DE19746868A1 - Use of tumour necrosis factor antagonists - Google Patents
Use of tumour necrosis factor antagonistsInfo
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- DE19746868A1 DE19746868A1 DE19746868A DE19746868A DE19746868A1 DE 19746868 A1 DE19746868 A1 DE 19746868A1 DE 19746868 A DE19746868 A DE 19746868A DE 19746868 A DE19746868 A DE 19746868A DE 19746868 A1 DE19746868 A1 DE 19746868A1
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- tnf
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- sepsis
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/241—Tumor Necrosis Factors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P31/02—Local antiseptics
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
- G01N33/6869—Interleukin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Abstract
Description
Die vorliegende Erfindung betrifft die Verwendung von TNF-Antago nisten bei der Behandlung von septischen Erkrankungen.The present invention relates to the use of TNF-Antago nest in the treatment of septic diseases.
Es ist bekannt, daß der Begriff Tumor Nekrose Faktor (TNF) zwei zytotoxische Faktoren (TNF-α und TNF-β) umfaßt, die größtenteils von aktivierten Lymphozyten und Monozyten gebildet werden.It is known that the term tumor necrosis factor (TNF) is two includes cytotoxic factors (TNF-α and TNF-β), for the most part of activated lymphocytes and monocytes.
In der EP 260 610 werden beispielsweise anti-TNF-Antikörper be schrieben, die bei Krankheiten, die mit einer Erhöhung von TNF im Blut verbunden sind, wie septischer Schock, Transplantatab stoßung, Allergien, Autoimmunkrankheiten, Schocklunge, Blutge rinnungsstörungen oder entzündlichen Knochenerkrankungen zur Inaktivierung von TNF einsetzbar sein sollen.For example, anti-TNF antibodies are described in EP 260 610 wrote that in diseases with an increase in TNF in the Blood-related, such as septic shock, graftab shock, allergies, autoimmune diseases, shock lung, blood coagulation disorders or inflammatory bone diseases Inactivation of TNF should be usable.
In medizinischen Lehrbüchern werden septische Erkrankungen als klinischer Sammelbegriff für Zustände definiert, bei denen - aus gehend von einem Herd - Entzündungserreger, z. B. Bakterien in die Blutbahn gelangen, wodurch ein großes Spektrum subjektiver und objektiver Krankheitserscheinungen ausgelöst wird. Weiterhin wird festgestellt, daß in Abhängigkeit vom Erregertyp, der Reaktions lage des Organismus, dem Primärherd und den wechselnden Organbe teiligungen das Krankheitsbild sehr variieren kann (Sturm et al. "Grundbegriffe der Inneren Medizin", 13. Auflage, Seite 570, Gu stav Fischer Verlag, Stuttgart, 1984).In medical textbooks, septic diseases are considered Clinical collective term defined for conditions in which - from going from a stove - inflammatory agents, e.g. B. bacteria in the Enter the bloodstream, creating a wide range of subjective and objective disease symptoms is triggered. Will continue found that depending on the type of pathogen, the response location of the organism, the primary focus and the changing organbe the clinical picture can vary widely (Sturm et al. "Basic terms of internal medicine", 13th edition, page 570, Gu stav Fischer Verlag, Stuttgart, 1984).
Für den komplexen pathophysiologischen Ablauf einer Sepsis wird die Beteiligung einer Reihe von Cytokinen diskutiert. Besonders TNF wird eine wichtige Rolle beim septischen Schock aufgrund tierexperimenteller Daten zugeschrieben (Beutler et al., Science 229, 869-871, 1985).For the complex pathophysiological course of sepsis the involvement of a number of cytokines is discussed. Especially TNF is played an important role in septic shock attributed to animal experimental data (Beutler et al., Science 229, 869-871, 1985).
Dies hat letztlich dazu geführt, daß klinische Studien zur Behandlung von Sepsispatienten mit anti-TNF-Antikörpern durchge führt wurden.Ultimately, this has led to clinical studies on Treatment of sepsis patients with anti-TNF antibodies were led.
