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WO2012043577A1 - Agent renversant pour anticoagulants - Google Patents

Agent renversant pour anticoagulants Download PDF

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Publication number
WO2012043577A1
WO2012043577A1 PCT/JP2011/072106 JP2011072106W WO2012043577A1 WO 2012043577 A1 WO2012043577 A1 WO 2012043577A1 JP 2011072106 W JP2011072106 W JP 2011072106W WO 2012043577 A1 WO2012043577 A1 WO 2012043577A1
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Prior art keywords
blood coagulation
carbonyl
compound
coagulation factor
complex
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English (en)
Japanese (ja)
Inventor
義行 森島
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • 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
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

  • the present invention relates to a reverse method using a reverse agent and / or reverse agent that reverses the anticoagulant action of an activated blood coagulation factor X inhibitor.
  • ⁇ Heparins, warfarins, etc. which are anticoagulants that suppress blood coagulation, are known as therapeutic agents for thrombosis and embolism.
  • an activated blood coagulation factor X inhibitor that directly acts on and inhibits activated blood coagulation factor X (hereinafter sometimes abbreviated as FXa) [ Hereinafter, it may be abbreviated as FXa inhibitor.
  • FXa inhibitor activated blood coagulation factor X inhibitor
  • FXa inhibitor activated blood coagulation factor X inhibitor that directly acts on and inhibits activated blood coagulation factor X
  • neutralizing agents or reverse agents for anticoagulant action of anticoagulants for example, protamine for heparins (protamine sulfate), vitamin K1 for warfarin and the like are known (for example, see Non-patent Documents 1 and 2).
  • protamine for heparins protamine sulfate
  • vitamin K1 for warfarin for example, see Non-patent Documents 1 and 2.
  • a non-specific hemostatic agent fresh frozen plasma (FFP) is known, but there is an optimal neutralizing agent or neutralizing method that can be applied depending on the individual anticoagulant. It is also known to be different.
  • FFP fresh frozen plasma
  • the neutralizing agent of the action varies depending on the action mechanism of the anticoagulant, the provision of an optimal neutralizing agent or neutralizing method for each drug having an anticoagulant action is in the treatment of thrombosis / embolism. It is important as a means of treatment in case of drug overdose and serious bleeding.
  • pharmacologically acceptable Salts or their hydrates have a strong direct inhibitory effect on FXa and prevent thrombosis / embolism, particularly deep vein thrombosis (DVT), venous thromboembolism (Venous) Prevention of thrombosis and embolism based on Thromboembolis (VTE) and non-valvular atrial fibrillation (NVAF) Therapeutic agent, as stroke prevention agents in patients with atrial fibrillation, usefulness in clinical trials it has been demonstrated (see, for
  • low-molecular-weight FXa inhibitors are useful for other anticoagulant thrombosis / embolism such as deep vein thrombosis, venous thrombosis / embolism (VTE), and non-valvular atrial fibrillation (NVAF).
  • VTE deep vein thrombosis
  • NVAF non-valvular atrial fibrillation
  • Thrombosis / embolism based, stroke prevention in patients with atrial fibrillation, cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, acute coronary syndrome (ACS), Buerger's disease, generalized intravascular Expected to have therapeutic effects on coagulation syndrome, thrombus formation after artificial valve / joint replacement, thrombus formation and re-occlusion after revascularization, multiple organ failure (MODS), thrombus formation during extracorporeal circulation, or blood coagulation during blood collection (For example, refer nonpatent literature 6).
  • Compound (1), a pharmacologically acceptable salt, or a hydrate thereof has a low risk of bleeding at a dose for preventing or treating a disease in clinical trials.
  • a bleeding accident occurs due to, for example, excessive administration of the compound (1), a pharmacologically acceptable salt, or a hydrate thereof, a reverse agent and / or reverse that reverses the anticoagulant action of the drug.
  • the method is not known.
