The assignee for this patent, patent number 8623908, is
Reporters obtained the following quote from the background information supplied by the inventors: "The present invention relates to novel therapeutic methods and pharmaceutical compositions for treating conditions associated with inhibition of interleukin-converting enzyme (ICE).
"Cytokines play an important role in a regulation of the immune system. Several studies indicate that variations in cytokine expression are associated with disease activity in immune mediated or inflammatory disorders, including autoimmune disorders (
"The sepsis syndrome is an excessive, acute inflammatory response to a variety of noxious insults, particularly bacterial infection. The role of cytokines in the pathogenesis of sepsis is complex since both deficient and excessive immune responses have been associated with this syndrome. Pro-inflammatory cytokines are, on the one hand, required locally for effective anti-bacterial effector mechanisms (J. Immunol. 145: 3762, 1990; Nature 381: 75, 1996; and Infect. Immun. 64: 5211, 1996), but on the other hand they are potentially toxic when secreted into the circulation (Nature 330: 662, 1987;
"IL-1.beta. is crucial for the induction of fever and acute-phase response during local tissue damage; in systemic inflammation it contributes to inflammatory reaction (
"The IL-1 family of cytokines, which include IL-18 and IL-1.beta., are key hormones of the immune system. Both IL-18 and IL-1.beta. are expressed and produced by various types of cells from hematopoetic and nonhematopoetic lineages, such as dendritic cells, monocytes/macrophages, microglia cells, keratinocytes, intestinal epithelial cells, etc. Recent studies emphasize the pathophysiological role of IL-18 and IL-1.beta. in a variety of neurodegenerative, autoimmune and inflammatory diseases, such as inflammation, hemaopoiesis and wound healing (Immunol. Today 7: 45-56, 1986).
"Interleukin-18 is an early signal in the development of T-lymphocyte helper type 1 (Th1) responses. It acts together with IL-12 to induce various cytokines, including IFN-.gamma., to activate Th1 cells. IFN-.gamma. is in turn responsible for inducing production of the soluble receptor protein, IL-18 binding protein (IL-18BP), a native down-regulator of IL-18 activity, which specifically binds IL-18 and neutralizes its biological activity in vitro and in vivo (Immunity 10: 127, 1999).
"IL-18 and IL-1.gamma. are expressed and produced in an inactive form, which requires activation by protease enzymes. The protease enzymes are divided into four families, (serine-, metallo-, aspartic- and cystein-proteases) based on their catalytic residues and mechanism of action. Whereas serine proteases utilize a nucleophilic hydroxyl of the serine residue and aspartic and metalloproteases posses carboxylates as active functionalities, the cysteine proteases have an active-site thiol-nucleophile.
"The caspase enzymes (Cysteine Aspartic-Specific Proteases) are a family of intracellular cysteine endopepetidases, which cleave their substrates after aspartate residues (Ann. Rev. Immunol. 17: 781-828, 1999). The caspases are divided into two classes, based on the lengths of their N-terminal prodomains. Caspases-1,-2,-4,-5,-8, and -10 have long prodomains; and caspases-3,-6,-7, and -9 have short prodomains.
"Caspase 1, which is also known and referred to herein, interchangeably, as interleukin-.beta.-converting enzyme (ICE), is expressed as a proenzyme of 45 kD in many tissues (
"ICE therefore plays an important role in physiological processes mediated by IL-1.beta. and IL-18.
"Various tellurium compounds have been described in the art as having immunomodulating properties. A particularly effective family of tellurium-containing compounds is taught, for example, in U.S. Pat. Nos. 4,752,614; 4,761,490; 4,764,461 and 4,929,739, whereby another effective family is taught, for example, in a recently filed U.S. Provisional Patent Application No. 60/610,660, which are all incorporated by reference as if fully set forth herein. The immunomodulating properties of this family of tellurium-containing compounds is described, for example, in U.S. Pat. Nos. 4,962,207, 5,093,135, 5,102,908 and 5,213,899, which are all incorporated by reference as if fully set forth herein.
