PH26684A - The use of imexone as an immune suppressive and pharmaceutical compositions containing them - Google Patents
The use of imexone as an immune suppressive and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- PH26684A PH26684A PH38984A PH38984A PH26684A PH 26684 A PH26684 A PH 26684A PH 38984 A PH38984 A PH 38984A PH 38984 A PH38984 A PH 38984A PH 26684 A PH26684 A PH 26684A
- Authority
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- Philippines
- Prior art keywords
- imexon
- cell
- immune
- proliferation
- cells
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title description 7
- 230000006028 immune-suppresssive effect Effects 0.000 title description 6
- BIXBBIPTYBJTRY-UHFFFAOYSA-N imexon Chemical compound NC1=NC(=O)N2CC12 BIXBBIPTYBJTRY-UHFFFAOYSA-N 0.000 abstract description 46
- 229950003978 imexon Drugs 0.000 abstract description 45
- 210000003719 b-lymphocyte Anatomy 0.000 abstract description 22
- 230000035755 proliferation Effects 0.000 abstract description 22
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 230000004913 activation Effects 0.000 abstract description 4
- 229940125721 immunosuppressive agent Drugs 0.000 abstract description 3
- 230000001991 pathophysiological effect Effects 0.000 abstract description 2
- 208000035475 disorder Diseases 0.000 abstract 1
- 239000003018 immunosuppressive agent Substances 0.000 abstract 1
- 208000031223 plasma cell leukemia Diseases 0.000 abstract 1
- 208000010626 plasma cell neoplasm Diseases 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 10
- 108010062580 Concanavalin A Proteins 0.000 description 9
- 239000011149 active material Substances 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 210000004698 lymphocyte Anatomy 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
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- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 4
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- PPQNQXQZIWHJRB-UHFFFAOYSA-N Methylcholanthrene Chemical compound C1=CC=C2C3=CC4=CC=C(C)C(CC5)=C4C5=C3C=CC2=C1 PPQNQXQZIWHJRB-UHFFFAOYSA-N 0.000 description 2
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- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
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- 229940104230 thymidine Drugs 0.000 description 2
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- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 2
- KOYMTVWMCXDJNV-UHFFFAOYSA-N 1-[(2-methoxy-6-methylpyridin-3-yl)methyl]aziridine-2-carbonitrile Chemical compound COC1=NC(C)=CC=C1CN1C(C#N)C1 KOYMTVWMCXDJNV-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- 108010036941 Cyclosporins Proteins 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
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- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
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- 229940045686 antimetabolites antineoplastic purine analogs Drugs 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
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- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229950003453 ciamexon Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- -1 cyclo- phosphamide Chemical class 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
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- 210000003734 kidney Anatomy 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
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- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- 229960000485 methotrexate Drugs 0.000 description 1
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- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
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- 229940049954 penicillin Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
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- 230000000069 prophylactic effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
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- 125000005624 silicic acid group Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
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- 230000004936 stimulating effect Effects 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Transplantation (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Prostheses (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to the use of 4-imino-1,3-diazabicyclo[3.1.0]hexan-2-one (imexon) as an immunosuppressive agent. Imexon selectively suppresses beta -lymphocyte activation and can be employed for the treatment of B-cell or plasma-cell leukaemia and neoplasms. Imexon is used in the treatment of those disorders in which polyclonal B-cell proliferation is of pathophysiological, symptomatic or clinical relevance such as, for example, for autoimmune diseases.
Description
The present invention is concerned with the use of imexon for the preparation of pharmaceutical compositions with an immunosuppressive action and is also concerned with pharmaceutical compos itiondbcon- 5 taining imexon in combination with a further active material. v -
In particular, the present invention is concerned with the use of imexon for the preparation of pharma- ceutical compositions for the treatment of autoimmune diseases, B cell and plasma cell neoplasias, 1ympho- blastic lymphomas, rejection reactions after tissue and organ transplants and viral and retroviral infections, for example AIDS or ARC (AIDS-related complex). In general, imexon can be used for the treatment of diseases in which a pathophysiologically increased B- : lymphocyte proliferation or B-lymphocyte activation is to be observed.
Imexon, which has the systematic designation 4- \ino-1,3-diazabicyclo-(3.1.0)-hexan-z-one, has the 70 following structural formula:-
HC —C— C= NH
N
: © ..-——- NH 0” © 25 with regard to its structure, imexon is not - | comparable with any other active compounds used therapeutically. J/The surprisingly found preferred
3 26634 action on B-lymphocutes also has no parallel with other previously known immunosuppressively-acting compounds. - Imexon and processes for the preparation thereof are known from U.S. Patent Specification No.4,083,987.