  • the subject of this invention is the reverse agent and / or reverse which reverses the prolonged blood coagulation time at the time of the overdose of compound (1), a pharmacologically acceptable salt, or those hydrates, or at the time of serious bleeding It is to provide a way to do.
  • the present inventors have studied various drugs capable of neutralizing the anticoagulant action of the compound (1), pharmacologically acceptable salts, or hydrates thereof, and prothrombin in an in vitro test using human plasma.
  • Dry human blood coagulation factor IX complex in which blood coagulation time prolonged by compound (1) is used as a hemophilia treatment agent or a blood coagulation factor IX deficiency treatment agent using time (PT) as an index [PPSB®-HT], dried human blood coagulation factor antibody bypassing active complex [Feiba®], and recombinant active factor VII (rFVIIa) are found to be shortened in a concentration-dependent manner
  • PT blood coagulation factor IX deficiency treatment agent
  • PT blood coagulation factor antibody bypassing active complex
  • rFVIIa recombinant active factor VII
  • the present invention provides the following (1) to (4).
  • (1a) a neutralizing agent for the coagulation action of an oral anticoagulant, A neutralizing agent which is one or more selected from a dried human blood coagulation factor antibody bypass activity complex, a dried human blood coagulation factor IX complex, and a recombinant recombinant factor VII.
  • FXa inhibitor is represented by the following formula (1)
  • N 1- (5-chloropyridin-2-yl) -N 2 -((1S, 2R, 4S) -4 which is an anticoagulant, for example, an FXa inhibitor -[(Dimethylamino) carbonyl] -2- ⁇ [(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino ⁇ cyclohexyl) ethanediamide
  • an anticoagulant for example, an FXa inhibitor -[(Dimethylamino) carbonyl] -2- ⁇ [(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino ⁇ cyclohexyl) ethanediamide
  • a reverse agent that reverses the anticoagulant effect of a drug when a pharmacologically acceptable salt or hydrate thereof increases the risk of bleeding due to misadministration or overdose
  • FIG. 4 is a graph showing the influence on prothrombin time (PT) by each of the dried human blood coagulation factor IX complex [PPSB (registered trademark) -HT] and compound (1) alone and in combination, and the results of Example 2
  • FIG. 5 is a graph showing the effect on prothrombin time (PT) by each of recombinant recombinant active factor VII (rFVIIa) and compound (1) alone and in combination, and the results of Example 3.
  • oral anticoagulant means a direct-acting low-molecular oral FXa inhibitor.
  • compound (1) a compound represented by the above formula (1) [hereinafter sometimes abbreviated as compound (1)] is preferable, and compound (1) is It may be a free form (free base) or a hydrate thereof, or may be a pharmacologically acceptable salt or a hydrate of a salt.
  • the pharmacologically acceptable salt of the compound represented by the formula (1) includes hydrochloride, sulfate, hydrobromide, hydroiodide, phosphate, nitrate, benzoate, methanesulfonic acid. Salt, 2-hydroxyethanesulfonate, p-toluenesulfonate, acetate, propanoate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate , Fumarate, malate, mandelate and the like.
  • the salt of the compound represented by the formula (1) is preferably hydrochloride or p-toluenesulfonate; p-Toluenesulfonate is particularly preferred.
  • N 1- (5-chloropyridin-2-yl) -N 2 -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2- ⁇ [(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino ⁇ cyclohexyl) ethanediamide
  • the free base (free form) of “FXa inhibitor” means “acid” of the above-mentioned salt (acid addition salt) and / or acid addition salt forming a hydrate with “FXa inhibitor”. And the compound excluding “water” in the hydrate.
  • the free base (free form) of the compound (1a) is the following formula (1)
  • the dose of the compound (1) represented by the formula (1) is the dose when converted into the compound (1) which is a free base (free form).
  • the FXa inhibitor N 1- (5-chloropyridin-2-yl) -N 2 -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2- ⁇ [(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino ⁇ cyclohexyl) ethanediamide / p-toluenesulfonate / monohydrate (compound 1a) Is preferably 5 mg to 90 mg as the free base (free form) [the above compound (1)]; 15 mg to 60 mg is more preferable.
