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 to (NSAIDs) include A183827, ABT963, aceclofenac, acemeta cin, acetyl salicylic acid, AHR10037, alclofenac, alminopro administration of the active agent that is not associated with a fen, ampiroXicam, amtolimetin guacil, apaZone, atliprofen carrier Substance. methyl ester, AU8001, benoxaprofen, benzydamine flufe 0016. The first, second, and third agents described above namate, bermoprofen, bezpiperylon, BF388, BF389, include active compounds, as well as any pharmaceutically BIRL790, BMS347070, bromfenac, bucloxic acid, buti acceptable derivatives such as their salts, pro-drugs, and Sol bufen, BW755C, C53, C73, C85, carprofen, CBS1108, cele Vates, if applicable. A salt, for example, can be formed coxib, CHF2003, chlorobiphenyl, choline magnesium trisali between an anion and a positively charged group (e.g., amino) cylate, CHX108, cimicoxib, cinnoxicam, clidanac, on an agent. Examples of Suitable anions include chloride, CLX1205, COX-2 inhibitors, CP331, CS502, CS706, bromide, iodide, Sulfate, nitrate, phosphate, citrate, methane D1367, darbufelone, deracoxib, dexketoprofen, DFP. DFU, Sulfonate, trifluoroacetate, acetate, chlorophenyoxyacetate, diclofenac potassium, diclofenac sodium, diclofenac sodium malate, tosylate, tartrate, fumarate, glutamate, glucuronate, misoprostol, diflunisal, DP155, DRF4367, E5110, E6087, lactate, glutarate, benzoate, embonate, glycolate, pamoate, eltenac, ER34122., esflurbiprofen, etoricoxib, etodolac, F025, aspartate, parachlorophenoxyisobutyrate, formate, succinate, felbinac ethyl, fenbufen, fenclofenac, fenclozic acid, fencloz cyclohexanecarboxylate, hexanoate, octonoate, decanoate, ine, fenoprofen, fentiazac, feprazone, filenadol, flobufen, flo hexadecanoate, octodecanoate, benzenesulphonate, tri rifenine, flosulide, flubichin methanesulfonate, flufenamic methoxybenzoate, paratoluenesulphonate, adamantanecar acid, fluprofen, flurbiprofen, FPL62064, FR122047, boxylate, glycoxylate, pyrrolidonecarboxylate, naphthalene FR123826, FR140423, FR188582, FS205397, furofenac, Sulphonate, 1-glucosephosphate, Sulphite, dithionate, and GR253035, GW406381, HAI 105, HAI106, HCT2035, HCT6015, HGP12, HN3392, HP977, HX0835. HYAL maleate. Likewise, a salt can also be formed between a cation AT2101, ibufenac, ibuproxam-beta-cyclodextrin, icoduli and a negatively charged group (e.g., carboxylate) on an num, IDEA070, iguratimod, imrecoxib, indoprofen, IP751, agent. Examples of Suitable cations include Sodium ion, isoxepac, isoxicam, KCT64, ketoprofen, L652343, L745337, potassium ion, magnesium ion, calcium ion, and an ammo L748731, L752860, L761066, L768277, L776967, L783003, nium cation Such as tetramethylammonium ion. In certain L784520, L791456, L804600, L818571, LAS33815, embodiments, the agents also include salts containing qua LAS34475, licofelone, LM 4108, lobuprofen, lomoxicam, ternary nitrogenatoms. Examples of pro-drugs include esters lumiracoxib, mabuprofen, meclofenamic acid, meclofe and other pharmaceutically acceptable derivatives, which, namate Sodium, mefenamic acid, meloxicam, mercaptoeth upon administration to a Subject, are capable of providing ylguanidine, mesoporphyrin, metoxibutropate, miroprofen, active compounds. A Solvate refers to a complex formed mofebutazone, mofezolac, MX1094, nabumetone, naproxen between an active compound and a pharmaceutically accept sodium, naproxen-sodium/metoclopramide, NCX1101, able solvent. Examples of pharmaceutically acceptable sol NCX284, NCX285, NCX4016, NCX4215, NCX530, niflu vents include water, ethanol, isopropanol, ethyl acetate, ace mic acid, nimeSulide, nitric oxide-based NSAIDs (NitroMed, tic acid, and ethanolamine. Lexington, Mass.), nitrofenac, nitroflurbiprofen, nitronaproxen, NS398, ocimum sanctum oil, ONO3144, 0017. Other examples of the salts include arginine, L-argi orpanoxin, oxaprozin, OXindanac, oXpinac, oxycodone/ibu nine; DL-lysine; Bismuth Salicylate Basic; Bismuth salicy profen, oxyphenbutazone, P10294, P54, P8892, pamicogrel, late; Magnesium; Diethylamine; sodium salt; imidazole; parcetasal, parecoxib, PD138387, PD145246, PD164387, Sodium Aminosalicylate; Isoniazid Aminosalicylate; Phys pelubiprofen, pemedolac, phenylbutaZone, piraZolac, piroxi ostigmine; Pregnenolone Acetylsalicylate; Choline Magne cam, piroxicam beta-cyclodextrin, piroXicam pivalate, pir sium Trisalycylate (Trilisate); Zinc Oxide: Iodide; Acetic profen, pranoprofen, resveratrol, R-ketoprofen, R-ketorolac, Acid Glacial Solution and Methyl. rofecoxib, RP66364, RU43526, RU54808, RWJ63556, 0018. Also within the scope of this invention is one or S19812, S2474, S33516, salicylsalicylic acid, salsalate, sati more compositions described above for use in treating a dis grel, SC236, SC57666, SC58125, SC58451, SFPP, ease described herein, and the use of Such a composition for SKF 105809, SKF86002, sodium salicylate, sudoxicam, sul the manufacture of a medicament for the treatment of a dis fasalazine, Sulindac, suprofen, SVT2016, T3788, TA60, tal ease described herein. metacin, talniflumate, taZofelone, tebufelone, tenidap, 0019. The details of one or more embodiments of the tenoxican, tepoxalin, tiaprofenic acid, tilmacoxib, tilnopro invention are set forth in the description below. Other fea fen arbamel, tinoridine, tiopinac, tioxaprofen, tolfenamic US 2009/0286760 A1 Nov. 19, 2009

acid, tolmetin, triflusal, tropesin, TY10222. TY10246, 0031 Serotonin 1A and 1D agonists such as: LY-165,163; TY10474, UR8962, ursolic acid, valdecoxib, WAY 120739, 0032 Serotonin 1A and 1 Eagonists such as: ergonovine WY28342, WY41770, Ximoprofen, YS134, Zaltoprofen, and BRL 54443 maleate salt; Zidometacin, and Zomepirac. Other examples of the first agent include acetaminophen, phenacetin, tramadol and the 0033 5-HT2A/2C agonists such as: DOI (2,5-dimethoxy like. 4-iodoamphetamine), mCPP (m-chlorophenyl-piperazine), 0023 Still other examples of the first agent include Aspi TFMPP (3-Trifluoromethylphenylpiperazine), mescaline, rin-arginine, Alxiling, L-arginine acetylsalicylic; Aspirin DMT, psilocin, 2C-B, lorcaserin, methylserotonin laleaste DL-lysine; Bismuth Salicylate Basic; Bismuth salicylate: salt and 1-(3-Chlorophenyl)piperazine HCl; Magnesium Salicylate; Diethylamine Salicylate: Salicylic 0034 Serotonin 2B agonist such as: BW 723C86: acid, Sodium salt; imidazole salicylate: Sodium Aminosali 0035) Serotonin receptor 2C modulators such as: (e.g., cylate; Isoniazid Aminosalicylate; Physostigmine Salicylate; BVT933, DPCA37215, IK264, PNU22394, WAY161503, Pregnenolone Acetylsalicylate: Choline Magnesium Trisaly R-1065, YM348, VER-3323 hemifumarate and those dis cylate (Trilisate); Salicylic Acid Zinc Oxide: Sodium Salicy closed in U.S. Pat. No. 3,914,250, WO 01/66548, WO late and Sodium Iodide; Salicylic Acid and Acetic Acid Gla cial Solution; and Methyl Salicylate. 