DE102005053679A1

DE102005053679A1 - Use of floroquinolones for producing medicament to treat and/or prevent e.g. immunosuppresion, viral and bacterial infections, respiratory tract diseases, digestive tract diseases, and influenza diseases

Info

Publication number: DE102005053679A1
Application number: DE102005053679A
Authority: DE
Inventors: Olaf Dr. Weber; Peter Dr. Seiler
Original assignee: Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2005-06-24
Filing date: 2005-11-10
Publication date: 2006-12-28
Also published as: WO2007000234A1

Abstract

Use of one or more fluoroquinolones (I) for producing medicament to treat and/or prevent immunosuppresion. An independent claim is also included for a kit, comprising containers separated from each other, which contains antitumor agents or antiviral agents. ACTIVITY : Immunosuppressive; Virucide; Antibacterial; Respiratory-Gen; Gastrointestinal-Gen. No biological data given. MECHANISM OF ACTION : None given.

Description

Die Erfindung betrifft die Verwendung von Fluorchinolonen zur Herstellung von Arzneimitteln zur Rekonstruktion von Funktionsstörungen des Immunsystems, wie z.B. die Therapie und/oder Prophylaxe von Immunosuppressionen. Bei den Fluorchinolonen kann es sich um antibakteriell wirksame oder um antibakteriell unwirksame Fluorchinolone handeln. Insbesondere betrifft die Erfindung die Verwendung von Moxifloxacin, Ciprofloxacin, Gatifloxacin, Enrofloxacin, Sparfloxacin, Clinafloxacin, Grepafloxacin, Trovafloxacin, Tosufloxacin, Temafloxacin, Norfloxacin, Rufloxacin, Fleroxacin, Danofloxacin, Sarafloxacin, Marbofloxacin, Orbifloxacin, Pradofloxacin oder Levofloxacin zur Herstellung eines Arzneimittels zur Behandlung von Immunsuppressionen.The The invention relates to the use of fluoroquinolones for the preparation of drugs for the reconstruction of functional disorders of the Immune system, e.g. the therapy and / or prophylaxis of immunosuppressions. The fluoroquinolones may be antibacterial or act to antibacterially inactive fluoroquinolones. Especially the invention relates to the use of moxifloxacin, ciprofloxacin, Gatifloxacin, enrofloxacin, sparfloxacin, clinafloxacin, grepafloxacin, Trovafloxacin, tosufloxacin, temafloxacin, norfloxacin, rufloxacin, Fleroxacin, danofloxacin, sarafloxacin, marbofloxacin, orbifloxacin, Pradofloxacin or levofloxacin for the manufacture of a medicinal product for the treatment of immunosuppression.

Immunsuppressionen können durch Krankheitszustände hervorgerufen werden oder mittels bestimmter Medikamente induziert werden. Hierbei kann man einerseits gezielt im Sinne der Therapie eine Immunsuppression hervorrufen (z.B. bei der Behandlung entzündlicher Erkrankungen oder bei Organtransplantationen zur Verhinderung einer Abstoßung des Transplantates, andererseits können Immunsuppressionen als unerwünschte Nebenwirkungen bestimmter Medikamente auftreten. Letzteres ist vor allem bei der Chemotherapie von Tumorerkrankungen von Bedeutung.immunosuppressions can by disease states be induced or induced by certain drugs become. On the one hand, this can be targeted in terms of therapy Cause immunosuppression (e.g., more inflammatory in the treatment Disease or organ transplantation to prevent rejection of the transplant, on the other hand, immunosuppressions as undesirable Side effects of certain medications occur. The latter is available all in the chemotherapy of tumors of importance.

Bei immunsupprimierten Patienten laufen die für Abwehr von Infektionserregern oder entarteter Zellen (z.B. Tumorzellen und deren Vorstufen) zuständigen Reaktionen gar nicht mehr oder nur noch in abgeschwächter Form ab. So können ansonsten harmlose Infektionskrankheiten für diese Patienten lebensbedrohlich sein, oder bestimmte Tumoren häufiger auftreten (1-7).at Immunosuppressed patients are running for defense against infectious agents or degenerate cells (e.g., tumor cells and their precursors) not at all or only in a weakened form. So can be otherwise harmless Infectious diseases for These patients may be life-threatening or certain tumors occur more frequently (1-7).

Während einer Chemotherapie ist die Immunsuppression eine schwere, oft die Behandlung begrenzende, unerwünschte Wirkung. Durch hämatopoetische Wachstumsfaktoren wird derzeit versucht, Ausmaß und Dauer der durch die Chemotherapie induzierten Immunsuppression zu verkürzen (8-10).During one Chemotherapy, immunosuppression is a severe, often treatment-limiting, undesirable Effect. By hematopoietic Growth factors is currently being attempted, extent and duration of chemotherapy to shorten induced immunosuppression (8-10).

Eine weitere Form der Immunsuppression kann aus der Immunevasion verschiedener Erreger hervorgehen. Immunevasionsmechanismen wurden z.B. von Viren, Bakterien und Parasiten, oder Tumorzellen als Strategien entwickelt, um einer Erkennung durch das Immunsystem zu entgehen oder das Immunsystem sogar aktiv zu unterdrücken (11-20).A Another form of immunosuppression may be different from the immunevasion Pathogens emerge. Immunevasion mechanisms have been described e.g. of viruses, Bacteria and parasites, or tumor cells designed as strategies to escape detection by the immune system or the immune system even actively suppress (11-20).

Neutropenisches Fieber ist eine ernste Komplikation bei Krebspatienten, die mit Chemotherapeutika behandelt wurden oder werden (21-24). Es besteht bei diesen Patienten die Gefahr einer generalisierten Infektion mit erheblicher Mortalitätsrate.neutropenic Fever is a serious complication in cancer patients with Chemotherapeutic agents have been or will be treated (21-24). It exists in these patients the risk of generalized infection with a significant mortality rate.

In kürzlich publizierten Berichten wurde die Anwendung von Moxifloxacin und Gatifloxacin bei neutropenischen Krebspatienten mit Fieber zur Behandlung von bakteriellen Infektionen propagiert (25-30).In recently Published reports have reported the use of moxifloxacin and Gatifloxacin in neutropenic cancer patients with fever for treatment propagated by bacterial infections (25-30).

Patienten, bei denen durch eine Chemotherapie eine Immunsuppression induziert wird, werden zur Zeit mit z.B. mit Kolonie stimulierenden Faktoren (z.B. G-CSF) behandelt. Eine ausreichende antibakterielle Wirkkomponente ist bei dieser Therapie nicht gegeben, so dass im Falle einer Infektion mit Antibiotika erweitert werden oder auf diese ausgewichen werden muss. In diesem Falle erfolgt die Therapie jedoch mitunter zu spät (8, 31-35).patients where chemotherapy induces immunosuppression is currently being used with e.g. colony stimulating factors (e.g. G-CSF). A sufficient antibacterial active component is not given in this therapy, so in case of infection be extended or dodged with antibiotics got to. In this case, however, the therapy may be too late (8, 31-35).

Außerdem kann bei der Therapie mit koloniestimulierenden Faktoren nicht ausgeschlossen werden, dass sich trotz eines verbesserten Blutbildes und verschiedener immunologischer Parameter (TNF-α, bone marrow colony forming units-cell counts, total neutrophil counts, IL-1, IL-6, IL-8, Fas, FasL, TNFR1) ein fördernder Einfluss auf weiter im Patienten residierende Tumorzellen im Sinne einer Rezidivierung der Tumorerkrankung oder Aktivierung der Metastasierung entwickelt (8, 34). Außerdem kann die Gabe von koloniestimulierenden Faktoren mit beträchtlichen Nebenwirkungen, wie akutem Respiratiory distress syndrome einhergehen, Todesfälle wurden hier beschrieben ([285702]Iddb). The reference is cited in the following reports: filgrastim. Updated on 23^rd June 2004. Originator: Amgen Inc lenograstim. Updated on 24^th March 2004. Originator: Chugai Pharmaceutical Co Ltd nartograstim. Updated on 28^th January 2003. Originator: Kyowa Hakko Kogyo Co Ltd, SCRIP World Pharmaceutical News 1998, 2324).In addition, therapy with colony-stimulating factors can not rule out the possibility that, despite an improved blood count and different immunological parameters (TNF-α, bone marrow colony-forming units-cell counts, total neutrophil counts, IL-1, IL-6, IL-1). 8, Fas, FasL, TNFR1) a promoting influence on further resident in the patient tumor cells in terms of a recurrence of the tumor disease or activation of metastasis developed (8, 34). In addition, the administration of colony-stimulating factors may be associated with significant side effects, such as acute respiratory distress syndrome; deaths have been described here ([285702] Iddb). The reference is cited in the following reports: filgrastim. Updated on 23 ^rd June 2004. Originator: Amgen Inc lenograstim. Updated on 24 ^th March 2004. Originator: Chugai Pharmaceutical Co Ltd nartograstim. Updated on 28 ^th January 2003. Originator: Kyowa Hakko Kogyo Co. Ltd, SCRIP World Pharmaceutical News 1998, 2324).