  • the FXa inhibitor N 1- (5-chloropyridin-2-yl) -N 2 -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2- ⁇ [(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino ⁇ cyclohexyl) ethanediamide, a salt thereof or a hydrate thereof Is administered to a patient in a dosage form such as a tablet together with a pharmacologically acceptable additive.
  • the FXa inhibitor N 1- (5-chloropyridin-2-yl) -N 2 -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2 contained in the administration formulation - ⁇ [(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino ⁇ cyclohexyl) ethanediamide free base (free form)
  • the content of (1)] is preferably 15 mg, 30 mg, 45 mg and 60 mg; particularly preferably 15 mg, 30 mg and 60 mg.
  • neutralizing agent or “reverse agent” in the present invention means an agent that neutralizes or reverses the anticoagulant action of the anticoagulant. Neutralizing or reversing the action may be understood as detoxifying side effects which are generally undesirable for the human body due to the action of drugs.
  • Anticoagulant “neutralizing agents” or “reverse agents” include dried human blood coagulation factor antibody bypass activity complex [Feiba®], dried human blood coagulation factor IX complex [PPSB®].
  • a dry human blood coagulation factor antibody bypassing active complex [Feiba®]
  • a dry human blood coagulation factor IX complex [PPSB®] — HT]
  • recombinant recombinant factor VII rFVIIa
  • the reverse action of the anticoagulant action in this specification was evaluated using prothrombin time (PT) and activated partial thromboplastin time (APTT) as indices.
  • the clotting time was measured using an automatic blood clotting time measuring machine (Amelung KC-10A micro (Trinity Biotech Plc.)).
  • thrombosis / embolism examples include the following “cerebral infarction, cerebral embolism, myocardial infarction, angina, pulmonary infarction, pulmonary embolism, acute coronary syndrome (ACS), Buerger's disease, deep vein thrombosis, Generalized intravascular coagulation syndrome, thrombus formation after prosthetic valve / joint replacement, thrombus formation and reocclusion after revascularization, multiple organ failure (MODS), thrombus formation during extracorporeal circulation or blood coagulation during blood collection, venous thrombus -One or more diseases selected from the group consisting of "embolism (VTE) and non-valvular atrial fibrillation (NVAF)” or the like, or thrombosis / embolism based on those diseases; It is not limited to.
  • VTE embolism
  • NVAF non-valvular atrial fibrillation
  • Thromboembolism includes the following cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, acute coronary syndrome (ACS), Buerger's disease, deep vein thrombosis, generalized intravascular coagulation syndrome Thrombus formation after prosthetic valve / joint replacement, Thrombus formation and reocclusion after revascularization, Multiple organ failure (MODS), Thrombus formation during extracorporeal circulation or Blood coagulation during blood collection, Venous thrombosis / embolism (VTE), And thrombosis / embolism based on non-valvular atrial fibrillation (NVAF); Preferred is thrombosis / embolism based on venous thrombosis / embolism (VTE) and non-valvular atrial fibrillation (NVAF).
  • VTE venous thrombosis / embolism
  • NVAF non-valvular atrial fibrill
  • formulation means an oral dosage form, together with an active ingredient and a pharmacologically acceptable additive, for example, in a dosage form such as a tablet, granule, powder, capsule or syrup. Be administered.
  • pharmacologically acceptable additive include an excipient, a disintegrant, a binder, a fluidizing agent, a lubricant, a coloring agent, and a brightening agent.
  • Feiba registered trademark
  • distilled water On the day of the experiment, Feiba (registered trademark) was dissolved in distilled water to prepare a 50 U / mL solution. This 50 U / mL solution was diluted with physiological saline to prepare solutions with concentrations of 15, 5, and 1.5 U / mL, and stored in ice for use in the test.
