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WO2018221480A1 - Agent thérapeutique contre la thrombose de la veine porte - Google Patents

Agent thérapeutique contre la thrombose de la veine porte Download PDF

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Publication number
WO2018221480A1
WO2018221480A1 PCT/JP2018/020441 JP2018020441W WO2018221480A1 WO 2018221480 A1 WO2018221480 A1 WO 2018221480A1 JP 2018020441 W JP2018020441 W JP 2018020441W WO 2018221480 A1 WO2018221480 A1 WO 2018221480A1
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WIPO (PCT)
Prior art keywords
days
administered
antithrombin iii
administration
portal
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Ceased
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PCT/JP2018/020441
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English (en)
Japanese (ja)
Inventor
千絵 田中
井上　貴之
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Nihon Pharmaceutical Co Ltd
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Nihon Pharmaceutical Co Ltd
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Priority to JP2019521217A priority Critical patent/JPWO2018221480A1/ja
Publication of WO2018221480A1 publication Critical patent/WO2018221480A1/fr
Anticipated expiration legal-status Critical
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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
    • 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

  • the present invention relates to a therapeutic agent for portal thrombosis, and particularly to a therapeutic agent for portal thrombosis containing antithrombin III (hereinafter also simply referred to as AT-III) as an active ingredient.
  • AT-III antithrombin III
  • Portal vein thrombus refers to a thrombus that appears in the biliary portal vein / portal trunk, and a thrombosis that appears in the splenic vein / superior mesenteric vein, which is associated with portal hypertension such as cirrhosis.
  • a sudden increase in pulse pressure is accompanied by acute exacerbation of the esophagus and gastric varices, rupture of varicose veins, increased ascites and splenomegaly, deterioration of liver function on blood tests, mild anemia due to increased spleen function, leukocyte and thrombocytopenia.
  • DIC disseminated intravascular coagulation syndrome
  • anticoagulant therapy is recommended for the treatment of portal vein thrombosis, but in patients with severe liver disorders such as cirrhosis, existing anticoagulants such as low molecular weight heparin and warfarin potassium are In principle, it is contraindicated, and there was a concern that the risk of bleeding was increased in patients with esophageal and gastric varices or in patients with portal hypertension.
  • a method using an AT-III preparation is also known. AT-III has a low risk of bleeding, inhibits AT-III supplementation and hypercoagulation, and eliminates portal thrombus by the action of secondary fibrinolytic system.
  • Non-Patent Document 1 a patient with portal thrombosis whose blood AT-III concentration decreased to 70% or less was administered AT-III at a dose of 1500 international units per day for 5 days. It is known that intravenous administration is performed and if the image diagnosis shows an improvement trend, the administration is repeated again (for example, Non-Patent Document 1).
  • An object of the present invention is to provide a novel technique that is more effective in the treatment of portal vein thrombosis.
  • the present inventor has conducted earnest research on more efficient thrombus disappearance or reduction (hereinafter, also simply referred to as thrombus reduction) in the treatment of portal vein thrombosis.
  • AT-III was administered to patients with portal vein thrombosis for 5 days to bring the blood AT-III concentration to the normal range (specifically, 80% or more), and during the subsequent treatment period (from the end of the first administration) It was discovered that the thrombus can be more efficiently reduced by adjusting the concentration of AT-III within this range (until the end of administration).
  • the inventors have found that blood AT-III concentration can be maintained within the above-mentioned range by re-administering AT-III within a predetermined interval after administration of AT-III for 5 days, thereby completing the present invention.
  • the gist of the present invention is as follows. [1] containing antithrombin III as an active ingredient, Patients with portal vein thrombosis receive 1000 to 3600 international units of antithrombin III per day for 5 days and are re-administered at the same and same time intervals at 0 to 4 days , A therapeutic agent for portal vein thrombosis. [2] 5 days of administration in an amount of 1000 to 3600 international units of antithrombin III administered per day is repeated up to 3 times, and the first and second and / or second and third administration intervals are 0 to The portal thrombosis therapeutic agent according to [1], which is 4 days.
  • [3] The portal vein thrombosis therapeutic agent according to [1] or [2], wherein the administration interval is 0 to 3 days.
