WO2007000234A1

WO2007000234A1 - Moxifloxacin therapeutic use for treating immune system functional disturbances

Info

Publication number: WO2007000234A1
Application number: PCT/EP2006/005569
Authority: WO
Inventors: Olaf Weber; Peter Seiler
Original assignee: Bayer Healthcare Ag
Priority date: 2005-06-24
Filing date: 2006-06-09
Publication date: 2007-01-04
Also published as: DE102005053679A1

Abstract

The invention relates to using fluoroquinolones for producing drugs for treating immune system functional disturbances, for example, for treating and/or preventing immunosuppresions.

Description

Therapeutic use of moxifloxacin to reconstitute dysfunction of the immune system

The invention relates to the use of fluoroquinolones for the preparation of medicaments for the reconstruction of disorders of the immune system, such as e.g. the therapy and / or prophylaxis of immunosuppressions. The fluoroquinolones may be antibacterially active or antibacterially inactive fluoroquinolones. In particular, 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 medicament for Treatment of immunosuppressants.

Immunosuppressants may be caused by disease states or induced by certain drugs. On the one hand, it is possible to induce immunosuppression specifically in the therapy (eg in the treatment of inflammatory diseases or in organ transplants to prevent rejection of the transplant, on the other hand, immunosuppressants may appear as undesirable side effects of certain medications, the latter being of particular importance in the chemotherapy of tumor diseases ,

In immunosuppressed patients, the reactions responsible for defense against infectious agents or degenerate cells (for example, tumor cells and their precursors) no longer take place or only to a lesser extent. Otherwise, harmless infectious diseases can be life-threatening for these patients, or certain tumors can occur more frequently (1-7).

During chemotherapy, immunosuppression is a severe, often treatment-limiting, undesirable effect. Hematopoietic growth factors are currently attempting to reduce the extent and duration of chemotherapy-induced immunosuppression (8-10).

Another form of immunosuppression may result from the immune evasion of various pathogens. 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 even actively suppress the immune system (11-20).

Neutropenic fever is a serious complication in cancer patients who have or have been treated with chemotherapy (21-24). There is a risk of generalized infection with a significant mortality rate in these patients. In recently published reports, the use of moxifloxacin and gatifloxacin in neutropenic cancer patients with fever has been advocated for the treatment of bacterial infections (25-30).

Patients in whom immunosuppression is induced by chemotherapy are currently being treated with e.g. treated with colony stimulating factors (e.g., G-CSF). A sufficient antibacterial active component is not given in this therapy, so that in case of infection with antibiotics to be extended or evaded. In this case, however, the therapy may be too late (8, 31-35).

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, TNFRl), a promoting influence on further resident in the patient tumor cells in terms of 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: lenograstim Amgen Ine. Updated on 24 ^lh March 2004. Originator: Chugai Pharmaceutical Co Ltd nartograstim. Updated on 28 " ¹ January 2003. Originator: Kyowa Hakko Kogyo Co Ltd, SCRIP World Pharmaceutical News 1998, 2324).

Accordingly, it is an object of the present invention to develop a new therapy for immunosuppressed patients in whom manifest neutropenia can not be detected and which is not associated with the potential danger of inducing recurrences in tumor patients. In addition, the therapy should be at the same time more favorable side effect profile than the use of colony-stimulating factors both physically and functionally reconstitute the immune response as well as to completely reconstitute before oportunistischen, hospital-associated, bacterial infections.

This object is achieved - as set forth in Examples 1 and 2 - by providing fluoroquinolone-containing drugs, in particular moxifloxacin-containing drugs for the treatment and / or prophylaxis of immunosuppressants.

