WO2003080076A1 - Nuevo uso terapéutico del ribósido de 5-aminoimidazol-4-carboxamida (acadesina) - Google Patents
Nuevo uso terapéutico del ribósido de 5-aminoimidazol-4-carboxamida (acadesina) Download PDFInfo
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- WO2003080076A1 WO2003080076A1 PCT/ES2003/000130 ES0300130W WO03080076A1 WO 2003080076 A1 WO2003080076 A1 WO 2003080076A1 ES 0300130 W ES0300130 W ES 0300130W WO 03080076 A1 WO03080076 A1 WO 03080076A1
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- acadesine
- compound
- lymphoproliferative disease
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- RTRQQBHATOEIAF-UUOKFMHZSA-N acadesine Chemical compound NC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RTRQQBHATOEIAF-UUOKFMHZSA-N 0.000 title claims abstract description 81
- RTRQQBHATOEIAF-UHFFFAOYSA-N AICA riboside Natural products NC1=C(C(=O)N)N=CN1C1C(O)C(O)C(CO)O1 RTRQQBHATOEIAF-UHFFFAOYSA-N 0.000 title claims abstract description 77
- 229960003000 acadesine Drugs 0.000 title claims abstract description 74
- 230000001225 therapeutic effect Effects 0.000 title abstract description 6
- DVNYTAVYBRSTGK-UHFFFAOYSA-N 5-aminoimidazole-4-carboxamide Chemical compound NC(=O)C=1N=CNC=1N DVNYTAVYBRSTGK-UHFFFAOYSA-N 0.000 title abstract 4
- 150000008223 ribosides Chemical class 0.000 title abstract 2
- 208000030289 Lymphoproliferative disease Diseases 0.000 claims abstract description 34
- 206010062113 splenic marginal zone lymphoma Diseases 0.000 claims abstract description 16
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims abstract description 11
- 201000003444 follicular lymphoma Diseases 0.000 claims abstract description 11
- 208000011580 syndromic disease Diseases 0.000 claims abstract description 9
- 201000007919 lymphoplasmacytic lymphoma Diseases 0.000 claims abstract description 8
- 230000001684 chronic effect Effects 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 6
- 208000028018 Lymphocytic leukaemia Diseases 0.000 claims abstract 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 13
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 11
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- NOTGFIUVDGNKRI-UUOKFMHZSA-N AICA ribonucleotide Chemical compound NC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(O)=O)O1 NOTGFIUVDGNKRI-UUOKFMHZSA-N 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 125000002723 alicyclic group Chemical group 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 210000003719 b-lymphocyte Anatomy 0.000 abstract description 24
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- 210000001744 T-lymphocyte Anatomy 0.000 abstract description 20
- 239000002777 nucleoside Substances 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- 229960000390 fludarabine Drugs 0.000 abstract description 4
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 abstract description 4
- 210000004698 lymphocyte Anatomy 0.000 abstract description 4
- 125000003835 nucleoside group Chemical group 0.000 abstract description 4
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 abstract description 3
- 206010062016 Immunosuppression Diseases 0.000 abstract description 3
- 230000002411 adverse Effects 0.000 abstract description 3
- 230000001506 immunosuppresive effect Effects 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract description 3
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- 229910019142 PO4 Inorganic materials 0.000 abstract 1
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- 108090000672 Annexin A5 Proteins 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 201000001268 lymphoproliferative syndrome Diseases 0.000 description 4
- 230000004987 nonapoptotic effect Effects 0.000 description 4
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 3
- 102000000412 Annexin Human genes 0.000 description 3
- 108050008874 Annexin Proteins 0.000 description 3
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
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- 230000006882 induction of apoptosis Effects 0.000 description 3
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- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 3
- -1 5-aminoimidazol-4-carboxamide riboside Chemical class 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
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- 239000010432 diamond Substances 0.000 description 2
- 230000009699 differential effect Effects 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
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- 108091007065 BIRCs Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
- 206010049993 Cardiac death Diseases 0.000 description 1
- 206010011906 Death Diseases 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- YXWOAJXNVLXPMU-ZXXMMSQZSA-N Fructose 2,6-diphosphate Chemical compound OP(=O)(O)O[C@]1(CO)O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O YXWOAJXNVLXPMU-ZXXMMSQZSA-N 0.000 description 1
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 1
- 102000055031 Inhibitor of Apoptosis Proteins Human genes 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
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- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000000063 antileukemic agent Substances 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940125710 antiobesity agent Drugs 0.000 description 1
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- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
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- 238000004113 cell culture Methods 0.000 description 1
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- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 210000003040 circulating cell Anatomy 0.000 description 1
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- 229940127089 cytotoxic agent Drugs 0.000 description 1
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- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000212 effect on lymphocytes Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- MIKKOBKEXMRYFQ-WZTVWXICSA-N meglumine amidotrizoate Chemical compound C[NH2+]C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I MIKKOBKEXMRYFQ-WZTVWXICSA-N 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
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- 229960005322 streptomycin Drugs 0.000 description 1
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- 238000010257 thawing Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Definitions
- the invention relates to the use of acadesine or acadesine precursors for the treatment of certain types of leukemia and lymphoma in humans.
