HK1158888A - Novel compositions and methods for treating hyperproliferative diseases - Google Patents

Description

Novel compositions and methods for treating hyperproliferative diseases

Cross reference to related applications

This application claims the benefit of U.S. provisional application 61/127,883 filed on 16/5/2008 and U.S. provisional application 61/212,072 filed on 7/4/2009, the contents of which are incorporated herein by reference in their entirety.

Background

According to the world health organization report, 500 million people die from cancer every year. Drug therapy is one of the three main therapies for cancer. At present, the anticancer direction is as follows: interfering or inhibiting cell division, regulating cell proliferation cycle, promoting tumor cell apoptosis, inhibiting angiogenesis, inhibiting oncogene, promoting tumor suppressor gene, tumor antigen, inhibiting telomerase and interfering with tumor cell information transmission.

In view of the high mortality associated with abnormal proliferative diseases, including cancer, there is a need in the art for effective treatments for benign proliferative diseases and cancer.

Summary of The Invention

The present invention is based on the following findings: certain combinations of known drugs are effective in treating hyperproliferative diseases, including cancer.

In one aspect, the present invention relates to a composition comprising a first agent (a) that has anti-inflammatory activity or is acetaminophen, phenacetin, tramadol, and the like, a second agent (B) that may be an oxidative phosphorylation inhibitor, an ionophore, or an adenosine 5' -monophosphate-activated protein kinase (AMPK) activator, and a third agent (C) that has or maintains 5-hydroxytryptamine activity.

The first agent can be any suitable anti-inflammatory compound (e.g., a non-steroidal anti-inflammatory compound) or acetaminophen, phenacetin, tramadol, and the like. Examples include aspirin, diclofenac (e.g., diclofenac potassium or diclofenac sodium), ibuprofen (e.g., dexibuprofen or lysine dexibuprofen), indomethacin, nimesulide, and COX-2 inhibitors (e.g., nitric oxide-based COX-2 inhibitors or Celebrex)(4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl)]Benzenesulfonamide)). Other examples of the first agent include aspirin-arginine, alizarin (axiling), L-arginine acetylsalicylic acid; aspirin-DL-lysine; bismuth subsalicylate; bismuth salicylate; magnesium salicylate; diethylamine salicylate; salicylic acid, sodium salt; imidazole salicylate; sodium aminosalicylate; isoniazid aminosalicylate; physostigmine salicylate; pregnenolone acetylsalicylate; choline magnesium trisalicylate (magnesium trisalicylate); zinc oxide salicylate; sodium salicylate and sodium iodide; salicylic and glacial acetic acid solutions and methyl salicylic acid.

The second agent is an oxidative phosphorylation inhibitor, an ionophore, or an AMPK activator. The term "oxidative phosphorylation inhibitor" refers to any suitable agent that inhibits oxidative phosphorylation, such as an oxidative phosphorylation uncoupler. Ionophores are lipid soluble molecules capable of transporting ions across the lipid bilayer of a cell membrane; AMPK activators are agents that activate AMPK to phosphorylate its substrates, such as acetyl-coa carboxylase and malonyl-coa decarboxylase. Examples of the second agent include metformin (e.g., metformin hydrochloride), phenformin, and buformin.

The third agent may be the following compound: which has or maintains at least one of 5-hydroxytryptamine activity and, when used in combination with the first and second agents, is effective in treating one or more of the diseases targeted by the present invention. Examples include 5-hydroxytryptamine (e.g., 5-hydroxytryptamine sulfate, 5-hydroxytryptamine creatinine sulfate complex, or 5-hydroxytryptamine hydrochloride) and 5-hydroxytryptamine reuptake inhibitors.

A preferred composition of the invention comprises aspirin, metformin hydrochloride and 5-hydroxytryptamine creatinine sulfate complex.

In another aspect, the present invention relates to a composition consisting essentially of a first agent, a second agent, and a third agent, the first agent having anti-inflammatory activity or being acetaminophen, phenacetin, tramadol, or the like; the second agent may be an oxidative phosphorylation inhibitor, an ionophore, or an AMPK activator; the third agent has 5-hydroxytryptamine activity. The term "consisting essentially of … …" as used herein defines a composition as three specific agents as well as agents that do not substantially affect their basic and novel properties (i.e., efficacy in treating the target disease as described herein). One example of such a composition comprises the three agents described above and a pharmaceutically acceptable carrier. The above composition may comprise 5-5000mg (e.g., 5-3000mg, 5-1500mg, or 5-1000mg) of the first agent, 1-5000mg (e.g., 1-3000mg, 1-1000mg, 1-500mg, or 1-100mg) of the second agent, and 0.1-1000mg (e.g., 0.1-100mg, 0.1-50mg, or 0.1-30mg) of the third agent, or amounts in the same ratio as calculated from the above amounts.