  • Recombinant active factor VII (rFVIIa) solution Recombinant active factor VII (rFVIIa) (NovoSeven (registered trademark); Lot No. X1002) was purchased from Novo Nordisk Pharma Co., Ltd. did.
  • rFVIIa was dissolved in distilled water to prepare a 0.6 mg / mL solution.
  • This 0.6 mg / mL solution was diluted with physiological saline to prepare solutions having a concentration of 10,000, 3000, and 1000 ng / mL, and stored in ice for use in the test.
  • Example 1 Human (Pooled) plasma was thawed in a 37 ° C. water bath and stored in ice for use in experiments. 45 ⁇ L of the solution of compound (1) (16.7 and 33.3 ⁇ g / mL) was added to 4455 ⁇ L of plasma. For control, 45 ⁇ L of 5% DMSO-saline solution was added to plasma.
  • PT was measured using an automatic blood coagulation time measuring machine (Amelung KC-10A micro, Trinity Biotech Plc.).
  • HemosIL PT-fibrinogen HS PLUS (Instrumentation Laboratory, Lot No. N0298458) was added to start coagulation, and the coagulation time was measured.
  • Human (Pooled) plasma was thawed in a 37 ° C. water bath and stored in ice for use in experiments.
  • 45 ⁇ L of the solution of compound (1) (16.7 and 33.3 ⁇ g / mL) was added to 4455 ⁇ L of plasma.
  • 45 ⁇ L of 5% DMSO-saline solution was added to plasma.
  • PT was measured using an automatic blood coagulation time measuring machine (Amelung KC-10A micro, Trinity Biotech Plc.) As follows.
  • Example 1 the PT of the control group as a control was 18.4 ⁇ 0.2 seconds (mean value ⁇ standard error, the same applies hereinafter).
  • Addition of 150 or 300 ng / mL concentration of compound (1) significantly extended PT to 31.5 ⁇ 0.2 seconds or 43.7 ⁇ 0.3 seconds, respectively.
  • Single administration (0.15, 0.5, and 1.5 U / mL) of dry human blood coagulation factor antibody bypass activity complex [Feiba®] shortened PT in a concentration-dependent manner.
  • Feiba® significantly shortened the PT prolongation caused by the addition of the compound (1) in a concentration-dependent manner.
  • the PT prolongation caused by the addition of 150 and 300 ng / mL of compound (1) is 19.5 ⁇ 0.1 seconds and The time was shortened to 25.0 ⁇ 0.1 seconds.
  • Example 2 The results of Example 2 are summarized in FIG.
  • the PT of the control group as a control was 17.8 ⁇ 0.0 seconds.
  • the addition of 150 or 300 ng / mL of compound (1) significantly extended PT to 30.7 ⁇ 0.2 seconds or 42.5 ⁇ 0.4 seconds, respectively.
  • [PPSB®-HT] (0.15, 0.5, and 1.5 U / mL) significantly shortened the PT prolongation due to the addition of Compound (1) in a concentration-dependent manner.
  • the PT extension with the addition of 150 and 300 ng / mL of compound (1) is 23.7 ⁇ 0.1 seconds and The time was shortened to 31.6 ⁇ 0.4 seconds.
  • Example 3 The results of Example 3 are summarized in FIG.
  • the PT of the control group as a control was 17.9 ⁇ 0.2 seconds.
  • the addition of 150 or 300 ng / mL of compound (1) significantly extended PT to 30.7 ⁇ 0.2 seconds or 43.1 ⁇ 0.3 seconds, respectively.
  • PT administration was significantly and concentration-dependently shortened by the single administration of recombinant recombinant factor VII (rFVIIa) (100, 300, and 1000 ng / mL).
  • rFVIIa recombinant recombinant factor VII
  • Administration of rFVIIa 100, 300, and 1000 ng / mL significantly shortened the PT prolongation caused by compound (1) in a concentration-dependent manner.
  • the PT prolongation by the addition of 150 and 300 ng / mL of compound (1) is 17.3 ⁇ 0.2 seconds and 24.2 ⁇ 0.3 seconds, respectively.