The compound is thereby described as being a cancero- statically-active therapeutic which displays immune- stimulating properties. The cancerostatic action was demonstrated on the basis of the inhibition of the tumour growth of Walker sarcoma 256 after the adminis- tration of imexon to rats. The immune-stimulating action can be deduced from experiments in which an increase of the leukocytes, as well as an increase of the number of the antibody-forming spleen cells could be observed after the administration of imexon. The pharmacological importance of imexon is, according tO this U.S. Patent Specification, tO be seen in the fact that imexon SO strongly impairs the growth of the rapidly dividing cancer cells that, under certain "circumstances, a regression of the tumours is possible.
According to U.S. Patent Specification No. 4,083,987, the advantageous action of imexon lies in the simult- aneous strengthening of the weakened immune defence system inherent in the body which accompanies the cancerostatic action.
In general, immune suppressives as such have been \ known for a long time from the prior art (Pharmazie unserer Zeil, 1, 2-.8/1972 and 12 _, 20-29/1983). The
—l- expression "immune suppression' used in this connection generally designates the various types of non-specific suppression of the immune response, for example with the help of antisera, ionising irradiations and special therapeutics.
The use of immune suppressive-acting chemo- therapeutics can be employed after the transplantation of tissue or organs and in the therapy of autoimmune diseases. They inhibit the proliferation of lympho- cytes by direct or indirect intervention into the synthesis of DNA or RNA. To this class of compounds belong cyclosporins, folic acid antagonists, purine analogues, alkylating compounds, such as cyclo- phosphamide, and certain corticosteroids. However, a disadvantage of these previously used immunosuppressives is the increased extent of observed susceptibility to infection of the treated organism which weakens the whole of the body's immune system and suppresses not only the humoral but also the cellular immune response.
The previously known artificially induced immune suppression could be achieved in various ways: by the administration of antigens, administration of specific antisera or antibodies, the use of other biological reagents, for example antilymphocyte antisera, by the use of immunosuppressively-active compounds, by radiation or by the surgical removal of lymphoid tissue.
2 Ll 3 A ‘) oO J x . -5-
The immunosuppressive properties of the immuno- suppressives at present known, for example cytostatics and corticosteroids, are dosage-dependent but non- selective, i.e. they act upon all immune-competent cells. These compounds inhibit not only the humoral but also the cellular immune response to a plurality of antigens and act non-specifically on T- and B- lymphocytes. Cyclosporin A, which at present is the most selective medicament, suppresses not only the proliferation of T-lymphocytes but also immune processes which are not T-cell-dependent.
Therefore, there is a great interest for immuno-
N suppressives which interfere specifically with patho- an oo | logically strengthened or increased immune mechanisms but without influencing the immune reactions which ; g Co take place normally in the body. Hitherto, such - specifically-active immunosuppressive substances are not known. - | Therefore, it is an object of the present invention to provide such a new immunosuppressively- active agent.
Surprisingly, we have now found that imexon solves this problem and can be used as an advantageous immune suppressive. 1t specifically suppresses the
B-cell proliferation or the B-cell activation. It can be advantageously used in the treatment of all diseases in which a polyclonal activation ox proliferation of
B-cells is of pathophysiological, symptomatic or clinical relevance.
In this sense, the treatment of the following diseases can, for example, be considered: autoimmune diseases, for example rheumatoid arthritis, diabetes mellitus Type 1, psoriasis, lupus systemicus erythematosus; rejection reactions after tissue or organ transplants, for example of skin, bone marrow and kidneys; viral or retroviral infections of any genesis, for example ARC (AIDS-related complex) and
AIDS, as well as their preliminary stages; B-cell leukaemias and lymphomas, for example chronic lymphatic leukaemia, lymphoblastic lymphoma, for example Burkitt's lymphoma and the like, or B-cell/ plasma cell neoplasias, for example plasmacytoma (multiple myeloma).
As autoimmune diseases, in the literature there are generally designated those diseases in which the formation of autoantibodies have a pathogenic significance. These autoantibodies are directed against the body's own antigens and thus bring about a destruction of the body's own organs, cells or - proteins. It is an object to suppress these diseased overreactions of the immune system with specifically- . 25 acting immune suppressives.
