WO2007054348A1 - Novel medicaments - Google Patents

Novel medicaments Download PDF

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Publication number
WO2007054348A1
WO2007054348A1 PCT/EP2006/010825 EP2006010825W WO2007054348A1 WO 2007054348 A1 WO2007054348 A1 WO 2007054348A1 EP 2006010825 W EP2006010825 W EP 2006010825W WO 2007054348 A1 WO2007054348 A1 WO 2007054348A1
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use according
inhibitor
kynurenine
modulator
acid
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PCT/EP2006/010825
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German (de)
French (fr)
Inventor
Christine SCHÜTT
Cornelia Kiank
Jan-Philip Zeden
Trung Nam Nguyen
Alexandra Westerholt
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Ernst-Moritz-Arndt-Universität Greifswald
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Publication of WO2007054348A1 publication Critical patent/WO2007054348A1/en

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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
    • 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
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides

Definitions

  • the present invention relates to modulators of tryptophan metabolism and their use in the therapy and / or prophylaxis of diseases and conditions which can be influenced by them, in particular for the treatment and / or prophylaxis of septic immune paralysis and / or multi-organ failure, depression and chronic stress states.
  • the causes of death are infections, multiple organ failure, circulatory shock or disseminated intravascular coagulation.
  • proinflammatory cytokines e.g. TNF
  • immune paralysis has been used to describe conditions in which the organism can no longer adequately respond to invading pathogens, leading to hyperinflammatory dysregulation, which is dominated by anti-inflammatory immunosuppressive regulations.
  • the state of immune paralysis is life-threatening because immune defense is largely eliminated, it is still unclear why and when which patient gets into an immune paralysis.
  • Tissue destruction, injuries or, for example, bacterial transgressions from the intestine (after blood loss, mental stress or surgery) lead to immune reactions against the invading pathogens.
  • the immune response may (but does not have to) lead to excessive tissue destruction and hypotension causing septic shock (overinflammatory reaction).
  • the sepsis syndrome can also end in an opposite decompensation, ie lead to the loss of immune competence. In such a state of immune paralysis, the immune response to pathogens has collapsed.
  • Indoleamine-2,3-dioxygenase is an enzyme which metabolizes the initial and pacing conversion of tryptophan to N-formyl kynurenine along the kynurenine pathway (Moffett et al. (2003) Immunology and Cell Biology 81: 247-265). ,
  • the cleavage product kynurenine triggers programmed cell death (apoptosis) mainly from the TH 1 subset of lymphocytes.
  • TH1 cells initiate a pro-inflammatory immune response, they secrete proinflammatory cytokines, including INF-gamma.
  • Kynurenine is further metabolized via two possible degradation pathways.
  • immune cells produce quinolinic acid, which is neurotoxic and, as an NMDA receptor agonist, produces neuronal cell death and thus damages the CNS.
  • kynurenic acid is produced, which is neuroprotective as a physiological antagonist of quinolinic acid and acts as an NMDA receptor antagonist.
  • Kynurenic acid suppresses LPS-inducible monocyte TNF synthesis in vitro (Wang et al., 2006, J Biol Chem 281: 22021-22028). Since tryptophan is a precursor molecule of serotonin synthesis, tryptophan deficiency causes depressive behavioral changes.
  • the inventors of the present invention have now been able to demonstrate for the first time that changes described with a state of immune paralysis, e.g. anti-inflammatory cytokine overweight, massive apoptotic cell deaths in lymphoid organs, leukocytopenia, lymphocytopenia and depressive behavior in animal experiments can be caused by the activation of the enzyme IDO (indoleamine-2,3-dioxygenase).
  • IDO indoleamine-2,3-dioxygenase
  • the inventors of the present invention have been able to demonstrate that the administration of modulators of tryptophan metabolism can prevent the susceptibility to infection, the anti-infilatory cytokine overweight and the development of depressive behavioral disorders.
  • ITS intensive care unit
  • the present invention provides the use of a modulator of tryptophan metabolism for the manufacture of a medicament for the therapy and / or prophylaxis of immune paralysis and / or multi-organ failure.
  • the present invention further provides the use of a modulator of tryptophan metabolism for the manufacture of a medicament for the therapy and / or prophylaxis of depression and chronic stress conditions.
  • the modulator of tryptophan metabolism is an indoleamine-2,3-dioxygeease (IDO) inhibitor.
  • IDO indoleamine-2,3-dioxygelose
  • IDO inhibitors are known and are described i.a. in WO 2004/093871, US Pat. No. 6,451,840 and Vottero et al., Biotechnol J. 2006, Mar. 1 (3), 282-288.
  • the IDO inhibitor is selected from 1-methyl-DL-tryptophan, ⁇ - (3-benzofuranyl) -DL-alanine, ⁇ - (3-benzo (b) thienyl) -DL-alanine, 6-nitro-L- tryptophan, indole-3-carbinol, 3,3 * -diindolylmethane, brassinine, 5-methylbrassinin, epigallocatechin gallate, 5-bromo-4-chloro-indoxyl-1,3-diacetate, 9-vinylcarbazole, acemetacin, 5-bromo-DL -tryptophan, 5-bromoindoxyl diacetate, phenyl-TH-DL-tryptophan, pyrrolidine dithio-carbamate, 4-phenylimidazole, propenyl-TH-DL- tryptophan, brassilexin, 3-amino-2-naphthenic acid, ⁇ -car
  • Tryptophan metabolism is an inhibitor of quinolinic acid pathway
  • Cynurenine metabolism is involved enzyme.
  • the inhibitor is a kynurenine 3-hydroxylase inhibitor, a kynureninase inhibitor or a 3-hydroxyanthranilic acid oxygenase inhibitor.
  • the kynurenine-3-hydroxylase inhibitor is preferably selected from vitamin B 6, nicotinylalanine, m-nitrobenzoylalanine, o-methoxybenzoylalanine and (1S, 2S) -2- (3,4-dichlorobenzoyl) cyclopropane-1-carboxylic acid, as well as their pharmaceutically compatible salts.
  • the kynureninase inhibitor is preferably selected from 5-bromodihydro-L-kynurenine, dihydro-L-kynurenine, (4R) -5-bromodihydro-L-kynureinine, (S) - (2-amino-4-bromophenyl) -L -cysteine S, S-dioxide, (S) - (2-amino-5-bromophenyl) -L-cysteine, S, S-dioxide, (S) -2-aminophenyl) -L-cysteine-S, S dioxide, and their pharmaceutically acceptable salts.
  • the 3-hydroxyanthranilic acid oxygenase inhibitor is preferably selected from 4-chloro-3-hydroxyanthranilic acid, 4-fluoro-3-hydroxyanthranilic acid and 4-bromo-3-hydroxyanthranilic acid, as well as their pharmaceutically acceptable salts.
  • the modulator of tryptophan metabolism is an inhibitor of kynurenine aminotransferases I or / and II.
  • Preferred is the use of an inhibitor that does not pass the blood-brain barrier.
  • these are selected from glutamine, ZiNC 165965, ⁇ -aminoadipic acid, quisqualic acid and DL-5-bromokynurenine.
  • the modulator is a monoclonal antibody or antibody fragment against kynurenine, kynurenic acid or quinolinic acid. These can be prepared in a conventional manner by coupling the antigen to a high molecular weight carrier for immunization.
  • the modulator may be a siRNA (small interfering RNA) specific for IDO mRNA.
  • SiRNAs can be isolated in a manner known per se to those skilled in the art, e.g. in EP-B1 1 214 945 and EP-B 1 1 144 623 (by AMYLAM).
  • siRNA gene silencing by siRNA is well known to those skilled in the art.
  • Paddison (2002) Genes Dev. 16, 948-958I, Elbashir (2002) Methods 26, 199-213; Novina (2002) Mat. Med. June 3, 2002; Donze (2002) Nucl. Acids Res. 30, e46; Paul (2002) Nat. Biotech 20, 505-508; Lee (2002) Nat. Biotech. 20, 500-505; Miyagashi (2002) Nat. Biotech. 20, 497-500; Yu (2002) PNAS 99, 6047-6052 or Brummelkamp (2002), Science 296, 550-553 describe the successful use of siRNA for gene knockout.