  • [4] The portal vein thrombosis therapeutic agent according to any one of [1] to [3], which is administered in an amount such that 1000 to 1800 international units of antithrombin III is administered per day.
  • [5] The portal vein thrombosis therapeutic agent according to any one of [1] to [4], which is administered to a patient with portal vein thrombosis whose blood antithrombin III concentration has decreased to 70% or less.
  • a method for treating portal thrombosis comprising administering antithrombin III to a patient in need thereof, The aforementioned method of treatment wherein 1000 to 3600 international units of antithrombin III are administered to a patient with portal vein thrombosis per day for 5 days, and the same dose and re-administration are performed at intervals of 0 to 4 days.
  • the administration of 1000 to 3600 international units of antithrombin III per day for 5 days is repeated up to 3 times, and the first and second doses and / or the second and third dose intervals are 0 to 4 days [6] ]
  • the treatment method of description [8] The treatment method according to [6] or [7], wherein the administration interval is 0 to 3 days.
  • [12] The administration of 1000 to 3600 international units per day for 5 days is repeated up to 3 times, and the administration interval of the first and second times and / or the second and third times is 0 to 4 days.
  • Antithrombin III [13] Antithrombin III according to [11] or [12], wherein the administration interval is 0 to 3 days.
  • [16] Use of antithrombin III in the manufacture of a medicament for treating portal vein thrombosis comprising: The drug is administered to patients with portal vein thrombosis in an amount of 1000 to 3600 international units of antithrombin III administered per day for 5 days, and re-administered at the same dose and during the same period at intervals of 0 to 4 days Said use is made. [17] 5 days of administration at an amount of 1000 to 3600 international units of antithrombin III administered per day is repeated up to 3 times, and the first and second and / or second and third administration intervals are 0 to Use according to [16], which is 4 days. [18] The use according to [16] or [17], wherein the dosing interval is 0 to 3 days.
  • Example 2 is a graph showing blood AT-III concentration according to Example 1.
  • 3 is a graph showing blood AT-III concentration according to Example 2.
  • 4 is a graph showing blood AT-III concentration according to Comparative Example 1.
  • the portal vein thrombosis therapeutic agent contains antithrombin III (AT-III) as an active ingredient.
  • AT-III antithrombin III
  • patients with portal vein thrombosis are administered for 5 days in an amount of 1000 to 3600 international units of AT-III administered per day, and at the same dose and at the same intervals of 0 to 4 days. Periodic re-administration takes place.
  • AT-III is not particularly limited, and examples thereof include those derived from humans and purified to such an extent that they can be used as pharmaceuticals.
  • AT-III-producing gene recombinant CHO cells and recombinant AT-III produced by transgenic animals are also used in the same manner. be able to.
  • AT-III preparations may be used, for example, blood donation nonthrone (registered trademark, the same applies hereinafter, manufactured by Nippon Pharmaceutical Co., Ltd.), Neuart (registered trademark, manufactured by Japan Blood Products Organization), Acoaran (Registered trademark, manufactured by Kyowa Hakko Kirin Co., Ltd.).
  • the portal vein thrombosis therapeutic agent of this embodiment may contain other components as long as the object of the present invention can be achieved, and is not particularly limited. Specifically, it can be configured to contain pharmacologically acceptable additives, stabilizers, pharmaceutically necessary components, and the like that are usually used in pharmaceuticals, such as carriers, excipients, and diluents. . Specific additives, stabilizers and the like include saccharides, organic acids or salts thereof such as sodium salts, amino acids or salts thereof such as sodium salts, surfactants, heparin, albumin and the like. You may make it contain a seed
  • saccharide examples include monosaccharides such as glucose and fructose, disaccharides such as sucrose, lactose and maltose, and sugar alcohols such as mannitol and sorbitol.
  • organic acid examples include citric acid, malic acid, tartaric acid and the like.
  • amino acids include lysine, aspartic acid, glutamic acid and the like.
  • surfactant examples include polyethylene glycol, Pluronic (registered trademark), and Vienna (registered trademark).
  • the portal thrombosis therapeutic agent of the present embodiment is not particularly limited, and can be produced by a conventional method by appropriately mixing AT-III, which is an active ingredient, with the above-described ingredients blended as necessary. Specifically, it is possible to adopt a mode in which conventional pharmacologically well-known forms and administration routes are applied to a subject such as a human, for example, powder, granule, tablet, capsule, syrup, injection It can be administered orally or parenterally as a pharmaceutical preparation. Among these, the mode of intravenous administration can be preferably used.
