DE19753383A1 - Use of abciximab to treat microcirculation disorders - Google Patents

Use of abciximab to treat microcirculation disorders

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Publication number
DE19753383A1
DE19753383A1 DE19753383A DE19753383A DE19753383A1 DE 19753383 A1 DE19753383 A1 DE 19753383A1 DE 19753383 A DE19753383 A DE 19753383A DE 19753383 A DE19753383 A DE 19753383A DE 19753383 A1 DE19753383 A1 DE 19753383A1
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Prior art keywords
abciximab
sepsis
microcirculation disorders
platelets
platelet
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DE19753383A
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German (de)
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Gundula Wiemann
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WIEMANN, GUNDULA, 45279 ESSEN, DE
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SCHWARZ RUEDIGER 70193 STUTTGART DE
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Priority to DE19753383A priority Critical patent/DE19753383A1/en
Priority to JP2000522947A priority patent/JP2001524534A/en
Priority to EP98965225A priority patent/EP1035868A1/en
Priority to CA002312824A priority patent/CA2312824A1/en
Priority to PCT/EP1998/007833 priority patent/WO1999027962A1/en
Publication of DE19753383A1 publication Critical patent/DE19753383A1/en
Withdrawn legal-status Critical Current

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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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    • 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
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    • A—HUMAN NECESSITIES
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
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Abstract

The present invention relates to the use of fibrinogen receptor-antagonists for preventing disseminated intravascular coagulation (DIC) related to sepsis or systemic inflammatory response syndrome (SIRS) in humans.

Description

Die Erfindung betrifft die Verwendung von Abciximab zur Behandlung von Mikrozirkulationsstörungen in Folge von Sepsis oder SIRS.The invention relates to the use of abciximab for the treatment of microcirculation disorders in Episode of sepsis or SIRS.

Hierbei sind unter Abciximab Fab-Fragmente eines monoklonalen Antikörpers gegen den GPIIb/IIIa-Rezeptor von Thrombozyten zu verstehen.Abciximab includes Fab fragments of a monoclonal antibody against the Understand GPIIb / IIIa receptor of platelets.

Stand der TechnikState of the art

Es ist bereits aus der Produktmonographie des Präparates Reopro(tm), Fa. Beiersdorf-Lilly und Fa. Centocor, bekannt, Abciximab zusätzlich zur Anwendung von Heparin und Acetylsalicylsäure zur Vermeidung von ischämischen kardialen Komplikationen bei Hochrisiko-Patienten anzuwenden, bei denen eine perkutane transluminale Koronarangioplastie durchgeführt wird. Wegen der bei der Anwendung auftretenden erhöhten Blutungshäufigkeit soll die Anwendung auf Patienten mit einem hohen Risiko für akute koronare Thrombosen beschränkt sein und auch hier nur dann erfolgen, wenn die Patenten zumindest eines der folgenden Kriterien aufweisen:
Angina pectoris mit folgenden Kennzeichen:
It is already known from the product monograph of the preparation Reopro (tm) from Beiersdorf-Lilly and from Centocor to use abciximab in addition to the use of heparin and acetylsalicylic acid to avoid ischemic cardiac complications in high-risk patients in whom percutaneous transluminal Coronary angioplasty is performed. Because of the increased bleeding frequency that occurs during use, use should be restricted to patients at high risk for acute coronary thrombosis and should only be carried out here if the patents have at least one of the following criteria:
Angina pectoris with the following characteristics:

  • - Therapieresistente Angina im Ruhezustand mit ischämischen ST-Veränderungen- Therapy-resistant angina at rest with ischemic ST changes
  • - Therapieresistente wiederholt auftretende Angina mit ischämischen ST-Veränderungen- Therapy-resistant, recurrent angina with ischemic ST changes
  • - Therapieresistente Postinfarktangina mit ischämischen ST-Veränderungen innerhalb von 7 Tagen nach Myokardinfarkt.- Therapy-resistant post-infarct angina with ischemic ST changes within 7 days after Myocardial infarction.