Furthermore, we have, surprisingly, found that imexon linhibits the proliferation of B-lymphocytes in
~7- a dosage-dependent manner.
Imexon can be used itself directly or in the form of physiologically acceptable addition salts.
In the meaning of the present invention, the expression "immune suppression’ is, in general, to comprise all aspects of the naturally-induced immunological Lon-responsiveness,artificially-induced non-responsiveness and pathologically-induced tolerance to auto- and foreign antigens.
The immune suppressive action of imexon could be demonstrated on the basis of the inhibition of the proliferation of human B-lymphocytes, the prolifer- ation being induced experimentally by the B-cell growth factor (BCGF).
Furthermore, the pharmacological properties of imexon could be characterised by concanavalin A (ConA) -induced proliferation of murine splenocytes (LTT), by phythaemagglutinin (PHA) -induced prolifer- ation of human lymphocytes, as well as by tumour growth inhibition assay (TGI).
In order to stimulate dormant B-cells to prolif- eration, two signals are necessary. The first signal is an activation signal which is brought about by an antigen Or anti-p. The transmission of this activating signal finally has the result that receptors for the
B-cell growth factor (BCGF) are expressed .on the B-cell surface. BCGF is a soluble lymphokine secreted by
T-cells with a molecular weight of 17,000 to 18,000 D.
The expression of BCGF receptors on the B-cells makes it possible for these to respond to the proliferation signal of BCGF. Normally, B-cells are converted by this two-signal process from the dormant state into the proliferative phase.
Imexon now suppresses this procedure specifically insofar as the concanavalin A (ConA)- and phyto- haemagglutinin (PHA) - induced lymphocyte proliferation, as well as the spontaneous proliferation of methyl- cholanthrene-induced fibrosarcoma cells (MethA), are not influenced or only in the case of 10 to 30 times higher concentrations. :
The antiretroviral action of imexon could be demonstrated on the basis of the Rauscher virus } leukaemia model (cf. Example 5). The influence of : imexon on the spontaneous formation of lymphomas and the synthesis of antinuclear autoantibodies in the mouse (Example 6) proves the effectiveness on an animal model for autoimmune diseases.
Imexon can also be used as a combination prepar- : ation with other immune suppressives, for example cyclosporin A, ciamexon Or azathioprine, as well as antiretrovirally-active substances, for example azidothymidine (AZT).
A combination of imexon with cytostatics is also possible, for example with cis-platinum complexes,
. 06684 -9- . such as cis-diaminodichloroplatinum, or with adriamycin, cyclophosphamide, vincristin, tamoxifen, methotrexate or 5-fluorouracil and the like. In this connection, the use of such combination preparations is of especial interest subsequent to a plasmaphaeresis for the monitoring of autoimmune diseases.
In the case of the use of a combination therapy, it is possible to administer the active materials in a so-called fixed combination, i.e. in a single pharma- ceutical formulation, in which both active materials are present simultaneously, or to use a so-called free combination in which the active materials are adminis-
Ri : tered in the form of pharmaceutical formulations ; vo k simultaneously or also successively in individually = 15 selectable dosage relationships.
For the preparation of pharmaceutical agents, imexon is mixed in known manner with appropriate : pharmaceutical carrier substances, possibly granulated and pressed, for example, into tablets or dragee cores.
A filling of the mixture into hard capsules is also possible. With the addition of appropriate adjuvants, a solution or suspension in water, an oil, for example olive oil, or a high molecular weight polymer, for example polyethylene glycol, can also be produced and administered in the form of injection solutions, soft gelatine capsules, syrups Or drops.
"As solid carrier materials, there can be used, for example, starches or starch derivatives, sugars, sugar alcohols, celluloses or cellulose derivatives, tensides, talc, highly dispersed silicic acids, high molecular weight fatty acids or the salts thereof, gelatine, agar-agar, calcium phosphate, animal or vegetable fats or waxes and solid high molecular weight polymers (such as polyethylene glycols or poly- vinylpyrrolidones). Compositions suitable for oral administration can, if desired, contain flavouring and sweetening materials.
The dosage of the active material imexon depends upon the age and sex of the individual, as well as upon the nature of the indications to be treated.
In principle, the treatment can be based on the fact that 0.1 to 100 mg. of imexon per kg. body weight can be administered daily orally, intravenously, subcutaneously or intramuscularly. However, it is preferred to use amounts of from 5 to 50 mg./kg. body weight and especially 5 to 20 mg./kg. body weight.
The dosages of the active material can be administered 1 to 3 times daily.