In einer vor kurzem veröffentlichten Mehrzentren-Phase II- Studie zur Behandlung von schwerer Sepsis mit einem murinen monoklonalen anti-TNF-Antikörper wurde allerdings gefunden, daß das Gesamtkol lektiv (80 Patienten) hinsichtlich Überlebensrate nicht von der Behandlung mit dem Antikörper profitierte. Lediglich die Pati enten mit erhöhten zirkulierenden TNF-Konzentrationen schienen von hochdosierter anti-TNF-Antikörper-Gabe hinsichtlich der Über lebenswahrscheinlichkeit zu profitieren (C.J.Fisher et al., Critical Care Medicine, Vol. 21, No. 3, Seite 318-327) . Weiterhin wird in dieser Studie auf eine Korrelation der Plasmawerte von TNF und IL-6 hingewiesen.In a recently published multi-center phase II study for the treatment of severe sepsis with a murine monoclonal anti-TNF antibody was found, however, that the total col lective (80 patients) in terms of survival not from the Treatment with the antibody benefited. Only the pati ducks with increased circulating TNF concentrations appeared to be of high-dose anti-TNF antibody administration with respect to the over probability of life to benefit (C.J. Fisher et al., Critical Care Medicine, Vol. 21, No. 3, pages 318-327). Farther In this study, a correlation between the plasma values of TNF and IL-6 noted.
Die Rolle, die das Cytokin Interleukin-6 (IL-6) bei der Sepsis spielt, ist unklar und widersprüchlich. Bei einigen Sepsispatien ten wurden erhöhte Serumspiegel an IL-6 gefunden (Hack et al., Blood 74, Nr. 5, 1704-1710, 1989).The role of the cytokine interleukin-6 (IL-6) in sepsis playing is unclear and contradictory. With some sepsis disorders increased serum levels of IL-6 were found (Hack et al., Blood 74, No. 5, 1704-1710, 1989).
Waage beschreibt, daß die Konzentrationen der Cytokine IL-6 und IL-8 mit der Schwere des Schocks korrelieren; daß sie aber nicht, weder allein noch in Kombination mit TNF, die Entwicklung eines Schocksyndroms hinsichtlich Lethalität beeinflussen (Waage in "Tumor Necrosis Factors", ed. B. Beutler, Raven Press, New York, 1992, Seite 275-283).Waage describes that the concentrations of the cytokines IL-6 and Correlate IL-8 with the severity of the shock; that they are not, neither alone nor in combination with TNF, the development of a Influence shock syndrome with regard to lethality (Libra in "Tumor Necrosis Factors," ed. B. Beutler, Raven Press, New York, 1992, pages 275-283).
Von einigen Wissenschaftlern wird IL-6 eine günstige Rolle beim septischen Schock zugeschrieben, da IL-6 in Form einer negativen Feedback-Kontrolle die LPS-induzierte TNF Produktion hemmt (Li bert et al. in "Tumor Necrosis Factor: Molecular and Cellular Biology and Clinical Relevance", ed. W. Fiers, Karger, Basel, 1993, Seite 126-131).Some scientists have found IL-6 to play a beneficial role in septic shock attributed to IL-6 in the form of a negative Feedback control inhibits LPS-induced TNF production (Li bert et al. in "Tumor Necrosis Factor: Molecular and Cellular Biology and Clinical Relevance ", ed. W. Fiers, Karger, Basel, 1993, pages 126-131).
WO 95/00291 lehrt TNF-Antagonisten als Medikamente zur Behandlung von Sepsis bei solchen Patienten, bei denen Interleukin-6 Serum werte von 500 pg/ml und mehr auftreten.WO 95/00291 teaches TNF antagonists as medications for treatment of sepsis in those patients who have interleukin-6 serum values of 500 pg / ml and more occur.
Es zeigte sich jedoch in klinischen Studien, daß die in WO 95/00291 offenbarte Behandlung nicht immer erfolgreich war.However, it has been shown in clinical studies that the in Treatment disclosed in WO 95/00291 was not always successful.