Akuter transmuraler Myokardinfarkt nicht älter als 12 Stunden, der folgendes Vorgehen erfordert:
Acute transmural myocardial infarction not older than 12 hours, which requires the following:

  • - direkter interventioneller Eingriff- direct interventional intervention
  • - Maßnahme bei nicht erfolgreicher thrombolytischer Therapie.- Measure in the event of unsuccessful thrombolytic therapy.

Angiographisch definierte, das Gefäßvolumen einengende Läsionen des Koronarkreislaufs
Angiographically defined lesions of the coronary circulation constricting the vascular volume

  • - 2 Merkmale einer Läsion Typ B- 2 characteristics of a type B lesion
  • - 1 Merkmal einer Läsion Typ C- 1 characteristic of a type C lesion
  • - 1 Merkmal einer Läsion Typ B bei Frauen < 65 Jahren und/oder bei Vorliegen eines Diabetes mellitus.- 1 characteristic of a type B lesion in women <65 years and / or in the presence of diabetes mellitus.

Es ist fernerhin bekannt, daß der Antikörper 7E3, der eine Entwicklungsvorstufe zu Abciximab darstellt, anfänglich durch seine Fähigkeit charakterisiert war, an GP IIb/IIIa-Rezeptoren sowohl ruhender als auch aktivierter Thrombozyten zu binden. Diese Rezeptoren sind bei der Bindung von fibrinogen an Thrombozyten von wesentlicher Bedeutung, wobei die Bindung von Fibrinogen an Thrombozyten eine Schlüsselrolle bei der Thrombozytenaggregation spielt.It is also known that antibody 7E3, which is a precursor to abciximab, was initially characterized by its ability to both quiescent at GP IIb / IIIa receptors also bind activated platelets. These receptors are involved in the binding of fibrinogen Platelets are essential, with the binding of fibrinogen to platelets a Plays a key role in platelet aggregation.

Bei der bekannten Anwendung von Abciximab wird als Dosierung zunächst intravenös eine Bolusinjektion (0,25 mg/kg Körpergewicht) mit anschließender kontinuierlicher intravenöser Infusion mit 10 µg/min empfohlenIn the known use of abciximab, a dose is initially given intravenously Bolus injection (0.25 mg / kg body weight) followed by continuous intravenous infusion with 10 µg / min recommended

Beschreibung der Erfindung; VorteileDescription of the invention; advantages

Erfindungsgemäß wird vorgeschlagen, Abciximab zur Behandlung von Mikrozirkulationsstörungen in Folge von Sepsis oder SIRS zu verwenden.According to the invention it is proposed to use abciximab for the treatment of microcirculation disorders Episode of sepsis or SIRS to use.

Überraschenderweise zeigt Abciximab eine besonders hohe Wirksamkeit bei der Vermeidung von Mikrozirkulationsstörungen bzw. Verbesserung der Mikrozirkulation nach einem Auftreten von Mikrozirkulationsstörungen, wie sie infolge von Sepsis oder SIRS auftreten. Hiermit kann vorteilhafter Weise das Risiko eines Multiorganversagens vermindert werden.Surprisingly, abciximab is particularly effective in preventing Microcirculation disorders or improvement of the microcirculation after an occurrence of Microcirculation disorders, such as those resulting from sepsis or SIRS. This can be more advantageous Way the risk of multi-organ failure can be reduced.