In yet another aspect, the invention relates to a method of treating a hyperproliferative disease. The method comprises administering to a subject in need thereof an effective amount of one or more of the above-described compositions. The above diseases also include their related conditions.

The term "treating" as used herein refers to administering one or more of the above-described compositions to a subject (who is suffering from, has symptoms of, or is predisposed to) the disease for the purpose of a therapeutic effect, e.g., curing, alleviating, altering, affecting, ameliorating, or preventing the disease, its symptoms, or a susceptibility to the disease.

The composition may be in a form suitable for any route of administration. For example, when the composition is administered orally, in certain embodiments, the invention can be administered via any pharmaceutically acceptable oral dosage form, including solids (e.g., tablets, capsules), liquids (e.g., syrups, solutions, and suspensions), orally dissolving dosage forms (e.g., orally disintegrating dosage forms, lozenges, and troches), powders, or granules.

The compositions may also be prepared as solutions or suspensions for parenteral administration. The composition may also be in a dry form ready for reconstitution (e.g., by addition of sterile water for injection) prior to parenteral administration. Parenteral administration includes administration to any body space or tissue, for example, intravenous, intraarterial, intramuscular, and subcutaneous. When the site of action of interest is a solid tumor, in certain embodiments, the composition can be injected directly into the tumor.

In certain other embodiments of the invention, one or more active compounds of the invention are bound to a carrier substance, such as a compound or molecule (e.g., an antibody), to facilitate transport of the one or more active compounds to the site of action of interest. In certain preferred embodiments, active compound B (useful for treating hyperproliferative tissue) is covalently bonded to an antibody that corresponds to a marker located on the hyperproliferative tissue. According to this aspect of the invention, it is expected that toxicity and side effects may be reduced because lower levels of active agent are able to provide the desired therapeutic effect as compared to administration of an active agent not associated with a carrier material.

The first, second and third agents described above include the active compounds and any pharmaceutically acceptable derivatives thereof, such as their salts, prodrugs and solvates, if any. For example, a salt may be formed between an anion and a positively charged group on the agent. Examples of suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, chlorophenoxyacetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate, benzoate, pamoate, glycolate, pamoate (pamoate), aspartate, p-chlorophenoxyisobutyrate, formate, succinate, cyclohexanecarboxylate, hexanoate, octanoate, decanoate, hexadecanoate, octadecanoate, benzenesulfonate, trimethoxybenzoate, p-toluenesulfonate, adamantanecarboxylate, glyoxylate, pyrrolidone carboxylate, naphthalenesulfonate, 1-glucose phosphate, sulfite, dithionate, and maleate. Likewise, salts can also be formed between cations and negatively charged groups (e.g., carboxylate groups) on the agent. Examples of suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations (e.g., tetramethylammonium). In certain embodiments, the agent further comprises a salt comprising a quaternary nitrogen atom. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which upon administration to a subject are capable of providing the active compound. Solvates refer to the complexes formed between the active compound and a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.

Other examples of the salt include arginine salt, L-arginine salt; DL-lysine; bismuth subsalicylate; bismuth salicylate; a magnesium salt; diethylamine; a sodium salt; imidazole; sodium aminosalicylate; isoniazid aminosalicylic acid; physostigmine; pregnenolone acetylsalicylate; choline magnesium trisalicylate (magnesium trisalicylate); zinc oxide; an iodine salt; glacial acetic acid solution and methyl.

The scope of the invention also includes one or more of the above compositions for use in the treatment of the diseases described herein, as well as the use of such compositions for the manufacture of a medicament for the treatment of the diseases described herein.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

Detailed Description

In certain embodiments, the compositions of the present invention may comprise three agents.