  • Vectors such as the pSUPER vector, or RNA polymain vectors, e.g. by Yu (2002) loc. cit .; Miyagishi (2002) loc. cit. or Brummelkamp (2002) loc. cit. described.
  • the modulator may be an anti-IDO aptamer specific for
  • Nucleic acid aptamers may be isolated in a manner known per se to those skilled in the art, e.g. by Pendergast et al. (2005, J Biomolecular Techniques 16: 224-234). Aptamers are also useful for intracellular targets.
  • the modulators of tryptophan metabolism may be used for Therapy and / or prophylaxis in sepsis, multi-organ failure (MOF), multi-organ dysfunction syndrome (MODS), polytrauma, severe acute necrotizing pancreatitis, acquired immunodeficiencies, depression, post-traumatic stress syndrome (PTSD), chronic stress conditions, burn-out syndrome, and Chronic fatigue syndrome (CFS) can be used.
  • MOF multi-organ failure
  • MODS multi-organ dysfunction syndrome
  • CFS Chronic fatigue syndrome
  • compositions of the novel modulators of tyrptophan metabolism can be formed with a variety of organic and inorganic acids and bases.
  • Exemplary acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanopropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride , hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oxalate
  • Basic nitrogen-containing groups can be e.g. with agents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, iodide and bromide, dialkyl sulfates such as dimethyl, diethyl, dipropyl, dibutyl and diamyl sulfates, long chain alkyl halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide, or aralkyl halides such as benzyl and phenethyl bromides.
  • agents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, iodide and bromide, dialkyl sulfates such as dimethyl, diethyl, dipropyl, dibutyl and diamyl sulfates, long chain alkyl halides such as decy
  • Pharmaceutically acceptable base addition salts include, but are not limited to, cations derived from alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, and the like, as well as non-toxic quaternary ammonium salts and amine cation, including, but not limited to Ammonium, Tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine and ethylamine.
  • exemplary amines which can be used to form base addition salts include benzazethine, dicyclohexylamine, hydrabin, N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and salts with Amino acids such as arginine or lysine.
  • one or at least one modulator of tryptophan metabolism according to the invention may be administered alone or in the form of pharmaceutical formulations, optionally with admixture of excipients and excipients customary in the art.
  • the formulations according to the invention can be formulated / prepared by customary methods and techniques known to the person skilled in the art. as described, for example, in Remington 's Remington 's Pharmaceutical Sciences, 15th Ed., Mack Publishing Co., New Jersey (1991).
  • Dosage forms for oral, parenteral (eg i.V., s.c., i.p., i.e., intrathecal) and local (eg topical, rectal, vaginal, buccal administration in the eye or by inhalation) application are preferred.
  • the formulations according to the invention can be used in particular as tablets (in particular enteric-coated tablets or modified-release tablets), capsules (hard and soft gelatin capsules), pills, granules, suppositories, ovules, ointment creams, gels, patches, TTS or else as emulsions, Suspensions, solutions or reconstitutable powders (also for parenteral administration) are present.
  • the present invention provides the use of neutralizing monoclonal antibodies or antibody fragments against kynurenine, kynurenic acid or quinolinic acid to remove tryptophan metabolites from human blood or serum.
  • the present invention provides the use of monoclonal antibodies against kynurenine, kynurenic acid or quinolinic acid for extracorporeal removal (immunoadsorption) of Tryptophan metabolites from human blood or serum ready.
  • the thus prepared blood or serum can then be reinfused to the patient.
  • the present invention provides for the first time a pharmaceutical composition for the therapy and / or prophylaxis of immune paralysis and / or multi-organ failure and the use of a modulator of tryptophan metabolism for the manufacture of a medicament for the therapy and / or prophylaxis of depression.

Abstract

The present invention relates to the use of a modulator of tryptophan metabolism for the manufacture of a medicament for the therapy and/or prophylaxis of immunotolerance and/or multiorgan failure, depression, post-traumatic stress syndrome (PTSD), burn-out syndrome and chronic fatigue syndrome (CFS).

Description

Neue Arzneimittel New medicines
Die vorliegende Erfindung betrifft Modulatoren des Tryptophanmetabolismus und ihre Verwendung bei der Therapie und/oder Prophylaxe von Erkrankungen und Zuständen die durch diese beeinflusst werden können, insbesondere zur Behandlung und/oder Prophylaxe von septischer Immunparalyse und /oder Multiorganversagen, Depressionen und chronischen Stresszuständen.The present invention relates to modulators of tryptophan metabolism and their use in the therapy and / or prophylaxis of diseases and conditions which can be influenced by them, in particular for the treatment and / or prophylaxis of septic immune paralysis and / or multi-organ failure, depression and chronic stress states.
Sepsis und ihre Komplikationen sind eine der Hauptursachen für Morbidität und Mortalität in der operativen Intensivmedizin. Mortalitätsraten von 50% bei schwerer Sepsis bis zu 80% bei Patienten mit septischen Schock bleiben seit Jahren unverändert, trotz fortschreitender Verfeinerung diagnostischer und therapeutischer Maßnahmen.Sepsis and its complications are a major cause of morbidity and mortality in surgical intensive care. Mortality rates from 50% in severe sepsis to 80% in patients with septic shock have remained unchanged for years, despite the ongoing refinement of diagnostic and therapeutic measures.
Die Todesursachen sind Infektionen, Multiorganversagen, Kreislaufschock oder disseminierte intravasale Gerinnung.The causes of death are infections, multiple organ failure, circulatory shock or disseminated intravascular coagulation.
Im Verlauf einer Sepsis geraten viele Patienten nach anfänglicher Hyperinflammation in einen immunparalytischen Zustand der lebensbedrohlich ist und u.a. durch eine herabgesetzte HLA-DR-Rezeptordichte auf Monozyten und ein Unvermögen der Zellen, proinflammatorische Zytokine, wie z.B. TNF, zu produzieren, charakterisiert ist.In the course of sepsis, many patients, after initial hyperinflammation, enter an immuno-paralytic state that is life-threatening, and so on. by a decreased HLA-DR receptor density on monocytes and an inability of the cells, proinflammatory cytokines, e.g. TNF, to produce, is characterized.
Der Begriff „Immunparalyse" ist für Zustände geprägt worden, bei dem der Organismus nicht mehr adäquat auf eindringende Erreger reagieren kann. Hier kommt es zu einer der Hyperinflammation gegenteiligen Dysregulation, bei der die anti-inflammatorischen immunsupprimierenden Regulationen dominieren. Der Zustand der Immunparalyse ist lebensbedrohlich, da die Immunabwehr weitgehend ausgeschaltet wird. Es ist bis heute nicht geklärt, warum und wann welcher Patient in eine Immunparalyse gerät. Gewebszerstörungen, Verletzungen oder z.B. bakterielle Übertritte aus dem Darm (nach Blutverlusten, psychischem Stress oder Operationen) führen zu Immunreaktionen gegen die eindringenden Erreger. Die Immunantwort kann (muss aber nicht) überschiessend zu Gewebszerstörung und Blutdruckabfall führen, die einen septischen Schock verursachen (überschiessende proinflammatorische Reaktion). Das Sepsis-Syndrom kann aber auch in einer gegenteiligen Dekompensation enden, d.h. zum Verlust der Immunkompetenz führen. In einem solchen Zustand der Immunparalyse ist die Immunantwort gegen Pathogene zusammengebrochen.The term "immune paralysis" has been used to describe conditions in which the organism can no longer adequately respond to invading pathogens, leading to hyperinflammatory dysregulation, which is dominated by anti-inflammatory immunosuppressive regulations.The state of immune paralysis is life-threatening because immune defense is largely eliminated, it is still unclear why and when which patient gets into an immune paralysis. Tissue destruction, injuries or, for example, bacterial transgressions from the intestine (after blood loss, mental stress or surgery) lead to immune reactions against the invading pathogens. The immune response may (but does not have to) lead to excessive tissue destruction and hypotension causing septic shock (overinflammatory reaction). However, the sepsis syndrome can also end in an opposite decompensation, ie lead to the loss of immune competence. In such a state of immune paralysis, the immune response to pathogens has collapsed.