Der vorgeschlagenen Verwendung liegt die Erkenntnis zugrunde, daß die sog. Endstrecke der Thrombozytenaktivierung durch die fibrinogenvermittelte Thrombozyten-Thrombozyten-Interaktion charakterisiert ist, welche nur durch eine Konformationsänderung des GP IIb/IIIa Komplexes auf der Oberfläche der Thrombozyten möglich wird, und dann eine Fibrinogenbindung zwischen 2 Fibrinogenrezeptoren zur Folge hat. Das symmetrische Fibrinogenmolekül überbrückt den Spalt zwischen den Glykoprotein-IIb/IIIa-Komplexen zweier benachbarter Thrombozyten. Mit Hilfe von In-vitro- Assays wurde gezeigt, daß c7E3 die GP IIb/IIIa abhängige Thrombozytenaggregation dosisabhängig hemmt , wobei diese Hemmung unabhängig davon ist,welcher Stimulus für die Plättchenaggregation wie z. B. ADP, Kollagen, Thrombin, Adrenalin etc. verwendet wurde.The proposed use is based on the knowledge that the so-called final section of the Platelet activation through fibrinogen-mediated platelet-platelet interaction is characterized, which only by a conformational change of the GP IIb / IIIa complex on the Platelet surface becomes possible, and then a fibrinogen bond between 2 Fibrinogen receptors. The symmetrical fibrinogen molecule bridges the gap between the glycoprotein IIb / IIIa complexes of two neighboring platelets. With the help of in vitro Assays have been shown that c7E3 is GP IIb / IIIa dependent platelet aggregation dose dependent inhibits, which inhibition is independent of which stimulus for platelet aggregation such as B. ADP, collagen, thrombin, adrenaline, etc. was used.

AusführungsbeispielEmbodiment

Die Applikation erfolgt überlicherweise mittels einer kontinuierlichen intravenösen Infusion bei einer Dosierung von weniger als 10 ug/min da hierdurch die Bindungskinetik so eingestellt werden kann, daß bestehende Gerinnungsvorgänge in Wund- und Operationsgebieten minimal beeinflußt werden.The application is usually carried out by means of a continuous intravenous infusion at a Dosage of less than 10 µg / min since this enables the binding kinetics to be set in such a way that existing coagulation processes in wound and surgical areas are minimally influenced.

Wichtig ist darüber hinaus der Zeitpunkt der Anwendung.The time of application is also important.

Während einer gramnegativen Sepsis droht die oft letal verlaufende Komplikation einer disseminierten intravasalen Gerinnung (DIC). Die disseminierte intravasale Gerinnung ist eine Frühkomplikation der Sepsis, bei der in den kleinen Gefäßen des großen arteriellen Kreislaufs Mikrothromben entstehen. Bei diesen Patienten besteht eine Blutungstendenz als Folge des unkontrollierten Verbrauchs von Thrombozyten und Gerinnungsfaktoren. Durch Fibrinbildung in den Gefäßen kommt es zu Ischämie und einer daraus resultierenden Funktionsstörung der Organe. Die intravaskuläre Fibrinbildung kann zur Akkumulation von Leukozyten in den Lungen beitragen; Thrombin erhöht die Durchlässigkeit der Gefäße. Die sich entwickelnde DIC kann so zum auslösenden Faktor eines akuten Atemnotsyndroms werden.During gram-negative sepsis, the often lethal complication of disseminated threatens intravascular coagulation (DIC). Disseminated intravascular coagulation is an early complication of Sepsis, in which microthrombi develop in the small vessels of the large arterial circuit. At these patients have a tendency to bleed as a result of the uncontrolled consumption of Platelets and coagulation factors. Fibrin formation in the vessels leads to ischemia and a resulting malfunction of the organs. The intravascular fibrin formation can Contribute to the accumulation of leukocytes in the lungs; Thrombin increases the permeability of the Vessels. The developing DIC can thus trigger an acute respiratory distress syndrome become.

Obwohl eine Aktivierung der Neutrophilen nicht selbst den Gerinnungsprozeß auslöst, kann sie bei Patienten mit Sepsis Zytokine induzieren, so daß sich Mikrothromben bilden.Although neutrophil activation does not trigger the clotting process itself, it can help Patients with sepsis induce cytokines so that microthrombi form.

Wesentlich für den Zeitpunkt ist, daß mit der vorgeschlagenen Dosierung nicht bestehende Thrombozytenaggregationen aufgelöst, sondern lediglich die Bildung von neuen Thrombozytenaggregationen unterdrückt werden soll. Soweit die Thrombozytenaggregation bereits eingesetzt hat; wird diese abgeschwächt und im weiteren Verlauf unterdrückt.It is essential for the point in time that the proposed dosage does not exist Platelet aggregations dissolved, but only the formation of new ones Platelet aggregation should be suppressed. So much for platelet aggregation has started; this is weakened and suppressed in the further course.