  • the plasma concentration of the blood coagulation factor VIII preparation at the clinical dose is estimated to be about 0.44 U / mL [package insert of Coordinate (R) FS]. In this study, the concentration was 0.001 to 6.7 U / mL Was used.
  • Compound (1) blood coagulation factor IX preparation [Chris machine (registered trademark) -M] is added to human plasma, and activated partial thromboplastin time (APTT) is measured using an automatic blood coagulation time measuring machine (Amelung KC-10A micro, (Thrinity Biotech Plc.).
  • the plasma concentration is estimated to be about 0.47 U / mL when Chris Machine (registered trademark) -M is administered at 50 U / kg (near clinical dose) [Chris Machine (registered trademark) -M package insert]. In this case, a concentration of 0.001 to 6.7 U / mL was used.
  • Rats were anesthetized with thiopentasodium (100 mg / kg, ip) 15 minutes after oral administration, and then fresh rat plasma (30 mL / kg / 2h: equivalent to 3 times the clinical dose) 30 minutes after oral administration was continuously administered into the jugular vein.
  • physiological saline (30 mL / kg / 2h) was continuously administered into the jugular vein.
  • Citrated blood was collected from the jugular vein 2 hours after the start of continuous intravenous infusion of fresh plasma. Plasma was separated from the collected blood, and PT was measured using an automatic blood coagulation time measuring machine (Amelung KC-10A micro, Trinity Biotech Plc.).
  • Compound (1) extended PT by 2.14 times.
  • Fresh plasma (FF) reduced PT prolongation by compound (1) from 2.14 times to 1.66 times at a dose 3 times higher than the clinical dose.
  • Comparative Example 4 Rats fasted overnight were orally administered compound (1) (10 mg / kg) suspended in 0.5% methylcellulose, and vitamin K2 (0.1 and 1 mg / kg) or distilled water was orally administered 30 minutes later. did.
  • Vitamin K2 0.1 and 1 mg / kg or distilled water was orally administered 30 minutes later. did.
  • One hour and 45 minutes after vitamin K2 administration the rats were anesthetized with thiopentasodium (100 mg / kg, ip), and citrated blood was collected from the inferior vena cava 15 minutes later. Plasma was separated from the collected blood, and PT was measured using an automatic blood coagulation time measuring machine (Amelung KC-10A micro, Trinity Biotech Plc.).
  • Compound (1) prolonged PT by 1.34 times 2.5 hours after oral administration. Vitamin K2 did not affect PT prolonged by compound (1).
  • Rats fasted overnight were anesthetized with thiopental sodium (0.1 g / kg, ip). From 15 minutes after anesthesia to the end of the experiment, 5% glucose solution or compound (1) was continuously administered from the jugular vein (1 mg / kg / h), and the bleeding time was measured 2 hours after the start of administration. Saline solution or tranexamic acid was injected over 2 minutes from the femoral vein 8 minutes before the bleeding time measurement. The bleeding time was measured by the plantar template method or the tail template method.
  • the rat was placed in a supine position, and a 5 mm long incision was made with a cutter knife in the sole of the right hind limb.
  • the blood was adsorbed on the filter paper every 30 seconds, and the time until blood did not bleed on the filter paper was measured up to 30 minutes. If the hemostasis was not stopped within 30 minutes, the bleeding time was 30 minutes.
  • the rat was placed in a supine position, and a 1 mm deep incision was made with a razor into the arterial portion 4 cm from the tip of the tail.
  • the blood was adsorbed on the filter paper every 15 seconds, and the time until blood did not bleed on the filter paper was measured up to 30 minutes.
  • plantar bleeding time was significantly prolonged by administration of compound (1).
  • administration of 30, 100 and 300 mg / kg tranexamic acid showed no inhibitory effect.
  • PT was extended 1.36 times, and the same PT extension was observed in the 30 mg / kg tranexamic acid combination group.
  • administration of compound (1) significantly prolonged rat tail bleeding time (the rate of extension was 1.77 times).