"One of the most promising compounds described in these patents is ammonium trichloro(dioxyethylene-O,O')tellurate, which is also referred to herein and in the art as AS101. AS101, as a representative example of the family of tellurium-containing compound discussed hereinabove, exhibits antiviral (Nat. Immun. Cell Growth Regul. 7(3):163-8, 1988; AIDS Res Hum Retroviruses. 8(5):613-23, 1992), and tumoricidal activity (Nature 330(6144):173-6, 1987;
"It has been suggested that AS101, as well as other tellurium-containing immunomodulators, stimulate the innate and acquired arm of the immune response. For example, it has been shown that AS101 is a potent activator of interferon (IFN) in mice (
"It has also been demonstrated that AS101 induces the secretion of a spectrum of cytokines, such as IL-1, IL-6 and TNF-.alpha., and that macrophages are one main target for AS101 (Exp. Hematol. 23(13):1358-66, 1995). AS101 was also found to inhibit IL-10 at the m-RNA level, which may cause an increase in IL-12 and IFN-.gamma. (Cell Immunol. 176(2):180-5, 1997;
"Other publications describing the immunomodulation properties of AS101 include, for example, 'The immunomodulator AS101 restores T(H1) type of response suppressed by Babesia rodhaini in BALB/c mice'. Cell Immunol 1998 February; 'Predominance of TH1 response in tumor-bearing mice and cancer patients treated with AS101'. J Natl Cancer Inst 1996 September; 'AS-101: a modulator of in vitro T-cell proliferation'. Anticancer Drugs 1993 June; 'The immunomodulator AS101 administered orally as a chemoprotective and radioprotective agent'. Int J Immunopharmacol 1992 May; 'Inhibition of the reverse transcriptase activity and replication of human immunodeficiency virus type 1 by AS101 in vitro'. AIDS Res Hum Retroviruses 1992 May; 'Immunomodulatory effects of AS101 on interleukin-2 production and T-lymphocyte function of lymphocytes treated with psoralens and ultraviolet A'. Photodermatol Photoimmunol Photomed 1992 February; 'Use and mechanism of action of AS101 in protecting bone marrow colony forming units-granulocyte-macrophage following purging with ASTA-Z 7557'. Cancer Res 1991 Oct. 15; 'The effect of the immunomodulator agent AS101 on interleukin-2 production in systemic lupus erythematosus (SLE) induced in mice by a pathogenic anti-DNA antibody'. Clin Exp Immunol 1990 March; 'Toxicity study in rats of a tellurium based immunomodulating drug, AS-101: a potential drug for AIDS and cancer patients'. Arch Toxicol 1989; 'The biological activity and immunotherapeutic properties of AS-101, a synthetic organotellurium compound'. Nat Immun Cell Growth Regul 1988; and 'A new immunomodulating compound (AS-101) with potential therapeutic application'. Nature 1987 Nov.
"AS-101 has also been shown to have protective effects against lethal and sublethal effects of irradiation and chemotherapy (Blood 85: 1555, 1995; J. Nat. Cancer Inst. 88: 1276, 1996; In.
"Moreover, AS101 can inhibit activity of STAT3 (Signal Transducer and Activator of Transcription 3) via IL-10 inhibition (Cancer Res. 64: 1843, 2004). When binding of IL-10 to the IL-10 receptor occurs, receptor-associated Janus activated kinase (Jak) tyrosin kinases are activated and stimulate downstream signaling. One of the main transcription factors being activated is STAT3. Activated, phosphorylated STAT3 is translocated to the nucleus and regulates specific gene expression (J. Immunol. 155: 1079, 1995). One of the target genes for STAT3 is vascular endothelial growth factor (VEGF) (Clin. Cancer Res. 8: 945, 2002; Oncogene 21: 2000, 2002; Oncogene 22: 319, 2003). This factor recently was found to be responsible for IL-18 induction (Cancer Res. 64: 304, 2004). Moreover, recently it was found that IL-1.beta. alone (Cancer Sci. 94: 244, 2003) and together with oncostatin-M (Oncogene 22: 8117, 2003) induces up to sevenfold higher VEGF expression due to their mutual influence on STAT3. The ability of AS101 to down-regulate STAT3, may contribute to the overall inhibitory effect.