Offenbar gibt es Fälle von Sepsis, die mit gutem Erfolg mit TNF- Antagonisten therapierbar sind, während in anderen Fällen eine Behandlung mit TNF-Antagonisten keinen Erfolg zeigt und sogar kontraindiziert ist.Apparently there are cases of sepsis that have had good results with TNF Antagonists can be treated, while in other cases one Treatment with TNF antagonists is unsuccessful and even is contraindicated.
Es bestand daher die Aufgabe, innerhalb der an Sepsis erkrankten Patienten diejenigen verläßlich und schnell zu identifizieren, die mit TNF-Antagonisten erfolgreich behandelbar sind.It was therefore the task within those suffering from sepsis Identify patients reliably and quickly that can be successfully treated with TNF antagonists.
Es wurde gefunden, daß die Behandlung von septischen Erkrankungen bei solchen Patienten erfolgreich ist, die folgende Merkmale auf weisen: It has been found to treat septic diseases Successful in such patients has the following characteristics point:
Der Interleukin-6 Serumspiegel ist ansteigend, d. h. innerhalb eines Meßintervalls, das mindestens dreißig Minuten beträgt, ist der später gemessene Wert höher als der zuerst gemessene Wert.The interleukin-6 serum level is increasing, i. H. within a measuring interval that is at least thirty minutes the later measured value is higher than the first measured value.
Patienten, die an einer Sepsis erkrankt sind und dieses Kriterium erfüllen, sind für eine Behandlung mit TNF-Antagonisten gut geei gnet.Patients with sepsis and this criterion are well suited for treatment with TNF-antagonists gnet.
Bevorzugt wird die Behandlung bei solchen Patienten durchgeführt bei denen der Interleukin-6 Serumspiegel im Meßintervall minde stens 500 pg/ml beträgt. Er kann jedoch aber auch deutlich über diesem Wert liegen und bis zu einer Größenordnung von einigen mg/ml betragen.The treatment is preferably carried out in such patients where the interleukin-6 serum level in the measuring interval is at least is at least 500 pg / ml. However, it can also be significantly higher this value and up to an order of magnitude of a few mg / ml.
Um festzustellen, ob der Interleukin-6 Serumspiegel (IL-6) an steigend ist, müssen mindestens zwei IL-6 Messungen durchgeführt werden.To determine if the interleukin-6 serum level (IL-6) is on is increasing, at least two IL-6 measurements must be carried out become.
Der zweite, spätere Meßwert soll in einem Zeitraum von 30 Minute:
bis 48 Stunden nach dem ersten IL-6 Meßwert erhoben werden (Meß
intervall)
Bevorzugt beträgt das Meßintervall 2-24, insbesondere
4-10 Stunden.The second, later measured value should be collected within a period of 30 minutes: up to 48 hours after the first IL-6 measured value (measuring interval)
The measurement interval is preferably 2-24, in particular 4-10 hours.
Die zu behandelnden Patienten befinden sich in der Regel unter intensivmedizinischer Behandlung, die ein Einhalten von strikten Meßintervallgrenzen manchmal nicht erlaubt.The patients to be treated are usually located under intensive care treatment that adheres to strict Measuring interval limits are sometimes not allowed.
Das Ausmaß des IL-6-Serumspiegelanstiegs zwischen den beiden Messungen ist für die erfindungsgemäße Verwendung nicht so ent scheidend.The extent of the IL-6 serum level increase between the two Measurements are not so ent for the use according to the invention outgoing.
Im Falle eines nicht-ansteigenden oder sogar abfallenden IL-6-Se rumspiegels im Meßintervall ist eine Behandlung mit TNF-Antagoni sten nicht zu empfehlen.In the case of a non-rising or even falling IL-6-Se rumspiegel in the measuring interval is a treatment with TNF-antagoni not recommended.
Die Serumkonzentrationen an IL-6 lassen sich mit üblichen Nach weisverfahren wie RIA oder ELISA bestimmen. Ein gut geeignetes Nachweissystem ist beispielsweise das "IL-6-EASIA" der Fa. Medgenix.The serum concentrations of IL-6 can be measured using the usual methods Determine pointing procedures such as RIA or ELISA. A well suited one The detection system is, for example, the "IL-6-EASIA" Medgenix.