Folglich ist es Aufgabe der vorliegenden Erfindung, eine neue Therapie für immunsupprimierte Patienten zu entwickeln, bei denen eine manifeste Neutropenie nicht nachgewiesen werden kann und die nicht mit der potentiellen Gefahr einer Induktion von Rezidiven bei Tumorpatienten assoziiert ist. Außerdem soll die Therapie bei möglichst günstigerem Nebenwirkungsprofil als beim Einsatz von koloniestimulierenden Faktoren gleichzeitig sowohl die Immunantwort physisch und funktionell rekonstituieren als auch bis zur vollständigen Rekonstitution effektiv vor oportunistischen, Krankenhaus-assoziierten, bakteriellen Infektionen abschirmen.consequently It is an object of the present invention to provide a new therapy for immunosuppressed patients to develop in which a manifest neutropenia has not been detected can not be and with the potential danger of induction of Recurrences associated with tumor patients. In addition, the therapy should be included preferably more favorable side effect profile than when using colony-stimulating factors simultaneously both reconstituting the immune response physically and functionally as well as to the complete Reconstitution effectively before oportunistic, hospital-associated, shield bacterial infections.

Diese Aufgabe wird – wie in Beispielen 1 und 2 dargelegt – gelöst durch die Bereitstellung Fluorchinolon-haltiger Arzneimittel, insbesondere Moxifloxacin-beinhaltender Arzneimittel zur Behandlung und/oder Prophylaxe von Immunsuppressionen.These Task becomes - like set forth in Examples 1 and 2 - solved by the provision Fluoroquinolone-containing medicines, in particular moxifloxacin-containing Medicaments for the treatment and / or prophylaxis of immunosuppressants.

Die Erfindung betrifftThe invention concerns

1. Use of one or more fluoroquinolones in a process for the preparation of a medicament for treatment and / or prophylaxis of immune suppression. Taking immunosuppressed Patients are understood to be humans and other warm-blooded animals, for by a reduction in the number of immunologically important cells, such as monocytes / macrophages, neutrophilic, basophilic and eosinophilic granulocytes, mast cells, Dendritic cells, natural Killer cells, T and B cells as well as impairing the functions of these Cells, such as phagocytosis, oxidative burst, cytokine and chemokine secretion, antigen presentation, T-killer cell activity, T-helper cell activity, T-suppressor cell activity, unconventional activity T cells, activity Conventional B2 and unconventional B1-B cells are at increased risk of infections or tumors. Immunosuppression can be medicated triggered (chemotherapy, for example) or for other causes (hereditary, Infectious diseases). Under immunosuppressive understands one states, where by a reduction in the number of immunologically important Cells such as monocytes / macrophages, neutrophils, basophils and eosinophils Granulocytes, mast cells, dendritic cells, natural Killer cells, T and B cells as well as impairing the functions of these Cells, such as phagocytosis, oxidative burst, cytokine and chemokine secretion, antigen presentation, T-killer cell activity, T helper cell activity, T-suppressor cell Aktiviät, Activity more unconventional T cells, activity Conventional B2 and unconventional B1-B cells are at increased risk of infections or tumors. Immunosuppression can be medicated triggered (chemotherapy, for example) or for other causes (hereditary, Infectious diseases).
2. Use according to point 1, wherein the fluoroquinolones are antibacterially active fluoroquinolones is.
3. Use according to point 1, wherein at least one fluoroquinolone is moxifloxacin.
4. Use according to point 1, wherein at least one fluoroquinolone is ciprofloxacin is.
5. Use according to point 1, wherein at least one fluoroquinolone is gatifloxacin.
6. Use according to point 1, wherein at least one fluoroquinolone is levofloxacin.
7. The invention also exceeds a use according to item 1, wherein the flourchinolone is a compound selected from the group consisting of moxifloxacin, ciprofloxacin, gatifloxacin, Enrofloxacin, sparfloxacin, clinafloxacin, grepafloxacin, trovafloxacin, Tosufloxacin, Temafloxacin, Norfloxacin, Rufloxacin, Fleroxacin, Danofloxacin, sarafloxacin, marbofloxacin, orbifloxacin, pradofloxacin and levofloxacin.
8. Use according to point 1, wherein the fluoroquinolones are antibacterial ineffective Fluoroquinolones acts.
9. Use according to point 1, wherein the fluoroquinolones are a mixture of antibacterial effective and inactive fluoroquinolones.
10. Use according to point 1, where the immunosuppressive conditions are states, due to malfunctions monocytes / macrophages.
11. Use according to point 10, wherein at least one fluoroquinolone is moxifloxacin is.
12. Use according to point 10, wherein at least one fluoroquinolone is gatifloxacin is.
13. Use according to point 10, wherein at least one fluoroquinolone is levofloxacin is.
14. Use according to point 10, wherein the flourchinolone is a compound selected from the group consisting of moxifloxacin, ciprofloxacin, gatifloxacin, Enrofloxacin, sparfloxacin, clinafloxacin, grepafloxacin, trovafloxacin, Tosufloxacin, Temafloxacin, Norfloxacin, Rufloxacin, Fleroxacin, Levofloxacin, danofloxacin, sarafloxacin, marbofloxacin, orbifloxacin and pradofloxacin.
15. Use of one or more fluoroquinolones in one Process for the preparation of a medicament for the treatment and / or Prophylaxis of immunosuppressants, which is a combined preparation with Medicines used for antitumoral therapy, such as Chemotherapeutic agents or cytostatic agents used become.
16. Use according to point 15, wherein the fluoroquinolone is a fluoroquinolone selected from the group consisting of moxifloxacin, ciprofloxacin, gatifloxacin, Enrofloxacin, sparfloxacin, clinafloxacin, grepafloxacin, trovafloxacin, Tosufloxacin, Temafloxacin, Norfloxacin, Rufloxacin, Fleroxacin, Levofloxacin, danofloxacin, sarafloxacin, marbofloxacin, orbifloxacin and pradofloxacin.
17. Use according to item 15 or 16, wherein the antitumor agent is an agent selected from the group consisting of asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, Dactinomycin, daunorubicin, Doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methothrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, precarbazine, raloxifene, streptozocin, tamoxifen , Thioguanine, topotecan, vinblastine, vincristine, vindesine, aminogluthethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2 ', 2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinylestradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, Fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentstatin, PALA, plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine, oxaliplatin, gemcitabine, capecitabine, epothilone and natural or synthetic derivatives, Tositumomab, Trabede ctin, and temozolomide, trastuzumab, cetuximab, bevacizumab, pertuzumab, ZD-1839 (Iressa), OSI-774 Tarceva), CI-1033, GW-2016, CP-724,714, HKI-272, EKB-569, STI-571 ( Gleevec), PTK-787, SU-11248, ZD-6474, AG-13736, KRN-951, CP-547, 632, CP-673,451 and sorafenib.
18. Use of fluoroquinolones in a process for the preparation a drug for the treatment and / or prophylaxis of immunosuppressive drugs, which is a combination preparation with antiviral drugs is.
19. Use according to point 18, the fluoroquinolone is selected from a fluoroquinolone the group consisting of moxifloxacin, ciprofloxacin, gatifloxacin, Enrofloxacin, sparfloxacin, clinafloxacin, grepafloxacin, trovafloxacin, tosufloxacin, Temafloxacin, norfloxacin, rufloxacin, fleroxacin, levofloxacin, Danofloxacin, sarafloxacin, marbofloxacin, orbifloxacin and pradofloxacin is.
20. Use according to point 18 or 19, wherein the antiviral agent is um an agent selected from the group consisting of interferon-β, interferon alfacon-1, interferon-α or pegylated Interferon-β, 3TC (lamivudine), adevovir, adevovir dipivoxil, entecavir, emtricitabine, Clevudine, L-dT, L-Fd4C acyclovir, valacyclovir, penciclovir, famciclovir Foscarnet, brivudine, ganciclovir, cidofovir, inhibitors of the helicase-primase complex, Ribavirin, lopinavir-ritonavir (Kaletra), AG7088, hexapeptidyl CMK, Ruprin trivir (AG7088), 3C protease inhibitors, pirodavir, pleconaril, soluble ICAM-1, amantidine, Symmetrel, flumadine, oseltamvir, zanamivir, tenofovir Disproxil fumarate (TDF), emtricitabine (FTC), didanosine (ddI), Stavudine (d4T), zidovudine (AZT), zalcitabine (ddC), efavirenz (EFV), nivirapine (NVP), delaviridine (DLV), atazanavir (ATV), ritonavir (RTV), amprenavir (APV), lopinavir / rironavir (LPV / RTV), nelfinavir (NFV), indinavir (IDV), saquinavir (SQV-SGC), enfuvirtide (7-20), etravirine (TMC-125), Capravirine, Tenovovir (PMPA).
21. Kit, containing separate containers, in each case the substances mentioned under point 15, 16, or 17 are included. Such a kit is suitable for the treatment of immunosuppressants, which are due to a chemotherapeutic tumor therapy.
22. Kit, containing separate containers, in each case the substances mentioned under point 18, 19, or 20 are included.
23. Use according to points 10, 15, 16, 17, 18, 19, 20, 21, or 22, wherein at least a fluoroquinolone with an antibacterially inactive fluoroquinolone is.
24. Use of one or more fluoroquinolones in one Process for the preparation of a medicament for the treatment and / or Prophylaxis of viral and bacterial mixed infections with substances from items 1-9, where the bacterial infection is around a secondary infection in an immunosuppressed patient.
25. Use according to point 24, where the viral infections are infections by viruses selected from the group consisting of the virus families Adenoviridae, Caliciviridae, Picornaviridae, Paramyxoviridae, Coronaviridae, Orthomyxoviridae, Retroviridae, Reoviridae, Bunyaviridae, Togaviridae, Herpesviridae, Parvoviridae and / or Papovaviridae.
26. Use according to points 24 or 25, which are diseases of the respiratory tract (e.g., SARS, influenza), the digestive tract and / or the skin with its appendages and connective tissue.
27. Use according to point 26, where the diseases are SARS or influenza.
28. Use according to points 1-16, which are immunosuppressive disorders occurring under the influence of treatment with cytotoxic chemotherapeutic agents are located.
29. Use according to point 28, which are immunosuppressants in cancer patients.
30. Use according to points 1-16, which are immunosuppressions produced by a Radiotherapy or radiation are conditional.
31. Use according to point 30, which is immunosuppressants in cancer patients.
32. Use of one or more fluoroquinolones in a process for the preparation of a medicament for the treatment and / or prophylaxis of radiation sickness after exposure to radioactive material.
33. Use according to point 32, which are fluoroquinolones selected from the group from moxifloxacin, ciprofloxacin, gatifloxacin, enrofloxacin, sparfloxacin, Clinafloxacin, Grepafloxacin, Trovafloxacin, Tosufloxacin, Temafloxacin, Norfloxacin, Rufloxacin, Fleroxacin, Danofloxacin, Sarafloxacin, Marbofloxacin, orbifloxacin, pradofloxacin and levofloxacin and / or non-antibacterial Fluochinolonen acts.