Die meisten Sepsis-Patienten versterben heute an einer Immunparalyse (Hotchkiss et al. (2003), N Engl J Med, 348 (2): 138-150).Most sepsis patients today die of immune paralysis (Hotchkiss et al. (2003), N Engl J Med, 348 (2): 138-150).
Kausale Therapien, diesen immunsuppressiven Zustand abzuwenden, sind bisher nicht verfügbar. Studien mit pro-inflammatorisch wirkenden Zytokinen, wie z.B. GM-CSF, INF-gamma oder TNF, die auf eine „Umkehr" der antiinflammatorischen in eine pro-inflammatorische Immunreaktion abzielen, waren nicht erfolgreich und führen u.U. zu einer überschiessenden proinflammatorischen Immunreaktion, die wiederum ihrerseits zum Tod durch septischen Schock führt (Echtenacher et al. (2003) Immunobiology, 208 (4): 381- 389, Volk et al. (2002) Critical Care, 6: 279-281, Hotchkiss et al. (2003) N Engl J Med, 348 (2): 138-150).Causal therapies to avert this immunosuppressive condition are not yet available. Studies with pro-inflammatory cytokines, such as GM-CSF, INF-gamma or TNF, which aim at "reversing" the anti-inflammatory into a pro-inflammatory immune response, have not been successful and may result in an excess proinflammatory immune response, which in turn leads to death from septic shock (Echtenacher et (2003) Immunobiology, 208 (4): 381-389, Volk et al (2002) Critical Care, 6: 279-281, Hotchkiss et al (2003) N Engl J Med, 348 (2): 138 -150).
lndolamin-2,3-dioxygenase (IDO) ist ein Enzym, welches die initiale und schrittmachende Umwandlung von Tryptophan zu N-Formylkynurenin entlang des Kynurenin-Stoffwechselweges metabolisiert (Moffett et al.(2003) Immunology and Cell Biology 81 : 247-265).Indoleamine-2,3-dioxygenase (IDO) is an enzyme which metabolizes the initial and pacing conversion of tryptophan to N-formyl kynurenine along the kynurenine pathway (Moffett et al. (2003) Immunology and Cell Biology 81: 247-265). ,
Das Spaltprodukt Kynurenin löst den programmierten Zelltod (Apoptose) v.a. von der TH 1 -Zeilsubpopulation unter den Lymphozyten aus. TH 1- Zellen initiieren eine pro-inflammatorische Immunantwort, sie sezernieren proinflammatorische Cytokine, u.a. INF-gamma. Kynurenin wird über zwei mögliche Abbauwege weiter metabolisiert. Zum einen produzieren Immunzellen Chinolinsäure, welche neurotoxisch wirkt und als NMDA-Rezeptor-Agonist neuronalen Zelltod erzeugt und somit das ZNS schädigt. Zum anderen entsteht Kynureninsäure, die als physiologischer Gegenspieler der Chinolinsäure neuroprotektiv ist und als NMDA- Rezeptorantagonist wirkt. Kynureninsäure supprimiert die LPS-induzierbare TNF- Synthese von Monozyten in vitro (Wang et al. 2006, J Biol Chem 281 : 22021 - 22028). Da Tryptophan ein Precursormolekül der Serotoninsynthese ist, erzeugt Tryptophanmangel depressive Verhaltensänderungen.The cleavage product kynurenine triggers programmed cell death (apoptosis) mainly from the TH 1 subset of lymphocytes. TH1 cells initiate a pro-inflammatory immune response, they secrete proinflammatory cytokines, including INF-gamma. Kynurenine is further metabolized via two possible degradation pathways. On the one hand, immune cells produce quinolinic acid, which is neurotoxic and, as an NMDA receptor agonist, produces neuronal cell death and thus damages the CNS. On the other hand, kynurenic acid is produced, which is neuroprotective as a physiological antagonist of quinolinic acid and acts as an NMDA receptor antagonist. Kynurenic acid suppresses LPS-inducible monocyte TNF synthesis in vitro (Wang et al., 2006, J Biol Chem 281: 22021-22028). Since tryptophan is a precursor molecule of serotonin synthesis, tryptophan deficiency causes depressive behavioral changes.
Einen Überblick über die Zusammenhänge von Trypthophanmetabolismus, Verhalten und Immunantwort gibt u.a. Moffett et al. (2003) Immunology and Cell Biology, 81 : 247-265.An overview of the relationships between tryptophan metabolism, behavior and immune response can be found, for example. Moffett et al. (2003) Immunology and Cell Biology, 81: 247-265.
Die Erfinder der vorliegenden Erfindung haben nun zum ersten Mal nachweisen können, dass Veränderungen, die mit einem Zustand der Immunparalyse beschrieben werden, wie z.B. anti-inflammatorisches Zytokinübergewicht, massive apoptotische Zelluntergänge in lymphoiden Organen, Leukozytopenie, Lymphozytopenie und depressives Verhalten im Tierexperiment durch die Aktivierung der Enzyms IDO (lndolamin-2,3-dioxygenase) verursacht werden können. Mäuse mit erniedrigten Tryptophan- und erhöhten Serumspiegeln von Kynureninsäure entwickeln spontan eine Pneumonie. Nach experimentellen Infektionen zeigen sie stark erhöhte bakterielle Disseminationen.The inventors of the present invention have now been able to demonstrate for the first time that changes described with a state of immune paralysis, e.g. anti-inflammatory cytokine overweight, massive apoptotic cell deaths in lymphoid organs, leukocytopenia, lymphocytopenia and depressive behavior in animal experiments can be caused by the activation of the enzyme IDO (indoleamine-2,3-dioxygenase). Mice with decreased tryptophan and elevated serum levels of kynurenic acid spontaneously develop pneumonia. After experimental infections, they show markedly increased bacterial disseminations.
Die Erfinder der vorliegenden Erfindung haben zum ersten Mal nachweisen können, dass durch Gabe von Modulatoren des Trytophanmetabolismus die Infektanfälligkeit , das anti-infalmmatorische Zytokin-Übergewicht und die Entwicklung depressiver Verhaltensstörungen verhindert werden können.For the first time, the inventors of the present invention have been able to demonstrate that the administration of modulators of tryptophan metabolism can prevent the susceptibility to infection, the anti-infilatory cytokine overweight and the development of depressive behavioral disorders.
Ferner konnten die Erfinder der vorliegenden Erfindung in einer prospektiven Studie an 100 Patienten einer intensiv-medizinischen Station (ITS) zeigen, dass Patienten mit Sepsis erniedrigte Tryptophanspiegel, erhöhte Kynurenin-, Kynureninsäure- und Chinolinsäurespiegel aufweisen. Dieser Befund korreliert mit den Markern einer Immunparalyse, wie der üblicherweise gemessenen Reduktion der HLA DR-Expression auf Monozyten im periphären Blut (siehe z.B. Docke et al. (1997), Nat. Med., 3: 678-681).Further, in a prospective study of 100 intensive care unit (ITS) patients, the present inventors demonstrated that patients with sepsis have low levels of tryptophan, increased levels of kynurenine, kynurenic acid, and quinoline. This finding correlates with the markers of immune paralysis, such as the commonly measured reduction in HLA DR expression on peripheral blood monocytes (see, eg, Docke et al., 1997, Nat. Med., 3: 678-681).
Ausgehend von den Therapieergebnissen im Maussystem wurde zudem gefunden, dass die Aktivierung von IDO ursächlich zur Entwicklung/Verstärkung einer Sepsis und eines Multiorganversagens führt.Based on the therapeutic results in the mouse system, it was also found that the activation of IDO leads to the development / enhancement of sepsis and multiple organ failure.