02/10169, WO 02/36596, WO 02/40456, and WO02/40457, 0024 Examples of the second agent can include, in addi WO 02/44152, WO 02/48124, WO 02/51844, and WO tion to those described above, 4,6-dinitro-ocresol, uncoupling 03/033479), the disclosures of which are incorporated by proteins (e.g., UCP1, UCP2, or UCP3), carbonyl cyanide reference in their entireties; p(trifluoromethoxy)phenyl-hydraZone, carbonyl cyanide 0036 5-HT3 agonists such as Phenylbiguanide, O-Meth m-chlorophenyl-hydraZone, C5 gene products, dinitrophenol ylserotonin HCl, SR 57227A and 1-(3-Chlorophenyl)bigu (e.g., 2,4-dinitrophenol), efrapeptin (A23871), guanethidine, anide HCl; chlorpromazine, amytal, secobarbital, rotenone, progester 0037 5-HT 4 agonist such as cisapride, mosapride citrate one, antimycin A, naphthoduinone, 8-hydroxyquinoline, car duhydrate and ML 10302: bon monoxide, cyanides, azides (e.g., NaN3), dicoumarin, 0038 5HT7 receptor agonist such as: 4-(2-pyridyl) pip bilirubin, bile pigment, ephedrine, hydrogen Sulfide, tet raiodothyronine, quercetin, 2.4-bis(p-chloroanilino)pyrimi erazines, LP12 hydrochloride hydrate, LP44 and quinoline dine, glyceraldehyde-3 phosphate dehydrogenase, oligomy derivatives; cin, tributyltin chloride, aurovertin, rutamycin, Venturicidin, 0039. Serotonin transporter inhibitors such as: imi mercurials, dicyclohexylcarbdiimide, Dio-9, m-chlorophe pramine; nyl-hydrazone mesoxalonitrile, ionomycin, calcium iono 0040 Serotonin reuptake inhibitors such as (e.g., arylpyr phores (e.g., A23 187, NMDA, CA 1001, or enniatin B), com rolidine compounds, phenylpiperazine compounds, ben pounds that increase the Ca+2 concentration in mitochondria Zylpiperidine compounds, piperidine compounds, tricyclic (e.g., atractyloside, bongkrekic acid, thapsigargin, amino gamma-carbolines dulloxetine compounds, pyrazinoquinoxa acid neurotransmitters, glutamate, N-methyl-D-aspartic acid, line compounds, pyridoindole compounds, piperidyindole carbachol, ionophores, inducers of potassium depolariza compounds, milnacipran, citalopram, Sertraline metabolite, tion), apoptogens (i.e., compounds that induce apoptosis), demethylsertraline, norfluoxetine, desmethylcitalopram, Valinomycin, gramicidin, nonactin, nigericin, lasalocid, and escitalopram, 1-fenfluramine, femoxetine, ifoxetine, cyan monensin. The second agent can be an AMPK activator (e.g., odothiepin, litoxetine, dapoxetine, nefazodone, cericlamine, metformin or phenformin, buformin, AICAR, thienopyri traZodone, mirtazapine, fluvoxamine, indalpine, indelox dones, resveratrol, nootkatone, thiazole, adiponectin, thiazo azine, milnacipran, paroxetine, Sibutramine, Zimeldine, traZ lidinediones, rosiglitaZone, pioglitaZone or dithiolethiones). odone hydrochloride, dexfenfluramine, bici fadine, Vilaz 0025. The third agent includes serotonin and its functional odone, desvenlafaxine, dulloxetine, amitriptyline, equivalents. Examples of the functional equivalents of sero butriptyline, desipramine, dosulepin, doxepin, lofepramine, tonin include: nortriptyline, protriptyline, trimipramine, amoxapnie, 0026 Serotonin 1A agonists such as: (e.g., arylpiperazine maprotiline, adhyperforin, bromopheniramine, chlorphe compounds, azaheterocyclylmethyl derivatives of hetero niramine, dextromethorphan, diphenhydramine, hyperforin, cycle-fused benzodioxans, or buspirone, 3-amino-dihydro ketamine, nefazodone, pethidine, phencyclidine, phe 1-benzopyrians and benzothiopyrians, (S)-4-3-2-(dim niramine, propoxyphene and those in U.S. Pat. No. 6,365, ethylamino)ethyl)-1H-indol-5-yl)methyl-2- 633, WO 01/27060, and WO 01/162341), the disclosures of oxazolidinone—311C90) and 8-OH-DPAT), which are hereby incorporated by reference in their entireties, 5-Carboxamidotyptamine hemiethanolate maleate salt, N.N- EPTI, 8-OH-DPAT, ProzacR) (fluoxetine hydrochloride) and Dipropyl-5-carboxamidotryptamine maleate salt, R(+)-UH Zoloft(R) (Sertraline hydrochloride); 301 HC1, S15535, gepirone, psilocybin, xaliproden HCl and 0041) Serotonin and noradrenaline reuptake inhibitors tandospirone; Such as: (e.g., Venlafaxine, Venlafaxine metabolite O-desm 0027 Serotonin 1B agonists such as: CGS-12066a, ethylvenlafaxine, clomipramine, and clomipramine metabo N-Methylduipazine dimaleate salt, rizatriptan and naratrip lite desmethylclomipramine); tan, 0042 Monoamine re-uptake inhibitors such as: (e.g., 0028 Serotonin 1C agonists such as: dexnorfenfluramine; amides); 0029 Serotonin 1A, 1B, 1D and 1F agonists such as 0043. Pyridazinone aldose reductase inhibitors such as: Sumatriptan and 5-Carboxamidotryptamine hemiethanolate (e.g., pyridaZinone compounds); maleate salt; 0044 Serotonergic agents, which are also stimulants of 0030 Serotonin 1B and 1D agonists such as: dihydroer serotonin receptors, such as: (e.g., ergoloid mesylate or per gotamine and GR46611; golide mesylate); US 2009/0286760 A1 Nov. 19, 2009

0045 Stimulants of serotonin synthesis such as: (e.g., ovial, intrasternal, intrathecal, intralesional, or intracranial vitamin B1, vitamin B3, vitamin B6, biotin, Sadenosylme injection, as well as any suitable infusion or injection tech thionine, folic acid, ascorbic acid, magnesium, coenzyme nique. Q10, or piracetam); 0053 Asterile injectable composition can be a solution or 0046 Serotonin receptor agonists such as: Rauwolscine, Suspension in a non-toxic parenterally acceptable diluent or Yohimbine, alpha.-Methyl-5-hydroxytryptamine, 1-(1- solvent, such as a solution in 1,3-butanediol. Examples of the Naphthyl)piperazine, metoclopramide, HTF-919, R-093877, acceptable vehicles and solvents that can be employed are Zolmitriptan, 5-Methoxy-N,N-dimethyltryptamine. 5-MEO mannitol, water, Ringer's Solution, and isotonic sodium chlo DIPT hydrochloride hydrate and lysergic acid diethylamide: ride solution. In addition, fixed oils are conventionally 0047 Serotonin precursors such as tryptophan; employed as a solvent or Suspending medium (e.g., synthetic 0048 Agents that promote serotonin release from nerve mono- or diglycerides). Fatty acid, Such as oleic acid and its terminals such as: fenfluramine, and norfenfluramine; glyceride derivatives are useful in the preparation of 0049 All of the compounds mentioned above are known injectables, as are natural pharmaceutically acceptable oils, drugs and are readily available to the public. Some of the Such as olive oil or castor oil, especially in their polyoxyethy drugs can be purchased from chemical companies, such as lated versions. Sigma-Aldrich, St. Louis, Mo. Where the drugs are not 0054 These oil solutions or suspensions can also contain readily available, in certain embodiments, one of ordinary a long chain alcohol diluent or dispersant, carboxymethyl skill in art will appreciate that the compounds can be organi cellulose, or similar dispersing agents. Other commonly used cally manufactured and identified according to accepted Stan Surfactants such as Tweens or Spans or other similar emulsi dards such as those found in the Merck Index, Remington's fying agents or bioavailability enhancers which are com Pharmaceutical Sciences, USP/NF, and foreign publications. monly used in the manufacture of pharmaceutically accept In certain embodiments, regimens for administering these able solid, liquid, or other dosage forms can also be used for drug compounds are well known and, if necessary, can be the purpose of formulation. easily re-established by an ordinary skilled clinician. Effec 0055. A composition for oral administration can be any tive doses will vary, as recognized by those skilled in the art, orally acceptable dosage form including capsules, tablets, depending on the type or degree of the disease to be treated; emulsions and aqueous Suspensions, dispersions, and solu the Subject's size, weight, age, and sex; the route of adminis tions. In the case of tablets, commonly used carriers include tration; the excipient usage; rate