Die Erfindung betrifft auch Arzneimittel, beinhaltend ein oder mehrere Flourchinolone, insbesondere antibakteriell wirksame Fluorchinolone, bevorzugt ein Flourchinolon ausgewählt aus der Gruppe bestehend aus Moxifloxacin, Ciprofloxacin, Gatifloxacin, Enrofloxacin, Sparfloxacin, Clinafloxacin, Grepafloxacin, Trovafloxacin, Tosufloxacin, Temafloxacin, Norfloxacin, Rufloxacin, Fleroxacin, Danofloxacin, Sarafloxacin, Marbofloxacin, Orbifloxacin, Pradofloxacin und Levofloxacin, besonders bevorzugt Moxifloxacin zur Behandlung von Immunsuppressionen.The The invention also relates to pharmaceutical compositions comprising one or more Flourchinolones, in particular antibacterial fluoroquinolones, preferably a flourchinolone selected from the group consisting from moxifloxacin, ciprofloxacin, gatifloxacin, enrofloxacin, sparfloxacin, Clinafloxacin, Grepafloxacin, Trovafloxacin, Tosufloxacin, Temafloxacin, Norfloxacin, Rufloxacin, Fleroxacin, Danofloxacin, Sarafloxacin, Marbofloxacin, orbifloxacin, pradofloxacin and levofloxacin, especially prefers moxifloxacin for the treatment of immunosuppressants.

Die Erfindung betrifft ebenfalls die Verwendung von einem oder mehreren Flourchinolonen, insbesondere antibakteriell wirksame Fluorchinolone, bevorzugt ein Flourchinolon ausgewählt aus der Gruppe bestehend aus Moxifloxacin, Ciprofloxacin, Gatifloxacin, Enrofloxacin, Sparfloxacin, Clinafloxacin, Grepafloxacin, Trovafloxacin, Tosufloxacin, Temafloxacin, Norfloxacin, Rufloxacin, Fleroxacin, Danofloxacin, Sarafloxacin, Marbofloxacin, Orbifloxacin, Pradofloxacin oder Levofloxacin, besonders bevorzugt Moxifloxacin zur Herstellung eines Arzneimittels zur Behandlung von Immunsuppressionen.The The invention also relates to the use of one or more Flourchinolones, in particular antibacterial fluoroquinolones, are preferred a flourchinolone is selected from the group consisting of moxifloxacin, ciprofloxacin, gatifloxacin, Enrofloxacin, sparfloxacin, clinafloxacin, grepafloxacin, trovafloxacin, Tosufloxacin, Temafloxacin, Norfloxacin, Rufloxacin, Fleroxacin, Danofloxacin, sarafloxacin, marbofloxacin, orbifloxacin, pradofloxacin or levofloxacin, more preferably moxifloxacin for production a drug for the treatment of immunosuppressive disorders.

Ein Kombinationspräparat kann die Wirkstoffe separat in getrennten Behältnissen enthalten. Die Wirkstoffe können aber auch zusammen in einer Darreichungsform vorliegen, z.B. gemeinsam mit geeigneten Begleitstoffen gepresst in einer Tablette.One combination preparation may contain the active substances separately in separate containers. The active ingredients can but also present together in a dosage form, e.g. together with suitable accompanying substances pressed in a tablet.

Die Erfindung betrifft auch Behandlungsmethoden, in denen die wie geschildert hergestellten Wirkstoffpräparate eingesetzt werden zur Behandlung von Immunsuppressionen. Bei diesen Behandlungsmethoden kann es sich auch um Kombinationstherapien handeln. Bevorzugt sind dabei Kombinationstherapien umfassend ein oder mehrere Fluorchinolon und ein oder mehrere in der Tumorbekämpfung eingesetzte Wirkstoffe, oder ein oder mehrere Fluorchinolone und ein oder mehrere antivirale Wirkstoffe. Besonders bevorzugt sind Kombinationstherapien unter Verwendung der spezifisch offenbarten Fluorchinolone mit den spezifisch offenbarten in der Tumortherapie eingesetzten Wirkstoffen oder mit den spezifisch offenbarten antiviralen Wirkstoffen. Die Verabreichung der Wirkstoffe kann bei einer Kombinationstherapie gleichzeitig, aber auch sequenziell nacheinander, auch in größeren Zeitabständen, erfolgen.The Invention also relates to methods of treatment in which as described Prepared drug preparations used for the treatment of immunosuppressants. In these Treatment methods may also be combination therapies. Combination therapies comprising one or more are preferred Fluoroquinolone and one or more agents used in the treatment of tumors Active substances, or one or more fluoroquinolones and one or more antiviral agents. Particularly preferred are combination therapies under Use of the specifically disclosed fluoroquinolones with the specific ones disclosed active ingredients used in tumor therapy or with the specifically disclosed antiviral agents. The administration the active ingredients can be used simultaneously in a combination therapy, but also sequentially, even at longer intervals, done.

Der Wirkstoff kann systemisch und/oder lokal wirken. Zu diesem Zweck kann er auf geeignete Weise appliziert werden, wie z.B. oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rektal, transdermal, conjunctival, otisch oder als Implantat.Of the Active substance can act systemically and / or locally. To this end it can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or implant.

Für diese Applikationswege kann der Wirkstoff in geeigneten Applikationsformen verabreicht werden.For this Application routes, the active ingredient in suitable forms of administration be administered.

Für die orale Applikation eignen sich bekannte, den Wirkstoff schnell und/oder modifiziert abgebende Applikationsformen, wie z.B. Tabletten (nicht überzogene sowie überzogene Tabletten, z.B. mit magensaftresistenten Überzüge versehene Tabletten oder Filmtabletten), Kapseln, Dragees, Granulate, Pellets, Pulver, Emulsionen, Suspensionen, Lösungen und Aerosole.For the oral Application are known, the drug quickly and / or modified delivery forms, e.g. Tablets (uncoated as well as coated Tablets, e.g. tablets provided with enteric coatings or Film-coated tablets), capsules, dragees, granules, pellets, powders, emulsions, Suspensions, solutions and aerosols.

Die parenterale Applikation kann unter Umgehung eines Resorptionsschrittes geschehen (intravenös, intraarteriell, intrakardial, intraspinal oder intralumbal) oder unter Einschaltung einer Resorption (intramuskulär, subcutan, intracutan, percutan, oder intraperitoneal). Für die parenterale Applikation eignen sich als Applikationsformen u.a. Injektions- und Infusionszu bereitungen in Form von Lösungen, Suspensionen, Emulsionen, Lyophilisaten und sterilen Pulvern.The Parenteral administration can bypass a resorption step happen (intravenously, intraarterial, intracardiac, intraspinal or intralumbar) or with absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneally). For the parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, Suspensions, emulsions, lyophilisates and sterile powders.