- Leukemia is a cancer of the tissues that make up the blood, characterized by a large increase in the number of white blood cells (leukocytes) in the circulation, bone marrow, or other tissues.
- the different leukemias are classified according to the course of the disease and the predominant type of white cell involved.
- Leukemias are defined as acute or chronic; and also as myelogenous (from the bone marrow) or lymphocytic (when lymphocytes are involved). These features are used to designate almost all cases of leukemia as one of the following four types: acute myelogenous, acute lymphocytic, chronic myelogenous, and chronic lymphocytic.
- the two main types of lymphocytes are B cells and T cells, or B cells and T cells.
- Glucocorticoids and other chemotherapeutic agents used in the clinic including nucleoside analogs cladribine (2-chloro-2'-deoxyadenosine) and fludarabine (9- ⁇ -D-arabino-2-fluoroadenine, used in the form of 5'- monophosphate), induce apoptosis (also called programmed cell death) in B cells of patients with chronic lymphatic leukemia type B (B-CLL), suggesting that apoptosis is the mechanism of its therapeutic action.
- fludarabine and other nucleosides are very effective in the treatment of type B chronic lymphatic leukemia (B-CLL), both alone and in combination with other agents.
- B-CLL Chronic lymphatic leukemia
- MCL mantle cell lymphoma
- follicular lymphoma FL
- lymphoplasmacytic lymphoma LPL
- Waldenstrom syndrome Waldenstrom syndrome
- Acadesine also called 5-amino-1- ⁇ -D-ribofuranosyl-1 H-imidazol-4-carboxamide, 5-aminoimidazol-4-carboxamide riboside, AlCA-riboside and AICAR, is a natural substance that has CAS RN 2627-69-2 and having the following formula, where the numbering of the hydroxyl groups is shown.
- Acadesine ⁇ '-monophosphate also called AICA ribotide and ZMP
- Clinical studies in patients undergoing coronary aortic deviation surgery demonstrate that treatment with acadesine, before and during surgery, can reduce early cardiac death and myocardial infarction (cf. eg: DT Mangano, Journal American Medical Association 1997, vol. 277, pp. 325-332).
- Phase III trials with acadesine have been conducted, indicating that it is safe when administered orally and intravenously.
- Granted patents and / or patent applications have been published that refer to the use of acadesine to: prevent tissue damage due to decreased blood flow (cf. US 4,912,092, US 5,817,640); treating neurodegenerative conditions (cf. US 5,187,162); prevent damage to the central nervous system (cf. US 5,236,908); treating obesity (cf. WO 0193873 A1); treating type 2 diabetes (cf. WO 0197816 A1) and treating conditions associated with insulin resistance (cf. WO 0209726 A1).
- Granted patents and / or patent applications have been published that refer to the use of acadesine 5'-monophosphate as a flavoring material (cf. US.
- Acadesine is known to be an inhibitor of apoptosis of various cells.
- acadesine inhibits glucocorticoid-induced apoptosis in quiescent thymocytes, that acadesine inhibits apoptosis caused by serum deprivation in fibroblasts that overexpress fructose 2,6-bisphosphate, and that acadesine inhibits ceramide-induced apoptosis in primary astrocytes. Therefore, if acadesine had any effect on lymphocyte apoptosis, acadesine would be expected to be an inhibitor of it.
- acadesine induces apoptosis in B cells from patients with type B lymphoproliferative disease, while T cells are unaffected.