The invention relates

1. Use of one or more fluoroquinolones in a process for the preparation of a medicament for the treatment and / or prophylaxis of immune suppressions. Immunosuppressed patients are people and other warm-blooded animals for whom the reduction of the number of immunologically important cells such as monocytes / macrophages, neutrophils, basophils and eosinophils, mast cells, dendritic cells, natural killer cells, T- and B-cells as well as an impairment of 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 T cell activity, conventional B2 and unconventional Bl activity B cells are at increased risk of infection or tumor disease. Immunosuppression may have been medically induced (eg chemotherapy) or caused by other causes (hereditary, infectious diseases). Immunosuppressive conditions are understood to mean conditions in which the number of immunologically important cells such as monocytes / macrophages, neutrophilic, basophilic and eosinophilic granulocytes, mast cells, dendritic cells, natural killer cells, T cells and B cells is reduced and their functions impaired Cells, such as phagocytosis, oxidative burst, cytokine and

Chemokine release, antigen presentation, T-killer cell activity, T-helper cell activity, T-suppressor cell activity, unconventional T-cell activity, activity of conventional B2 and unconventional Bl-B cells increase the risk of infection or tumor disease consists. Immunosuppression may have been medically induced (e.g., chemotherapy) or due to other causes (hereditary, infectious diseases).

2. Use according to item 1, wherein the fluoroquinolones are antibacterially active fluoroquinolones.

3. Use according to item 1, wherein at least one fluoroquinolone is moxifloxacin.

4. Use according to item 1, wherein at least one fluoroquinolone is ciprofloxacin.

5. Use according to item 1, wherein at least one fluoroquinolone is gatifloxacin.

6. Use according to item 1, wherein at least one fluoroquinolone is levofloxacin. 7. The invention also surpasses 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 acts.

8. Use according to item 1, wherein the fluoroquinolones are antibacterially inactive fluoroquinolones.

9. Use according to item 1, wherein the fluoroquinolones is a mixture of antibacterially active and inactive fluoroquinolones.

10. Use according to item 1, wherein the immunosuppressants are states which are caused by disorders of the monocytes / macrophages.

11. Use according to item 10, wherein at least one fluoroquinolone is moxifloxacin.

12. Use according to item 10, wherein at least one fluoroquinolone is gatifloxacin.

13. Use according to item 10, wherein at least one fluoroquinolone is levofloxacin.

14. Use according to item 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 a process for the preparation of a medicament for the treatment and / or prophylaxis of immunosuppressive, which is a combination preparation with medicaments, which are used for antitumoral therapy, such as chemotherapeutic agents or cytostatic agents , 16. Use according to item 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'-difluorodeoxycytidines, docetaxel, erythrohydroxynonyladenine,

Ethinyl estradiol, 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, toositumomab, 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.

18. The use of fluoroquinolones in a process for the preparation of a medicament for the treatment and / or prophylaxis of immunosuppressants, which is a combination preparation with antiviral medicaments.

19. Use according to item 18, 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. 20. Use according to item 18 or 19, wherein the antiviral agent is 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, ganciclpvir, cidofovir, inhibitors of

Helicase-primase complex, ribavirin, lopinavir-ritonavir (Kaletra), AG7088, hexapeptidyl CMK, ruprin trivir (AG7088), 3C protease inhibitors, pirodavir, pleconaril, soluble ICAM-I, amantidine, Symmetrel, flumadine, oseltamvir, zanamivir, tenofovir disproxil Fumarate (TDF), emtricitabine (FTC), didanosine (ddl), 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).

21. Kit, containing containers separated from each other, in each of which the active ingredients mentioned under point 15, 16, or 17 are included. Such a kit is suitable for the

Treatment of immunosuppressive reactions due to chemotherapeutic tumor therapy.

22. Kit, containing separate containers, in each of which the active ingredients mentioned under point 18, 19, or 20 are included.

23. Use according to items 10, 15, 16, 17, 18, 19, 20, 21 or 22, wherein at least one fluoroquinolone is an antibacterially inactive fluoroquinolone.

24. Use of one or more fluoroquinolones in a 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, wherein the bacterial infection is a secondary infection in an immunosuppressed patient.