Für die sonstigen Applikationswege eignen sich z.B. Inhalationsarzneiformen (u.a. Pulverinhalatoren, Nebulizer), Nasentropfen/-lösungen, Sprays; lingual, sublingual oder buccal zu applizierende Tabletten oder Kapseln, Suppositorien, Ohren- und Augen-präparationen, Vaginalkapseln, wässrige Suspensionen (Lotionen, Schüttelmixturen), lipophile Suspensionen, Salben, Cremes, Milch, Pasten, Streupuder oder Implantate.For the others Application routes are suitable, e.g. Inhalation medicines (i.a. Powder inhalers, nebulizers), nasal drops / solutions, sprays; lingual, sublingual or buccal tablets or capsules to be applied, suppositories, Ear and eye preparations, Vaginal capsules, watery Suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, milk, pastes, scattering powders or implants.

Die Wirkstoffe können in an sich bekannter Weise in die angeführten Applikationsformen überführt werden. Dies geschieht unter Verwendung inerter nichttoxischer, pharmazeutisch geeigneter Hilfsstoffe. Hierzu zählen u.a. Trägerstoffe (z.B. mikrokristalline Cellulose), Lösungsmittel (z.B. flüssige Polyethylenglycole), Emulgatoren (z.B. Natriumdodecylsulfat), Dispergiermittel (z.B. Polyvinylpyrrolidon), synthetische und natürliche Biopolymere (z.B. Albumin), Stabilisatoren (z.B. Antioxidantien wie Ascorbinsäure), Farbstoffe (z.B. anorganische Pigmente wie Eisenoxide) oder Geschmacks- und/oder Geruchskorrigentien.The Active ingredients can be converted in a conventional manner in the mentioned application forms. This is done using inert nontoxic, pharmaceutical suitable adjuvants. Which includes et al excipients (e.g., microcrystalline cellulose), solvents (e.g., liquid polyethylene glycols), Emulsifiers (e.g., sodium dodecyl sulfate), dispersants (e.g. Polyvinylpyrrolidone), synthetic and natural biopolymers (e.g., albumin), Stabilizers (e.g., antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxides) or flavor and / or Odors.

Im Allgemeinen hat es sich als vorteilhaft erwiesen, bei parenteraler Applikation Mengen von etwa 0.001 bis 10 mg/kg, vorzugsweise etwa 0.01 bis 5 mg/kg Körpergewicht zur Erzielung wirksamer Ergebnisse zu verabreichen. Bei oraler Applikation beträgt die Menge etwa 0.01 bis 25 mg/kg, vorzugsweise etwa 0.1 bis 10 mg/kg Körpergewicht.In general, it has proven to be advantageous for parenteral administration amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg of body weight to achieve effective results. When administered orally, the amount is about 0.01 to 25 mg / kg, preferably about 0.1 to 10 mg / kg of body weight.

Trotzdem kann es gegebenenfalls erforderlich sein, von den genannten Mengen abzuweichen, und zwar in Abhängigkeit von Körpergewicht, Applikationsweg, individuellem Verhalten gegenüber dem Wirkstoff, Art der Zubereitung und Zeitpunkt bzw. Intervall, zu welchem die Applikation erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der vorgenannten Mindestmenge auszukommen, während in anderen Fällen die genannte obere Grenze überschritten werden muss. Im Falle der Applikation größerer Mengen kann es empfehlenswert sein, diese in mehreren Einzelgaben über den Tag zu verteilen.Nevertheless it may be necessary, if necessary, of the quantities mentioned to deviate, depending on of body weight, Route of administration, individual behavior towards the active substance, type of Preparation and time or interval to which the application he follows. So it can in some cases be sufficient, with less than the aforementioned minimum quantity to get along while in other cases exceeded the mentioned upper limit must become. In case of application of larger quantities it may be recommended be to distribute these in several single doses throughout the day.

BeispieleExamples

Beispiel 1example 1

In immunkompetenten Mäusen wurde eine funktionelle Immunsuppression durch die Applikation eines zytotoxischen Medikamentes (Carboplatin) ausgelöst. Dabei wurde die Dosis so gewählt, dass eine Verminderung der Anzahl der neutrophilen Granulozyten (Neutropenie) nicht bestand. Dieser Zustand wurde mittels FACS kontrolliert.In immunocompetent mice was a functional immunosuppression by the application of a cytotoxic drug (carboplatin). The dose was like that selected that a reduction in the number of neutrophils granulocytes (Neutropenia) did not exist. This condition was controlled by FACS.

Weibliche C57BL/6 Mäuse wurden mit 57mg/kg Carboplatin intravenös (i.v.) behandelt an den Tagen 1, 5 und 9 des Experiments. An den Tagen 10, 11 und 12 wurden die Mäuse mit Moxifloxacin intraperitoneal (i.p.) behandelt. Dabei erhielt eine Gruppe Mäuse 22,5 mg/kg/Tag, verteilt auf drei Dosen à 7,5 mg/kg, und eine zweite Gruppe Mäuse 67,5 mg/kg/Tag, verteilt auf drei Dosen à 21,5 mg/kg. Eine dritte Gruppe wurde als Kontrolle anstelle von Moxifloxacin mit dH20 i.p. behandelt. Eine vierte Gruppe wurde als Kontrolle anstelle von Carboplatin 0,9% Kochsalzlösung i.v. behandelt und anstelle von Moxifloxacin mit dH20 i.p. behandelt.Female C57BL / 6 mice were treated with 57 mg / kg carboplatin intravenously (i.v.) on the days 1, 5 and 9 of the experiment. On days 10, 11 and 12, the Mice with Treated moxifloxacin intraperitoneally (i.p.). It received a group Mice 22.5 mg / kg / day, divided into three doses of 7.5 mg / kg, and a second Group of mice 67.5 mg / kg / day, divided into three doses of 21.5 mg / kg. A third Group was used as a control in place of moxifloxacin with dH20 i.p. treated. A fourth group was used as a control instead of carboplatin 0.9% saline iv treated and instead of moxifloxacin with dH20 i.p. treated.

Am Tag 9 und Tag 15 des Experiments wurde den Mäusen Blut entnommen. Die peripheren Blutleukozyten wurden einer FACS-Analyse (FACScalibur, BD, Heidelberg, D), sowie einem Phagozytose- und einem Burst-Test (Orpegen, Heidelberg, D) unterzogen.At the Day 9 and day 15 of the experiment were bled from the mice. The peripheral Blood leukocytes were subjected to FACS analysis (FACScalibur, BD, Heidelberg, D), as well as a phagocytosis and a burst test (Orpegen, Heidelberg, D) subjected.

Folgende Oberflächenmoleküle wurden analysiert:
CD3-ε/CD4/CD8-α zur Charakterisierung der T-Zell Subtypen
sIgM/CD23/CD45R zur Charakterisierung der B-Zell Subtypen
CD3-ε/CD25/CD69 zur Charakterisierung der T-Zell Aktivierungszustände
CD19/CD25/CD69 zur Charakterisierung der B-Zell Aktivierungszustände.The following surface molecules were analyzed:
CD3-ε / CD4 / CD8-α for the characterization of T-cell subtypes
sIgM / CD23 / CD45R for the characterization of B-cell subtypes
CD3-ε / CD25 / CD69 for the characterization of the T-cell activation states
CD19 / CD25 / CD69 for the characterization of B-cell activation states.