Somit stellt die vorliegende Erfindung die Verwendung eines Modulators des Tryptophanmetabolimus zur Herstellung eines Arzneimittels zur Therapie und/oder Prophylaxe einer Immunparalyse und/oder eines Multiorganversagens bereit.Thus, the present invention provides the use of a modulator of tryptophan metabolism for the manufacture of a medicament for the therapy and / or prophylaxis of immune paralysis and / or multi-organ failure.
Dies geschieht durch die Verhinderung der massiven Apoptose von TH 1 -Zellen und die Verhinderung des anti-inflammatorischen Übergewichts durch Blockade des Tryptophankatabolismus über den Kynureninabbauweg oder Blockade/Entfernung der toxischen Metaboliten bzw. Verabreichung von Antagonisten dieser toxischen Metaboliten.This is done by preventing the massive apoptosis of TH 1 cells and preventing the anti-inflammatory excess weight by blocking the tryptophan catabolism via the kynurenine degradation pathway or blocking / removing the toxic metabolites or administering antagonists of these toxic metabolites.
Somit stellt die vorliegende Erfindung zudem die Verwendung eines Modulators des Tryptophanmetabolismus zur Herstellung eines Arzneimittel zur Therapie und/oder Prophylaxe von Depression und chronischen Stresszuständen.Thus, the present invention further provides the use of a modulator of tryptophan metabolism for the manufacture of a medicament for the therapy and / or prophylaxis of depression and chronic stress conditions.
In einer Ausführungsform der Erfindung ist der Modulator des Tryptophanmetabolismus ein lndolamin-2,3-dioxygeηase (IDO) Inhibitor.In one embodiment of the invention, the modulator of tryptophan metabolism is an indoleamine-2,3-dioxygeoase (IDO) inhibitor.
IDO-Inhibitoren sind bekannt und werden u.a. in WO 2004/093871 , US 6,451 ,840 und Vottero et al., Biotechnol J. 2006, Mar. 1 (3), 282-288 beschrieben.IDO inhibitors are known and are described i.a. in WO 2004/093871, US Pat. No. 6,451,840 and Vottero et al., Biotechnol J. 2006, Mar. 1 (3), 282-288.
Bevorzugt ist der IDO-Inhibitor ausgewählt aus 1-Methyl-DL-tryptophan, ß-(3- Benzofuranyl)-DL-alanin, ß-(3-Benzo(b)thienyl)-DL-alanin, 6-Nitro-L-tryptophan, lndol-3-carbinol, 3,3*-diindolylmethan, Brassinin, 5-Methylbrassinin, Epigallocatechingallat, 5-Brom-4-chlor-indoxyl-1 ,3-diacetat, 9-Vinylcarbazol, Acemetacin, 5-Brom-DL-tryptophan, 5-Bromindoxyldiacetat, Phenyl-TH-DL- tryptophan, Pyrrolidin-dithio-carbamat, 4-Phenylimidazol, Propenyl-TH-DL- tryptophan, Brassilexin, 3-Amino-2-naphthensäure, ß-Carbolin, 3-Butyl-ß- carbolin, 6-Fluor-3-carbomethoxy-ß-carbolin, 6-lsothiocyanat-3-carbomethxy(-ß- carbolin, 3-Propoxy-ß-carbolin, 3-Carboxy-ß-carbolin, 3-Carbopropoxy-ß-carbolin, 3-Nitro-ß-cabolin, 3-Carbo-tert.-butoxy-ß-carbolin, Annulin C und Norharman, sowie deren pharmazeutisch verträgliche Salze.Preferably, the IDO inhibitor is selected from 1-methyl-DL-tryptophan, β- (3-benzofuranyl) -DL-alanine, β- (3-benzo (b) thienyl) -DL-alanine, 6-nitro-L- tryptophan, indole-3-carbinol, 3,3 * -diindolylmethane, brassinine, 5-methylbrassinin, epigallocatechin gallate, 5-bromo-4-chloro-indoxyl-1,3-diacetate, 9-vinylcarbazole, acemetacin, 5-bromo-DL -tryptophan, 5-bromoindoxyl diacetate, phenyl-TH-DL-tryptophan, pyrrolidine dithio-carbamate, 4-phenylimidazole, propenyl-TH-DL- tryptophan, brassilexin, 3-amino-2-naphthenic acid, β-carboline, 3-butyl-β-carboline, 6-fluoro-3-carbomethoxy-β-carboline, 6-isothiocyanato-3-carbomethoxy (-β-carboline, 3 -Propoxy-β-carboline, 3-carboxy-β-carboline, 3-carbopropoxy-β-carboline, 3-nitro-β-caboline, 3-carbo-tert-butoxy-β-carboline, Annulin C and Norharman, and the like their pharmaceutically acceptable salts.
In einer weiteren Ausführungsform der Erfindung ist der Modulator desIn a further embodiment of the invention, the modulator of the
Tryptophanmetabolismus ein Inhibitor eines am Chinolinsäureweg desTryptophan metabolism is an inhibitor of quinolinic acid pathway
Kynureninmetabolismus beteiligten Enzyms ist.Cynurenine metabolism is involved enzyme.
Hierbei ist es bevorzugt, dass der Inhibitor ein Kynurenin-3-hydroxylase-lnhibitor, ein Kynureninase-Inhibitor oder ein 3-Hydroxyanthranilsäure-Oxygenase-lnhibitor ist.Hereby it is preferred that the inhibitor is a kynurenine 3-hydroxylase inhibitor, a kynureninase inhibitor or a 3-hydroxyanthranilic acid oxygenase inhibitor.
Bevorzugt ist der Kynurenin-3-hydroxylase-lnhibitor ausgewählt aus Vitamin B 6, Nicotinylalanin, m-Nitrobenzoylalanin, o-Methoxybenzoylalanin und (1S,2S)-2- (3,4-Dichlorbenzoyl)cyclopropan-1 -carbonsäure, sowie deren pharmazeutisch verträglichen Salzen.The kynurenine-3-hydroxylase inhibitor is preferably selected from vitamin B 6, nicotinylalanine, m-nitrobenzoylalanine, o-methoxybenzoylalanine and (1S, 2S) -2- (3,4-dichlorobenzoyl) cyclopropane-1-carboxylic acid, as well as their pharmaceutically compatible salts.
Ferner ist der Kynureninase-Inhibitor vorzugsweise ausgewählt aus 5- Bromdihydro-L-kynurenin, Dihydro-L-kynurenin, (4R)-5-Bromdihydro-L- kynureinin, (S)-(2-Amino-4-bromphenyl)-L-cystein-S,S-dioxid, (S)-(2-Amino-5- bromphenyl)-L-cystein-,S,S-dioxid, (S)-2-Aminophenyl)-L-cystein-S,S-dioxid, sowie deren pharmazeutisch verträglichen Salzen.Further, the kynureninase inhibitor is preferably selected from 5-bromodihydro-L-kynurenine, dihydro-L-kynurenine, (4R) -5-bromodihydro-L-kynureinine, (S) - (2-amino-4-bromophenyl) -L -cysteine S, S-dioxide, (S) - (2-amino-5-bromophenyl) -L-cysteine, S, S-dioxide, (S) -2-aminophenyl) -L-cysteine-S, S dioxide, and their pharmaceutically acceptable salts.
Der 3-Hydroxyanthranilsäure-Oxygenase-lnhibitor ist vorzugsweise aus 4-Chlor- 3- hydroxyanthranilsäure, 4-Fluor-3-hydroxyanthranilsäure und 4-Brom-3- hydroxyanthranilsäure, sowie deren pharmazeutisch verträglichen Salzen ausgewählt.The 3-hydroxyanthranilic acid oxygenase inhibitor is preferably selected from 4-chloro-3-hydroxyanthranilic acid, 4-fluoro-3-hydroxyanthranilic acid and 4-bromo-3-hydroxyanthranilic acid, as well as their pharmaceutically acceptable salts.