of metabolism, rate of excre lactose and corn starch. Lubricating agents, such as magne tion, and the possible co-usage with other therapeutic treat sium Stearate, are also typically added. For oral administra ment. In certain embodiments, coadministration of other tion in a capsule form, useful diluents include lactose and drugs can lead to increased or decreased metabolism and or dried corn starch. When aqueous Suspensions or emulsions excretion requiring an adjustment in dose. In certain other are administered orally, the active ingredient can be sus embodiments, where one or more of the active agents are pended or dissolved in an oily phase combined with emulsi bound to plasma proteins, coadministration of other drugs fying or Suspending agents. If desired, certain Sweetening, that effect the extent of binding may also require an adjust flavoring, or coloring agents can be added. ment of dose. The daily dose of the compositions described 0056. A nasal aerosol or inhalation composition can be above can be 5-10,000 mg (e.g., 10-5000 or 10-3,000 mg) of prepared according to techniques well known in the art of the first agent, 1-5,000 mg (e.g., 2-1,000 or 2-3,000 mg) of the pharmaceutical formulation. For example, Such a composi second agent, and 0.1-1,000 mg (e.g., 1-50 mg) of the third tion can be prepared as a solution in Saline, employing benzyl agent. alcohol or other suitable preservatives, absorption promoters 0050. In certain preferred embodiments the human dose of to enhance bioavailability, fluorocarbons, and/or other solu the composition of the present invention is about 5-5,000 mg bilizing or dispersing agents known in the art. of metformin, about 1-5,000 mg aspirin and about 0.1-1,000 0057. A composition for topical administration can be mg serotonin creatinine complex. In certain more preferred prepared inform of an ointment, agel, a plaster, an emulsion, embodiments, the human dose of the composition is about a lotion, a foam, a cream of a mixed phase or amphiphilic 1000 mg of metformin, about 400 mg aspirin and about 4 mg emulsion system (oil/water-water/oil mixed phase), a lipo serotonin creatinine complex administered as multiple daily Some, a transfersome, a paste, or a powder. doses. In certain further preferred embodiments, this dose is 0.058 Any of the compositions described above can also administered three times a day. be administered in the form of suppositories for rectal admin 0051 One aspect of this invention features a method of istration. It also can be designed Such that the composition is administering an effective amount of one or more of the released in the intestine. For example, the composition is above-mentioned compositions to a subject for treating a confined in a solid Sub-unit or a capsule compartment that has disease described herein. Such a subject can be identified by respectively a matrix or a wall or a closure comprising an a health care professional Such as a clinician based on results enteric polymer which dissolves or disperses at the pH of the from any suitable diagnostic method. “An effective amount Small or large intestine to release the drug Substance in the refers to the amount of one or more compositions described intestine. Suitable such polymers have been described above, herein that is required to confer a therapeutic effect on a for example with reference to U.S. Pat. No. 5,705,189. treated subject. 0059. In certain embodiments, the carrier in the pharma 0052 To practice the method of the present invention, in ceutical composition must be “acceptable' in the sense that it certain embodiments, one or more of the above-described is compatible with the active ingredient of the composition compositions can be administered parenterally, orally, (and preferably, capable of Stabilizing the active ingredient) nasally, rectally, topically, or buccally. The term “parenteral and not deleterious to the subject to be treated. One or more as used herein refers to Subcutaneous, intracutaneous, intra solubilizing agents can be utilized as pharmaceutical excipi venous, intramuscular, intraarticular, intraarterial, intrasyn ents for delivery of an active compound. Examples of other US 2009/0286760 A1 Nov. 19, 2009

carriers include colloidal silicon oxide, magnesium Stearate, cells) and the stroma that the neoplastic cells induce and in cellulose, sodium lauryl sulfate, and D&C Yellow if 10. which they are dispersed. Different types of solid tumors are named for the type of cells that form them. Examples of solid Benign Tumors tumors are sarcomas, carcinomas, and lymphomas. 0060. The compounds and methods of the present inven 0065 “Solid tumor means a locus of tumor cells where tion are also suitable for treatment of variety of benign the majority of the cells are tumor cells or tumor-associated tumors. Exemplary benign tumors include: Adrenal tumors cells. Such as adenoma, Adrenal Pheochromocytoma and Adrenal 0.066 More particularly, tumor here refers to either benign Ganglioneuroma; Brain tumors such as Meningioma and (not cancerous) or malignant tumors. Adenoma; Peripherial Nerve tumors such as Neurofibroma and Schwannoma; Liver tumors such as Adenoma; Thyroid Malignant Tumors tumors such as Follicular Adenoma; Parathyroid tumors such as Adenoma; Thymus tumors such as Thymoma; Salivary 0067 Examples of malignant tumors include but not lim Gland tumors such as Pleomorphic Adenoma; Small Intestine ited to: Breast cancer: tumor Such as Villous Adenoma; Colon tumors such as Tubu 1. Ductal carcinoma: A1. Ductal Carcinoma In Situ (DCIS): lovillous Adenoma, Adenomatous Polyp of Colon and Poly Comedocarcinoma, Cribriform, Papillary, Micropapillary; posis Coli; Pancreas tumors such as Serous Cystadenoma; A2. Infiltrating Ductal Carcinoma (IDC): Tubular Carci Islettumors such as Pancreatic Islet Cell Tumor; Nasopharyn noma, Mucinous (Colloid) Carcinoma, Medullary Carci gyl tumors such as Nasal Angiofibroma: Ovary tumors such noma, Papillary Carcinoma, Metaplastic Carcinoma, Inflam as: Atypical Proliferating Mucinous Neoplasm, Brenner matory Carcinoma Tumor of Ovary, Mucinous Cystadenoma, Papillary cystad 2. Lobular Carcinoma: B1. Lobular Carcinoma In Situ enoma, Dermoid Cyst of Ovary, Ovarian Teratoma, Ovarian (LCIS); B2. Invasive lobular carcinoma Fibroma, Luteoma and Struma ovarii; Uterus tumors such as Uterine Cellular Leiomyoma and Leiomyoma; Placenta 3. Paget’s Disease of the Nipple tumors such as Chorioangioma, Partial hydatidiform mole, Complete Hydatidiform and Mole: Bone tumors such as Cav 0068. Female Reproductive System ernous Hemangioma and Giant Cell Tumor; Soft Tissue 0069 CERVIX UTERI: Cervical intraepithelial neopla tumors such as Cavernous hemangioma, Desmoid Tumor, sia, grade I, Cervical intraepithelial neoplasia, grade II. Cer lipoma, Myelolipoma and osteochondroma; Joint tumors vical intraepithelial neoplasia, grade III (Squamous cell car Such as Synovial Chondromatosis: Lung tumors such as Car cinoma in situ), Keratinizing Squamous Cell Carcinoma, cinoid Tumor, Granular Cell Tumor and Hemangioma: Myo Nonkeratinizing Squamous Cell Carcinoma, Verrucous Car cardium tumors such as Atrial Myxoma; Breast tumors such cinoma, Adenocarcinoma in situ, Adenocarcinoma in situ, as Fibroadenoma, Intraductal Papilloma and Schwannoma; endocervical type, Endometrioid adenocarcinoma, Clear cell Kidney tumors