Folgende Myelozyten-Funktionen wurden analysiert:
Phagozytose von FITC-markierten, Serum-opsonisierten, Hitze-inaktivierten E. coli (Phagoassay, Orpegen, Heidelberg, D)
Induktion von reaktiven Sauerstoff- und Stickstoff-Radikalen (Phagoburstassay, Orpegen, Heidelberg, D)The following myelocyte functions were analyzed:
Phagocytosis of FITC-labeled, serum-opsonized, heat-inactivated E. coli (Phagoassay, Orpegen, Heidelberg, D)
Induction of Reactive Oxygen and Nitrogen Radicals (Phagoburstassay, Orpegen, Heidelberg, D)

Überraschenderweise wurde gefunden, dass durch Gabe von verschiedenen Dosen Moxifloxacin an diese Mäuse eine funktionelle Rekonstitution verschiedener Funktionen des Immunsystemes erzielt werden konnte. Dies sind im Einzelnen:

1. Am Tag 15 nach Behandlungsbeginn, das entspricht Tag 3 nach letzter Moxifloxacin-Behandlung, war die Phagozytose-Aktivität der Blut-Monozyten von Carboplatin plus Moxifloxacin behandelter Mäuse vollständig rekonstituiert und vergleichbar zu derjenigen von Blut-Monozyten Placebo-behandelter Mäuse. Zum gleichen Zeitpunkt war die Phagozytose-Aktivität von Blut-Monozyten aus Mäusen, welche nur mit Carboplatin behandelt waren, um einen Faktor 3–5 reduziert im Vergleich zu derjenigen von Blut-Monozyten Placebo-behandelter Mäuse. Die Ergebnisse sind in 1 dargestellt.
2. Die Phagozytose-Aktivitäten von neutrophilen Granulozyten aus peripherem Blut waren zu keinem Zeitpunkt und durch keine Behandlung beeinflusst.
3. Am Tag 15 nach Behandlungsbeginn, i.e. am Tag 3 nach letzter Moxifloxacin-Behandlung, war die oxidative burst-Aktivität der Blut-Monozyten von Carboplatin plus Moxifloxacin behandelter Mäuse vollständig rekonstituiert und vergleichbar zu derjenigen von Blut-Monozyten Placebo-behandelter Mäuse. Zum gleichen Zeitpunkt war die oxidative burst-Aktivität von Blut-Monozyten aus Mäusen, welche nur mit Carboplatin behandelt waren, um einen Faktor 3–5 reduziert im Vergleich zu derjenigen von Blut-Monozyten Placebo-behandelter Mäuse.
4. Die oxidative burst-Aktivitäten von neutrophilen Granulozyten aus peripherem Blut waren zu keinem Zeitpunkt und durch keine Behandlung beeinflusst.
5. Am Tag 15 nach Behandlungsbeginn, i.e. am Tag 3 nach letzter Moxifloxacin-Behandlung, war die pan T-Zell Population (CD3+, CD4+ und CD8+ T-Zellen) von Carboplatin plus Moxifloxacin behandelter Mäuse partiell rekonstituiert und erreichte 30–50% der T-Zell Population Placebo-behandelter Mäuse. Zum gleichen Zeitpunkt war die T-Zell Population aus Mäusen, welche nur mit Carboplatin behandelt waren, um über 90 reduziert im Vergleich zu der T-Zell Population Placebo-behandelter Mäuse. Diese Ergebnisse sind in 2 dargestellt.
6. Am Tag 15 nach Behandlungsbeginn, i.e. am Tag 3 nach letzter Moxifloxacin-Behandlung, war die pan B-Zell Population (sIgM+/CD23+/CD45R+ B-Zellen) von Carboplatin plus Moxifloxacin behandelter Mäuse partiell rekonstituiert und erreichte 30–50% der B-Zell Population Placebo-behandelter Mäuse. Zum gleichen Zeitpunkt war die B-Zell Population aus Mäusen, welche nur mit Carboplatin behandelt waren, um über 90 % reduziert im Vergleich zu der B-Zell Population Placebo-behandelter Mäuse. Diese Ergebnisse sind in 2 dargestellt.
7. Am Tag 15 nach Behandlungsbeginn, i.e. am Tag 3 nach letzter Moxifloxacin-Behandlung, war der Aktivierungszustand der T-Zell Population (CD19–/CD25+/CD69+ T-Zellen) von Carboplatin plus Moxifloxacin behandelter Mäuse vollständig rekonstituiert und erreichte höhere Werte als diejenigen der T-Zell Population Placebo-behandelter Mäuse. Zum gleichen Zeitpunkt war der Aktivierungszustand der T-Zell Population aus Mäusen, welche nur mit Carboplatin behandelt waren, um über 70 % reduziert im Vergleich zu der T-Zell Population Placebo-behandelter Mäuse. Diese Ergebnisse sind in 3 dargestellt.
8. Am Tag 15 nach Behandlungsbeginn, i.e. am Tag 3 nach letzter Moxifloxacin-Behandlung, war der Aktivierungszustand der B-Zell Population (CD19+/CD25+/CD69+ B-Zellen) von Carboplatin plus Moxifloxacin behandelter Mäuse vollständig rekonstituiert und erreichte höhere Werte als diejenigen der B-Zell Population Placebo-behandelter Mäuse. Zum gleichen Zeitpunkt war der Aktivierungszustand der B-Zell Population aus Mäusen, welche nur mit Carboplatin behandelt waren, um über 70 % reduziert im Vergleich zu der B-Zell Population Placebo-behandelter Mäuse. Diese Ergebnisse sind in 3 dargestellt.

Surprisingly, it was found that by administering various doses of moxifloxacin to these mice a functional reconstitution of various functions of the immune system could be achieved. These are in detail:

1. On day 15 after initiation of treatment, corresponding to day 3 after the last moxifloxacin treatment, the phagocytic activity of the blood monocytes of carboplatin plus moxifloxacin of treated mice was completely reconstituted and comparable to that of blood monocytes of placebo-treated mice. At the same time, the phagocytic activity of blood monocytes from mice treated with carboplatin alone was reduced by a factor of 3-5 compared to that of blood monocytes of placebo-treated mice. The results are in 1 shown.
2. The phagocytic activities of peripheral blood neutrophil granulocytes were not affected at any time and by any treatment.
3. On day 15 after initiation of treatment, ie on day 3 after the last moxifloxacin treatment, the oxidative burst activity of blood monocytes of carboplatin plus moxifloxacin of treated mice was completely reconstituted and comparable to that of blood monocytes of placebo-treated mice. At the same time, the oxidative burst activity of blood monocytes from mice treated with carboplatin alone was reduced by a factor of 3-5 compared to that of blood monocytes from placebo-treated mice.
4. The oxidative burst activities of peripheral blood neutrophil granulocytes were not affected at any time and by any treatment.
5. On day 15 post treatment initiation, ie on day 3 after the last moxifloxacin treatment, the pan T cell population (CD3 +, CD4 + and CD8 + T cells) of carboplatin plus moxifloxacin treated mice was partially reconstituted, reaching 30-50% of the T-cell population of placebo-treated mice. At the same time, the T-cell population from mice treated with carboplatin alone was over 90 redu in comparison with the T-cell population of placebo-treated mice. These results are in 2 shown.
6. On day 15 after initiation of treatment, ie on day 3 after the last moxifloxacin treatment, the pan B cell population (sIgM + / CD23 + / CD45R + B cells) of carboplatin plus moxifloxacin treated mice was partially reconstituted, reaching 30-50% of the B-cell population of placebo-treated mice. At the same time, the B-cell population of mice treated with carboplatin alone was reduced by over 90% compared to the B-cell population of placebo-treated mice. These results are in 2 shown.
7. On day 15 after initiation of treatment, ie on day 3 after the last moxifloxacin treatment, the activation state of the T-cell population (CD19- / CD25 + / CD69 + T cells) of carboplatin plus moxifloxacin-treated mice was completely reconstituted and reached higher than those of the T-cell population of placebo-treated mice. At the same time, the activation state of the T cell population from mice treated with carboplatin alone was reduced by over 70% compared to the T cell population of placebo-treated mice. These results are in 3 shown.
8. On day 15 post treatment initiation, ie on day 3 after last moxifloxacin treatment, the activation state of the B cell population (CD19 + / CD25 + / CD69 + B cells) of carboplatin plus moxifloxacin treated mice was completely reconstituted and reached higher levels than those B-cell population of placebo-treated mice. At the same time, the activation state of the B-cell population from mice treated with carboplatin alone was reduced by over 70% compared to the B-cell population of placebo-treated mice. These results are in 3 shown.

Beispiel 2Example 2

Immunkompetente Mäuse wurden mit syngenen Melanomzellen transplantiert. Die Behandlung des Melanoms mit Carboplatin wurde alternierend durch die Behandlung mit Moxifloxacin (Experiment 1) oder Moxifloxacin, Levofloxacin und Clarithromycin (Experiment 2) ergänzt. Die daraus resultierende Immun-Suppression durch Carboplatin bzw. die anschliessende Immun-Restauration durch Moxifloxacin wurde indirekt gemessen durch den Einfluss auf die Kontrolle des Melanom-Wachstums.Immunocompetent Mice were transplanted with syngeneic melanoma cells. Treatment of melanoma with carboplatin was alternating by treatment with moxifloxacin (Experiment 1) or moxifloxacin, levofloxacin and clarithromycin (Experiment 2) added. The resulting immune suppression by carboplatin or the subsequent immune restoration by moxifloxacin was measured indirectly by the influence on the Control of melanoma growth.