Somit orientiert sich die vorgeschlagene Dosierung an den bekannten Werten, die bei nicht oder wenig aktivierten Thrombozyten ausreichen, um eine Thrombozytenaggregation zu unterdrücken, zumindest aber zu vermindern.Thus, the proposed dosage is based on the known values, the little or no activated platelets are sufficient to suppress platelet aggregation, at least but to diminish.

Es sind grundsätzlich 2 Vorgehensweisen möglich:
There are basically two approaches:

  • - eine prophylaktische Gabe von Abciximab unmittelbar nach der Diagnose einer Sepsis oder eines SIRS. Hierbei kann die vorgeschlagene Dosierung insbesondere dann auch unterschritten werden, wenn der Grad der Aktivierung der Thrombozyten und die Anzahl der freien Thrombozyten nicht wesentlich von ihren Normalwerten abweichen.- Prophylactic administration of abciximab immediately after diagnosis of sepsis or SIRS. In this case, the proposed dosage can also be fallen below, in particular if the degree of platelet activation and the number of free platelets is not differ significantly from their normal values.
  • - eine Gabe von Abciximab, sobald erkannt ist, daß die Aktivierung der Thrombozyten ansteigt und gleichzeitig die Anzahl der freien Thrombozyten sinkt. Hier ist die vorgeschlagene Dosierung als Dosierungsempfehlung anzusehen, der kurzfristig leicht überschritten werden kann, bis sich die genannten Werte, zumindest aber die Tendenz dieser Werte, stabilisiert haben.- Abciximab is administered as soon as it is recognized that platelet activation increases and at the same time the number of free platelets decreases. Here is the suggested dosage as  Dosage recommendation to look at, which can easily be exceeded in the short term until the mentioned values, or at least the tendency of these values, have stabilized.

Die vorgeschlagene Anwendung findet ihre Grenze dort, wo sich bei Patienten mit exzessivem Blutungsrisiko allgemein die Anwendung von Thrombozytenaggregationshemmern verbietet.The proposed application finds its limit where there is excessive use in patients Bleeding risk generally prohibits the use of platelet aggregation inhibitors.

Claims (1)

Verwendung von Abciximab zur Behandlung von Mikrozirkulationsstörungen in Folge von Sepsis oder SIRSUse of abciximab to treat microcirculatory disorders resulting from sepsis or SIRS
DE19753383A 1997-12-02 1997-12-02 Use of abciximab to treat microcirculation disorders Withdrawn DE19753383A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
DE19753383A DE19753383A1 (en) 1997-12-02 1997-12-02 Use of abciximab to treat microcirculation disorders
JP2000522947A JP2001524534A (en) 1997-12-02 1998-12-02 Use of a fibrinogen receptor antagonist to prevent disseminated intravascular coagulation
EP98965225A EP1035868A1 (en) 1997-12-02 1998-12-02 Use of a fibrinogen receptor-antagonist for preventing disseminated intravascular coagulation
CA002312824A CA2312824A1 (en) 1997-12-02 1998-12-02 Use of a fibrinogen receptor-antagonist for preventing disseminated intravascular coagulation
PCT/EP1998/007833 WO1999027962A1 (en) 1997-12-02 1998-12-02 Use of a fibrinogen receptor-antagonist for preventing disseminated intravascular coagulation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19753383A DE19753383A1 (en) 1997-12-02 1997-12-02 Use of abciximab to treat microcirculation disorders

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DE19753383A1 true DE19753383A1 (en) 1999-06-10

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WO (1) WO1999027962A1 (en)

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WO2010075861A2 (en) 2008-12-30 2010-07-08 Thrombologic Aps Methods of identifying critically ill patients at increased risk of development of organ failure and compounds for the treatment hereof
CN114796215B (en) * 2022-05-27 2023-07-07 贵州医科大学 Application of tirofiban in preparing medicine for treating human respiratory syncytial virus infection

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WO1996019475A1 (en) * 1994-12-22 1996-06-27 Smithkline Beecham Corporation Fibrinogen receptor antagonists

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