Die Konzentration an IL-6 kann auch über einen Aktivitätstest, bei dem beispielsweise C-reaktives Protein getestet wird, bestimmt werden. The concentration of IL-6 can also be determined using an activity test, where, for example, C-reactive protein is tested, be determined.
Da unterschiedliche Meßverfahren oder Testsysteme bei der glei chen Messung manchmal voneinander abweichende Ergebnisse liefern, empfiehlt es sich, entweder das gleiche Meßverfahren bzw. Test system für die Bestimmung der IL-6 Werte einzusetzen oder - bei Verwendung unterschiedlicher Systeme - diese gegeneinander zu ei chen.Since different measuring methods or test systems in the same measurement sometimes yield different results, it is recommended to use either the same measurement method or test system for determining the IL-6 values or - at Use of different systems - these against each other chen.
Als TNF-Antagonisten geeignet sind anti-TNF-Antikörper, TNF- Rezeptoren und lösliche Fragmente davon, TNF-Bindeproteine oder solche TNF-Derivate, die noch TNF-Rezeptorbindung besitzen, aber keine TNF-Aktivität mehr aufweisen. Solche TNF-Antagonisten sind dadurch gekennzeichnet, daß sie bereits gebildetes TNF abfangen und nicht an den TNF-Rezeptor gelangen lassen oder daß sie mit TNF um den Rezeptor konkurrieren.Suitable TNF antagonists are anti-TNF antibodies, TNF- Receptors and soluble fragments thereof, TNF binding proteins or such TNF derivatives that still have TNF receptor binding, however no longer have TNF activity. Such TNF antagonists are characterized in that they catch TNF already formed and not get to the TNF receptor or that they with TNF compete for the receptor.
Geeignet für die erfindungsgemäße Verwendung sind aber auch TNF- Antagonisten, die die Bildung oder Freisetzung von TNF verhin dern. Solche Substanzen inhibieren beispielsweise die Genexpres sion von TNF oder die Freisetzung von TNF aus Vorläuferformen. Geeignete TNF-Antagonisten sind beispielsweise Inhibitoren der TNF-Convertase.However, TNF- are also suitable for the use according to the invention. Antagonists that prevent TNF from forming or releasing other. Such substances inhibit gene expressions, for example sion of TNF or the release of TNF from precursors. Suitable TNF antagonists are, for example, inhibitors of TNF convertase.
TNF-antagonistischen Aktivitäten sind beispielsweise von Xanthin derivaten, Glucocorticoiden, Prostaglandin E 2, Thalidomid, In terleukin-4, Interleukin-10, Granulozyten Stimulating Factor (G-CSF), Cyclosporin, α-Antitrypsin beschrieben. Daher sind auch solche Verbindungen als TNF-Antagonisten geeignet.TNF antagonistic activities are, for example, from Xanthine derivatives, glucocorticoids, prostaglandin E 2, thalidomide, In terleukin-4, interleukin-10, granulocyte stimulating factor (G-CSF), cyclosporin, α-antitrypsin. Therefore, too such compounds are suitable as TNF antagonists.
Die für die erfindungsgemäße Verwendung geeigneten TNF-Antagoni sten sind beispielsweise von Mariott et al. DDT, Vol. 2, No. 7, July 1997 und in der dort zitierten Literatur beschrieben.The TNF antagonist suitable for the use according to the invention For example, Mariott et al. DDT, Vol. 2, No. 7, July 1997 and in the literature cited there.
Besonders bevorzugt für die erfindungsgemäße Verwendung sind anti-TNF-Antikörper und deren Fragmente.Are particularly preferred for the use according to the invention anti-TNF antibodies and their fragments.
Die zur erfindungsgemäßen Verwendung geeigneten anti-TNF-Anti körper sind bekannt (EP 260 610, EP 351 789, EP 218 868). Es können sowohl polyklonale als auch monoklonale Antikörper verwendet werden. Weiterhin sind auch TNF-bindende Antikörper fragmente wie Fab- oder F(ab')2-Fragmente oder single-chain- Fv-Fragmente geeignet.The anti-TNF antibodies suitable for use according to the invention are known (EP 260 610, EP 351 789, EP 218 868). Both polyclonal and monoclonal antibodies can be used. Furthermore, TNF-binding antibody fragments such as Fab or F (ab ') 2 fragments or single-chain Fv fragments are also suitable.