Männliche C57BL/6 Mäuse wurden mit 10⁶ B16F10 Melanomzellen sub cutan (s.c.) unter die rechte Flanke transplantiert. Nach 3 Tagen wurden die Mäuse auf ihr Melanomwachstum kontrolliert und randomisiert. An den Tagen 3, 6 und 9 wurde mit 75 mg/kg Carboplatin intravenös (i.v.) behandelt. An den Tagen 4, 5, 7, 8, 10 und 11 wurden die Mäuse mit 20 mg/kg Moxifloxacin (Experiment 1) bzw. mit 20 mg/kg Moxifloxacin, Levofloxacin oder Clarithromycin (Experiment 2) intraperitoneal (i.p.) behandelt. Eine Kontrollgruppe wurde anstelle von Antibiotika mit dH₂O i.p. behandelt. Eine weitere Gruppe wurde als Kontrolle anstelle von Carboplatin mit 0,9% Kochsalzlösung i.v. behandelt und anstelle von Moxifloxacin mit dH₂O i.p. behandelt.Male C57BL / 6 mice were transplanted under the right flank with 10 ⁶ B16F10 melanoma cells subcutaneously (sc). After 3 days, mice were monitored for melanoma growth and randomized. On days 3, 6 and 9, 75 mg / kg carboplatin was intravenously (iv) treated. On days 4, 5, 7, 8, 10 and 11 the mice were treated with 20 mg / kg moxifloxacin (experiment 1) or with 20 mg / kg moxifloxacin, levofloxacin or clarithromycin (experiment 2) intraperitoneally (ip). A control group was treated with dH ₂ O ip instead of antibiotics. Another group was treated iv with 0.9% saline as a control instead of carboplatin and ip treated with dH ₂ O instead of moxifloxacin.

Überraschenderweise wurde gefunden, dass durch Gabe von Moxifloxacin eine funktionelle Restauration des Immunsystemes erzielt werden konnte, welche die Kontrolle des Tumorwachstums durch Carboplatin synergistisch verstärkte. Ein ähnlicher, wenn auch geringerer Synergismus wurde durch die Behandlung mit Levofloxacin erreicht. Die Resultate sind im einzelnen:Surprisingly was found to be functional by administration of moxifloxacin Restoration of the immune system could be achieved, which the Control of tumor growth by carboplatin synergistically enhanced. A similar, though also lesser synergism was achieved by treatment with levofloxacin reached. The results are in detail:

Experiment 1Experiment 1

1. The melanomas grew exponentially in saline / dH 2 O-treated animals within 14 days and reached a calculated volume of 2000 mm 3 ( 4 and 5 , Experiment 1).
2. The melanomas in saline / moxifloxacin-treated animals grew comparable to melanomas in saline / dH 2 O-treated animals ( 4 and 5 , Experiment 1). This means that moxifloxacin has no anti-tumor effect.
3. The melanomas in carboplatin / dH 2 O-treated animals grew significantly slowed and at a lower final calculated volume compared to melanomas in saline / dH 2 O-treated animals ( 4 and 5 Experiment 1).
4. The melanomas in carboplatin / moxifloxacin-treated animals grew significantly slowed and at a lower final calculated volume compared to melanomas in carboplatin / dH 2 O-treated animals ( 4 and 5 Experiment 1). This means that the immune restoration caused by the moxifloxacin treatment synergistically supports the anti-tumor treatment with carboplatin.

Experiment 2Experiment 2

1. The melanomas grew exponentially in saline / dH 2 O-treated animals within 14 days and reached a calculated volume of 2000 mm 3 ( 4 and 5 , Experiment 2).
2. The melanomas in carboplatin / dH 2 O-treated animals grew markedly slowed and at a lower final calculated volume compared to melanomas in saline / dH 2 O-treated animals ( 4 and 5 , Experiment 2).
3. The melanomas in carboplatin / moxifloxacin-treated animals grew significantly slower and at a lower final calculated volume Comparison to melanomas in carboplatin / dH 2 O-treated animals ( 4 and 5 , Experiment 2). This means that the immune restoration caused by the moxifloxacin treatment synergistically supports the anti-tumor treatment with carboplatin, analogously to Experiment 1.
4. A lesser, analogous effect was achieved by treatment with levofloxacin ( 4 and 5 , Experiment 2).

Beschreibung der Figurendescription the figures

1: Phagozytose von peripheren Blut-Monozyten. Periphere Maus-Leukozyten von 6 Mäusen per Gruppe wurden zu gleichen Volumina vereint und mit FITC-markierten E. coli inkubiert. Phagozytose wurde quantifiziert durch FACS-Analyse fokussiert auf Monozyten. Die Analysen fanden statt am Tag 8, d.h. vor der dritten Carboplatin-Behandlung (A; vgl. Behandlungsschema unten) und am Tag 14, d.h. nach der dritten Carboplatin- und nach drei Moxifloxacin-Behandlungen (B). Dargestellt sind Prozent phagozytierende Monozyten pro Totalpopulation lebender Monozyten. Phagozytose wurde gemessen nach Inkubation bei 37°C (gefüllte Symbole). Kontrollproben zur Messung unspezifischer Fluoreszent wurden bei 0°C inkubiert (offene Symbole). Die Fluoreszenz von FITC nicht-phagozytierter, extrazellulärer E. coli wurde gequentscht mit Trypanblau. 1 : Phagocytosis of peripheral blood monocytes. Peripheral mouse leukocytes from 6 mice per group were combined in equal volumes and incubated with FITC-labeled E. coli. Phagocytosis was quantified by FACS analysis focused on monocytes. The analyzes took place on day 8, ie before the third carboplatin treatment (A, see treatment scheme below) and on day 14, ie after the third carboplatin and after three moxifloxacin treatments (B). Shown are percent phagocytic monocytes per total population of live monocytes. Phagocytosis was measured after incubation at 37 ° C (filled symbols). Control samples for measuring nonspecific fluorescence were incubated at 0 ° C (open symbols). The fluorescence of FITC non-phagocytosed extracellular E. coli was quenched with trypan blue.

Die peripheren Leukozyten stammten aus Mäusen, die nach folgendem Schema behandelt worden waren:

1) 0.9% NaCl intra venös (i.v.) an den Tagen 0, 4 und 8; dH₂O intra peritoneal (i.p.) an den Tagen 9, 10 und 11, dreimal pro Tag (Kreise)
2) Carboplatin 57mg/kg in 0.9% NaCl i.v. an den Tagen 0, 4 und 8; dH₂O i.p. an den Tagen 9, 10 und 11, dreimal pro Tag (Quadrate)
3) Carboplatin 57mg/kg in 0.9% NaCl i.v. an den Tagen 0, 4 und 8; Moxifloxacin 22.5 mg/kg in dH₂O i.p. an den Tagen 9, 10 und 11, aufgeteilt auf drei Dosen pro Tag (aufrechte Dreiecke)
4) Carboplatin 57mg/kg in 0.9% NaCl i.v. an den Tagen 0, 4 und 8; Moxifloxacin 67.5 mg/kg in dH₂O i.p. an den Tagen 9, 10 und 11, aufgeteilt auf drei Dosen pro Tag (abrechte Dreiecke)
5) 0.9% NaCl i.v. an den Tagen 0, 4 und 8; Moxifloxacin 67.5 mg/kg in dH₂O i.p. an den Tagen 9, 10 und 11, aufgeteilt auf drei Dosen pro Tag (Diamanten).

The peripheral leukocytes were from mice treated according to the following scheme:

1) 0.9% NaCl intra venous (iv) on days 0, 4 and 8; dH ₂ O intraperitoneally (ip) on days 9, 10 and 11, three times a day (circles)
2) carboplatin 57mg / kg in 0.9% NaCl iv on days 0, 4 and 8; dH ₂ O ip on days 9, 10 and 11, three times a day (squares)
3) carboplatin 57mg / kg in 0.9% NaCl iv on days 0, 4 and 8; Moxifloxacin 22.5 mg / kg in dH ₂ O ip on days 9, 10 and 11, divided into three doses per day (upright triangles)
4) Carboplatin 57 mg / kg in 0.9% NaCl iv on days 0, 4 and 8; Moxifloxacin 67.5 mg / kg in dH ₂ O ip on days 9, 10 and 11, divided into three doses per day (triangles on the right)
5) 0.9% NaCl iv on days 0, 4 and 8; Moxifloxacin 67.5 mg / kg in dH ₂ O ip on days 9, 10 and 11 divided into three doses per day (diamonds).

2: Charakterisierung von Lymphozyten-Subpopulationen. Periphere Maus-Leukozyten von 6 Mäusen per Gruppe wurden zu gleichen Volumina vereint und für folgende Oberflächenantigene gefärbt:
CD3-ε/CD4/CD8-α zur Charakterisierung der T-Zell Subtypen.
sIgM/CD23/CD45R zur Charakterisierung der B-Zell Subtypen. 2 : Characterization of lymphocyte subpopulations. Peripheral mouse leukocytes from 6 mice per group were combined in equal volumes and stained for the following surface antigens:
CD3-ε / CD4 / CD8-α for the characterization of T-cell subtypes.
sIgM / CD23 / CD45R for the characterization of B-cell subtypes.

