal cavity after CLP, whereas no bacteria were cultured in shams (P ⁇ 0.01). Aerobe and anaerobe bacterial load were reduced after rhAT lavage (0.4 ⁇ 0.3 *10 6 CFU/mL and 1.1 ⁇ 0.4 *10 6 CFU/mL) as compared with saline lavage (19.1 ⁇ 7.9 *,10 6 CFU/mL and 13.9 ⁇ 7.6 *10 6 CFU/mL; P ⁇ 0.05 and P ⁇ 0.01 , respectively).
- Peritoneal rhAT lavage efficiently inhibited intra-abdominal coagulation for several days, as was demonstrated by prolonged intra-abdominal clotting times up to 72 h after rhAT lavage (being 96 h after induction of peritonitis by CLP), although AT activity itself was below detection limits.
- the half-life time of AT or elimination time
- the half-life time of AT is 48-56 h, but in severe sepsis plasma half-life time decreases to 8-12 h [28].
- the consequences of AT administration have been demonstrated over a longer period of time [7,29].
- AT inhibits the TF/FVIIa complex, ;and FDCa, FXa and FXIa, thereby inhibiting thrombin formation [4,9, 1O] 4
- thrombin' could be complexed into TAT and, in addition, fibrin formation will be reduced, which was demonstrated at histopathology (peritoneum and liver) and by lower D-dimer concentrations [28,30,31].
- intraabdominal cytokine production and leukocyte recruitment were both reduced, as were histopathology scores of peritoneum, encompassing the degree of influx of inflammatory cells. This indicates reduced local inflammation [30].
- Intra-abdominal fibrinolysis (t- PA/PAI-1 ratio) was even further decreased by rhAT lavage. This is likely to be due to reduced intra-abdominal fibrin deposition, thereby reducing the need for activation of fibrinolysis [32]. Formation of thrombin, a target protease for PAI-I, is reduced due to complexation with AT [28], resulting in augmented PAI-I concentrations and subsequently reduced t-PA concentrations. Thus, peritoneal rhAT lavage reduced intra-abdominal coagulation and inflammation activation.
- AT Because coagulation and inflammation are cross-linked and AT has both anticoagulant and anti-inflammatory characteristics, it is difficult to distinguish between anticoagulant and anti-inflammatory effects.
- anticoagulant properties of AT reduced the generation of thrombin [4,9,10], which plays a role in inflammation by inducing cytokine production and neutrophil attraction [1,16].
- AT itself stimulates endothelial cells to produce prostacyclin, which inhibits recruitment and activation of neutrophils as well as synthesis of pro-inflammatory cytokines such as IL-8 arid.
- IL-6 the latter of which is a well- known activator of coagulation in sepsis [13,38].
- intraabdominal administration of a high dose of rhAT by peritoneal lavage reduced intraabdominal coagulation activation and fibrin formation, without severe derangements in coagulation that could lead to serious bleeding complications, and concomitantly improved i bacterial clearance and inflammatory responses. This resulted in reduced inflammation and coagulation activation in the pulmonary compartment, and ultimately in survival.
- Minnema MC Chang AC, Jansen PM, Lubbers YT, Pratt BM, Wbittaker BG,
- Opal SM Opal SM, Kessler CM, Roemisch J 3 Knaub S. Antithrombin, heparin, and heparan sulfate. Crit Care Med 2002; 30: S325-31.
- Plasma cytokine measurements augment prognostic scores as indicators of outcome in patients with severe sepsis. Shock 2005; 23: 488—93.
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AU2007347228A AU2007347228A1 (en) | 2007-02-14 | 2007-02-14 | Intraperitoneal administration of antithrombin III, related compositions and methods |
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EP1023902A1 (en) * | 1999-01-28 | 2000-08-02 | Aventis Behring Gesellschaft mit beschränkter Haftung | Pharmaceutical preparation for the treatment of inflammatory processes |
JP2002060345A (en) * | 2000-08-21 | 2002-02-26 | Mochida Pharmaceut Co Ltd | Prophylactic and therapeutic agent for disease associated with abnormality in blood coagulation ability |
WO2006014519A1 (en) * | 2004-07-07 | 2006-02-09 | The General Hospital Corporation | Direct activation of atiii in whole blood and plasma |
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EP1023902A1 (en) * | 1999-01-28 | 2000-08-02 | Aventis Behring Gesellschaft mit beschränkter Haftung | Pharmaceutical preparation for the treatment of inflammatory processes |
JP2002060345A (en) * | 2000-08-21 | 2002-02-26 | Mochida Pharmaceut Co Ltd | Prophylactic and therapeutic agent for disease associated with abnormality in blood coagulation ability |
WO2006014519A1 (en) * | 2004-07-07 | 2006-02-09 | The General Hospital Corporation | Direct activation of atiii in whole blood and plasma |
Non-Patent Citations (7)
Title |
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DATABASE WPI Week 200241, Derwent World Patents Index; AN 2002-377470, XP002467750 * |
DICKNEITE ET AL: "Preclinical evaluation of antithrombin III in experimental sepsis and DIC", BLOOD, W.B. SAUNDERS, PHILADELPHIA, VA, US, vol. 92, no. 10, SUPPL 1, 15 November 1998 (1998-11-15), pages 357A, XP002116842, ISSN: 0006-4971 * |
MAMMEN ET AL: "Antithrombin: its physiological importance and role in DIC", SEMINARS IN THROMBOSIS AND HEMOSTASIS, STUTTGART, DE, vol. 24, no. 1, 1998, pages 19 - 25, XP002116846, ISSN: 0094-6176 * |
NIELSEN J D ET AL: "The effect of antithrombin on the systemic inflammatory response in disseminated intravascular coagulation", BLOOD COAGULATION & FIBRINOLYSIS, RAPID COMMUNICATIONS, OXFORD,OXFORD, GB, vol. 9, no. SUPPL 3, November 1998 (1998-11-01), pages S11 - S15, XP002116843, ISSN: 0957-5235 * |
OKAJIMA ET AL: "New therapeutic implications of antithrombin III replacement in disseminated intravascular coagulation and multiple organ failure", INTENSIVMEDIZIN UND NOTFALLMEDIZIN, STEINKOPFF, DARMSTADT, DE, vol. 33, no. 1, February 1996 (1996-02-01), pages 5 - 11, XP002116845, ISSN: 0175-3851 * |
OKAJIMA K ET AL: "The anti-inflammatory properties of antithrombin III: new therapeutic implications", SEMINARS IN THROMBOSIS AND HEMOSTASIS, STUTTGART, DE, vol. 24, no. 1, 1998, pages 27 - 32, XP002116841, ISSN: 0094-6176 * |
RISBERG B ET AL: "Antithrombin: Facts and new hypotheses", BLOOD COAGULATION & FIBRINOLYSIS, RAPID COMMUNICATIONS, OXFORD,OXFORD, GB, vol. 9, no. SUPPL 3, November 1998 (1998-11-01), pages S03 - S06, XP002116844, ISSN: 0957-5235 * |
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EP3278814A4 (en) * | 2015-03-31 | 2018-10-31 | Kyowa Hakko Kirin Co., Ltd. | Therapeutic composition containing antithrombin gamma |
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