Ferner sind auch humanisierte oder humane anti-TNF-Antikörper oder deren TNF-bindende Fragmente gut geeignet, da diese Moleküle in menschlichen Patienten keine anti-Maus-Antigenizität verur sachen sollten. Furthermore, humanized or human anti-TNF antibodies are also or their TNF-binding fragments well suited because of these molecules did not cause anti-mouse antigenicity in human patients should do things.
Es können auch Gemische von verschiedenen anti-TNF-Antikörpern oder von anti-TNF-Antikörpern und TNF-Rezeptor-Fragmenten als Wirkstoff verwendet werden.Mixtures of various anti-TNF antibodies can also be used or of anti-TNF antibodies and TNF receptor fragments as Active ingredient can be used.
Zur vorliegenden Erfindung gehören pharmazeutische Zubereitungen, die neben nicht-toxischen, inerten pharmazeutisch geeigneten Trägerstoffen die anti-TNF-Antikörper enthalten, sowie Verfahren zur Herstellung dieser Zubereitungen.The present invention includes pharmaceutical preparations which in addition to non-toxic, inert pharmaceutically suitable Carriers that contain anti-TNF antibodies and methods for the preparation of these preparations.
Die Formulierung der anti-TNF-Antikörper geschieht in für bio technisch hergestellte Wirkstoffe üblicher Weise, in der Regel als Flüssigformulierung oder Lyophilisat (siehe z. B. Hagers Hand buch der pharmazeutischen Praxis, Bd. 2, 5. Auflage, 1991, S. 720, ISBN 3-540-52459-2). Die Herstellung der oben aufgeführten pharmazeutischen Zubereitungen erfolgt in üblicher Weise nach be kannten Methoden, z. B. durch Mischen des oder der Wirkstoffe mit dem oder mit den Trägerstoffen.The anti-TNF antibody is formulated for bio industrially manufactured active ingredients in the usual way, usually as a liquid formulation or lyophilisate (see e.g. Hager's hand book of pharmaceutical practice, vol. 2, 5th edition, 1991, p. 720, ISBN 3-540-52459-2). The manufacture of those listed above Pharmaceutical preparations are carried out in the usual way according to be knew methods, e.g. B. by mixing the active ingredient (s) with with or with the carriers.
Im allgemeinen hat es sich als vorteilhaft erwiesen, den oder die für die erfindungsgemäße Verwendung geeigneten Wirkstoffe in Ge samtmengen von etwa 0,1 bis etwa 100, vorzugsweise 0,1 bis 10 mg/kg Körpergewicht je 24 Stunden, ggf. in Form mehrerer Einzel gaben oder als Dauerinfusion und ggf. über eine Therapiedauer von mehreren Tagen hinweg zur Erzielung der gewünschten Ergebnisse zu verabreichen. Die Applikation kann als intravenöse Kurzinfusion der Einzelgaben oder als kontinuierliche Langzeitinfusion der Tagesdosis über 24 Stunden erfolgen. Eine Einzelgabe enthält den oder die Wirkstoffe vorzugsweise in Mengen von etwa 0,1 bis etwa 10 mg/kg Körpergewicht. Es kann jedoch erforderlich sein, von den genannten Dosierungen abzuweichen und zwar in Abhängigkeit von Alter und Größe des zu behandelnden Patienten sowie der Art und der Schwere der zugrundeliegenden Erkrankung, der Art der Zube reitung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabreichung erfolgt. Die Erfindung ist in dem folgenden Beispiel weiter veranschau licht.In general, it has proven advantageous to use the or the active substances suitable for the use according to the invention in Ge total amounts from about 0.1 to about 100, preferably 0.1 to 10 mg / kg body weight per 24 hours, possibly in the form of several individual given or as a continuous infusion and possibly over a therapy duration of several days to achieve the desired results administer. The application can be an intravenous short infusion of single doses or as a continuous long-term infusion of Daily dose over 24 hours. A single dose contains the or the active ingredients preferably in amounts from about 0.1 to about 10 mg / kg body weight. However, it may be necessary from the deviations mentioned doses, depending on Age and size of the patient to be treated as well as the type and the severity of the underlying disease, the type of accessory riding and the application of the drug and the period or interval within which the administration takes place. The invention is further illustrated in the following example light.