25. Use according to item 24, wherein 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 acts. 26. Use according to items 24 or 25, which are diseases of the respiratory tract (eg SARS, influenza), the digestive tract and / or the skin with its appendages and the connective tissue.

27. Use according to item 26, wherein the diseases are SARS or influenza.

28. Use according to items 1-16, which are immunosuppressants that are under the influence of a treatment with cytotoxic chemotherapeutic agents.

29. Use according to item 28, which is immunosuppressants in cancer patients.

30. Use according to items 1-16, which are immunosuppressive conditions caused by radiotherapy or radiation.

31. Use according to item 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 item 32, which is fluoroquinolones 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 and / or non-antibacterial fluoquinolones.

The invention also relates to medicaments containing one or more flourchinolones, in particular antibacterially active fluoroquinolones, preferably a flourchinolone 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, more preferably moxifloxacin for the treatment of immunosuppressive activity.

The invention also relates to the use of one or more flourchinolones, in particular antibacterially active fluoroquinolones, preferably a flourchinolone 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, particularly preferably Moxifloxacin for the manufacture of a medicament for Treatment of immunosuppressants.

A combination preparation may contain the active ingredients separately in separate containers. However, the active ingredients may also be present together in a dosage form, e.g. together with suitable accompanying substances pressed in a tablet.

The invention also relates to treatment methods in which the drug preparations prepared as described are used for the treatment of immunosuppressants. These treatments may also be combination therapies. Preference is given to combination therapies comprising one or more fluoroquinolone and one or more agents used in the treatment of tumors, or one or more fluoroquinolones and one or more antiviral agents. Particularly preferred are combination therapies using the specifically disclosed fluoroquinolones with the specifically disclosed drugs used in tumor therapy or with the specifically disclosed antiviral agents. The administration of the active ingredients can be carried out simultaneously or sequentially in combination therapy, even at longer intervals.

The active substance can act systemically and / or locally. For this purpose it can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctivae otic or implant.

For these administration routes, the active ingredient can be administered in suitable administration forms.

For oral administration are known, the drug rapidly and / or modified donating application forms, such. Tablets (uncoated and coated tablets, for example enteric coated tablets or film-coated tablets), capsules, dragees, granules, pellets, powders, emulsions, suspensions, solutions and aerosols.

Parenteral administration can be carried out bypassing a resorption step (intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or using absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration, suitable application forms include injection and infusion. preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

For the other routes of administration are suitable, for example Inhalation medicaments (including powder inhalers, nebulizers), nasal drops / solutions, sprays; lingual, sublingual or buccal tablets or capsules to be applied, suppositories, ear and ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, milk, pastes, scattering powders or implants.

The active compounds can be converted in a manner known per se into the stated administration forms. This is done using inert non-toxic, pharmaceutically suitable excipients. These include u.a. Carriers (eg, microcrystalline cellulose), solvents (eg, liquid polyethylene glycols), emulsifiers (eg, sodium dodecyl sulfate), dispersants (eg, polyvinylpyrrolidone), synthetic and natural biopolymers (eg, albumin), stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides ) or flavor and / or odor remedies.

In general, it has been found to be beneficial to administer parenterally administered 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.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day. Examples

example 1

In immunocompetent mice, functional immunosuppression was induced by the application of a cytotoxic drug (carboplatin). The dose was chosen so that a reduction in the number of neutrophils (neutropenia) did not exist. This condition was controlled by FACS.

Female C57BL / 6 mice were treated with 57 mg / kg carboplatin intravenously (i.v.) on days 1, 5 and 9 of the experiment. On days 10, 11 and 12, the mice were treated with moxifloxacin intraperitoneally (i.p.). One group of mice received 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 a 21.5 mg / kg. A third group was used as a control in place of moxifloxacin with dH2O i.p. treated. A fourth group was administered as a control in place of carboplatin 0.9% saline i.v. treated and instead of moxifloxacin with dH2O i.p. treated.