The specific immunosuppressive action of imexon is demonstrated by the following Examples:
Example 1.
BCGF-dependent proliferation of human B-lymphocytes.
The enrichment of peripheral human B-cells and
06084 -11- the BCGF proliferation assay were carried out as © follows (Cf. Eur. J. Immun., 16, 1350/1986) :
Enriched human B-lymphocytes were washed twice with complete RPMI 1640 medium (streptomycin/penicillin,
L-glutamine, 7-mercaptoethanol, FCS) and adjusted to 3 x 105 cells/ml. 160 ml. of this suspension were pipetted into cach well of microtitre plates. As pseudoantigen, there were added thereto 10 ml. of a solution of HFC pS-1gG (300 pg./ml.) and, as growth factor, 20 pl. BCGF (Cellular Products Incorporated).
To this were pipetted 20 pl. of the compound to be tested in 10 fold concentration. The cultures were incubated for ‘a total of 140 hours at 37°C. with 5% carbon dioxide and 95% relative atmospheric humidity. 16 hours before the conclusion of the incubation period, each culture was pulsed with 1 pCi of a (3H]-thymidine solution. ‘At the end of the experiment, the cells were collected with a harvester and the incorporated radio- activity determined in a liquid scintillation counter.
Example 2.
Concanavalin A (ConA) -induced proliferation of murine splenocytes.
Spleen cells (4 x 10°) of CB6F, mice were incubated for a total of 48 hours with 0.5 pg./ml. ConA : Co 25 in microtitre plates (Nunc GmbH, Wiesbaden, Federal : Republic of Germany) and various concentrations of imexon in 6 fold batches. 5 hours before the »
termination of the incubation period, the cultures were pulsed with [3t]-thymidine and subsequently harvested on glass fibre filter platelets by means of a multi- sample harvester (Skatron A.S., Lier, Morway). The filter platelets were dried and the radioactivity was determined in a Packard scintillation spectrometer.
Example 3.
Phythaemagglutinin (PHA) -induced proliferation of human lymphocytes. 1 ml. of human whole blood was diluted with 500 pg. PHA solution (500 pg./ml.) and diluted with 48 ml. DMEM medium. 200 pl. amounts of this batch were mixed with 20 pl. of the imexon concentration to be tested in 6 fold batches and incubated for 4 days.
After pulsing with (3H]-thymidine, incubation was continued for a further 94 hours, followed by harvests ing and evaluation as described in Example 2.
Example 4.
Tumour growth inhibition assay (TGI).
A methylcholanthrene-induced fibrosarcoma cell line (MethA) was obtained from our own tumour cell bank and passed intraperitoneally into CB6F, mice. 1 x 10% MethA cells were incubated with the imexon concentration to be tested in DMEM medium for 48 hours. 3 hours before the end of the incubation time, pulsing was carried out with [34]-thymidine, followed by harvesting and evaluated as described in
Example 2.
oo ~13-
The values given in the following Table 1 show the results of a representative experiment. They are the results of the investigations with imexon in the
TGI, LTT (ConA, PHA) as well as in the BCGF assay, i.e. the influence of imexon on the proliferation of the MethA sarcoma cell, T-lymphocytes and B-cells is shown. Imexon suppressed significantly and specifically the BCGF-induced B-cell proliferation at a concentration of 1 pg./ml., whereas the lymphocyte proliferation induced either by ConA or PHA was only significantly inhibited at concentrations of > 10 pg./ml. Further- : more, the spontaneous proliferation of MethA sarcoma
Co cells was also only significantly suppressed at > 10 pg./ml.