In einer weiteren Ausführungsform der Erfindung ist der Modulator des Tryptophanmetabolismus ein Inhibitor der Kynurenin-Aminotransferasen I oder/ und II. Bevorzugt ist die Verwendung eines Inhibitors, der nicht die Blut-Hirn- Schranke passiert. In einer bevorzugten Ausführungsform sind diese ausgewählt aus Glutamin, ZiNC 165965, α-Aminoadipinsäure, Quisqualinsäure und DL-5- Bromkynurenin.In another embodiment of the invention, the modulator of tryptophan metabolism is an inhibitor of kynurenine aminotransferases I or / and II. Preferred is the use of an inhibitor that does not pass the blood-brain barrier. In a preferred embodiment, these are selected from glutamine, ZiNC 165965, α-aminoadipic acid, quisqualic acid and DL-5-bromokynurenine.
In noch einer weiteren Ausführungsform ist der Modulator ein monoklonaler Antikörper oder Antikörperfragment gegen Kynurenin, Kynureninsäure oder Chinolinsäure. Diese können in an sich bekannter Weise durch Kopplung des Antigens an einen hochmolekularen Carrier zur Immunisierung hergestellt werden.In yet another embodiment, the modulator is a monoclonal antibody or antibody fragment against kynurenine, kynurenic acid or quinolinic acid. These can be prepared in a conventional manner by coupling the antigen to a high molecular weight carrier for immunization.
Ferner kann der Modulator eine siRNA (small interfering RNA) sein, welche spezifisch für IDO mRNA ist.Further, the modulator may be a siRNA (small interfering RNA) specific for IDO mRNA.
SiRNA können in für den Fachmann an sich bekannter Weise, wie z.B. in EP-B1 1 214 945 und EP-B 1 1 144 623 (von AMYLAM) beschrieben, hergestellt werden.SiRNAs can be isolated in a manner known per se to those skilled in the art, e.g. in EP-B1 1 214 945 and EP-B 1 1 144 623 (by AMYLAM).
Ferner ist die Genausschaltung mittels siRNA dem Fachmann aus dem Stand der Technik bekannt. So beschreiben z.B. Paddison (2002) Genes Dev. 16, 948- 958I, Elbashir (2002) Methods 26, 199-213; Novina (2002) Mat. Med. June 3, 2002; Donze (2002) Nucl. Acids Res. 30, e46; Paul (2002) Nat. Biotech 20, 505- 508; Lee (2002) Nat. Biotech. 20, 500-505; Miyagashi (2002) Nat. Biotech. 20, 497-500; Yu (2002) PNAS 99, 6047-6052 oder Brummelkamp (2002), Science 296, 550-553 die erfolgreiche Verwendung von siRNA zur Genausschaltung. Hierbei können z.B. Vektoren wie der pSUPER VeKtor, oder RNA pollll Vektoren eingesetzt werden, wie z.B. von Yu (2002) loc. cit.; Miyagishi (2002) loc. cit. oder Brummelkamp (2002) loc. cit. beschrieben.Further, gene silencing by siRNA is well known to those skilled in the art. Thus, e.g. Paddison (2002) Genes Dev. 16, 948-958I, Elbashir (2002) Methods 26, 199-213; Novina (2002) Mat. Med. June 3, 2002; Donze (2002) Nucl. Acids Res. 30, e46; Paul (2002) Nat. Biotech 20, 505-508; Lee (2002) Nat. Biotech. 20, 500-505; Miyagashi (2002) Nat. Biotech. 20, 497-500; Yu (2002) PNAS 99, 6047-6052 or Brummelkamp (2002), Science 296, 550-553 describe the successful use of siRNA for gene knockout. Here, e.g. Vectors such as the pSUPER vector, or RNA polymain vectors, e.g. by Yu (2002) loc. cit .; Miyagishi (2002) loc. cit. or Brummelkamp (2002) loc. cit. described.
Ferner kann der Modulator ein Anti-IDO-Aptamer sein, welches spezifisch fürFurthermore, the modulator may be an anti-IDO aptamer specific for
IDO ist.IDO is.
Nukleinsäure-Aptamere können in für den Fachmann an sich bekannter Weise, wie z.B. von Pendergast et al. (2005, J Biomolecular Techniques 16: 224 - 234) beschrieben, hergestellt werden. Aptamere sind auch für intrazelluläre Targets verwendbar.Nucleic acid aptamers may be isolated in a manner known per se to those skilled in the art, e.g. by Pendergast et al. (2005, J Biomolecular Techniques 16: 224-234). Aptamers are also useful for intracellular targets.
Insbesondere können die Modulatoren des Trypthophanmetabolismus zur Therapie und/oder Prophylaxe bei Sepsis, Multiorganversagen (MOF), Multiorgan Dysfunktions-Syndrom (MODS), Polytrauma, schwerer akuter nekrotisierender Pankreatitis, erworbenen Immundefizienzen, Depression, Posttraumatischem Stress-Syndrom (PTSD), chronischen Stresszuständen, Burn-out Syndrom, und Chronic Fatigue Syndrom (CFS) verwendet werden.In particular, the modulators of tryptophan metabolism may be used for Therapy and / or prophylaxis in sepsis, multi-organ failure (MOF), multi-organ dysfunction syndrome (MODS), polytrauma, severe acute necrotizing pancreatitis, acquired immunodeficiencies, depression, post-traumatic stress syndrome (PTSD), chronic stress conditions, burn-out syndrome, and Chronic fatigue syndrome (CFS) can be used.
Pharmazeutisch verträgliche Salze der erfindungsgemässen Modulatoren des Tyrptophanmetabolismus können mit einer Vielzahl von organischen und anorganischen Säuren und Basen gebildet werden. Beispielhafte Säureadditionssalze umfassen Acetat, Adipat, Alginat, Ascorbat, Aspartat, Benzoat, Benzolsulfonat, Bisulfat, Borat, Butyrat, Citrat, Camphorat, Camphersulfonat, Cyclopentanpropionat, Digluconat, Dodecylsulfat, Ethansulfonat, Fumarat, Glucoheptanoat, Glycerophosphat, Hemisulfat, Heptanoat, Hexanoat, Hydrochlorid, hydrobromid, Hydroiodid, 2- Hydroxyethansulfonat, Lactat, Maleat, Methansulfonat, 2-Naphthalensulfonat, Nicotinat, Nitrat, Oxalat, Pamoat, Pectinat, Persulfat, 3-Phenyl sulfonat, 3- Phenylpropionat, Phosphat, Picrat, Pivalat, Propionat, Salicylat, Succinat, Sulfat, Sulfonat, Tartrat, Thiocyanat, Toluolsulfonate wie Tosylat, Undecanoat oder dergleichen.Pharmaceutically acceptable salts of the novel modulators of tyrptophan metabolism can be formed with a variety of organic and inorganic acids and bases. Exemplary acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanopropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride , hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenyl sulfonate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, Succinate, sulfate, sulfonate, tartrate, thiocyanate, toluenesulfonates such as tosylate, undecanoate or the like.
Basische stickstoffenthaltende Gruppen können z.B. mit Agentien wie Niederalkylhalogeniden wie Methyl-, Ethyl-, Propyl und Butylchlorid ,- iodid und - bromid, Dialkylulfaten wie Dimethyl-, diethyl-, Dipropyl-, Dibutyl und Diamylsulfaten, langkettigen Alkylhalogeniden wie Decyl, Lauryl, Myristyl und Stearylchlorid, -bromid und iodid, oder Aralkylhalogeniden wie Benzyl und Phenethylbromiden quarternisiert werden.Basic nitrogen-containing groups can be e.g. with agents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, iodide and bromide, dialkyl sulfates such as dimethyl, diethyl, dipropyl, dibutyl and diamyl sulfates, long chain alkyl halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide, or aralkyl halides such as benzyl and phenethyl bromides.