On day 9 and day 15 of the experiment, the mice were bled. The peripheral blood leukocytes were subjected to a FACS analysis (FACScalibur, BD, Heidelberg, D), as well as a phagocytosis and a burst test (Orpegen, Heidelberg, D).

The following surface molecules were analyzed:

CD3-ε / CD4 / CD8-α for the characterization of the T-cell subtypes

slgM / CD23 / CD45R to characterize the 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.

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) 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, equivalent to day 3 after the last moxifloxacin treatment, the phagocytosis activity of the blood monocytes of carboplatin plus was

Moxifloxacin treated mice completely reconstituted and comparable to that of blood monocytes 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 as compared to that of blood monocytes of placebo-treated mice. The results are shown in FIG.

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, i.e. on day 3 after the last moxifloxacin treatment, the oxidative burst activity of blood monocytes of carboplatin plus moxifloxacin-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 3-5 as 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 after start of treatment, i.e. 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 and reached 30-50% of the T cell population placebo-treated mice. At the same time, the T-cell was

Population from mice treated with carboplatin alone was reduced by over 90% compared to the T-cell population of placebo-treated mice. These results are shown in FIG.

6. On day 15 post treatment initiation, 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 was Population from mice treated with carboplatin reduced by over 90% compared to the B-cell population of placebo-treated mice. These results are shown in FIG.

7. On day 15 after initiation of treatment, i.e. 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 levels 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

Figure 3 shown.

8. On day 15 after initiation of treatment, i.e. on day 3 after the 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 of the B-cell population 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 shown in FIG.

Example 2

Immunocompetent mice were transplanted with syngeneic melanoma cells. Treatment of the melanoma with carboplatin was alternately supplemented by treatment with moxifloxacin (Experiment 1) or moxifloxacin, levofloxacin and clarithromycin (Experiment 2). 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.

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 replaced with dH ₂ O instead of antibiotics treated ip. 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.

Surprisingly, it was found that by administration of moxifloxacin, a functional restoration of the immune system could be achieved, which increased the control of tumor growth by carboplatin syriergistisch. Similar, albeit lesser, synergism was achieved by treatment with levofloxacin. The results are in detail:

Experiment 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 (FIGS. 4 and 5, FIG.

Experiment 1).

2. The melanomas in saline / moxifloxacin-treated animals grew comparable to melanomas in saline / dH ₂ O-treated animals (Figures 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 lower final calculated volume compared to melanomas in saline / dH ₂ O-treated animals (Figures 4 and 5 Experiment 1).

4. The melanomas in carboplatin / moxifloxacin-treated animals grew significantly slower and at lower final calculated volume compared to melanomas in carboplatin / dH ₂ O-treated animals (Figures 4 and 5 Experiment 1). This means that the

Immune restoration induced by the moxifloxacin treatment synergistically supports the anti-tumor treatment with carboplatin.

Experiment 2

Experiment 2).

2. The melanomas in carboplatin / dH ₂ O-treated animals grew significantly slower and at lower final calculated volume compared to melanomas in saline / dH ₂ O-treated animals (Figures 4 and 5, Experiment 2). 3. The melanomas in carboplatin / moxifloxacin-treated animals grew significantly slower and at a lower final calculated volume compared to melanomas in carboplatin / dt ^ O-treated animals (Figures 4 and 5, experiment T). 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 (Figures 4 and 5, Experiment 2).

Description of the figures

Figure 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.

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).

FIG. 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 the T-cell subtypes.

slgM / CD23 / CD45R to characterize the B-cell subtypes. The surface staining was quantified by FACS analysis focused on lymphocytes according to the manufacturer's instructions (BD Biosciences, Heidelberg, D). The analyzes took place on day 14, ie after the third carboplatin and after three moxifloxacin treatments. Shown are percent of positively stained cells per total population of live lymphocytes.

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)

FIG. 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 to characterize the T-cell activation states.

CD19 / CD25 / CD69 for the characterization of B-cell activation states.

The treatment of the mice and evaluation of the FACS staining took place analogously to the description of FIG.