such as Congenital Mesoblastic Nephroma; adenocarcinoma, Adenosquamous carcinoma, Adenoid cys and Skin tumors such as Giant Congenital Intradermal Nevus: tic carcinoma, Small cell carcinoma, Undifferentiated carci Kidney tumors such as Congenital Mesoblastic Nephroma. Oa 0061 The present composition can be administered for the 0070 CORPUS UTERI: Endometrioid carcinoma, treatment of hyperproliferative disorders. The term “hyper Adenocarcinoma, Adenocanthoma (adenocarcinoma with proliferative disorders' refers to excess cell proliferation that squamous metaplasia), Adenosquamous carcinoma (mixed is not governed by the usual limitation of normal growth. The adenocarcinoma and squamous cell carcinoma, Mucinous term denotes malignant as well as nonmalignant cell popula adenocarcinoma, Serous adenocarcinoma, Clear cell adeno tions. The excess cell proliferation can be determined by carcinoma, Squamous cell adenocarcino, Undifferentiated reference to the general population and/or by reference to a adenocarcinoma particular patient, e.g. at an earlier point in the patient's life. 0071 OVARY: Serous cystadenoma, Serous cystadeno Hyperproliferative cell disorders can occur in different types carcinoma, Mucinous cystadenoma, Mucinous cystadenocar of animals and in humans, and produce different physical cinoma, Endometrioid tumor, Endometrioid adenocarci manifestations depending upon the affected cells. noma, Clear cell tumor, Clear cell cystadenocarcinoma, 0062 Hyperproliferative cell disorders include tumors as Unclassified tumor well as nontumors. A “tumor here refers to an abnormal 0072 VAGINA.: Squamous cell carcinoma, Adenocarci mass of tissue that results from excessive cell division that is Oa uncontrolled and progressive, also called a neoplasm. 0073 VULVA: Vulvar intraepithelial neoplasia, grade I, 0063 Examples of tumors include a variety of solid tumor Vulvar intraipithelial neoplasia, grade II, Vulvar intraepithe Such as laryngeal tumors, brain tumors, other tumors of the lial neoplasia, grade III (squamous cell carcinoma in situ), head and neck; colon, rectal and prostate tumors; breast and Squamous Cell Carcinoma, Verrucous carcinoma, Padget's thoracic Solid tumors; ovarian and uterine tumors; tumors of disease of the Vulva, Adenocarcinoma, NOS, Basal cell car the esophagus, stomach, pancreas and liver, bladder and gall cinoma, NOS, Bartholin's gland carcinoma bladder tumors; skin tumors such as melanomas; and the like, and a fluid tumor such as leukemia. (0074) Male Reproductive System 0064. A “solid tumor, as used herein, refers to an abnor (0075 PENIS: Squamous Cell Carcinoma mal mass of tissue that usually does not contain cysts or liquid 0076 PROSTATE: Adenocarcinoma, Sarcoma, Transi areas. Solid tumors may be benign (not cancerous), or malig tional cell carcinoma of the prostate nant (cancerous). Solid tumors have a distinct structure that 0077 TESTIS. Seminomatous tumor. Nonseminomatous mimics that of normal tissues and comprises two distinct but tumor, Teratoma, Embryonal carcinoma, Yolk sac tumor, interdependent compartments: the parenchyma (neoplastic Choriocarcinoma US 2009/0286760 A1 Nov. 19, 2009

0078 CARDIAC: sarcoma (angiosarcoma, fibrosarcoma, (0099 STOMACH: Adenocarcinoma, Papillary adenocar rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, cinoma, Tubular adenocarcinoma, Mucinous adenocarci fibroma, lipoma and teratoma noma, Signet ring cell carcinoma, Adenosquamous carci 0079 Respiratory System noma, Squamous cell carcinoma, Small cell carcinoma, 0080) LARYNX: Squamous cell carcinoma Undifferentiated carcinoma, Lymphoma, Sarcoma, Carci 0081 PLEURAL MESOTHELIOMA: Primary pleural noid tumor mesothelioma 0100 SMALL INTESTINE: adenocarcinoma, lym I0082 PHARYNX: Squamous cell carcinoma phoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, I0083) Lung hemangioma, lipoma, neurofibroma, fibroma 0084 1. Squamous cell carcinoma (epidermoid carci 0101 Urinary System noma), Variant: Spindle cell; 0102 KIDNEY: Renal cell carcinoma, Carcinoma of 0085 2. Small cell carcinoma. Other cell carcinoma, Inter Bellini's collecting ducts, Adenocarcinoma, Papillary, Tubu mediate cell type, Combined oat cell carcinoma; lar carcinoma, Granular cell carcinoma, Clear cell carcinoma I0086 3. Adenocarcinoma: Acinar adenocarcinoma, Pap (hypemephroma), Sarcoma of the kidney, Nephroblastoma, illary adenocarcimoma, Bronchiolo-alveolar carcinoma, Nephroblastoma Solid carcinoma with mucus formation; (0103 RENAL PELVIS AND URETER: Transitional cell 0087. 4. Large cell carcinoma: Giant cell carcinoma, Clear carcinoma, Papillary transitional cell carcinoma carcinoma, cell carcinoma, Sarcoma; Squamous cell carcinoma, Adenomcarcinoma 0088 Gastrointestinal Tract 0104 URETHRA: Transitional cell carcinoma, Squa I0089 AMPULLA OF VATER: Primary adenocarcinoma, mous cell carcinoma, Adenocarcinoma Carcinoid tumor, Lymphoma 0105 URINARY BLADDER: Carcinoma in situ, Transi 0090 ANAL CANAL: Adenocarcinoma, Squamous cell tional urothelial cell carcinoma, Papillary transitional cell carcinoma, Melanoma carcinoma, Squamous cell carcinoma, Adenocarcinoma, 0091) EXTRAHEPATIC BILE DUCTS: Carcinoma in Undifferentiated situ, Adenocarcinoma, Papillary adenocarcinoma, Adenocar 01.06 Muscle, Bone, and Soft Tissue cinoma, intestinal type. Mucinous adenocarcinoma, Clear BONE: A. Bone-forming: Osteosarcoma; B. Cartilage-form cell adenocarcinom, Segnet-ring cell carcinoma, Adenosqua ing: Chondrosarcoma, Mesenchymal chondrosarcoma, C. mous carcinoma, Squamous cell carcinoma, Small cell (oat) Giant cell tumor, malignant, D. Ewing's sarcoma, E. Vascular carcinoma, Undifferentiated carcinoma, Carcinoma, NOS, tumors: Hemangioendothelioma, Hemangiopericytoma, Sarcoma, Carcinoid tumor Angiosarcoma; F. Connective tissue tumors: Fibrosarcoma, 0092 COLON AND RECTUM: Adenocarcinoma in situ, Liposarcoma, Malignant mesenchymoma, Undifferentiated Adenocarcinoma, Mucinous adenocarcinoma (colloid type; greater than 50% mucinous carcinoma), Signet ring cell car sarcoma; G. Other tumors: Chordoma, Adamantinoma of cinoma (greater than 50% signet ring cell), Squamous cell long bones (epidermoid) carcinoma, Adenosquamous carcinoma, Small 0107 SOFT TISSUES: Alveolar soft-part sarcoma, cell (oat cell) carcinoma, Undifferentiated carcinoma, Carci Angiosarcoma, Epithelioid sarcoma, Extraskeletal chondro noma, NOS, Sarcoma, Lymphoma, Carcinoid tumor sarcoma, Fibrosarcoma, Leiomyosarcoma, Liposarcoma, 0093 ESOPHAGUS: squamous cell carcinoma, adeno Malignant fibrous histiocytoma, Malignanthemangiopericy carcinoma, leiomyosarcomalymphoma toma, Malignant mesenchymoma, Malignant Schwannoma, 0094 GALLBLADDER: Adenocarcinoma, Adenocarci Rhabdomyosarcoma, Synovial sarcoma, Sarcoma, NOS noma, intestinal type, Adenosquamous carcinoma, Carci (0.108 NERVOUS SYSTEM: skull (osteoma, heman noma in situ, Carcinoma, NOS, Clear cell adenocarcinoma, gioma, granuloma, Xanthoma, osteitis deformans), meninges Mucinous adenocarcinoma, Papillary adenocarcinoma, Sig (meningioma, meningiosarcoma, gliomatosis), brain (astro net-ring cell carcinoma, Small cell (oat cell) carcinoma, cytoma, medulloblastoma, glioma, ependymoma, germi Squamous cell carcinoma, Undifferentiated carcinoma noma (pilealoma), glioblastoma multiform, oligodendro 0095 LIP AND ORAL CAVITY: Squamous cell carci glioma, Schwannoma, retinoblastoma, congenital