- type B lymphoproliferative diseases that is, syndromes or diseases due to an excess in the number and / or function of B lymphocytes, which include, These include but are not limited to: Type B chronic lymphatic leukemia (B-CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), lymphoplasmacytic lymphoma ( LPL) and Waldenstrom syndrome (WS).
- B-CLL Type B chronic lymphatic leukemia
- SZL splenic marginal zone lymphoma
- MCL mantle cell lymphoma
- FL follicular lymphoma
- LPL lymphoplasmacytic lymphoma
- Waldenstrom syndrome Waldenstrom syndrome
- the differential effect of acadesine on B and T lymphocytes is an important advantage of this invention, because it means that the side effect Adverse immunosuppression is small when acadesine is used as a therapeutic agent. In particular this represents an advantage over the use of fludarabine and other nucleosides known in the art.
- Another important advantage of the invention is the selectivity and concentration of acadesine necessary to induce apoptosis.
- the inventors have studied the effects of acadesine on different cell lines, including Jurkat (T-cell lymphoma), JVM-2, MCF-7 (breast cancer cell line), 293, Hela (cen / cancer cell line ix) and HUH7 (liver cancer cell line), and all of these cell lines have been found to be less sensitive to acadesine than the B cells of patients with type B chronic lymphatic leukemia (B-CLL).
- B-CLL chronic lymphatic leukemia
- acadesine is well tolerated in healthy individuals when administered intravenously, reaching plasma concentrations (200 ⁇ M) in the range of apoptosis-producing B cells in patients with B-CLL.
- One aspect of the present invention relates to the use of a compound of formula (I), as defined above, which is acadesine or a bioprecursor of acadesine, or a pharmaceutically acceptable solvate or salt thereof, for the preparation of a medicament for the treatment of humans suffering from type B lymphoproliferative diseases.
- type B lymphoproliferative diseases are B-CLL, SMZL, MCL, FL, LPL, WS and lymphoproliferative syndromes without specific diagnosis, respectively .
- the compound of formula (I) -R 2 , -R 3 and -R 5 are independently selected from the group consisting of -H, -PO (OH) 2 , -PO (OH) -O- PO (OH) 2 and -PO (OH) -O- PO (OH) -O-PO (OH) 2 .
- the compound of formula (I) is selected from the group consisting of acadesine and acadesine ⁇ '-monophosphate.
- the compound of formula (I) is acadesine.
- FIG. 1 illustrates the cytotoxic effect of acadesine in the cells of patients with B-CLL, showing the percentage of viability of the cells of 5 patients in response to a 24h incubation with various doses of acadesine.
- FIG. 2 illustrates the cytotoxic effect of acadesine in cells from patients with B-CLL, showing the effect of incubation for 24h with (+) or without (-) 0.5 mM acadesine on the percentage of cell viability of 20 patients.
- FIG. 3 illustrates the differential cytotoxic effect of acadesine on B cells (circles and black diamonds) and T cells (circles and white diamonds) of two patients with B-CLL.
- FIG. 4 shows a comparison between the induction of apoptosis in B and T cells of 18 patients with B-CLL and of 4 healthy donors (N), after incubation with 0.5 mM acadesine for 24h.
- FIG. 5 shows the results of seven samples from SMZL patients.
- FIG. 6 shows the results of two samples from patients with lymphoproliferative syndrome without a specific diagnosis.
- DETAILED DESCRIPTION OF PARTICULAR REALIZATIONS
- Lymphocytes were cultured, immediately after thawing, at a concentration between 2 and 5x10 6 cells / ml in RPMI 1640 culture medium (Biological Industries, Beit Haemek, Israel) which was supplemented with 10% fetal bovine serum (Gibco-BRL , Paisley, GB), 1% glutamine, and 1% penicillin-streptomycin, at 37 ° C in a humid atmosphere with 5% carbon dioxide.
- Apoptosis was determined by annexin V binding. Phosphatidylserine exposure was quantified by surface annexin V staining, as previously described (cf. B. Bellosillo et al., Blood 1998, vol. 92, pp. . 1406-1414). To analyze apoptosis in the T cells of the samples, 500,000 cells were incubated with the indicated factors for 24 h.
- the cells were then washed in a phosphate-buffered saline (PBS) solution, and incubated in 50 ⁇ l of annexin-binding buffer with APC-conjugated anti-CD3 antibody and PE-conjugated antibody CD19 for 10 minutes in the dark.