Behandlung von Sepsispatienten mit einem murinen anti-TNF-Anti körperfragment (F(ab')2), genannt MAK 195F (INN: AFELIMOMAB).Treatment of sepsis patients with a murine anti-TNF antibody fragment (F (ab ') 2 ) called MAK 195F (INN: AFELIMOMAB).
In einer multizentrischen klinischen Studie wurden insgesamt 251 Patienten mit schwerer Sepsis analysiert, die entweder mit einem anti-TNF-Antikörperfragment (Afelimomab) oder als Kontrollpatien ten behandelt wurden. In a multicenter clinical trial, a total of 251 Patients with severe sepsis analyzed with either a anti-TNF antibody fragment (afelimomab) or as control patient were treated.
Von den 251 Patienten hatten 47 einen ansteigenden, 178 einen ab steigenden IL-6 Serumspiegel.Of the 251 patients, 47 had a rising, 178 had a falling rising IL-6 serum levels.
Die Figur zeigt, daß in der Gruppe mit ansteigendem IL-6 Wert durch die Behandlung eine Senkung der Mortalität erreichbar ist (55,6% Mortalität gegenüber 69% bei Kontrolle).The figure shows that in the group with increasing IL-6 value treatment can reduce mortality (55.6% mortality versus 69% control).
Bei der Gruppe, die einen abfallenden IL-6 Serumspiegel aufwies, ist durch die Behandlung mit MAK 195 F kein Erfolg sichtbar; es zeigt sich im Gegenteil sogar ein negativer Einfluß durch die Be handlung (Mortalität beträgt 54,7% gegenüber 50,6% bei der Kon troll-Gruppe).In the group that had a falling IL-6 serum level, no success is visible through treatment with MAK 195 F; it on the contrary, there is even a negative influence from the Be action (mortality is 54.7% compared to 50.6% for the con troll group).
Die Behandlungsgruppe erhielt zusätzlich zur Standardtherapie der Sepsis das Prüfpräparat Afelimomab über einen Zeitraum von 3 Ta gen als insgesamt neunmalige Kurzinfusion über 15 Minuten in jew. achtstündigen Abständen in der Einzeldosis von jeweils 1 mg/kg Körpergewicht. Die Kontrollgruppe erhielt neben der Standardthe rapie der Sepsis zusätzlich ein pharmakologisch unwirksames Scheinpräparat (Placebo) in gleichem Applikationsschema.The treatment group received in addition to the standard therapy Sepsis the investigational drug Afelimomab over a period of 3 days as a total of nine short infusions over 15 minutes in each case. eight hour intervals in a single dose of 1 mg / kg each Body weight. The control group received the Standardthe Therapy of sepsis is also a pharmacologically ineffective Mock preparation (placebo) in the same application scheme.
Das Ergebnis dieser klinischen Studie belegt deutlich, daß die Behandlung von schwerer Sepsis mit anti-TNF-Antikörpern besonders erfolgreich verläuft, wenn solche Sepsispatienten behandelt wer den, die einen ansteigenden IL-6 Serumspiegel aufweisen. Pati enten, die einen abfallenden IL-6-Serumspiegel aufweisen, sollten demzufolge nicht mit TNF-Antagonisten behandelt werden.The result of this clinical study clearly shows that the Treatment of severe sepsis with anti-TNF antibodies in particular is successful if such sepsis patients are treated those that have increasing IL-6 serum levels. Pati ducks that have a falling IL-6 serum level should consequently not treated with TNF-antagonists.
Claims (7)
- (a) Bestimmung des Interleukin-6 Serumspiegels des Patienten zu einem ersten Zeitpunkt t1
- (b) Bestimmung des Interleukin-6 Serumspiegels zu einem zwei
ten Zeitpunkt t2, der mindestens 30 Minuten nach dem er
sten Zeitpunkt t1 liegt und Bestimmung des Verhältnisses
- (c) für den Fall, daß V < 1 ist erfolgt eine Behandlung mit TNF-Antagonisten.