Examples of the first agent may include steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drugs. Examples of steroidal anti-inflammatory drugs include glucocorticoids, hydrocortisone, cortisone, beclomethasone, dipropionate, betamethasone, dexamethasone, prednisone, methylprednisolone, triamcinolone, fluocinolone, fludrocortisone, and beclomethasone propionate salts.

Examples of non-steroidal anti-inflammatory drugs (NSAIDs) include a183827, ABT963, aceclofenac, acemetacin, acetylsalicylic acid, AHR10037, alclofenac, alminoprofen, ampiroxicam, guazatimedine, azapropazone, alisprofen methyl ester; AU8001, benoxaprofen, benzydamine flufenamic acid, bermoprofen, benperilon (bezpiperylon), BF388, BF389, BIRL790, BMS347070, bromfenac, bucloxic acid, butibufen, BW755C, C53, C73, C85, carprofen, CBS1108, celecoxib, CHF2003, chlorobiphenyl, choline magnesium trisalicylate, CHX108, cimicib, cinoxicam, clidanac, CLX1205, COX-2 inhibitors, CP331, CS502, CS706, D1367, dabrafilon, delacoxib (deracoxib), dexketoprofen, DFP, DFU, potassium, diclofenac sodium, diclofenac nafamoxol, diflufenisal, DP155, DRF4367, E5110, E6087, efec acid, ER34122, flufenamic acid, diclofenac sodium fenclofenamic acid, diclofenac sodium fenflurbiprofen, etoprofen, etofenflurbiprofen, etofen, etofenflurbiprofen, flurbiprofen, etofen, flurbiprofen, etofen, flurbiprofen, ibuprofen, fludroxin mesylate (flubichin methosulfonate), flufenamic acid, fluprofen, flurbiprofen, FPL62064, FR122047, FR123826, FR140423, FR188582, FS205397, furofenac, GR253035, GW406381, HAI105, HAI106, HCT2035, HCT6015, HGP12, HN3392, HP977, hxx 0835.hyal AT2101, ibufenac, ibuprox- β -cyclodextrin, icodullinum, IDEA 070070070070, erimod, erexib, indoprofen, IP751, soxepac, isoxicam, KC764, ketoprofen, L652343, L5337, L748731, L752860, L7616, L7617, L967, L300783, L457820, L796, L33857, ibuprofen, tp30076873, ibuprofen, diclofenac, ibuprofen, diclofenac, ibuprofen, diclofenac sodium chloride, ibuprofen 338180, ibuprofen hydrochloride, ibuprofen, diclofenac, ibuprofen hydrochloride, ibuprofen, NCX1101, NCX284, NCX285, NCX4016, NCX4215, NCX530, niflumic acid, nimesulide, nitric oxide-based NSAIDs (Nitromed, Lexington, MA), nitrophenolic acid (nitrofenac), nitroflurbiprofen, nitronaproxen, NS398, basil oil, ONO3144, oxyphenbutazone, oxaprozin, hydroxyindac, oxypinn, oxycodone/ibuprofen, oxybutyric acid, P10294, P54, P8892, pamigrel, Pasitaxacum, parecoxib, PD 387138138, PD145246, PD 164164387, Pebiprofen, pemetrexec, phenylbutazone, pirazolac, piroxicam beta-cyclodextrin, piroxicam pivalate, pirprofen, pranoprofen, resveratrol, R-ketoprofen, felbinac, 4357526, rosuvastatin, RU 5866364, RU 33236, RU 3368, RU 83, RU 245768, RU 3368, RSVP 83, RU 3368, RU 83, RU 3368, RU 83, RSP 68, RSP, S86236, S245768, RSP 3, S245768, sulfasalazine, sulindac, suprofen, SVT2016, T3788, TA60, tammethacin, talniflumate, tazofelone, terbufuron, tenidap, tenoxicam, tiposalin, tiaprofenic acid, temazexib, tioprofen, tiotropium, tenofovir, tioxaprid, tioxapril, tolfenamic acid, tolmetin, triflusal, indomethacin (tropesin), TY10222, TY10246, TY10474, UR8962, ursolic acid, valdecoxib, WAY120739, WY28342, WY41770, simofen, YS134, zaltoprofen, zidometacin, and zomepirac. Other examples of the first agent include acetaminophen, phenacetin, tramadol, and the like.