"Furthermore, it was found that although AS101 shows no inhibition of serine, metallo, and aspartic proteases, it inhibits cysteine proteases, via a catalytic thiol oxidation (Inorg. Chem. 37: 1704-1712, 1998).
"In addition to its immunomodulatory effect, AS101 is also characterized by low toxicity. Toxicity tests have shown that LD50 values in rats following intravenous and intramuscular administration of AS101 are 500-1000 folds higher than the immunologically effective dose.
"Hence, while the prior art teaches various primary and secondary roles of tellurium-containing compounds such as AS101 as immunomodulators, it fails to teach the involvement of tellurium-containing compounds in inhibition of caspase-1/IL-1.beta.-converting enzyme (ICE).
"In view of the findings that a myriad of medical conditions is associated with ICE, there is a widely recognized need for and it would be highly advantageous to have, novel agents that are capable of inhibiting ICE and hence can be beneficially utilized in the treatment of such conditions."
In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "The present invention teaches methods and pharmaceutical compositions for treating conditions associated with inhibition of interleukin-converting enzyme (ICE).
"According to one aspect of the present invention there is provided a method of inhibiting interleukin-1.beta.-converting enzyme in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one tellurium-containing compound.
"According to another aspect of the present invention there is provided a method of treating a condition in which inhibition of interleukin-1.beta.-converting enzyme is beneficial, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one tellurium-containing compound.
"According to yet another aspect of the present invention there is provided a use of at least one tellurium-containing compound in the preparation of a medicament for treatment of a condition in which inhibition of interleukin-1.beta.-converting enzyme is beneficial.
"According to still another aspect of the present invention there is provided a pharmaceutical composition identified for use in the treatment of a condition in which inhibition of interleukin-1.beta.-converting enzyme is beneficial, comprising at least one tellurium-containing compound and a pharmaceutically acceptable carrier.
"According to further features in preferred embodiments of the invention described below, the pharmaceutical composition is packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of conditions associated with inhibition of interleukin-converting enzyme
"The condition treatable by the methods or compositions of the present invention may comprise, for example, an IL-1 mediated disease, an inflammatory disease, an autoimmune disease, a destructive bone disorder, a proliferative disorder, an infectious disease, a degenerative disease, a disease associated with cell death, an excess dietary alcohol intake disease, retinal disorders, uveitis, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, scarring, graft vs host disease, organ transplant rejection, organ apoptosis after burn injury, osteoporosis, leukemia's and related disorders, myelodysplastic syndrome, multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, haemorrhagic shock, sepsis, septic shock, burns, Shigellosis, Alzheimer's disease, Huntington's disease, Kennedy's disease, prion disease, cerebral ischemia, epilepsy, myocardial ischemia, acute and chronic heart disease, myocardial infarction, congestive heart failure, atherosclerosis, coronary artery bypass graft, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, HIV-related encephalitis, aging, neurological damage due to stroke, ulcerative colitis, traumatic brain injury, spinal cord injury, hepatitis-B, hepatitis-C, hepatitis-G, yellow fever, dengue fever, or Japanese encephalitis, various forms of liver disease, renal disease, polycystic kidney disease, H. pylori-associated gastric and duodenal ulcer disease, HIV infection, tuberculosis, an immunotherapy for the treatment of various forms of cancer, organ failure, meningitis and a complication associated with coronary artery bypass grafts.
"According to further features in preferred embodiments of the invention described below, the tellurium-containing compound of the present invention is a compound comprising at least one tellurium dioxide moiety and optionally and preferably is at least one of tellurium dioxide (TeO.sub.2) per se, an organic complex of TeO.sub.2 (as detailed hereinbelow), a compound having general Formula I:
"##STR00001## a compound having general Formula II:
"##STR00002## and a compound having general Formula III:
"each of t, u and v is independently 0 or 1;
"each of m and n is independently an integer from 0 to 3;
"Y is selected from the group consisting of ammonium, phsophonium, potassium, sodium and lithium;
"X is a halogen atom; and
"each of R.sub.1-R.sub.14 is independently selected from the group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate and sulfonamido.
"Preferably, the tellurium-containing compound has the general Formula I.