tumors), Oa spinal cord neurofibroma, meningioma, glioma, sarcoma) 0096 LIVER: hepatoma (hepatocellular carcinoma), cho 0109 HEMATOLOGY: blood (myeloid leukemia (acute langiocarcinoma, hepatoblastoma, angiosarcoma, hepatocel and chronic), acute lymphloblastic leukemia, chronic lym lular adenoma, hemangioma phocytic leukemia, myeloproliferative diseases, multiple 0097. EXOCRINE PANCREAS: Duct cell carcinoma, myeloma, myelodysplastic syndrome), Hodgkin's disease, Pleomorphic giant cell carcinoma, Giant cell carcinoma, non-Hodgkin’s lymphoma (malignant lymphonoma); osteoclastoid type, Adenocarcinoma, Adenosquamous carci 0110. Endocrine System noma, Mucinous (colloid) carcinoma, Cystadenocarcinoma, THYROID GLAND: Papillary carcinoma (including those Acinar cell carcinoma, Papillary carcinoma, Small cell (oat with follicular foci). Follicular carcinoma, Medullary carci cell) carcinoma, Mixed cell typed, Carcinoma, NOS, Undif noma, Undifferentiated (anaplastic) carcinoma ferentiated carcinoma, Endocrine cell tumors arising in the NEUROBLASTOMA: Sympathicoblastoma, Sympa islets of Langerhans, Carcinoid thicogonioma, Malignant ganglioneuroma, Gangliosympa 0098 SALIVARY GLANDS: Acinic (acinar) cell carci thicoblastma, Ganglioneuroma noma, Adenoid cystic carcinoma (cylindroma), Adenocarci 0111 Skin noma, Squamous cell carcinoma, Carcinoma in pleomorphic Squamous cell carcinoma, Spindle cell variant of squamous adenoma (malignant mixed tumor), Mucoepidermoid carci cell carcinoma, Basal cell carcinoma, Adenocarcinoma noma, Well differentiated (low grade), Poorly differentiated developing from Sweat or sebaceous gland, Malignant Mela (high grade) Oa US 2009/0286760 A1 Nov. 19, 2009

0112 Eye cer cells to normal cells, one finds a decrease in the proportion 0113 THE CONJUNCTIVA: Carcinoma of the conjunc of G1 phase cells in cancer, an increase in the proportion of tiva; cells in synthesis in cancer and an increase in the proportion 0114 THE EYELID: Basal cell carcinoma, Squamous of cells in G2 phase and S phase. cell carcinoma, Sebaceous cell carcinoma; 0115 THE LACRIMAL GLAND: Adenocarcinoma, Adenoid cystic carcinoma, Carcinoma in pleomorphic Example 1 adenoma, Mucoepidermoid carcinoma, Squamous cell carci noma, I0127. In Example 1, B2OL (Metformin 1 mM+aspirin 0.4 0116 THE EYELID: Melanoma of the eyelid mM+serotonin creatinine sulfate complex 0.002 mM) and 0117 THE UVEA: Spindle cell melanoma, Mixed cell B2OH (Metformin 10 mM+aspirin 4 mM+serotonin creati melanoma, Epithelioid cell melanoma nine sulfate complex 0.02 mM) were tested to determine the 0118 SARCOMA OF THE ORBIT: Soft tissue tumor, effect on the cell cycle of pancreatic cancer cells after 24 Sarcoma of bone hours. Each of the cell samples were then tested in a flow 0119 RETINOBLASTOMA: Retinoblastoma 0120 Examples of nontumor hyperproliferative disorders cytometer. The testing methodology and equipment used are include but not limited to myelodysplastic disorders; cervical set forth as follows. Cells were harvested and washed twice carcinoma-in-situ; familial intestinal polyposes such as Gard with phosphate buffered saline, (PBS) and fixed in 70% cold ner syndrome; oral leukoplakias; histiocytoses; keloids; ethanol at 4°C. overnight. Before analysis, cells were washed hemangiomas; inflammatory arthritis; hyperkeratoses and twice with PBS, containing 1% bovine serumalbumin (BSA), papulosquamous eruptions including arthritis. Also included then resuspended with 400 ul PBS and treated with 100 g/ml are viral induced hyperproliferative diseases such as warts RNase A (Roche Diagnostics) and 50 ug/ml propidium iodide and EBV induced disease (i.e., infectious mononucleosis), (PI) (Sigma). After incubation for 30 min at 37°C., the cells scar formation, blood vessel proliferative disorders such as were subjected to DNA content analysis. propidium iodide, restenosis, atherosclerosis, in-stent Stenosis, vascular graft restenosis, etc.; fibrotic disorders; psoriasis; glomerular (PI) fluorescence was analyzed with a FACS calibur flowcy nephritis; macular degenerative disorders; benign growth dis tometer, (Becton Dickinson). Data from at least 10,000 cells orders such as prostate enlargement and lipomas; autoim were analyzed with software. The results of a control group as mune disorders and the like. well as the two active treatment groups are set forth in Table 0121 The present composition can also be administered 1 below. for the treatment of Cardiac dysrhythmias, including but not limited to the Wolff-Parkinson-White syndrome and atrio TABLE 1 Ventricular nodal reentrant tachycardia Ventricular tachycar dia (VT), atrial tachycardias, atrial flutter and atrial fibrilla Effect of B2OL Metformin + aspirin + serotonin creatinine sulfate complex tionsupraventricular tachycardias. and B2OH Metformin + aspirin + serotonin creatinine sulfate complex 0122) The present composition can also be administered on Pancreatic Cancer Cells after 24 Hours for the treatment of Endometriosis, uterine fibroid (Uterine leiomyomata) menorrhagia, cervical erosion, cervical polyp. Group G1 S G2 and the like. Control 63% 35.5% 1.5% 0123. The present composition can also be administered B2OL Metformin 87.30% 9.40% 3.30% for the treatment of the defects or disorders of intervertebral 1 mM + aspirin discs include but not limited to annular fissures, fragmenta 0.4 mM + serotonin tion of the nucleus pulposus, and contained herniation a her creatinine Sulfate niated intervertebral disc. degenerative intervertebral discs. complex 0.002 mM 0.124. The compositions described above can be prelimi Metformin 10 mM + 88.70% 7.80% 3.40% narily screened for their efficacy in treating above-described aspirin 4 mM + diseases by an in vitro assay and then confirmed by animal Serotonin creatinine experiments (See Examples 1-9 below) and clinic trials. Hav Sulfate complex ing the information set forth in the present invention, other methods will also be apparent to those of ordinary skill in the O.O2 mM art. 0.125. The specific examples below are to be construed as I0128. The results indicate that Metformin-i-aspirin-i-sero merely illustrative, and not limitative of the remainder of the tonin creatinine Sulfate complex can block pancreatic cancer disclosure in any way whatsoever. Without further elabora tion, it is believed that one skilled in the art can, based on the cells in G1 phase from progressing into S phase and G2 phase description herein, utilize the present invention to its fullest after 24 hours as the two treatment groups have a higher extent. All of the publications cited herein are incorporated by proportion of cancer cells in the G1 phase. reference in their entirety. Example 2 DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS I0129. In Example 2, the testing procedure according to 0126 Cells can exist in different periods of a cell cycle Example 1 above was carried out for 48 and 72 hours com Such as: G1 phase cells, S phase cells, (indicating synthesis paring the control group to a B20L treatment group. The and doubling of DNA), and G2 phase cells. Comparing can results are provided in Table 2 below. US 2009/0286760 A1 Nov. 19, 2009