Die Oberflächenfärbung wurde quantifiziert durch FACS-Analyse fokussiert auf Lymphozyten gemäß Angaben des Herstellers (BD Biosciences, Heidelberg, D). Die Analysen fanden statt am Tag 14, d.h. nach der dritten Carboplatin- und nach drei Moxifloxacin-Behandlungen. Dargestellt sind Prozent positiv gefärbter Zellen pro Totalpopulation lebender Lymphozyten.The Surface staining was quantified by FACS analysis focused on lymphocytes as reported of the manufacturer (BD Biosciences, Heidelberg, D). The analyzes found instead of on day 14, i. after the third carboplatin and after three Moxifloxacin treatments. Shown are percent of positively stained cells per total population of living lymphocytes.

1) 0.9% NaCl intra venös (i.v.) an den Tagen 0, 4 und 8; dH₂O intra peritoneal (i.p.) an den Tagen 9, 10 und 11, dreimal pro Tag (offener Balken)
2) 0.9% NaCl i.v. an den Tagen 0, 4 und 8; Moxifloxacin 67.5 mg/kg in dH₂O i.p. an den Tagen 9, 10 und 11, aufgeteilt auf drei Dosen pro Tag (gestreifter Balken)
3) Carboplatin 57mg/kg in 0.9% NaCl i.v. an den Tagen 0, 4 und 8; dH₂O i.p. an den Tagen 9, 10 und 11, dreimal pro Tag (gefüllter Balken)
4) Carboplatin 57mg/kg in 0.9% NaCl i.v. an den Tagen 0, 4 und 8; Moxifloxacin 67.5 mg/kg in dH₂O i.p. an den Tagen 9, 10 und 11, aufgeteilt auf drei Dosen pro Tag (karrierter Balken)

1) 0.9% NaCl intra venous (iv) on days 0, 4 and 8; dH ₂ O intraperitoneally (ip) on days 9, 10 and 11, three times a day (open bar)
2) 0.9% NaCl iv on days 0, 4 and 8; Moxifloxacin 67.5 mg / kg in dH ₂ O ip on days 9, 10 and 11, divided into three doses per day (striped bar)
3) carboplatin 57mg / kg in 0.9% NaCl iv on days 0, 4 and 8; dH ₂ O ip on days 9, 10 and 11, three times a day (filled bar)
4) Carboplatin 57 mg / kg in 0.9% NaCl iv on days 0, 4 and 8; Moxifloxacin 67.5 mg / kg in dH ₂ O ip on days 9, 10 and 11, divided into three doses per day (checked bar)

3: Charakterisierung von Lymphozyten -Aktivierungszuständen. Periphere Maus-Leukozyten von 6 Mäusen per Gruppe wurden zu gleichen Volumina vereint und für folgende Oberflächenantigene gefärbt:
CD19 negativ/CD25/CD69 zur Charakterisierung der T-Zell Aktivierungszustände.
CD19/CD25/CD69 zur Charakterisierung der B-Zell Aktivierungszustände. 3 : Characterization of lymphocyte activation states. Peripheral mouse leukocytes from 6 mice per group were combined in equal volumes and stained for the following surface antigens:
CD19 negative / CD25 / CD69 for characterization of T cell activation states.
CD19 / CD25 / CD69 for the characterization of B-cell activation states.

Die Behandlung der Mäuse und Auswertung der FACS-Färbungen fand analog der Beschreibung zu 2 statt.The treatment of the mice and evaluation of the FACS staining was analogous to the description 2 instead of.

4: Verlauf des Melanomwachstums bis 13 Tage post Transplantation. C57BL/6 männliche Mäuse wurden mit 10⁶ B16F10 Maus-Melanomzellen s.c. unter die rechte Flanke transplantiert. Das Tumorwachstum wurde mit einer Schieblehre (Plexx, NL) vermessen und zum Tumorvolumen errechnet gemäss der Formel (a × b²) × 0.5, wobei a die längere und b die kürzere Seite des vermessenen Elipsoids repräsentiert. Dargestellt sind die Mediane der errechneten Tumorvolumina pro Gruppe in mm³ ±Standardabweichung Experiment 1) oder die Mediane (Experiment 2). Folgende Behandlungsgruppen wurden auf Tumorwachstum untersucht: 4 : Course of melanoma growth up to 13 days post transplantation. C57BL / 6 male mice were transplanted under the right flank with 10 ⁶ B16F10 mouse melanoma cells sc. The tumor growth was measured with a caliper (Plexx, NL) and calculated to the tumor volume according to the formula (a × b ² ) × 0.5, where a represents the longer and b the shorter side of the measured ellipsoid. Shown are the medians of the calculated tumor volumes per group in mm ³ ± standard deviation experiment 1) or the medians (experiment 2). The following treatment groups were examined for tumor growth:

Experiment 1:Experiment 1:

1) Untreated (open square)
2) 0.9% NaCl intra venous (iv) on days 3, 6 and 9; dH 2 O intraperitoneally (ip) on days 4, 5, 7, 8, 10 and 11 (open circle)
3) 0.9% NaCl i.v. on days 3, 6 and 9; Moxifloxacin [20 mg / kg] i.p. on days 4, 5, 7, 8, 10 and 11 (open triangle)
4) Carboplatin 75 mg / kg in 0.9% NaCl iv on days 3, 6 and 9; dH 2 O ip on days 4, 5, 7, 8, 10 and 11 (filled square)
5) Carboplatin 75 mg / kg in 0.9% NaCl i.v. on days 3, 6 and 9; Moxifloxacin [20 mg / kg] i.p. on days 4, 5, 7, 8, 10 and 11 (filled Circle)

Experiment 2Experiment 2

1) 0.9% NaCl intra venous (iv) on days 3, 6 and 9; dH 2 O intraperitoneally (ip) on days 4, 5, 7, 8, 10 and 11 (open circle)
2) Carboplatin 75 mg / kg in 0.9% NaCl iv on days 3, 6 and 9; dH 2 O ip on days 4, 5, 7, 8, 10 and 11 (filled square)
3) Carboplatin 75 mg / kg in 0.9% NaCl i.v. on days 3, 6 and 9; Moxifloxacin [20 mg / kg] i.p. on days 4, 5, 7, 8, 10 and 11 (filled Circle)
4) Carboplatin 75 mg / kg in 0.9% NaCl i.v. on days 3, 6 and 9; Levofloxacin [20 mg / kg] i.p. on days 4, 5, 7, 8, 10 and 11 (open rhombus)

5: Errechnete Endvolumina der Melanome 13 Tage post Transplantation. 5 : Calculated final volumes of melanoma 13 days post transplantation.

C57BL/6 männliche Mäuse wurden mit 10⁶ B16F10 Maus-Melanomzellen s.c. unter die rechte Flanke transplantiert. Das Tumorwachstum wurde mit einer Schieblehre (Plexx, NL) vermessen und zum Tumorvolumen errechnet gemäss der Formel (a × b²) × 0.5, wobei a die längere und b die kürzere Seite des vermessenen Elipsoids repräsentiert. Dargestellt sind die Mediane der errechneten Tumorvolumina pro Gruppe in mm³. Folgende Behandlungsgruppen wurden auf Tumorwachstum untersucht:C57BL / 6 male mice were transplanted under the right flank with 10 ⁶ B16F10 mouse melanoma cells sc. The tumor growth was measured with a caliper (Plexx, NL) and calculated to the tumor volume according to the formula (a × b ² ) × 0.5, where a represents the longer and b the shorter side of the measured ellipsoid. Shown are the medians of the calculated tumor volumes per group in mm ³ . The following treatment groups were examined for tumor growth:

Experiment 1Experiment 1

1) 0.9% NaCl intra venous (iv) on days 3, 6 and 9; dH 2 O intraperitoneally (ip) on days 4, 5, 7, 8, 10 and 11 (open circle)
2) 0.9% NaCl i.v. on days 3, 6 and 9; Moxifloxacin [20 mg / kg] i.p. on days 4, 5, 7, 8, 10 and 11 (open triangle)
3) Carboplatin 75 mg / kg in 0.9% NaCl iv on days 3, 6 and 9; dH 2 O ip on days 4, 5, 7, 8, 10 and 11 (filled square)
4) Carboplatin 75 mg / kg in 0.9% NaCl i.v. on days 3, 6 and 9; Moxifloxacin [20 mg / kg] i.p. on days 4, 5, 7, 8, 10 and 11 (filled Circle)

Experiment 2Experiment 2

1) 0.9% NaCl intra venous (iv) on days 3, 6 and 9; dH 2 O intraperitoneally (ip) on days 4, 5, 7, 8, 10 and 11 (open circle)
2) Carboplatin 75 mg / kg in 0.9% NaCl iv on days 3, 6 and 9; dH 2 O ip on days 4, 5, 7, 8, 10 and 11 (filled square)
3) Carboplatin 75 mg / kg in 0.9% NaCl i.v. on days 3, 6 and 9; Moxifloxacin [20 mg / kg] i.p. on days 4, 5, 7, 8, 10 and 11 (filled Circle)
4) Carboplatin 75 mg / kg in 0.9% NaCl i.v. on days 3, 6 and 9; Levofloxacin [20 mg / kg] i.p. on days 4, 5, 7, 8, 10 and 11 (open rhombus)
5) Carboplatin 75 mg / kg in 0.9% NaCl i.v. on days 3, 6 and 9; Clarithromycin [20 mg / kg] i.p. on days 4, 5, 7, 8, 10 and 11 (open triangle)

Die statistische Signifikanz wurde ermittelt über eine Varianzanalyse nach Kruskall-Wallis und einem nachgestellten Signifikanz-Test nach Dunn für nicht-normal verteilte Werte (überprüft nach χ²-Anpassungstest). * = p < 0.05). Ausreißer wurden ermittelt nach Dixons-Ausreißertest und eliminiert. * = p < 0.05.The statistical significance was determined using an analysis of variance according to Kruskall-Wallis and a postponed significance test according to Dunn for non-normally distributed values (verified after χ ² adaptation test). * = p <0.05). Outliers were determined after Dixon's outlier test and eliminated. * = p <0.05.