Pharmazeutisch verträgliche Basenadditionssalze umfassen, sind aber nicht beschränkt auf von Alkali- und Erdalkalimetallen abgeleiteten Kationen wie Natrium-, Lithium-, Kalium-, Calcium-, Magnesium-, Aluminiumsalzen und dergleichen sowie nicht toxischen quartären Ammoniumsalzen und Aminkationenand, umfassend, aber nicht beschränkt auf Ammonium, Tetramethylammonium, Tetraethylammonium, Methylamin, Dimethylamin, Trimethylamin, Triethylamin und Ethylamin. Weitere beispielhafte Amine welche zur Bildung von Basenadditionssalzen verwendet werden können umfassen Benzazethin, Dicyclohexylamin, Hydrabin, N-Methyl-D-glucamin, N-Methyl-D- glucamid, t-Butylamin, Diethylamin, Ethylendiamin, Ethanolamin, Diethanolamin, Piperazin und Salze mit Aminosäuren wie Arginin oder Lysin.Pharmaceutically acceptable base addition salts include, but are not limited to, cations derived from alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, and the like, as well as non-toxic quaternary ammonium salts and amine cation, including, but not limited to Ammonium, Tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine and ethylamine. Other exemplary amines which can be used to form base addition salts include benzazethine, dicyclohexylamine, hydrabin, N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and salts with Amino acids such as arginine or lysine.
Gemäß der vorliegenden Erfindung können ein oder mindestens ein erfindungsgemäßer Modulator des Tryptophanmetabolismus für sich alleine oder in Form von pharmazeutischen Formulierungen gegebenenfalls unter Beimischung von im Fachgebiet üblichen Hilfsstoffen und Exzipienten verabreicht werden. Die erfindungsgemäßen Formulierungen können nach üblichen dem Fachmann bekannten Verfahren und Techniken formuliert/hergestellt werden; wie z.B. in Remington's Remington's Pharmaceutical Sciences, 15. Auflage., Mack Publishing Co., New Jersey (1991) beschrieben.According to the present invention, one or at least one modulator of tryptophan metabolism according to the invention may be administered alone or in the form of pharmaceutical formulations, optionally with admixture of excipients and excipients customary in the art. The formulations according to the invention can be formulated / prepared by customary methods and techniques known to the person skilled in the art. as described, for example, in Remington 's Remington 's Pharmaceutical Sciences, 15th Ed., Mack Publishing Co., New Jersey (1991).
Bevorzugt sind hierbei Darreichungsformen zur oralen, parenteralen (z. B. i.V., s.c, i.p., i.e., intrathekal) und lokalen ( z. B. topisch, rectal, vaginal, buccal Applikation im Auge oder durch Inhalation) Applikation.Dosage forms for oral, parenteral (eg i.V., s.c., i.p., i.e., intrathecal) and local (eg topical, rectal, vaginal, buccal administration in the eye or by inhalation) application are preferred.
Somit können die erfindungsgemäßen Formulierungen insbesondere als Tabletten (insbesondere auch magensaftresistent überzogene Tabletten oder Tabletten mit modifizierter Wirkstofffreigabe), Kapseln (Hart- und Weichgelatinekapseln), Pillen, Granulate, Suppositorien, Ovula, Salben Cremes, Gele, Pflaster , TTS oder auch als Emulsionen, Suspensionen, Lösungen oder rekonstituierbare Pulver (auch zur parenteralen Applikation) vorliegen.Thus, the formulations according to the invention can be used in particular as tablets (in particular enteric-coated tablets or modified-release tablets), capsules (hard and soft gelatin capsules), pills, granules, suppositories, ovules, ointment creams, gels, patches, TTS or else as emulsions, Suspensions, solutions or reconstitutable powders (also for parenteral administration) are present.
In einer weiteren Ausführungsform stellt die vorliegende Erfindung die Verwendung von neutralisierenden monoklonalen Antikörpern oder Antikörperfragmenten gegen Kynurenin, Kynureninsäure oder Chinolinsäure zur Entfernung von Tryptophanmetaboliten aus Humanblut oder-serum bereit.In another embodiment, the present invention provides the use of neutralizing monoclonal antibodies or antibody fragments against kynurenine, kynurenic acid or quinolinic acid to remove tryptophan metabolites from human blood or serum.
In einer weiteren Ausführungsform stellt die vorliegende Erfindung die Verwendung von monoklonalen Antikörpern gegen Kynurenin, Kynureninsäure oder Chinolinsäure zur extrakorporalen Entfernung (Immunadsorption) von Tryptophanmetaboliten aus Humanblut oder -serum bereit. Das so aufbereitete Blut bzw. Serum kann dann dem Patienten wieder infundiert werden.In a further embodiment, the present invention provides the use of monoclonal antibodies against kynurenine, kynurenic acid or quinolinic acid for extracorporeal removal (immunoadsorption) of Tryptophan metabolites from human blood or serum ready. The thus prepared blood or serum can then be reinfused to the patient.
Beispielexample
Durch orale Applikation von 1 -Methyltryptophan durch das Trinkwasser konnte in der Maus die experimentelle Entwicklung einer Immunparalyse verhindert werden. Im Gegensatz zu den unbehandelten Tieren behielten die 1-MT gefütterten Tiere ihre normale Abwehrkraft, experimentelle bakterielle Infektionen abzuwehren (z.B. E. coli, S. typhimurium, experimentelle Peritonitis). Während unbehandelte Tiere in Immunparalyse massive T-Zellapoptosen, eine antiinflammatorische Reaktionslage, T-Zellanergie, Störungen der Phagozytosefunktionen und depressives Verhalten aufwiesen, zeigten die behandelten Tiere keine solchen Veränderungen.Oral administration of 1-methyltryptophan to drinking water prevented the experimental development of immune paralysis in the mouse. In contrast to the untreated animals, the 1-MT fed animals retained their normal immunity to fend off experimental bacterial infections (e.g., E. coli, S. typhimurium, experimental peritonitis). While untreated animals showed massive T-cell apoptosis, an anti-inflammatory reaction, T-cell anergy, phagocytic disorders, and depressive behavior in immune paralysis, the treated animals showed no such changes.
Die Verminderung von experimentell induzierter Immunosupression durch 1-MT und der erhöhte Tryptophan-Abbau werden in Tabellen 1 und 2 dargestellt. The reduction of experimentally induced immunosuppression by 1-MT and the increased tryptophan degradation are presented in Tables 1 and 2.
Tabelle 1.Table 1.
Verminderung von experimentell induzierter Immunosuppression durch Behandlung mit 1 -Methyltryptophan (1-MT) gestresst ungestresst, gestresst, ungestresst, mit 1-MT mit 1 -MT unbehandelt unbehandelt behandelt behandeltReduction of experimentally induced immunosuppression by treatment with 1-methyltryptophan (1-MT) stressed, unstressed, stressed, unstirred, treated with 1-MT with 1-MT untreated untreated
SSS für Depressions- 9.3 ± 2.6* 14.0 + 4.4 ähnliches VerhaltenSSS for depression 9.3 ± 2.6 * 14.0 + 4.4 like behavior
IL10 [pg/ml] nach 42 h 162.9 ± 202.7* 416.8 ± 303.0 $ 305.7 ± 50.1 244.5 ± 311.2IL10 [pg / ml] after 42 h 162.9 ± 202.7 * 416.8 ± 303.0 $ 305.7 ± 50.1 244.5 ± 311.2
LPS Stimulation derLPS stimulation of
Splenocytensplenocytes
IL10 [pg/ml] nach 42 h 0 ± 0 125.9 ± 6.1$ 31.6 ± 30.3 47.1 ± 36.5 anti-CD3/anti-CD28 Stimulation derIL10 [pg / ml] after 42 h 0 ± 0 125.9 ± 6.1 $ 31.6 ± 30.3 47.1 ± 36.5 anti-CD3 / anti-CD28 stimulation of
Splenocytensplenocytes
cfu/ml Blut 24 h nach 3x10 ± 10.5x105± 2.3 0.1x105± 1.6x10s± 1.5 Infection mit E. coli 3.1x10 5* x10 5 $ 0.1x105 x105 cfu / ml blood 24 h after 3x10 ± 10.5x10 5 ± 2.3 0.1x10 5 ± 1.6x10 s ± 1.5 Infection with E. coli 3.1x10 5 * x10 5 $ 0.1x10 5 x10 5
cfu/g Milz 24 h nach 20.7x105± 286.3x105± 90.5 x105± 14.1x105±cfu / g spleen 24 h after 20.7x10 5 ± 286.3x10 5 ± 90.5 x10 5 ± 14.1x10 5 ±
Infection mit E. coli 20.3x105" 262.2 x105 $$$ 14.3x105 18.1 x105 Infection with E. coli 20.3x10 5 " 262.2 x10 5 $$$ 14.3x10 5 18.1 x10 5
1.5
Figure imgf000011_0001
Infection mit E. coli1.5
Figure imgf000011_0001
Infection with E. coli
p<0.05; "p<0.01 ; p<0.001 Vergleich von gestressten Mäusen mit oder ohne 1-MTp <0.05;" p <0.01; p <0.001 Comparison of stressed mice with or without 1-MT
Behandlungtreatment
$p<0.05; $$p<0.01 ; $$$p<0.001 Vergleich von gestressten Mäusen mit ungestressten $ p <0.05; $$ p <0.01; $$$ p <0.001 Comparison of stressed mice with unstressed ones
Mäusen ohne 1-MT Behandlung; Vergleich mittels Mann-Whitney U-TestMice without 1-MT treatment; Comparison by Mann-Whitney U-Test
SSS - Stress Severity Score; cfu - colony forming units (Kolonie bildende Einheiten) Tabelle 2.SSS - Stress Severity Score; cfu - colony forming units Table 2.