and equipment used are set forth as follows. Pancreatic cancer TABLE 2 cells were subcultured into 96-well plates at approximately 4x10" cells per ml and allowed to adhere for 24 h at 37° C. Effect of B2OL Metformin + aspirin + serotonin creatinine sulfate complex before being treated with the drug. Cell viability was assessed on Pancreatic Cancer Cells after 48 and 72 Hours using the Dojindo Cell Counting Kit-8. The cell viability was Group G1 S G2 in direct proportion to the absorbance at 450 nm. Accordingly, the cell viability was expressed as the absorbance at 450 nm. The effect of B2OL on cell cycle in 48 hours All experiments were performed in triplicate on three sepa Control 47% 46.20% 6.60% rate occasions. The results of a control group as well as the Metformin 1 mM + 71.70% 25.40% 2.90% two active treatment groups are set forth in Table 4 below. aspirin 0.4 mM + serotonin creatinine sulfate complex TABLE 4 O.OO2 mM The effect of B2OL on cell cycle in 72 hours Effect of different dosages of Metformin + aspirin + serotonin creatinine Sulfate complex on Proliferation Speed of Pancreatic Cancer Cells after Control 57% 37.40% S.80% 24, 48 and 72 Hours Metformin 1 mM + 63.80% 31.50% 4.60% aspirin 0.4 mM + Group 24 H 48 H 72H serotonin creatinine sulfate complex Control O.89 0.053 1805 O.O33 Metformin 1 0.725 0.047** 0.787 0.066** O.OO2 mM mM + aspirin 0.4 mM + Serotonin 0130. The results indicate that Metformin-i-aspirin-i-sero creatinine tonin creatinine Sulfate complex can block pancreatic cancer Sulfate complex cells in G1 phase from progressing into S phase and G2 phase O.OO2 mM Metformin 10 after 24, 48 and 72 hours as the two treatment groups have a mM + aspirin higher proportion of cancer cells in the G1 phase. 4 mM + Serotonin Example 3 creatinine Sulfate complex 0131. In Example 3, different dosages of Metformin--as 0.02 mM pirin-i-serotonin creatinine Sulfate complex were tested to determine the effect on the cell cycle of breast cancer cells after 24 hours. Each of the cell samples were then tested in a flow cytometer according to the procedures set forth in I0134. The results indicate that different dosage of Met Example 1 above. The results of a control group as well as the formin-i-aspirin-i-serotonin creatinine Sulfate complex can two active treatment groups are set forth in Table 3 below. inhibit pancreatic cancer cell proliferation and the effects are time and dose dependent. TABLE 3 Effect of different dosages of Metformin + aspirin + serotonin creatinine Example 5 sulfate complex on Breast Cancer Cells after 24 Hours I0135) In Example 5, Metformin 5 mM; Metformin 5 Group G1 S G2 mM+aspirin 2 mM; and Metformin 5 mM--aspirin 2 mM+se Control 43% 46.10% 10.6% rotonin creatinine sulfate complex 0.001 mM were tested to (Metformin 1 mM + 59.60% 36.30% 4.10% determine the effect on cell cycle on B16 (mice melanoma aspirin 0.4 mM + serotonin creatinine cells) during the G1, Sand G2 cell phases. The procedure for Sulfate complex testing using the flow cytometer was carried out as set forth in 0.002 mM) Example 1 above. The results are set forth in Table 5 below. Metformin 10 mM + 73.80% 20.00% 6.20% aspirin 4 mM + TABLE 5 serotonin creatinine Sulfate complex Effect of Metformin 5 mM, Metformin 5 mM + aspirin 2 mM, and O.O2 mM Metformin 5 mM + aspirin 2 mM + serotonin creatinine Sulfate complex 0.01 mM on B16 mice melanoma cells during G1, 0132) The results indicate that B20 different dosages of S and G2 cell phases. Metformin-i-aspirin-i-serotonin creatinine Sulfate complex can Group G1 S G2 blockbreast cancer cells in G1 phase from progressing into S Control 64 12.8 23.1 phase cells after 24 hours as the two treatment groups have a Metformin 5 mM 71.8 4.6 23.6 lower proportion of cancer S phase cells. Metformin 5 mM + 82.4 6.0 11.6 aspirin 2 mM Example 4 Metformin 5 mM + 85.1 6.9 8.0 aspirin 2 mM + serotonin creatinine 0133. In Example 4, different dosages of Metformin--as Sulfate complex pirin-i-serotonin creatinine Sulfate complex were tested to O.O1 mM determine the effect on proliferation speed of pancreatic can cer cells after 24, 48 and 72 hours. The testing methodology US 2009/0286760 A1 Nov. 19, 2009

0136. The results indicate that metformin was effective. Metformin-i-aspirin had better effect metformin alone, while TABLE 7 metformin-i-aspirin-i-serotonin creatinine Sulfate complex is The kill ratio of different compositions and different better than metformin-i-aspirin. action times on HepG-2 cells Example 6 24 hr (%) 48 hr (%) Metformin 0.975 + 0.004** O.995 O.OO4** 100 mM + aspirin 40 mM + 0137 In Example 6, Metformin 50 mM.; Metformin 100 Serotonin mM, Metformin 150 mM; and metformin 200 mM were creatinine Sulfate tested to determine the kill effect on breast cancer cells after complex 0.2 mM Metformin 100 mM + 3, 12 and 24 hours. The testing methodology and equipment indomethacin 30 mM + used are set forth as follows. Breast cancer cells were subcul Serotonin creatinine Sulfate complex 0.2 mM tured into 96-well plates at approximately 4x10" cells per ml Metformin 100 mM + 0.935 + 0.022** 0.974 0.007** and allowed to adhere for 24h at 37° C. before being treated nimeSulide 30 mM + Serotonin creatinine with the drug. Cell viability was assessed using the Dojindo Sulfate complex 0.2 mM Cell Counting Kit-8. The cell viability was in direct propor Metformin 100 mM + 0.925 + 0.027** 0.971 - 0.005** tion to the absorbance at 450 nm. Accordingly, the cell viabil celebrex 30 mM + Serotonin creatinine ity was expressed as the absorbance at 450 nm. All experi Sulfate complex 0.2 mM ments were performed in triplicate on three separate Metformin 100 mM + 0.957 OO15** 0.975 + 0.009** occasions. The results are set forth in Table 6 below showing Piroxicam33 mM + Serotonin creatinine the kill ratio (compared to control group) of different concen Sulfate complex 0.2 mM trations and different action times of metformin on MCF-7 Metformin 100 mM + O.964 O.O16** 0.981 - 0.007** diclofenac25 mM + cells (breast cancer cells). Serotonin creatinine Sulfate complex 0.2 mM TABLE 6 Metformin 100 mM + 0.757. O.115** O.969 O.O14** acetaminophen Effect of metformin on MCF-7 kill ratio of Breast Cancer 17 mM + serotonin Cells after 3, 12 and 24 Hours creatinine Sulfate

Time hydrochloride 17 mM + Concentration 3 h (%) 12 h (%) 24h (%) Serotonin creatinine sulfate complex 0.2 mM Metformin O.139 O.O41** O.397 0.042** O.404 - 0.061** 50 mM Metformin 0.1230.057** 0.353 0.083** 0.542 0.095** 0140. The results indicate that Metformin+serotonin crea 100 mM tinine Sulfate complex-different compounds with anti-in Metformin O.318 O.O32** O.488 O.O36** O.887 O.O68** flammatory activity, acetaminophen, and tramadol (different 150 mM first agent), can kill the live cancer cells well, and the effect is Metformin 0.321 - 0.07** O.769 O.O88** O.983 0.018* better than metformin only. 200 mM Example 8 *p < 0.05, 0.141. In Example8, phenformin (different second agent)+ **p < 0.01 serotonin creatinine Sulfate complex+different compounds with anti-inflammatory activity or acetaminophen, or trama 0138. The results indicate that Metformin was effective, dol, were tested to determine the kill effect on liver cancer can kill breast cancer cell and the effects are time and dose cells after 24 and 48 hours. The testing methodology and dependent. equipment was carried out as set forth in Example 6 above. The results are set forth in Table 8 below showing the kill ratio (compared to control group) of different compositions and Example 7 different action times on HepG-2 cells.