  • the portal vein thrombosis therapeutic agent of the present embodiment may be in the form of a liquid preparation, but AT-III is prepared as a lyophilized product together with a pharmacologically acceptable additive and dissolved before use. It is good also as a formulation of an aspect.
  • AT-III is prepared as an about 1-100 AT-III international unit / ml solution with distilled water for injection or sterile purified water at the time of use, more preferably a physiologically isotonic salt concentration and a physiologically preferred pH value (pH 6 to 6). 8).
  • the portal thrombosis therapeutic agent of the present embodiment is administered for 5 days in an amount of 1000 to 3600 international units of antithrombin III administered per day, and the same dose (1000 to 1000 per day) at intervals of 0 to 4 days. (3600 international units) and re-administration during the same period (5 days).
  • the 0-day interval means that re-administration is started on the next day after the administration is completed without leaving an interval until the administration is resumed.
  • the dose of AT-III during a given administration period may be within the range of 1000 to 3600 international units per day, and the daily dose is consistent with the daily dose during other periods. I don't need it. Further, even within the same 5-day period, the daily dose may be the same or different.
  • the administration target is not particularly limited as long as it is a patient with portal vein thrombosis, but the effect of the therapeutic agent of the present embodiment is enhanced by being a patient with portal vein thrombosis with AT-III decreased to 70% or less. Therefore, it is more preferable that it is an adult patient (20 years or older) with portal vein thrombosis whose AT-III is reduced to 70% or less.
  • a patient with portal vein thrombosis refers to a person who has a thrombus in at least one of the portal vein, main portal vein, splenic vein, and superior mesenteric vein, which are blood vessels of the portal vein system.
  • International units are defined by titer labeling based on biologics standards.
  • the titer was accurately determined for 3 hours at 37.0 ⁇ 0.5 ° C by adding a certain amount of thrombin to the 3rd International Standard for Antithrombin, Concentrate, Human, NIBSC code: 06/166. The reaction is carried out by warming and the antithrombin activity is measured. Further, plasma-derived AT-III is used, for example, at 1000 to 3000 international units per day, and recombinant AT-III is used, for example, at 1200 to 3600 international units per day.
  • the intermediate AT-III concentration is maintained in the range of 80% or more, the effect on thrombus reduction and the like can be enhanced.
  • the blood AT-III concentration is preferably maintained within the range of 80 to 160%, more preferably 90 to 150%.
  • the human blood AT-III concentration can be measured by the synthetic substrate method.
  • the synthetic substrate method is a method in which heparin is added to form an AT-III-heparin complex, and its thrombin inactivation ability is measured using a chromogenic synthetic substrate for thrombin.
  • a chromogenic synthetic substrate for thrombin For example, S-2238 (HD-Phe-Pip-Arg-pNA ⁇ 2HCl, manufactured by Sekisui Medical Co., Ltd.) can be used as a chromogenic synthetic substrate for thrombin.
  • the administration of 1000 to 3600 international units of AT-III per day for 5 days is repeated up to 3 times, the first and second times and It is preferable that the second and third administration intervals be 0 to 4 days.
  • the AT-III dose is preferably 1000 to 1800 international units per day (more preferably 1500 international units per day).
  • the administration interval is preferably 0 to 3 days, more preferably 1 to 3 days, and even more preferably 2 to 3 days.
  • the therapeutic agent of this embodiment is intravenously administered for 5 days.
  • Image diagnosis such as contrast-enhanced CT examination and ultrasonic Doppler examination is performed 0 to 4 days after the end of the first treatment, and portal vein thrombus is evaluated.
  • the therapeutic agent of the present embodiment is administered at the same dose and at the same time as the first administration 0 to 4 days after the completion of the first administration. Additional administration (first time) is performed.
  • imaging diagnosis is performed 0 to 4 days after the end of the additional administration (first time).
  • the therapeutic agent of the present embodiment was added at the same dose and during the same period 0 to 4 days after the completion of the additional administration (first time) Dosing (second time). Then, after completion of the additional administration (second time) (for example, one day after the completion of the additional administration (second time)), an image diagnosis is performed, and an effect relating to thrombus reduction or the like is evaluated.