Verstärkte(r) Tryptophan-Abbau und Kynurenin-Bildung in schwer kranken septischen Patienten auf der Intensivstation. Blutproben die während der Immunparalyse, definiert durch eine reduzierte monozytische HLA DR Expression, erhalten wurden, wurden mit Blutproben von gesunden Freiwilligen verglichen (n=13/Gruppe).Increased tryptophan degradation and kynurenine formation in critically ill septic patients in the intensive care unit. Blood samples obtained during immunoparalysis, defined by reduced monocytic HLA DR expression, were compared to blood samples from healthy volunteers (n = 13 / group).
Septische Patienten Gesunde Kontrollen p WertSeptic patients Healthy controls p value
Tryptophan [μ M] 27.8 ± 11.5 48.3 ± 6.3 2.2 x10"5 Tryptophan [μ M] 27.8 ± 11.5 48.3 ± 6.3 2.2 x10 "5
Kynurenin [μM] 2.2 x10"5 Kynurenine [μM] 2.2 x10 "5
5.0 ± 0.6 3.9 ± 0.35.0 ± 0.6 3.9 ± 0.3
Vergleich mittels Mann-Whitney U-TestComparison by Mann-Whitney U-Test
Somit stellt die vorliegende Erfindung erstmals ein Arzneimittel zur Therapie und/oder Prophylaxe einer Immunparalyse und/oder eines Multiorganversagens und die Verwendung eines Modulators des Tryptophanmetabolimus zur Herstellung eines Arzneimittels zur Therapie und/oder Prophylaxe von Depressionen bereit. Thus, the present invention provides for the first time a pharmaceutical composition for the therapy and / or prophylaxis of immune paralysis and / or multi-organ failure and the use of a modulator of tryptophan metabolism for the manufacture of a medicament for the therapy and / or prophylaxis of depression.

Claims

Patentansprüche claims
1. Verwendung eines Modulators des Kynureninabbauweges des Tryptophanmetabolismus zur Herstellung eines Arzneimittels zur Therapie und/oder Prophylaxe einer Immunparalyse und/oder eines Multiorganversagens.1. Use of a modulator of Kynureninabbauweges the tryptophan metabolism for the manufacture of a medicament for the therapy and / or prophylaxis of immune paralysis and / or a multi-organ failure.
2. Verwendung eines Modulators des Kynureninabbauweges des Tryptophanmetabolimus zur Herstellung eines Arzneimittels zur Therapie und/oder Prophylaxe von Depressionen.2. Use of a modulator of Kynureninabbauweges the tryptophan metabolism for the manufacture of a medicament for the therapy and / or prophylaxis of depression.
3. Verwendung nach Anspruch 1 oder 2, wobei der Modulator des Tryptophanmetabolismus ein lndolamin-2,3-dioxygenase (IDO) Inhibitor ist.Use according to claim 1 or 2, wherein the modulator of tryptophan metabolism is an indoleamine 2,3-dioxygenase (IDO) inhibitor.
4. Verwendung nach Anspruch 1 oder 2, wobei der Modulator des Tryptophanmetabolismus ein Inhibitor eines am Chinolinsäureweg des Kynureninmetabolismus beteiligten Enzyms ist.Use according to claim 1 or 2, wherein the modulator of tryptophan metabolism is an inhibitor of an enzyme involved in quinolate pathway of kynurenine metabolism.
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5. Verwendung nach Anspruch 1 , 2 oder 4, wobei der Inhibitor ein Kynurenin-3-hydroxylase-lnhibitor ist.Use according to claim 1, 2 or 4, wherein the inhibitor is a kynurenine 3-hydroxylase inhibitor.
6. Verwendung nach Anspruch 1 , 2 oder 4, wobei der Inhibitor ein Kynureninase-Inhibitor ist.Use according to claim 1, 2 or 4, wherein the inhibitor is a kynureninase inhibitor.
7. Verwendung nach Anspruch 1 , 2 oder 4, wobei der Inhibitor ein 3- Hydroxyanthranilsäure-Oxygenase-Inhibitor ist.Use according to claim 1, 2 or 4, wherein the inhibitor is a 3-hydroxyanthranilic acid oxygenase inhibitor.
8. Verwendung nach Anspruch 1 wobei der Inhibitor ein Kynureninaminotransferase-Inhibitor ist.Use according to claim 1 wherein the inhibitor is a kynurenine aminotransferase inhibitor.
9. Verwendung nach Anspruch 1 oder 2, wobei der Modulator ein monoklonaler Antikörper oder Antikörperfragment gegen Kynurenin, Kynureninsäure oder Chinolinsäure ist.9. Use according to claim 1 or 2, wherein the modulator is a monoclonal antibody or antibody fragment against kynurenine, Kynureninsäure or quinolinic acid is.
10. Verwendung nach Anspruch 1 oder 2 wobei der Modulator siRNA oder ein Nukleinsäure-Aptamer ist, welche spezifisch für IDO mRNA sind.Use according to claim 1 or 2, wherein the modulator is siRNA or a nucleic acid aptamer specific for IDO mRNA.
11. Verwendung nach Anspruch 1 oder 2 wobei der Modulator siRNA oder ein Nukleinsäure-Aptamer ist, welche spezifisch für Kynurenin-3-hydroxylase mRNA sind.11. Use according to claim 1 or 2 wherein the modulator is siRNA or a nucleic acid aptamer specific for kynurenine-3-hydroxylase mRNA.
12. Verwendung nach Anspruch 1 oder 2 wobei der Modulator siRNA oder ein Nukleinsäure-Aptamer ist, welche spezifisch für Kynureninase mRNA sind.12. Use according to claim 1 or 2 wherein the modulator siRNA or a nucleic acid aptamer which are specific for kynureninase mRNA.
13. Verwendung nach Anspruch 1 oder 2 wobei der Modulator siRNA oder ein Nukleinsäure-Aptamer ist, welche spezifisch für 3-Hydroxyanthranilsäure- Oxygenase mRNA sind.Use according to claim 1 or 2, wherein the modulator is siRNA or a nucleic acid aptamer specific for 3-hydroxyanthranilic acid oxygenase mRNA.
14. Verwendung nach Anspruch 1 oder 2 wobei der Modulator siRNA oder ein Nukleinsäure-Aptamer ist, welche spezifisch für Kynureninaminotransferase mRNA sind.14. Use according to claim 1 or 2 wherein the modulator is siRNA or a nucleic acid aptamer which are specific for kynurenine aminotransferase mRNA.