0.139. In Example 7. Metformin-i-serotonin creatinine sul TABLE 8 fate complex-different compounds with anti-inflammatory The kill ratio of different compositions and different activity or acetaminophen or tramadol (different first agent), actions time on HepG-2 cells were tested to determine the kill effect on liver cancer cells after 24 and 48 hours. The testing methodology and equip 24 hours (%) 48 hours (%) ment was carried out as set forth in Example 6 above. The Phenformin O.936 O.O16** O.991 O.OO6** results are set forth in Table 7 below showing the kill ratio 2 mM + aspirin 40 mM + Serotonin (compared to the control group), of different compositions creatinine Sulfate and different action times on HepG-2 cells (liver cancer complex 0.2 mM cells). US 2009/0286760 A1 Nov. 19, 2009 10

0144. The results indicate that B10Metformin 50 mg/kg+ TABLE 8-continued aspirin 40 mg/kg+serotonin creatinine Sulfate complex 0.4 The kill ratio of different compositions and different mg/kg can eliminate hepatoma Volume in KM mice at the rate actions time on HepG-2 cells of 94.1%. 24 hours (%) 48 hours (%) Example 10 Phenformin 2 mM + 0.762, O.O32** O.920 O.O2** indomethacin 30 mM + serotonin (0145. In Example 10, the effect of B10 Metformin 50 creatinine Sulfate mg/kg+aspirin 40 mg/kg+serotonin creatinine Sulfate com complex 0.2 mM Phenformin 2 mM + plex 0.4 mg/kg was tested to determine the effect on the nimeSulide 30 mM + weight and Volume of transplanted human hepatoma in hair Serotonin creatinine less mice relative to a 10% GS group and a dehydration sulfa ex 0.2 mM Phen mM + 0.957 0.002** alcohol group. The procedures for performing this test were celebrex 30 mM + as follows. Hep G2 cells were prepared at 25*10° cells/ml and Serotonin creatinine sulfa ex 0.2 mM 0.2 ml of the cell suspension (5*10 cells) was injected in an Phen mM + exposed mouse mammary fat pad. When tumors achieved the Piroxicam33 mM + required size (0.5 cm), animals would be treated with 50 ul of Serotonin creatinine sulfa ex 0.2 mM B10, dehydrated alcohol or 10% glucose solution once daily Phen mM + O.96S O.OO6** 0.9920.005** for 6 days. During 12 days after the last injection, tumor diclo mM + Volume will be assessed by measuring tumor dimensions Serotonin creatinine sulfa ex 0.2 mM (long (L) and short (S)) and estimated it as V=0.52*L*S. 12 Phen mM + O.940 O.O22** 0.991 - 0.005** days after the last injection, mice would be sacrificed and acetaminophen 7 mM + serotonin tumors would be dissected, weighed and stored in a formaline creatinine Sulfate solution for further evaluation.). Volume was measured complex 0.2 mM before and after treatment for each group. The results includ Phenformin 2 mM + 0.721 0.027** O.940 O.OO4** tramadol ing the change in volume are set forth in Table 7 below. hydrochloride 7 mM + serotonin TABLE 10 creatinine Sulfate complex 0.2 mM The effect of B10 on the weight and volume of hepatona in KM mice Volume 0142. The results indicate that phenformin (different sec Before After ond agent)+serotonin creatinine Sulfate complex-i-com Group Treatment Treatment Changes pounds with different anti-inflammatory activity or acetami 10% G.S. 172 65.5 444 199 15.8% nophen, tramadol, can kill the live cancer cell well and the Dehydration ethanol 188: 119 89 - 120** 52.7% effect is better than metformin only. Metformin 50 mg/kg+ 180 128 1.05 2.09** 199.4% aspirin 40 mg/kg+ Serotonin creatinine Sulfate Example 9 complex 0.4 mg/kg 0143. In Example 9, the effect of B10 (Metformin 50 mg/kg+aspirin 40 mg/kg+serotonin creatinine Sulfate com plex 0.4 mg/kg) was tested to determine the effect on volume of hepatoma in Strain Kunming Mice (KM) relative to a 10% 0146 The results indicate that B10 can eliminate glucose saline (GS) group. The drugs were administered by hepatoma volume in hairless mice at the rate 99.4%, com intratumor injection, twice a day for 3 days. Volume was pared to the dehydration ethanol group rate of 52.7%. measured before and after treatment for each group. The results including the change in volume are set forth in Table 6 Example 11 below. 0147 In Example 11, the effect of B3 (Metformin 50 TABLE 9 mg/kg+celebrex 10 mg/kg+serotonin creatinine Sulfate com The effect of B10 Metformin 50 mg/kg+ aspirin 40 mg/kg + plex 0.4 mg/kg) was tested to determine the effect on metasta Serotonin creatinine Sulfate complex 0.4 mg/kg on the volume sis of hepatoma carcinoma H22 cells. Fifty thousand (50,000) of hepatona in KM mice mice hepatoma carcinoma H22 cells were injected into the Group Before Drug After Drug abdominal cavity of KM mice, and then administered 10% 10% G.S. (glucose saline) 321 - 54 388 - 275 G.S. in the control group, or Metformin 50 mg/kg+celebrex Metformin 50 mg/kg + aspirin 40 mg/kg + 219 68 13 6** 10 mg/kg+serotonin creatinine Sulfate complex 0.4 mg/kg Serotonin creatinine Sulfate complex two times a day for only the first 30 days in the active treat 0.4 mg/kg ment group. After treatment was stopped, Survival time was observed. The results of the active treatment group and the 10% G.S. group are set forth in Table 8 below. US 2009/0286760 A1 Nov. 19, 2009

groups had a lower oncogenesis rate than the control group TABLE 11 (90%). Therefore, these drugs can decrease the rate of trans plantation of tumor cells. Survival Data of KM Mice Treated with Metformin 50 mg/kg+ celebrex 10 mg/kg + serotonin creatinine Sulfate complex 0.4 mg/kg three times a day for 30 days Other Embodiments Number Surviving 0151. All of the features disclosed in this specification Group 120 Days Survival Time may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature 10% G.S. 2f12 64.8 27.8 serving the same, equivalent, or similar purpose. Thus, unless Metformin 50 mg/kg+ celebrex 9,12 95 : 37.9* 10 mg/kg + serotonin creatinine expressly stated otherwise, each feature disclosed is only an Sulfate complex 0.4 mg/kg example of a generic series of equivalent or similar features. From the above description, one skilled in the art can easily (n = 12, p < 0.05, **p < 0.01) ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can 0148. The results indicate that the metformin 50 mg/kg+ make various changes and modifications of the invention to celebrex 10 mg/kg+serotonin creatinine Sulfate complex 0.4 adapt it to various usages and conditions. Thus, other embodi mg/kg group, 9 mice Survived 120 days, and in the control ments are also within the scope of the following claims. group only 2 mice Survived. The active drug group Survival What is claimed is: time was also better than control group indicating that this 1. A composition for treating a hyperproliferative disease, drug therapy can extend mice Survival time and reduce cancer comprising: cell transplantation rate. a first agent selected from the group consisting of: (i) an agent that possesses anti-inflammatory activity, (ii) Example 12 acetaminophen, (iii) phenacetin, (iv) tramadol and their pharmaceutically acceptable salts, pro-drugs and sol vates thereof, and 0149. In Example 12, the effect of B3 and B10 was tested a second agent is selected from the group consisting of an to determine the effect on oncogenesis rate of hepatoma car oxidative phosphorylation inhibitor, an ionophore, and cinoma H22 cells in KM mice. Fifty thousand (50,000) mice an adenosine 5-monophosphate-activated protein kinase hepatoma carcinoma H22 cells were injected Subcutaneously (AMPK) activator. into KM mice. Treatment groups consisted of B3 and B10, 2. The composition of claim 1, wherein the hyperprolifera administered three times a day for 30 days. After the drug was tive disease is a benign, such as a benign tumor. stopped, the mice were observed for the presence of tumor 3. The composition of claim 1, wherein the hyperprolifera tissue to determine whether oncogenesis has occurred. The tive disease is cancerous. results of the B10 and B3 treatment groups and the G.S. group 4. The composition of claim 1, that decreases proliferation are set forth in Table 9 below. of hyperproliferative cells. 