- Cells were diluted with annexin binding buffer to a volume of 250 ⁇ l and incubated with 0.5 ⁇ l of anti-annexin antibody V-FITC for 15 min in the dark. 250 ⁇ l of binding buffer was added to annexin and 5 ⁇ l of propidium iodide (Pl) just before analysis by flow cytometry. The results were analyzed using the Cell Quest software.
- PBS phosphate-buffered saline
- Acadesine induces apoptosis in cells from patients with B-CLL, SMZL and lymphoproliferative disease without specific diagnosis.
- acadesine induced apoptosis in a dose dependent manner, as illustrated in FIG. 1.
- the cells of 5 patients were incubated for 24 h with various doses of acadesine, as indicated.
- V Viability
- Pl propidium iodide uptake
- Viability was determined by analysis of phosphatidylserine exposure, and is expressed as a percentage of non-apoptotic cells.
- FIG. 3 shows the result corresponding to two representative patients.
- Viability was determined as non-apoptotic T cells (CD3 + / CD19-) (empty symbols) or non-apoptotic B cells (CD3- / CD19 +) (filled symbols), and was expressed as the percentage of viability with respect to untreated cells.
- T cells from patients with type B chronic lymphatic leukemia (B-CLL) were resistant to acadesine-induced apoptosis up to a dose of 1 mM. Higher concentrations of acadesine (2-4 mM) only slightly affected the viability of T cells.
- FIG. 4 shows a comparison between the induction of apoptosis in B and T cells of patients with B-CLL and healthy donors (N).
- Cells from 18 patients and 4 healthy donors were incubated with 0.5 mM acadesine for 24 h. Viability was expressed as the mean value ⁇ standard deviation. Viability was found to be markedly reduced in B cells, but not in T cells. These results indicate that B cells are much more sensitive to acadesine-induced apoptosis than T cells.
- FIG. 5 and FIG. 6 show the comparison between the induction of apoptosis in B and T cells of patients with SMZL and lymphoproliferative syndrome without specific diagnosis. Viability was found to be reduced in B cells but not in T cells. These results indicate that B cells are much more sensitive than T cells to acadesine-induced apoptosis.
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- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
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Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
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US10/508,305 US7560435B2 (en) | 2002-03-21 | 2003-03-20 | Therapeutic use of riboside of 5-aminoimidazole-4-carboxamide (acadesine) |
NZ535850A NZ535850A (en) | 2002-03-21 | 2003-03-20 | Novel therapeutic use of riboside of 5-aminoimidazole-4-carboxamide (acadesine) |
SI200330380T SI1508333T1 (sl) | 2002-03-21 | 2003-03-20 | Nova terapevtska uporaba ribozida 5-aminoimidazol-4-karboksamida (akadezina) |
DE60305485T DE60305485T2 (de) | 2002-03-21 | 2003-03-20 | Neue therapeutische verwendung des ribosid von 5-aminoimidazol-4- carbonsäureamid (acadesin) |
JP2003577902A JP5085004B2 (ja) | 2002-03-21 | 2003-03-20 | 5−アミノイミダゾール−4−カルボキサミドリボシド(アカデシン)の新規な治療上の使用 |
AU2003214275A AU2003214275B2 (en) | 2002-03-21 | 2003-03-20 | Novel therapeutic use of riboside of 5-aminoimidazole-4-carboxamide (acadesine) |
CA002479674A CA2479674C (en) | 2002-03-21 | 2003-03-20 | New therapeutic use of 5-aminoimidazole-4-carboxamide riboside (acadesine) |
MXPA04009191A MXPA04009191A (es) | 2002-03-21 | 2003-03-20 | Nuevo uso terapeutico del ribosido de 5-aminoimidazol-4-carboxamida (acadesina). |
EP03709839A EP1508333B1 (en) | 2002-03-21 | 2003-03-20 | Novel therapeutic use of riboside of 5-aminoimidazole-4- carboxamide (acadesine) |