  • the interval between re-administration at the same dose and during the same period is set to 0 to 4 days. Since the blood AT-III concentration during the period from the end of administration to the end of re-administration can be maintained in the range of 80% or more, the effect of reducing the thrombus due to the administration of AT-III can be enhanced. As a result, although there are differences among individuals, the period required for treatment can be shortened, so that it can be expected to contribute to reducing the burden on the patient.
  • Example administration schedule A patient who had a blood AT-III concentration of 70% or less and had portal vein thrombus by blood tests and imaging tests at the time of hospitalization was intravenously administered with an AT-III preparation at 1500 international units / day for 5 days.
  • the portal vein thrombosis is evaluated by imaging (contrast CT or ultrasonic Doppler) after the period of time according to each example from the end of the first administration, and it is judged that there is a tendency to improve the thrombus compared to before the first administration.
  • the AT-III preparation was intravenously administered (additional administration (first time)) at 1500 international units / day for 5 days.
  • additional administration first time
  • the AT-III preparation was intravenously administered (additional administration (second time)) at 1500 international units / day for 5 days. Imaging was performed after the end of the additional administration (second time). Post-administration observation was performed from the final AT-III preparation administration start day to 21st day (Example 2) or 20th day (Example 3).
  • Blood AT-III concentration (%) is measured by the synthetic substrate method before administration of the AT-III preparation, after the first administration, after the additional (first time) administration, after the additional (second time) administration, and also after the end of the administration. Went. For example, in Example 2, the measurement was made on the 14th day after observation and the 21st day after observation.
  • AT-III freeze-dried preparation (trade name: Blood Donation Nonthrone: manufactured by Nippon Pharmaceutical Co., Ltd.) was dissolved in water for injection.
  • the AT-III preparation was used and intravenously administered 1500 international units per day for AT-III.
  • FIG. 1 shows the blood AT-III concentration of the patient.
  • CT image inspection is performed with a CT apparatus of 64 rows or more at a tube voltage of about 120 kV, a scanning speed of about 0.5 sec / rot, a contrast agent iodine concentration of 240 mgI / mL to 350 mgI / mL, and a contrast medium injection speed of 3.0 mL / sec.
  • Photographing was performed, and evaluation was performed using a reconstructed image having a slice thickness of 1.25 mm or less.
  • the blood AT-III concentration was maintained at 100% or more, and in CT image evaluation, a tendency to decrease was observed every 5 days (first administration, first addition), and additional (second) Later, the thrombus shrunk.
  • Example 3 For patients with liver cirrhosis type B with portal vein thrombus, the AT-III preparation 1500 international units / day was administered intravenously (initial administration) for 5 days, followed by an additional first administration after 3 days. An additional second dose was performed one day after the first dose.
  • FIG. 2 shows the blood AT-III concentration of the patient.
  • CT image inspection is performed using a CT apparatus having 64 rows or more, a tube voltage of about 120 kV, a scanning speed of about 0.5 sec / rot, a contrast agent iodine concentration of 240 mgI / mL or more, 350 mgI / mL or less, and a contrast medium injection speed of 3.0 mL / sec.
  • the evaluation was performed using a reconstructed image having a slice thickness of 1.25 mm or less.
  • the blood AT-III concentration was maintained at 100% or more, and in the CT image evaluation, a tendency to reduce the thrombus was observed every 5 days (initial administration, first administration), additional (2 After the second), the thrombus has shrunk.
  • FIG. 3 shows the blood AT-III concentration in the patient.
  • CT image inspection is performed with a CT apparatus having 64 rows or more, a tube voltage of about 120 kV, a scan speed of about 0.5 sec / rot, a contrast medium iodine concentration of 240 mgI / mL or more, 350 mgI / mL or less, and a contrast medium injection speed of 3.0 mL / sec.
  • the evaluation was performed using a reconstructed image having a slice thickness of 1.25 mm or less.
  • the AT-III concentration reached 100% or more, but the CT image evaluation after the first administration was slightly reduced.
  • the AT-III value 7 days after the first administration decreased to 63%.
  • the present invention relates to a portal vein thrombosis therapeutic agent, and particularly to a portal vein thrombosis therapeutic agent containing antithrombin III as an active ingredient. Very useful in the treatment of portal vein thrombosis.