- (a) Determination of the patient's interleukin-6 serum level at a first time t 1
- (b) Determination of the interleukin-6 serum level at a second time t 2 , which is at least 30 minutes after the first time t 1 , and determination of the ratio
- (c) in the event that V <1, treatment with TNF antagonists is carried out.
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19746868A DE19746868A1 (en) | 1997-10-23 | 1997-10-23 | Use of tumour necrosis factor antagonists |
| IL13508398A IL135083A0 (en) | 1997-10-23 | 1998-10-15 | Application of tnf antagonists as medicaments for treating septic diseases |
| CA002306790A CA2306790A1 (en) | 1997-10-23 | 1998-10-15 | Application of tnf antagonists as medicaments for treating septic diseases |
| HU0100105A HUP0100105A3 (en) | 1997-10-23 | 1998-10-15 | Application of tnf antagonists as medicaments for treating septic diseases |
| CNB988105144A CN1163272C (en) | 1997-10-23 | 1998-10-15 | Application of TNF antagonists as medicaments for treating septic diseases |
| EP98955459A EP1024831A2 (en) | 1997-10-23 | 1998-10-15 | Application of tnf antagonists as medicaments for treating septic diseases |
| JP2000517740A JP2001521009A (en) | 1997-10-23 | 1998-10-15 | Use of a TNF antagonist as a medicament for treating septic disease |
| BR9813114-1A BR9813114A (en) | 1997-10-23 | 1998-10-15 | Use of TNF antagonists to produce medicines, commercial package, and process to establish whether a patient suffering from sepsis should be treated with TNF antagonists |
| AU12284/99A AU756167B2 (en) | 1997-10-23 | 1998-10-15 | Application of TNF antagonists as medicaments for treating septic diseases |
| KR1020007004361A KR20010024549A (en) | 1997-10-23 | 1998-10-15 | Application of TNF Antagonists as Medicaments for Treating Septic Diseases |
| PCT/EP1998/006545 WO1999021582A2 (en) | 1997-10-23 | 1998-10-15 | Application of tnf antagonists as medicaments for treating septic diseases |
| ZA9809615A ZA989615B (en) | 1997-10-23 | 1998-10-22 | The use of TNF antagonists as drugs for treating septic 39disorders. |
| NO20001894A NO20001894D0 (en) | 1997-10-23 | 2000-04-12 | Use of TNF antagonists as drugs for the treatment of septic diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19746868A DE19746868A1 (en) | 1997-10-23 | 1997-10-23 | Use of tumour necrosis factor antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19746868A1 true DE19746868A1 (en) | 1999-04-29 |
Family
ID=7846420
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19746868A Withdrawn DE19746868A1 (en) | 1997-10-23 | 1997-10-23 | Use of tumour necrosis factor antagonists |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1024831A2 (en) |
| JP (1) | JP2001521009A (en) |
| KR (1) | KR20010024549A (en) |
| CN (1) | CN1163272C (en) |
| AU (1) | AU756167B2 (en) |
| BR (1) | BR9813114A (en) |
| CA (1) | CA2306790A1 (en) |
| DE (1) | DE19746868A1 (en) |
| HU (1) | HUP0100105A3 (en) |
| IL (1) | IL135083A0 (en) |
| NO (1) | NO20001894D0 (en) |
| WO (1) | WO1999021582A2 (en) |
| ZA (1) | ZA989615B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004012766A1 (en) * | 2002-08-02 | 2004-02-12 | Goldberg, Evgeny Danilovich | Method for correcting immune responses and medicinal agent |
| US8637030B2 (en) | 2010-07-15 | 2014-01-28 | Oleg I. Epshtein | Combination pharmaceutical composition and methods of treating functional diseases or conditions of gastrointestinal tract |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2181297C2 (en) | 2000-06-20 | 2002-04-20 | Эпштейн Олег Ильич | Method of treatment of pathological syndrome and medicinal agent |