CY20061101133T CY1105417T1 (el) | 2002-03-21 | 2006-08-11 | Νεα θepαπευτικη χρηση ριβοσιδιου 5-αμινοϊμιδαζολο-4-καρβοξαμιδιου (ακαδεσινη) |
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ES200200760A ES2192495B1 (es) | 2002-03-21 | 2002-03-21 | Nuevo uso terapeutico del ribosido de 5-aminoimidazol-4-carboxamida (acadesina). |
ESP200200760 | 2003-03-21 |
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US (1) | US7560435B2 (es) |
EP (1) | EP1508333B1 (es) |
JP (2) | JP5085004B2 (es) |
KR (1) | KR101007044B1 (es) |
AT (1) | ATE326976T1 (es) |
AU (1) | AU2003214275B2 (es) |
CA (1) | CA2479674C (es) |
CY (1) | CY1105417T1 (es) |
DE (1) | DE60305485T2 (es) |
DK (1) | DK1508333T3 (es) |
ES (2) | ES2192495B1 (es) |
MX (1) | MXPA04009191A (es) |
PT (1) | PT1508333E (es) |
SI (1) | SI1508333T1 (es) |
WO (1) | WO2003080076A1 (es) |
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CA2602291C (en) | 2005-03-28 | 2015-08-11 | Pericor Therapeutics, Inc. | Treatments for preventing or reducing adverse effects in a patient having decreased left ventricular function |
US20070082859A1 (en) * | 2005-10-07 | 2007-04-12 | Stover Richard R | Formulations of AICA riboside |
WO2008086341A1 (en) * | 2007-01-09 | 2008-07-17 | Pericor Therapeutics, Inc. | Methods. compositions, and formulations for preventing or reducing adverse effects in a patient |
US8461192B2 (en) * | 2007-09-13 | 2013-06-11 | The University Of South Florida | Method of selectively inhibiting PKCiota |
CA2739463C (en) * | 2008-10-03 | 2018-07-03 | Pericor Therapeutics, Inc. | Methods and compositions for treatment of acute heart failure |
US20100323979A1 (en) * | 2009-06-16 | 2010-12-23 | Weis-Amon Angelika B | Methods and compositions for inhibiting proliferation of aneuploid cells |
US8895520B2 (en) | 2011-10-26 | 2014-11-25 | Universite Nice Sophia Antipolis | Method for treating a human patent suffering from Myeloid Neoplasias using 5-aminoimidazole-4-carboxamide |
KR101498942B1 (ko) * | 2012-09-06 | 2015-03-05 | 한올바이오파마주식회사 | 결핵 치료용 약학적 조성물 |
JP2019504071A (ja) | 2016-01-15 | 2019-02-14 | ザ・ウイスター・インステイテユート・オブ・アナトミー・アンド・バイオロジー | がんを処置するための方法及び組成物 |
CA3107170A1 (en) | 2018-08-06 | 2020-03-12 | Skylark Bioscience Llc | Amp-activated protein kinase activating compounds and uses thereof |
US11779590B2 (en) | 2020-10-30 | 2023-10-10 | Skylark Bioscience Llc | AMP-activated protein kinase activating compounds and uses thereof |
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JPS5461195A (en) * | 1977-10-21 | 1979-05-17 | Takeda Chem Ind Ltd | N2-substituted phenyl-2,6-diaminonebularin |
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Also Published As
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EP1508333A1 (en) | 2005-02-23 |
ES2264525T3 (es) | 2007-01-01 |
CA2479674A1 (en) | 2003-10-02 |
ES2192495B1 (es) | 2005-02-16 |
ES2192495A1 (es) | 2003-10-01 |
EP1508333B1 (en) | 2006-05-24 |
US20050233987A1 (en) | 2005-10-20 |
JP5085004B2 (ja) | 2012-11-28 |
DE60305485T2 (de) | 2007-03-15 |
AU2003214275B2 (en) | 2006-02-09 |
MXPA04009191A (es) | 2004-11-26 |
US7560435B2 (en) | 2009-07-14 |
AU2003214275A1 (en) | 2003-10-08 |
JP2005520851A (ja) | 2005-07-14 |
ATE326976T1 (de) | 2006-06-15 |
CA2479674C (en) | 2009-12-22 |
DE60305485D1 (de) | 2006-06-29 |
KR20050115820A (ko) | 2005-12-08 |
JP2010180230A (ja) | 2010-08-19 |
CY1105417T1 (el) | 2010-04-28 |
DK1508333T3 (da) | 2006-09-25 |
SI1508333T1 (sl) | 2006-10-31 |
PT1508333E (pt) | 2006-10-31 |
KR101007044B1 (ko) | 2011-01-12 |
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