  • administration of 30 and 100 mg / kg tranexamic acid showed no inhibitory effect.
  • the compound (1) prolongs PT by 1.33 times, and the PT in the tranexamic acid combination group similarly prolongs PT, and no inhibitory effect on PT prolongation by administration of compound (1) was observed.
  • tranexamic acid showed a reverse action of compound (1) at doses of 30, 100, and 300 mg / kg, with respect to prolonged bleeding time by compound (1) using rat plantar and tail bleeding time models. There wasn't.
  • the present invention relates to a reverse agent that reverses the anticoagulant action of a drug in the event that a bleeding accident occurs due to, for example, excessive administration of compound (1), a pharmacologically acceptable salt, or a hydrate thereof. Alternatively, it can be used as a reverse method.

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Abstract

La présente invention vise à permettre d'obtenir: un agent renversant qui renverse les effets anticoagulants d'un inhibiteur de FXa ; et/ou un procédé de renversement utilisant ledit agent renversant. La solution consiste en un agent renversant pour un anticoagulant oral, ledit agent renversant provoquant le caillot. Ledit agent de formation du caillot est un ou plusieurs des suivants : un complexe séché qui a pour effet de circonvenir des anticorps pour un facteur de coagulation de sang humain; un complexe séché du facteur IX de coagulation du sang humain; et un facteur VII activé recombiné.
PCT/JP2011/072106 2010-09-28 2011-09-27 Agent renversant pour anticoagulants Ceased WO2012043577A1 (fr)

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JP2010216617 2010-09-28
JP2010-216617 2010-09-28

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CN114681597A (zh) * 2022-03-11 2022-07-01 兆科药业（合肥）有限公司 蝰蛇蛇毒血凝酶在制备用于逆转凝血因子Xa抑制剂的抗凝作用的药物中的应用

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BIJSTERVELD,N.R. ET AL.: "Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers", CIRCULATION, vol. 106, no. 20, 2002, pages 2550 - 2554 *
BIJSTERVELD,N.R. ET AL.: "Recombinant factor VIIa reverses the anticoagulant effect of the long- acting pentasaccharide idraparinux in healthy volunteers", BRITISH JOURNAL OF HAEMATOLOGY, vol. 124, no. 5, 2004, pages 653 - 658 *
EERENBERG,E.S. ET AL.: "Prothrombin Complex Concentrate Reverses the Anticoagulant Effect of Rivaroxaban In Healthy Volunteers", BLOOD, vol. 116, November 2010 (2010-11-01) *
FURUGOHRI,T. ET AL.: "DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles", J THROMB HAEMOST, vol. 6, no. 9, 2008, pages 1542 - 1549, XP002659799, DOI: doi:10.1111/J.1538-7836.2008.03064.X *
GRUBER,A. ET AL.: "Potential of Activated Prothrombin Complex Concentrate and Activated Factor VII to Reverse the Anticoagulant Effects of Rivaroxaban in Primates. Abstr. 3825", BLOOD, vol. 112, 2008 *
MORISHIMA,Y. ET AL.: "Anti-Inhibitor Coagulant Complex, Prothrombin Complex Concentrate, and Recombinant Factor VIIa Reverse Prothrombin Time Prolonged by Edoxaban In Human Plasma", BLOOD, vol. 116, November 2010 (2010-11-01) *
TENPU BUNSHO ET AL., FEIBA CHUSHAYO 500, FEIBA CHUSHAYO 1000, no. 13, 2008 *
TENPU BUNSHO, CHUSHAYO NOVOSEVEN (R) 1.2MG, CHUSHAYO NOVOSEVEN (R) 4,8MG, no. 10, March 2010 (2010-03-01) *
TENPU BUNSHO, PPSB (R)-BT JOCHUYO 200 TAN'I 'NICHIYAKU', PPSB (R)-BT JOCHUYO 500 TAN'I 'NICHIYAKU', no. 14, 2009 *

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