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(12) Patent Application Publication (10) Pub. No.: US 2009/0286760 A1 Chen (43) Pub US 20090286760A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0286760 A1 Chen (43) Pub. Date: Nov. 19, 2009 (54) NOVEL COMPOSITIONS AND METHODS Publication Classification FORTREATING HYPERPROLIFERATIVE (51) Int. Cl. DISEASES A613/60 (2006.01) A63L/35 (2006.01) (76) Inventor: Chien-Hung Chen, Forest Hills, A6II 3/167 (2006.01) A6II 3/55 (2006.01) NY (US) A63L/45 (2006.01) A6II 3/196 (2006.01) Correspondence Address: A63L/92 (2006.01) FSH & RICHARDSON P.C. A6II 3/405 (2006.01) P.O. BOX 1022 A6II 3/4436 (2006.01) MINNEAPOLIS, MN 55440-1022 (US) A6IP35/00 (2006.01) (52) U.S. Cl. ......... 514/165; 514/646; 514/629; 514/635; 514/406; 514/567; 514/570; 514/415: 514/342 (21) Appl. No.: 12/467,640 (57) ABSTRACT The invention relates to a composition that includes a first (22) Filed: May 18, 2009 agent selected including an agent that possesses anti-inflam matory activity or acetaminophen, phenacetin, tramadol and Related U.S. Application Data the like; a second agent selected from the group consisting of an oxidative phosphorylation inhibitor, an ionophore, and an (60) Provisional application No. 61/127,883, filed on May adenosine 5-monophosphate-activated Protein kinase 16, 2008, provisional application No. 61/212,072, (AMPK) activator, a third agent that possesses or maintains filed on Apr. 7, 2009. serotonin activity. US 2009/0286760 A1 Nov. 19, 2009 NOVELCOMPOSITIONS AND METHODS cell membranes; and an AMPK activator is an agent that FORTREATING HYPERPROLIFERATIVE activates AMPK to phosphorylate its Substrates, e.g., acetyl DISEASES CoA carboxylase and malonyl-CoA decarboxylase. Examples of the second agent include metformin (e.g., met CROSS-REFERENCE TO RELATED formin chloride), phenformin and buformin. APPLICATIONS 0008. The third agent can be a compound possessing or 0001. This application claims benefit to U.S. Provisional maintaining at least one of the serotonin's activities and, Application Ser. No. 61/127,883, filed May 16, 2008, and when used in combination with the first and second agents, U.S. Provisional Application Ser. No. 61/212,072, filed Apr. effectively treats one or more of the target diseases of this 7, 2009, the contents of which are incorporated herein by invention. Examples include serotonin (e.g., serotonin Sul reference in their entirety. fate, serotonin creatinine Sulfate complex, or serotonin hydro chloride) and a serotonin re-uptake inhibitor. BACKGROUND 0009. A preferred composition of the present invention 0002. According to the World Health Organization, there contains aspirin, metformin hydrochloride, and serotonin are five million people dying from cancer every year. Drug creatinine Sulfate complex. treatment is one of the three major therapies for cancer. At 0010. In another aspect, the invention features a composi present, the anticancer directions are as follows: Interfere tion consisting essentially of a first agent that possesses anti with or inhibit cell division, Regulate cell generation cycle, inflammatory activity or acetaminophen, phenacetin, trama Promote tumor cell to apoptosis, Inhibit angiogenesis, Inhibit oncogene, Promote tumor Suppressing gene, Tumor antigen, dol and the like, a second agent that can be an oxidative Inhibitor of telomerase and Interfere with information trans phosphorylation inhibitor, an ionophore, or an AMPK activa fer of tumor cells. tor, and a third agent that possesses serotonin activity. The 0003. In view of the high mortality rates associated with term "consisting essentially of used herein limits a compo abnormal proliferative diseases including cancer, there exists sition to the three specified agents and those that do not a need in the art for an effective treatment for benign prolif materially affect its basic and novel characteristics, i.e., the erative diseases as well as cancer. efficacy in treating a target disease described herein. An example of such a composition contains the above-mentioned SUMMARY three agents and a pharmaceutically acceptable carrier. The compositions described above can contain 5-5,000 mg (e.g., 0004. This invention is based on the discovery that a com 5-3,000 mg, 5-1,500 mg or 5-1,000 mg) of the first agent, bination of certain known drugs is effective in treating hyper 1-5,000 mg (e.g., 1-3000 mg, 1-1,000 mg, 1-500 mg. or 1-100 proliferative diseases including cancer. mg) of the second agent, and 0.1-1,000 mg (e.g., 0.1-100 mg. 0005. In one aspect, the invention features a composition 0.1-50 mg. or 0.1-30 mg) of the third agent, or in quantities of that includes (A) a first agent that possesses anti-inflamma the same ratio as that calculated based on the above amounts. tory activity or acetaminophen, phenacetin, tramadol and the like, a second agent (B) that can be an oxidative phosphory 0011. In still another aspect, the invention features a lation inhibitor, an ionophore, or an adenosine 5'-monophos method for treating hyperproliferative diseases. The method phate-activated Protein kinase (AMPK) activator, and a third includes administering to a subject in need thereof an effec agent (C) that possesses or maintains serotonin activity. tive amount of one or more of the compositions described 0006. The first agent can be any suitable anti-inflamma above. The diseases mentioned above also include their asso tory compound (e.g., non-steroidal anti-inflammatory com ciated disorders. pounds) or acetaminophen, phenacetin, tramadol and the like. (0012. The term “treating or “treatment” used herein Examples include aspirin, diclofenac (e.g., diclofenac potas refers to administering one or more above-described compo sium or diclofenac sodium), ibuprofen (e.g., dexibuprofen or sitions to a subject, who has a disease described above, a dexibuprofen lysine), indomethacin, nimeSulide, and a symptom of such a disease, or a predisposition toward Such a COX-2 inhibitor (e.g., a nitric oxide-based COX-2 inhibitor disease, with the purpose to conferatherapeutic effect, e.g., to or Celebrex(R) (4-5-(4-methylphenyl)-3-(trifluoromethyl)- cure, relieve, alter, affect, ameliorate, or prevent the disease, 1H-pyrazol-1-yl)benzenesulfonamide)). Other examples of the symptom of it, or the predisposition toward it. the first agent include Aspirin-arginine, Alxiling, L-arginine 0013 The composition described above can be in form acetylsalicylic; Aspirin-DL-lysine; Bismuth Salicylate suitable for any route of administration. For example, when Basic; Bismuth salicylate; Magnesium Salicylate; Diethy the composition is orally administered, the present invention lamine Salicylate; Salicylic acid, sodium salt; imidazole sali in certain embodiments may be administered by any pharma cylate; Sodium Aminosalicylate; Isoniazid Aminosalicylate; ceutically acceptable oral dosage form including, Solids (e.g., Physostigmine Salicylate; Pregnenolone Acetylsalicylate; tablets, capsules), liquids (e.g., syrups, solutions and Suspen Choline Magnesium Trisalycylate (Trilisate); Salicylic Acid sions), orally dissolving dosage forms (e.g., orally disinte Zinc Oxide: Sodium Salicylate and Sodium Iodide; Salicylic grating dosage forms, lozenges and troches), powders or Acid and Acetic Acid Glacial Solution; and Methyl Salicy granules. late. 0014. The compositions may also be prepared for 0007. The second agent is an oxidative phosphorylation parenteral administration as a solution, or Suspension. The inhibitor, ionophore or AMPKactivator). The term “oxidative compositions may also be in dry form ready for reconstitution phosphorylation inhibitor” refers to any suitable agents that (e.g., with the additional of sterile water for injection), prior to inhibit oxidative phosphorylation, Such as oxidative phos parenteral administration. Parenteral administration includes phorylation uncouplers. An ionophore is a lipid-soluble mol administration into any body space or tissue, for example ecule capable of transporting anion across the lipid bilayer of intravenous, intra-arterial, intramuscular and Subcutaneous. US 2009/0286760 A1 Nov. 19, 2009 Where the intended cite of action is a solid tumor, in certain tures, objects, and advantages of the invention will be appar embodiments the composition may be injected directly into ent from the description and from the claims. the tumor. 0.015. In certain other embodiments of the invention, one DETAILED DESCRIPTION or more active compounds of the present invention are asso 0020. In certain embodiments, a composition of this ciated with a carrier Substance Such as a compound or mol invention can include three agents. ecule (e.g., an antibody), to facilitate the transport of the one 0021 Examples of the first agent can include steroidal or more active compounds to the intended cite of action. In anti-inflammatory drugs and non-steroidal anti-inflammatory certain preferred embodiments, active compound B (useful drugs. Examples of steroidal anti-inflammatory drugs include for treating a hyperproliferating tissue), is covalently bonded glucocorticoids, hydrocortisone, cortisone, beclomethasone, to an antibody that corresponds to a marker located on the dipropionate, betamethasone, dexamethasone, prednisone, hyperproliferative tissue. According to this aspect of the methylprednisolone, triamcinolone, fluocinolone acetonide, invention, it is contemplated that toxicity and adverse effects fludrocortisone, and beclometaSone propionate. can be reduced because lower levels of the active agent are 0022. Examples of non-steroidal anti-inflammatory drugs capable of providing the desired therapeutic effect relative
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