The results of the above experiments are summarised in the following Table 1:
0 od + + x + 4 5 «© HR + &®
Oo SS oo © wv Ao Fg , a } on oo » 0 O [aN] — on 52 ~~ [oll] PC - : og i
O ~i od 3 a OO «A nn 0 © > 259 A on un wy o Ta) oN I £ 8 I wn ~ ~N 3 Ow ~ = a — —
S I~ Cee em me me mem [n. OQ. jas ‘ co : 3a} B
SE Pe — ~N ~ F — oo r~ — Q ~F Oo ~~ I~ © oo TF [Ta Nn © wn oo oO 0 nn SF i ~~ = 0
Aa od ® 3 42 0 5 5 rok ok » Q oa oo oo oo on wn pe 1 > oo oo = rH 1
Q B t
IS) YJ 52 A > imeem ee em — . er rrr = mmr an —t Q - — Q 00 3 Nn J 0 [ee] oO ol a co ~~ wn uw o i O r~ [aN oO U 5 0 ~ =~ oO ~~ «© © ~— I vu WO A FF oo n oO. |e] — 3 wn {~~ 3 0 ~ TS or ™ E ™ nw on a oo wo of ~ & 1% 0 0 r~ ol un ZF I © Q oN BR wn I~ © © [ea] > — = 4 nn oo wy
BS) nn TF TF I
O ~ a g A 9 8 = Ar As 3, © 8 & < + — © » er 1 5 oo ~~ oo © o o
MH n I= oN a ~ | 1 oN
Q J] 52 A 1
Q Ug [5 — - > 0 — Q - Lo — es - 3] O Q
I a c sa) A ol
Q a oO Oo © wv oo =~ on oO — ~ Wn o~ x nr IF = wo — a [a] SO [a] QO oa oa ~~ — a wn gh — oy
Y ~ oo, eee =~ o 0 i | on nn on nn > Oo ~
Oo <3 r~ oc © oo ow mM — 1 ™ Ti 0 Sx rn © I = <2 ~ . o QJ [oN] ol & 0 >» J ND
Q o ol — — oA o » | — — =~ § . i p=. 0
Oo 2a ¥ * + ul G5 Ho ~ tn FF r~ 9 ~~ a 1 oa on \ 1 — 1 & 2 se
Ud in :
Oo nn Oo ~~ un 0 9 — ol — ~ ~ a jo] 0 — nN on wn a0 on oo oo
Oo nm Oo A fan} Oo o = og 3a] aN nH . . oO oC i CL oo © = =~ o~ F —~ 9 OO rio / Vv os 1X own n= > ~ oo
Sal? LY no oo x FF 2 r~ a, oo
Q a 4 unr un ~~ oN ~—~ ~N cm mond ~~ — ! i ao 0 :
QO 8 H a
No |S] oO o oo oO — . . q a0 o oO on ~— oO (=)
S a Q — — ~~ [&D]
-15- 26 ’
Example OS.
Antiretroviral action of imexon in the Rauscher virus leukaemia model. 8 to 9 week old female Balb/c mice were infected with 0.2 ml. of spleen homogenate of infected animals (diluted 1:2 in PBS). From day 0 (or day -1) up to day 13, the animals were treated intraperitoneally daily with the given dosage of the active material.
On day 7 and on day 14, animals of the individual treatment groups were sacrificed and the spleen weight determined as a measure of the viraemia.
In the following Table 7 are summarised the + results of the investigations. ImeXxon controlled the virus-caused increased weight of the spleen in the game dosage range as azidothymidine.
Ure oO QQ
Oo oO Ei + — ~~ ~ — oO Oo — — — — o ~~ ~ — . +1 ~~ ~ or +1 ~~ ~
Q oO “ +i = +
O od OO oH QQ [ERTal > —r— 0 > OO : od —O « NN [3] NO « 54 0 « 0 0 . aN — O or oO — — or OO — ~ ol 0g
NS re] ~~ ~~ — ~ oO [=] oO © (e] — — o — —~
Q oO +i ~~ ~ OO + oO o> — +1 — +1 —
QO un ~~ OO ~~ oo = 0 —i o B= — CO an - > — OO » 00 9 oO o —i
ET — * * Oe ~~ « 0 Oe - . oO ~O . oO oN —
Lo Q [o}
Dg . . . oo oe ol © «© —Y ~ Oo ~~ ~~ ~ oo ~~ ~~
N 0 ~~ o oN je] oO © ~N o Oo <Q ~~ — — — — — — oS o +1 co +
Cc © od bp Q OQ bh Q 00 \O @ M 4 a o XM be ~~ [e)) 0n oJ ~ — OO oF ~ ~NO » 00 o o « e oe [oN] . oOo
Q = co Nr g | HV coo NO 5 — ~ ~~ - fo Q | - - i U : Ee . X 0 0 au Q Oo ox an oO oO o —_ — ~N ~~ — — > o o oo = + ~~ ~ — — o> 0 O +! o EN ~
O —H © Cc > 0 OO Q +1 +o Oo <F 0 3 "a O — — 0g NO "~~ oO © 0 © OU — oe — 0) . ON q > 9 oO oo += [A oN. — Ha oO — 5 0d
U4 MQ oO © [4}] ~~ ~~ ~~ ~~ coo ~~ (=) O ~~ o oO
OM 0 — — 0 — — or o 2c +1 ~— ~— 23 +) ~~ ~ SN 2 — 0 +1 0 +1 J
[3] Oo QA — nN Q OO od bp o> oF ~ QO > ~ Oo O Q -~ «© oO « ON [of OO N TN fs noe O — + ov oe — + “oe oN Pd 0 — A, OO oN — 0 OO — OO oO gy : 0 .