Figure 4: Course of melanoma growth to 13 days post transplantation. C57BL / 6 male mice were transplanted under the right flank with 10 ⁶ Bl 6F10 mouse melanoma cells sc. The tumor growth was measured with a caliper gauge (Plexx, NL) and calculated according to the formula according to the formula (axb ² ) x 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:

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 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)

Figure 5: Calculated final volumes of melanoma 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 gauge (Plexx, NL) and calculated according to the formula according to the formula (axb ² ) x 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 1

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 1 1 (open triangle)

3) Carboplatin 75 mg / kg in 0.9% NaCl iv on days 3, 6 and 9; dH ₂ O ip in the days

4, 5, 7, 8, 10 and 1 1 (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 2

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)

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)

The statistical significance was determined using a variance analysis according to Kruskall-Wallis and a postponed significance test according to Dünn for non-normally distributed values (verified after χ ² - adaption test). * = p <0.05). Outliers were determined after Dixon's outlier test and eliminated. * = p <0.05. References:

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Claims

claims:

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

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

3. Use according to claim 1, wherein one or more fluoroquinolones is one or more fluoroquinolones selected from the group consisting of moxifloxacin, ciprofloxacin, gatifloxacin, enrofloxacin, sparfloxacin, clinafloxacin, grepaflexacin, trovafloxacin, tosufloxacin, temafloxacin, norfloxacin, rufloxacin,

Fleroxacin, levofloxacin, danofloxacin, sarafloxacin, marbofloxacin, orbifloxacin and pradofloxacin.

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

5. Use according to claim 1, wherein the fluoroquinolones are antibacterially inactive fluoroquinolones.

6. Use according to claim 1, wherein the fluoroquinolones is a mixture of antibacterially active and inactive fluoroquinolones.

7. Use according to claim 1, wherein the immunosuppressive conditions are caused by disorders of monocytes / macrophages.

8. Use according to claim 7, wherein one or more fluoroquinolones are one or more flourchinolones selected from the group consisting of moxifloxacin, ciprofloxacin, gatifloxacin enrofloxacin, sparfloxacin, clinafloxacin, grepafloxacin, trovafloxacin, tosufloxacin, temafloxacin, norfloxacin, rufloxacin,

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

10. Use according to claim 7, wherein at least one fluoroquinolone is an antibacterially active fluoroquinolone.

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

12. The use of one or more fluoroquinolones in a process for the preparation of a medicament for the treatment and / or prophylaxis of viral and bacterial mixed infections with substances from claims 1-6, wherein the bacterial infection is a secondary infection in a immunosuppremed patient.

13. Use according to claim 12, wherein 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.

14. Use according to claims 12 and 13, wherein it handlet diseases of the respiratory tract, the digestive tract and / or the skin with its appendages and the connective tissue.

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

Use according to claims 1-12, which are immunosuppressants which are under the influence of a treatment with cytotoxic chemotherapeutic agents.

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

Use according to claims 1-12 or 16, which are immunosuppressive conditions caused by radiotherapy or radiation.

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

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

21. Use according to claim 20 which 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 / or non-antibacterial

Fluoquinolones act.

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

23. 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.

24. Use according to claim 22 or 23, 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-mercapto-purine, 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, semustin, teniposide, testosterone propionate,

Thiotepa, trimethylmelamine, uridine, and vinorelbine, oxaliplatin, gemcitabine, capecitabine, epothilone and natural or synthetic derivatives, toositumomab, 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.

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

26. Use according to claim 25, 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 25 or 26, wherein the antiviral agent is 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-I, amantidine, Symmetrel, flumadine, oseltamvir, zanamivir, Tenofovir disproxil fumarate (TDF), emtricitabine (FTC), didanosine (ddl), 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).

28. Kit, containing separate containers, in each of which the active ingredients mentioned in claim 22, 23, or 24 are included.

29. Kit, containing separate containers, in each of which the active ingredients mentioned in claim 25, 26, or 27 are included.