| UA76639C2 (en) | 2002-08-02 | 2006-08-15 | Олєг Ільіч Епштєйн | Homeopathic medication and method for treating erectile dysfunctions |
| RU2309732C1 (en) | 2006-03-13 | 2007-11-10 | Олег Ильич Эпштейн | Pressed solid oral formulation of medicinal preparation and method for preparing solid oral formulation of medicinal preparation |
| SG187038A1 (en) | 2010-07-15 | 2013-02-28 | Oleg Iliich Epshtein | A method of increasing the effect of an activated-potentiated form of an antibody |
| EP2415461B1 (en) * | 2010-07-24 | 2012-10-31 | Roche Diagnostics GmbH | Stabilization of interleukin 6 in serum based solutions |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2638652B2 (en) * | 1988-07-18 | 1997-08-06 | カイロン・コーポレーション | Monoclonal antibody reacting with cachectin |
| GB9109645D0 (en) * | 1991-05-03 | 1991-06-26 | Celltech Ltd | Recombinant antibodies |
| NZ278607A (en) * | 1994-02-07 | 1999-05-28 | Knoll Ag | Use of tnf antagonists for treating disorders involving elevated serum levels of il-6 wherein the serum levels are 500pg/ml or above |
-
1997
- 1997-10-23 DE DE19746868A patent/DE19746868A1/en not_active Withdrawn
-
1998
- 1998-10-15 KR KR1020007004361A patent/KR20010024549A/en not_active Application Discontinuation
- 1998-10-15 CA CA002306790A patent/CA2306790A1/en not_active Abandoned
- 1998-10-15 IL IL13508398A patent/IL135083A0/en unknown
- 1998-10-15 EP EP98955459A patent/EP1024831A2/en not_active Withdrawn
- 1998-10-15 HU HU0100105A patent/HUP0100105A3/en unknown
- 1998-10-15 JP JP2000517740A patent/JP2001521009A/en active Pending
- 1998-10-15 CN CNB988105144A patent/CN1163272C/en not_active Expired - Fee Related
- 1998-10-15 BR BR9813114-1A patent/BR9813114A/en not_active IP Right Cessation
- 1998-10-15 AU AU12284/99A patent/AU756167B2/en not_active Withdrawn - After Issue
- 1998-10-15 WO PCT/EP1998/006545 patent/WO1999021582A2/en not_active Application Discontinuation
- 1998-10-22 ZA ZA9809615A patent/ZA989615B/en unknown
-
2000
- 2000-04-12 NO NO20001894A patent/NO20001894D0/en not_active Application Discontinuation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004012766A1 (en) * | 2002-08-02 | 2004-02-12 | Goldberg, Evgeny Danilovich | Method for correcting immune responses and medicinal agent |
| EA008605B1 (en) * | 2002-08-02 | 2007-06-29 | Олег Ильич ЭПШТЕЙН | Medical agent for correcting pathological immune responses |
| US8637030B2 (en) | 2010-07-15 | 2014-01-28 | Oleg I. Epshtein | Combination pharmaceutical composition and methods of treating functional diseases or conditions of gastrointestinal tract |
Also Published As
| Publication number | Publication date |
|---|---|
| AU756167B2 (en) | 2003-01-09 |
| CN1277556A (en) | 2000-12-20 |
| JP2001521009A (en) | 2001-11-06 |
| HUP0100105A2 (en) | 2001-05-28 |
| ZA989615B (en) | 2000-04-20 |
| IL135083A0 (en) | 2001-05-20 |
| CA2306790A1 (en) | 1999-05-06 |
| HUP0100105A3 (en) | 2003-08-28 |
| AU1228499A (en) | 1999-05-17 |
| WO1999021582A3 (en) | 1999-07-15 |
| KR20010024549A (en) | 2001-03-26 |
| CN1163272C (en) | 2004-08-25 |
| NO20001894L (en) | 2000-04-12 |
| EP1024831A2 (en) | 2000-08-09 |
| NO20001894D0 (en) | 2000-04-12 |
| WO1999021582A2 (en) | 1999-05-06 |
| BR9813114A (en) | 2000-08-15 |
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