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Abstract

Le problème décrit par la présente invention est de fournir une nouvelle technique qui est plus efficace dans le traitement de la thrombose de la veine porte. La solution selon l'invention porte sur un agent thérapeutique contre la thrombose de la veine porte qui contient une antithrombine III utilisée comme principe actif, qui est administré à des patients souffrant d'une thrombose de la veine porte selon une posologie d'administration d'antithrombine III de 1 000 à 3 600 UI/jour pendant 5 jours, et qui est ré-administré à un intervalle de 0 à 4 jours selon la même posologie et pendant la même période.
PCT/JP2018/020441 2017-05-30 2018-05-29 Agent thérapeutique contre la thrombose de la veine porte Ceased WO2018221480A1 (fr)

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JP2019521217A JPWO2018221480A1 (ja) 2017-05-30 2018-05-29 門脈血栓症治療剤

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JP2017-107194 2017-05-30
JP2017107194 2017-05-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4566597A1 (fr) 2023-12-05 2025-06-11 Hospital Clínic de Barcelona Statines utiles dans le traitement de dysfonctionnements vasculaires splachniques

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
MURAKAMI, SATOSHI ET AL.: "Discussion of Effectiveness of AT -III Dosage for Portal Thrombosis", THROMBOSIS, vol. 41, pages A131 *
OKUWAKI, YUSUKE ET AL.: "Effectiveness of AT -3 Pharmaceutical Dosage for Portal Thrombosis", JAPANESE JOURNAL OF PORTAL HYPERTENSION, vol. 11, no. 1, pages 72 *
TADA, KAZUHIRO ET AL.: "A Case of Liver Cirrhosis with Portal Thrombosis in which Antithrombin III was Highly Effective", KANZO, vol. 42, no. 3, 2001, pages A544 *
TAKATORI, H. ET AL.: "Danaparoid sodium monotherapy for portal vein thrombosis in cirrhotic patients is as effective as combination therapy with antithrombin III", HEPATOLOGY, vol. 58, no. 4, 2013, pages 894A *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4566597A1 (fr) 2023-12-05 2025-06-11 Hospital Clínic de Barcelona Statines utiles dans le traitement de dysfonctionnements vasculaires splachniques
WO2025119986A1 (fr) 2023-12-05 2025-06-12 Hospital Clínic De Barcelona Statines utiles dans le traitement de dysfonctionnements vasculaires splanchniques

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