15. Verwendung nach einem der vorhergehenden Ansprüche 1 und 3 bis 14 zur Therapie und/oder Prophylaxe bei Sepsis, Multiorganversagen (MOF), Multiorgan Dysfunktions Syndrom (MODS), Polytrauma, schwerer akuter nekrotisierender Pankreatitis oder erworbenen Immundefizienzen.15. Use according to one of the preceding claims 1 and 3 to 14 for therapy and / or prophylaxis in sepsis, multi-organ failure (MOF), multi-organ dysfunction syndrome (MODS), polytrauma, severe acute necrotizing pancreatitis or acquired immunodeficiencies.
16. Verwendung nach einem der vorhergehenden Ansprüche 2 bis 14 zur Therapie und/oder Prophylaxe von Depressionen, Posttraumatischem Stress-Syndrom (PTSD), chronischen Stresszuständen, Burn-out Syndrom oder Chronic Fatigue Syndrom (CFS).16. Use according to one of the preceding claims 2 to 14 for the therapy and / or prophylaxis of depression, post-traumatic stress syndrome (PTSD), chronic stress conditions, burn-out syndrome or chronic fatigue syndrome (CFS).
17. Verwendung nach einem der Ansprüche 1 , 2, 3, 15, oder 16, wobei der IDO-Inhibitor ausgewählt ist aus 1-Methyl-DL-tryptophan, ß-(3- Benzofuranyl)-DL-alanin, ß-(3-Benzo(b)thienyl)-DL-alanin, 6-Nitro-L- tryptophan, lndol-3-carbinol, 3,3'-diindolylmethan, Brassinin, 5- Methylbrassinin, Epigallocatechingallat, 5-Brom-4-chlor-indoxyl-1 ,3- diacetat, 9-Vinylcarbazol, Acemetacin, 5-Brom-DL-tryptophan, 5- Bromindoxyldiacetat, Phenyl-TH-DL-tryptophan. Pyrrolidin-dithio- carbamat, 4-Phenylimidazol, Propenyl-TH-DL-tryptophan, Brassilexin, 3- Amino-2-naphthensäure, ß-Carbolin, 3-Butyl-ß-carbolin, 6-Fluor-3- carbomethoxy-ß-carbolin, 6-lsothiocyanat-3-carbomethxy(-ß-carbolin, 3- Propoxy-ß-carbolin, 3-Carboxy-ß-carbolin, 3-Carbopropoxy-ß-carbolin, 3- Nitro-ß-cabolin, 3-Carbo-tert.-butoxy-ß-carbolin, Annulin C und Norharman, sowie deren pharmazeutisch verträglichen Salzen.17. Use according to any one of claims 1, 2, 3, 15, or 16, wherein the IDO inhibitor is selected from 1-methyl-DL-tryptophan, ß- (3-benzofuranyl) -DL-alanine, ß- (3 Benzo (b) thienyl) -DL-alanine, 6-nitro-L- tryptophan, indole-3-carbinol, 3,3 '-diindolylmethan, Brassinin, 5- Methylbrassinin, epigallocatechin gallate, 5-bromo-4-chloro-indoxyl-1, 3- diacetate, 9-vinylcarbazole, acemetacin, 5-bromo-DL -tryptophan, 5-bromoindoxyl diacetate, phenyl-TH-DL-tryptophan. Pyrrolidine dithio carbamate, 4-phenylimidazole, propenyl TH-DL-tryptophan, brassilexin, 3-amino-2-naphthenic acid, β-carboline, 3-butyl-β-carboline, 6-fluoro-3-carbomethoxy-β- carboline, 6-isothiocyanato-3-carbomethoxy (-β-carboline, 3-propoxy-β-carboline, 3-carboxy-β-carboline, 3-carbopropoxy-β-carboline, 3-nitro-β-caboline, 3-carbo tert-butoxy-.beta.-carboline, Annulin C and Norharman, and their pharmaceutically acceptable salts.
18. Verwendung nach einem der Ansprüche 1 , 2, 4, 5, 15 oder 16, wobei der Kynurenin-3-hydroxylase-lnhibitor ausgewählt ist aus Vitamin B6, Nicotinylalanin, m-Nitrobenzoylalanin, o-Methoxybenzoylalanin und (1S,2S)-2-(3,4-Dichlorbenzoyl)cyclopropan-1 -carbonsäure, sowie deren pharmazeutisch verträglichen Salzen..18. Use according to any one of claims 1, 2, 4, 5, 15 or 16, wherein the kynurenine-3-hydroxylase inhibitor is selected from vitamin B6, nicotinylalanine, m-nitrobenzoylalanine, o-methoxybenzoylalanine and (1S, 2S) - 2- (3,4-dichlorobenzoyl) cyclopropane-1-carboxylic acid, and their pharmaceutically acceptable salts.
19. Verwendung nach einem der Ansprüche 1 , 2, 4, 6, 15 oder 16, wobei der Kynureninase-Inhibitor ausgewählt ist aus 5-Bromdihydro-L-kynurenin, Dihydro-L-kynurenin, (4R)-5-Bromdihydro-L-kynureinin, (S)-(2-Amino-4- bromphenyl)-L-cystein-S,S-dioxid, (S)-(2-Amino-5-bromphenyl)-L-cystein- ,S,S-dioxid und (S)-2-Aminophenyl)-L-cystein-S,S-dioxid, sowie deren pharmazeutisch verträglichen Salzen.,Use according to any one of claims 1, 2, 4, 6, 15 or 16, wherein the kynureninase inhibitor is selected from 5-bromodihydro-L-kynurenine, dihydro-L-kynurenine, (4R) -5-bromo-dihydro-L -kynureinine, (S) - (2-amino-4-bromophenyl) -L-cysteine-S, S-dioxide, (S) - (2-amino-5-bromophenyl) -L-cysteine, S, S- dioxide and (S) -2-aminophenyl) -L-cysteine-S, S-dioxide, and their pharmaceutically acceptable salts.
20. Verwendung nach Anspruch 1 , 2, 4, 7, 15 oder 16, wobei der 3- Hydroxyanthranilsäure-Oxygenase-Inhibitor ausgewählt ist aus 4-Chlor-3- hydroxyanthranilsäure, 4-Fluor-3-hydroxyanthranilsäure und 4-Brom-3- hydroxyanthranilsäure, sowie deren pharmazeutisch verträglichen Salzen.Use according to claim 1, 2, 4, 7, 15 or 16, wherein the 3-hydroxyanthranilic acid oxygenase inhibitor is selected from 4-chloro-3-hydroxyanthranilic acid, 4-fluoro-3-hydroxyanthranilic acid and 4-bromo-3 - Hydroxyanthranilsäure, and their pharmaceutically acceptable salts.
21. Verwendung nach Anspruch 1 , 2, 8, 15 oder 16, wobei der Kynurenin- Aminotransferase-Inhibitor ausgewählt ist aus Glutamin, ZiNC 165965, α- Aminoadipinsäure, Quisqualinsäure und DL-5-Bromkynurenin sowie deren pharmazeutisch verträglichen Salzen. 21. Use according to claim 1, 2, 8, 15 or 16, wherein the kynurenine aminotransferase inhibitor is selected from glutamine, ZiNC 165965, α-aminoadipic acid, quisqualic acid and DL-5-bromokynurenine and their pharmaceutically acceptable salts.
22. Verwendung von monoklonalen Antikörpern oder Antikörperfragmenten gegen Kynurenin, Kynureninsäure oder Chinolinsäure zur Neutralisation und/ oder extrakorporalen Entfernung dieser Tryptophanmetabolite. 22. Use of monoclonal antibodies or antibody fragments against kynurenine, kynurenic acid or quinolinic acid for the neutralization and / or extracorporeal removal of these Tryptophanmetabolite.
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KR20200102747A (en) * 2019-02-22 2020-09-01 경희대학교 산학협력단 Composition for preventing or treating post traumatic stress disorder comprising epigallocatechin gallate
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