"According to an embodiment in which the tellurium-containing compound has general Formula I, preferably t, u and v are each 0. More preferably, each of R.sub.1, R.sub.8, R.sub.9 and R.sub.10 is hydrogen; more preferably X is a halogen atom, most preferably the halogen atom is chloro. More preferably, Y is ammonium. The preferred compound according to this embodiment is referred to hereinafter as AS101.
"According to still further features in the described preferred embodiments of the methods of the present invention, administration may be effected by a route selected from the group consisting of inhalation, oral, buccal, rectal, transmucosal, transdermal, intradermal, transnasal, intestinal and/or parenteral routes; intramuscular, subcutaneous and/or intramedullary injection routes; intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, and/or intraocular injection routes; and/or direct injection into a tissue region.
"Preferably, for systemic administration, a therapeutically effective amount of a compound of formula I, II or III ranges from about 0.01 mg/m.sup.2/day to about 20 mg/m.sup.2/day and, more preferably, from about 0.01 m g/m.sup.2/day to about 10 mg/m.sup.2/day.
"According to still further features in the described preferred embodiments of the methods and uses of the present invention, the tellurium-containing compound forms a part of a pharmaceutical composition, further comprising a pharmaceutically acceptable carrier. Preferably, a concentration of tellurium-containing compound of formula I, II or III in the carrier ranges from about 0.01 weight percent to about 50 weight percents, more preferably from about 0.1 weight percent to about 25 weight percents, of the total weight of the composition. Optionally, the pharmaceutical composition may further comprise at least one additional active agent, including, but not limited to, an antineoplastic agent, an immunomodulator, an interferon and a non-steroidal anti-inflammatory drug (such as oxicams, piroxicam, isoxicam, tenoxicam, sudoxicam, CP-14,304, salicylates, aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, fendosal, acetic acid derivatives, diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, ketorolac, fenamates, mefenamic, meclofenamic, flufenamic, niflumic, tolfenamic acids, propionic acid derivatives, ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen, pyrazoles, phenylbutazone, oxyphenbutazone, feprazone, azapropazone, trimethazone and derivatives, esters, salts and mixtures thereof).
"According to still further features in the described preferred embodiments of the methods or compositions of the present invention, the composition may optionally further comprise at least one ingredient selected from the group consisting of a humectant, a deodorant agent, an antiperspirant, a sun screening agent, a sunless tanning agent, a pH adjusting agent, a chelating agent, a preservative, an emulsifier, an occlusive agent, an emollient, a thickener, a solubilizing agent, a penetration enhancer, an anti-irritant, a colorant, a propellant and a surfactant.
"The pharmaceutical composition may be packaged in a packaging material and identified in print, in or on the packaging material, for use in treating a condition in which inhibition of interleukin-.beta.-converting enzyme is beneficial.
"Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
"As used herein the term 'method' refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
"As used herein, the term 'treating' includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
"The term 'comprising' means that other steps and ingredients that do not affect the final result can be added. This term encompasses the terms 'consisting of' and 'consisting essentially of'.
"The phrase 'consisting essentially of' means that the composition or method may include additional ingredients and/or steps, but only if the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method.
"As used herein, the term 'pharmaceutically acceptable' means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. Herein, the phrases 'physiologically suitable carrier' and 'pharmaceutically acceptable carrier' are interchangeably used and refer to an approved carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered conjugate.
"As used herein, the singular form 'a,' 'an,' and 'the' include plural references unless the context clearly dictates otherwise. For example, the term 'a compound' or 'at least one compound' may include a plurality of compounds, including mixtures thereof.
"Throughout this disclosure, various aspects of this invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
"Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases 'ranging/ranges between' a first indicate number and a second indicate number and 'ranging/ranges from' a first indicate number 'to' a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween."
For more information, see this patent: Albeck, Michael; Sredni, Benjamin. Use of Tellurium Compounds for Inhibition of Interleukin-Converting Enzyme. U.S. Patent Number 8623908, filed
Keywords for this news article include: Antineoplastics, Drugs, Cancer, Serine, Caspases, Genetics, HIV/AIDS, Oncology, Protease, Arthritis, Chemicals, Chemistry, Cytokines, Hepatitis, Sclerosis, Treatment, Chalcogens, Hematology, Immunology,
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