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Claims

Use of one or more fluoroquinolones in a process for the preparation of a medicament for treatment and / or prophylaxis of immunosuppressants.

Use according to claim 1, wherein the fluoroquinolones are antibacterially active fluoroquinolones is.

Use according to claim 1, wherein one or more fluoroquinolones is an or selected several fluoroquinolones from the group consisting of moxifloxacin, ciprofloxacin, gatifloxacin, Enrofloxacin, sparfloxacin, clinafloxacin, grepafloxacin, trovafloxacin, Tosufloxacin, Temafloxacin, Norfloxacin, Rufloxacin, Fleroxacin, Levofloxacin, danofloxacin, sarafloxacin, marbofloxacin, orbifloxacin and pradofloxacin.

Use according to claim 1, wherein the fluoroquinolone is moxifloxacin.

Use according to claim 1, wherein the fluoroquinolones are antibacterial ineffective Fluoroquinolones acts.

Use according to claim 1, wherein the fluoroquinolones are a mixture of antibacterial effective and inactive fluoroquinolones.

Use according to claim 1, wherein the immunosuppressive conditions are due to malfunctions monocytes / macrophages.

Use according to claim 7, wherein one or more fluoroquinolones is an or several flourchinolones selected from the group consisting of moxifloxacin, ciprofloxacin, gatifloxacin Enrofloxacin, sparfloxacin, clinafloxacin, grepafloxacin, trovafloxacin, Tosufloxacin, Temafloxacin, Norfloxacin, Rufloxacin, Fleroxacin, Levofloxacin, danofloxacin, sarafloxacin, marbofloxacin, orbifloxacin and pradofloxacin.

Use according to claim 7, wherein the fluoroquinolone is moxifloxacin.

Use according to claim 7, wherein at least one fluoroquinolone is an antibacterial effective fluoroquinolone is.

Use according to claim 7, wherein at least one fluoroquinolone is an antibacterial inactive fluoroquinolone.

Use of one or more fluoroquinolones in a process for the preparation of a medicament for treatment and / or prophylaxis of viral and bacterial mixed infections with substances from claims 1-6, where the bacterial infection is a secondary infection in an immunosuppressed patient.

Use according to claim 12, where the viral infections are infections by viruses selected from the group consisting of the virus families Adenoviridae, Caliciviridae, Picornaviridae, Paramyxoviridae, Coronaviridae, Orthomyxoviridae, Retroviridae, Reoviridae, Bunyaviridae, Togaviridae, Herpesviridae, Parvoviridae and / or Papovaviridae.

Use according to claims 12 and 13, which are diseases of the respiratory tract, the Digestive tract and / or the skin with its appendages as well connective tissue handlet.

Use according to claim 14, where the diseases are SARS or influenza.

Use according to claims 1-12, these are immunosuppressions that are found under the Influence of a Treatment with cytotoxic chemotherapeutic agents.

Use according to claim 16, which are immunosuppressants in cancer patients.

Use according to claims 1-12 or 16, which are immunosuppressions produced by Radiotherapy or radiation are conditional.

Use according to claim 18, which is immunosuppressants in cancer patients.

Use of one or more fluoroquinolones in a process for the preparation of a medicament for treatment and / or prophylaxis of radiation sickness after exposure to radioactive Material.

Use according to claim 20, wherein it is fluoroquinolones selected from the group consisting of moxifloxacin, ciprofloxacin, gatifloxacin, enrofloxacin, sparfloxacin, clinafloxacin, Grepafloxacin, trovafloxacin, tosufloxacin, temafloxacin, norfloxacin, rufloxacin, fleroxacin, levofloxacin, danofloxacin, sarafloxacin, marbofloxacin, Orbifloxacin and pradofloxacin and not / or antibacterial Fluochinolonen acts.

Use of one or more fluoroquinolones in a process for the preparation of a medicament for treatment and / or prophylaxis of immunosuppressive, which is a combination preparation with Medicines used for antitumoral therapy, such as Chemotherapeutic agents or cytostatic agents used become.

Use according to claim 22, wherein the fluoroquinolone is a fluoroquinolone selected from the group consisting of moxifloxacin, ciprofloxacin, gatifloxacin, Enrofloxacin, sparfloxacin, clinafloxacin, grepafloxacin, trovafloxacin, Tosufloxacin, Temafloxacin, Norfloxacin, Rufloxacin, Fleroxacin, Levofloxacin, danofloxacin, sarafloxacin, marbofloxacin, orbifloxacin and pradofloxacin.

Use according to claim 22 or 23, which is the antitumor agent is an agent selected from the group consisting from asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, Cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, Daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, Hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, Lomustine, mechlorethamine, 6-mercaptopurine, mesna, methothrexate, Mitomycin C, mitoxantrone, prednisolone, prednisone, precarbazine, raloxifene, streptozocin, Tamoxifen, thioguanine, topotecan, vinblastine, vincristine, vindesine, Aminogluthethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, Diethylstilbestrol, 2 ', 2'-difluorodeoxycytidines, Docetaxel, erythrohydroxynonyladenine, ethinylestradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, Flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, Megestrol acetate, melphalan, mitotane, paclitaxel, pentstatin, PALA, Plicamycin, semustin, teniposide, testosterone propionate, thiotepa, Trimethylmelamine, uridine, and vinorelbine, oxaliplatin, gemcitabine, Capecitabine, epothilone and natural or synthetic derivatives, Tositumomab, Trabedectin, and Temozolomide, Trastuzumab, cetuximab, bevacizumab, pertuzumab, ZD-1839 (Iressa), OSI-774 Tarceva), CI-1033, GW-2016, CP-724,714, HKI-272, EKB-569, STI-571 (Gleevec), PTK-787, SU-11248, ZD-6474, AG-13736, KRN-951, CP-547, 632, CP-673,451 and sorafenib.

Use of fluoroquinolones in a process for the manufacture of a medicament for the treatment and / or prophylaxis of immunosuppressants, which is a combination preparation with antiviral Arrnei means.

Use according to claim 25, the fluoroquinolone is selected from a fluoroquinolone the group consisting of moxifloxacin, ciprofloxacin, gatifloxacin, Enrofloxacin, sparfloxacin, clinafloxacin, grepafloxacin, trovafloxacin, Tosufloxacin, Temafloxacin, Norfloxacin, Rufloxacin, Fleroxacin, Levofloxacin, danofloxacin, sarafloxacin, marbofloxacin, orbifloxacin and pradofloxacin.

Use according to claim 25 or 26, wherein the antiviral agent is a Medium selected from the group consisting of interferon-β, interferon alfacon-1, interferon-α or pegylated Interferon-β, 3TC (lamivudine), adevovir, adevovir dipivoxil, entecavir, emtricitabine, Clevudine, L-dT, L-Fd4C acyclovir, valacyclovir, penciclovir, famciclovir Foscarnet, brivudine, ganciclovir, cidofovir, inhibitors of the helicase-primase complex, Ribavirin, lopinavir-ritonavir (Kaletra), AG7088, hexapeptidyl CMK, Ruprin trivir (AG7088), 3C protease inhibitors, pirodavir, pleconaril, soluble ICAM-1, Amantidine, Symmetrel, Flumadine, Oseltamvir, Zanamivir, Tenofovir disproxil fumarate (TDF), emtricitabine (FTC), didanosine (ddI), stavudine (d4T), zidovudine (AZT), zalcitabine (ddC), efavirenz (EFV), nivirapine (NVP), delaviridine (DLV), atazanavir (ATV), ritonavir (RTV), amprenavir (APV), lopinavir / rironavir (LPV / RTV), nelfinavir (NFV), indinavir (IDV), saquinavir (SQV-SGC), enfuvirtide (T-20), etravirine (TMC-125), Capravirine, Tenovovir (PMPA).

Kit, containing containers separated from each other, in each of which mentioned under claim 22, 23, or 24 active ingredients are included.

Kit, containing containers separated from each other, in each of which mentioned under claim 25, 26, or 27 agents are included.