5. The composition of claim 1, further comprising a third TABLE 12 agent that possesses or maintains serotonin activity. Oncogenesis Rate for Weeks 1, 2, 3, 4, 6 and 8 After Inoculation and 6. The composition of claim 5, wherein the hyperprolifera Treatment with B10 (Metformin 50 mg/kg+ aspirin 40 mg/kg + tive disease is a tumor and said composition kills a portion of serotonin creatinine Sulfate complex 0.4 mg/kg) and B3 the tumor. (Metformin 50 mg/kg+ celebrex 10 mg/kg + 7. The composition of claim 5, wherein the hyperprolifera serotonin creatinine sulfate complex 0.4 mg/kg tive disease is a tumor and said composition inhibits metasta Time after administration sis of the tumor. of drug and Oncogenesis Rate 8. A method of treating a hyperproliferative disease com prising administering an effective amount of a composition Group 1 w 2 w 3 w 4 w 6 w 8 w comprising aspirin or celecoxib and their pharmaceutically GS 60 70 70 8O 90 90 acceptable salts, pro-drugs and Solvates thereof and met Metformin 50 mg/kg + 10 2O 2O 2O 2O 2O aspirin40 mg/kg + formin or phenphormin and their pharmaceutically accept Serotonin able salts, pro-drugs and Solvates thereof to patient in need creatinine thereof. Sulfate complex 9. The method of claim 8, wherein the composition further 0.4 mg/kg Metformin 50 mg/kg + 30 50 50 50 50 50 comprises a third agent that possesses or maintains serotonin celebrex 10 mg/kg + activity. Serotonin 10. The method of claim 8 or 9, wherein the composition is creatinine administered parenterally or orally. Sulfate complex 11. The method of claim 8 or 9, wherein the hyperprolif 0.4 mg/kg erative disease is a solid tumor and the composition is injected directly into the tumor. 0150. The results indicate that 8 weeks after the drugs 12. The method of claim 8 or 9, wherein the composition were administered, the Metformin 50 mg/kg+aspirin 40 decreases proliferation. mg/kg+serotonin creatinine Sulfate complex 0.4 mg/kg group 13. The method of claim 8 or 9, wherein the composition only had a 20% oncogenesis rate. The Metformin 50 mg/kg+ kills cells that cause the hyperproliferative disease. celebrex 10 mg/kg+serotonin creatinine Sulfate complex 0.4 14. The method of claim 8 or 9, wherein the composition mg/kg only had a 50% oncogenesis rate. Both active drug inhibits metastasis of hyperproliferative cells. US 2009/0286760 A1 Nov. 19, 2009

15. The method of claim 8 or 9, wherein the hyperprolif ine, L-arginine acetylsalicylic; Aspirin-DL-lysine, and sero erative disease is a benign. tonin creatinine Sulfate complex or serotonin hydrochloride. 16. The method of claim 8 or 9, wherein the hyperprolif 27. The composition of claim 17 or 18, wherein the com erative disease is cancer. position further comprises a pharmaceutically acceptable car 17. A composition, comprising: 1. a first agent selected from the group consisting of: (i) an 28. The composition of claim 18, wherein the composition agent that possesses anti-inflammatory activity, (ii) consists essentially of the first, second, and third agents. 29. The composition of claims 17 or 18, wherein the second acetaminophen, (iii) phenacetin, and (iv) tramadol; and agent is an AMPK activator. a second agent selected from the group consisting of an 30. The composition of claim 29, wherein the composition oxidative phosphorylation inhibitor, an ionophore, and consists essentially of the first, second, and third agents. an adenosine 5-monophosphate-activated protein kinase 31. The composition of claim 29, wherein the AMPK acti (AMPK) activator. vator is selected from the group consisting of metformin, 18. The composition of claim 17, further comprising a third phenformin, buformin, AICAR, thienopyridones, resveratrol, agent that possesses or maintains serotonin activity. nootkatone, thiazole, adiponectin, thiazolidinediones, 19. The composition of claim 17 or 18, wherein the second rosiglitaZone, pioglitaZone and dithiolethiones. agent is selected from the group consisting of metformin, 32. The composition of claim 17 or 18, wherein the second phenforminand buforminand their pharmaceutically accept agent is an oxidative phosphorylation inhibitor or ionophore. able salts, pro-drugs and Solvates thereof. 33. A method for treating a hyperproliferative disease, 20. The composition of claim 17 or 18, wherein the first comprising administering to a subject in need thereof an agent is a non-steroidal anti-inflammatory compound. effective amount of a composition containing a first agent 21. The composition of claim 17 or 18, wherein the first selected from the group consisting of: (i) an agent that pos agent is aspirin, diclofenac, ibuprofen, indomethacin, sesses anti-inflammatory activity, (ii) acetaminophen, (iii) acetaminophen, nimeSulide, and their pharmaceutically phenacetin, and (iv) tramadol; and a second agent selected acceptable salts, pro-drugs and solvates thereof or a COX-2 from the group consisting of an oxidative phosphorylation inhibitor. inhibitor, an ionophore, and an AMPK activator; and a third 22. The composition of claim 17 or 18, wherein the first agent that possesses or maintains serotonin activity. agent is aspirin, Aspirin-arginine, L-arginine acetylsalicylic, 34. The method of claim 33, wherein the composition consists essentially of the first, second, and third agents. Aspirin-DL-lysine or celecoxib. 35. The method of claim33, wherein the second agent is an 23. The composition of claim 18, wherein the third agent is AMPK activator. serotonin or a serotonin re-uptake inhibitor. 36. The method of claim 33, wherein the second agent is an 24. The composition of claim 23, wherein the third agent is oxidative phosphorylation inhibitor or ionophore. serotonin Sulfate, serotonin creatinine Sulfate complex, or 37. The method of claim 33, wherein the hyperproliferative serotonin hydrochloride. disease is a benign tumor. 25. The composition of claim 18, wherein the composition 38. The method of claim 33, wherein the hyperproliferative contains 1-5000 mg of the first agent, 5-5000 mg of the disease is a malignant tumor. second agent, and where a third agent is present, 0.1-1000 mg 39. The method of claim 33, wherein the hyperproliferative of the third agent; or in quantities of the same ratio. disease is a Solid tumor. 26. The composition of claim 18, wherein the composition contains metformin hydrochloride, aspirin or Aspirin-argin c c c c c