A 8 oO
Q «© ~~ ~~ ~~ ~~ ~~ ~~ Q
Sood on uy nm Va] uy 0 oe 22 + ~~ ~ OQ +1 ~~ ~~ = 2 a +1 0 +1 a © [a NO Q A wy M <Q ~ > — — ol o> O — un I) [3s] « — OO » lo} — OQ « C7 0 a -— . . Oe — 1 . . Oe gE Ou oN] ~N OD. oO NO 2 oO wl a} oe] ~~ ~~ ~~ ~~ Wn uq > bo bo b0 0 —
Qo ~ ~—r ~~ ~~ [4+] 4 5 n a oJ J 2 2 .
LC £ Lc c c a ~~ Q bo a0 od od © 2 3 TQ Tu en 33 4 3 2 C3 [+4 oc ~— oc — 3
Q 8 F Q g ~ Q — Q — . — . ~~ o [a8 o [a [4] [a [a 0 [3 o o
. : -17-
Example 6.
Action of imexon in the case of autoimmune diseases.
With increasing age, the mouse strain MRL 1lpr/lpr develops increasingly spontaneously lymphadenoma and
SLE-like symptoms, for example the synthesis of anti- nuclear autoantibodies. For the jnvestigation of the prophylactic effect of imexon on the development of these symptoms, 11 week old MRL mice were treated intraperitoneally once daily with the given dosages of imexon and cyclophosphamide. The number of lympha- . denomas and the concentration of antinuclear antibodies were documented. In the case of the investigation of oo tv. “the therapeutic potency of imexon, MRL mice, after each animal had developed at least one | ymphadenoma (about 14 week old animals), were also treated once daily with the given dosages of imexon and cyclophosphamide.
The measurement parameters were again the number of 1ymphadenomas, as well as the autoantibody titre.
The results of these investigations have shown that imexon, in the case of very good compatibility, lowers the number of spontaneously arising lymphadenomas and the concentration of DNA-specific antibodies. The effectiveness of imexon was also shown in the case of therapeutic use with animals already having lymphomas .
The number of 1ymphadenomas decreased dependent upon the dosage, a8 well as the titre of the autoantibodies.
Example 7.
Preparation of a pharmaceutical formulation of imexon.
A film tablet with, for example, 100 g. of active material and which has the following composition has proved to be an appropriate pharmaceutical composition: weight /unit/mg. imexon 100.000 lactose monohydrate 63.000 boly- (0-carboxymethyl)-starch, sodium salt 7.000 boly-(1-vinyl-2-pyrrolidone) 25,000 4.000 oo poly- (0-carboxymethyl)-starch sodium salt 3.000 : microcrystalline cellulose 20.000 highly dispersed silicon dioxide 1.500 magnesium stearate 1.500 core weight 200.000 ———
The film tablets were then produced in the usual way by the film drageeing of the imexon cores obtained.
Film tablets with, for example 10 mg., 50 mg.» 200 mg. and 500 mg. of active material were produced in a corresponding manner .
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DE3825667A DE3825667A1 (en) | 1988-07-28 | 1988-07-28 | USE OF IMEXON AS IMMUNOSUPPRESSIVE |
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KR900001369A (en) | 1990-02-27 |
DK175199B1 (en) | 2004-07-05 |
EP0352652A2 (en) | 1990-01-31 |
IL91138A (en) | 1994-10-21 |
HU206827B (en) | 1993-01-28 |
IE892448L (en) | 1990-01-28 |
EP0352652B1 (en) | 1995-01-25 |
IE66680B1 (en) | 1996-01-24 |
ATE117551T1 (en) | 1995-02-15 |
DK363389D0 (en) | 1989-07-21 |
HUT52378A (en) | 1990-07-28 |
JP2848634B2 (en) | 1999-01-20 |
DE58908926D1 (en) | 1995-03-09 |
AU619027B2 (en) | 1992-01-16 |
AU3887789A (en) | 1990-02-01 |
JPH0288521A (en) | 1990-03-28 |
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DK363389A (en) | 1990-01-29 |
PT91293A (en) | 1990-02-08 |
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