Other examples of the first agent also include aspirin-arginine, rubine, L-arginine acetylsalicylic acid; aspirin-DL-lysine; bismuth subsalicylate; bismuth salicylate; magnesium salicylate; diethylamine salicylate; sodium salt of salicylic acid; imidazole salicylate; sodium aminosalicylate; isoniazid aminosalicylic acid; physostigmine salicylate; pregnenolone acetylsalicylate; choline magnesium trisalicylate (magnesium trisalicylate); zinc oxide salicylate; sodium salicylate and sodium iodide; salicylic acid and glacial acetic acid solutions and methyl salicylic acid.

In addition to the above, examples of the second agent may include 4, 6-dinitro-o-cresol, uncoupling protein (e.g., UCP1, UCP2, or UCP3), carbonyl cyanide p- (trifluoromethoxy) phenyl-hydrazone, carbonyl cyanide m-chlorophenyl-hydrazone, a C5 gene product, dinitrophenol (e.g., 2, 4-dinitrophenol), peptin (efrapeptin) (a23871), guanethidine, chlorpromazine, pentobarbital, secobarbital, rotenone, progesterone, antimycin a, naphthoquinone, 8-hydroxyquinoline, carbon monoxide, cyanide, azide (e.g., NaN3), dicoumarol, bilirubin, ephedrine, hydrogen sulfide, tetraiodothyronine, quercetin, 2, 4-bis (p-chloroanilino) pyrimidine, glyceraldehyde-3 phosphate dehydrogenase, oligomycin, tributyltin chloride, tin chloride, stannic chloride, and the like, Aureomycin (aurovertin), rutaxomycin, staphylocidin, mercuric compounds, dicycloethylcarbodiimide, Dio-9, m-chlorophenyl-hydrazone malononitrile, ionomycin (ionomycin), calcium ionophores (e.g., A23187, NMDA, CA 1001 or enniatin B), increasing Ca in mitochondria⁺²Concentrations of compounds (such as atractyloside, mircotiana acid, thapsigargin, amino acid neurotransmitters, glutamate, N-methyl-D-aspartate, carbachol, ionophores, potassium depolarization inducers), apoptotic agents (i.e., compounds that induce apoptosis), valinomycin, gramicin, nonactin, nigericin, lasalocid, and monensin. The second agent may be an AMPK activator (e.g., metformin or phenformin, buformin, AICAR, thienopyridone, resveratrol, nootkatone, thiazole, adiponectin, a thiazolidinedione, rosiglitazone, pioglitazone, or dithiolethione).

The third agent includes 5-hydroxytryptamine and functional equivalents thereof. Examples of functional equivalents of 5-hydroxytryptamine include:

5-hydroxytryptamine 1A agonists such as: (e.g., aryl piperazine compounds, azaheterocyclylmethyl derivatives of heterocycle-fused benzodioxans, or buspirone, 3-amino-dihydro- [1] -benzopyran and benzothiopyran, (S) -4- [ [3- [2- (dimethylamine) ethyl ] -1H-indol-5-yl ] methyl ] -2-oxazolidinone- - -311C90) and 8-OH-DPAT), 5-carboxamido tryptamine hemiglycolate maleate, N-dipropyl-5-carboxamido tryptamine maleate, R (+) -UH-301HCl, S15535, gepirone, siloxib, zariton hydrochloride, and tandospirone;

5-hydroxytryptamine 1B agonists such as: CGS-12066a, N-methyl quinpiperazine dimaleate, rizatriptan and naratriptan;

5-hydroxytryptamine 1C agonists such as: dexfenfluramine (dexnofenfluramine);

5-hydroxytryptamine 1A, 1B, 1D, and 1F agonists such as: sumatriptan and 5-carboxamidotritamine hemiglycolate maleate;

5-hydroxytryptamine 1B and 1D agonists such as: dihydroergotamine and GR 46611;

5-hydroxytryptamine 1A and 1D agonists such as: LY-165, 163;

5-hydroxytryptamine 1A and 1E agonists such as: ergometrine and BRL 54443 maleate;

5-HT 2A/2C agonists such as: DOI (2, 5-dimethoxy-4-iodophenylpropylamine), mCPP (m-chlorophenyl-piperazine), TFMPP (3-trifluoromethylphenylpiperazine), Mascarine, DMT, dephosphorylated nudiflorin (psilocin), 2C-B, lorcaserin (lorcaserin), methyl 5-hydroxytryptamine maleate (methyterotonin hydrochloride), and 1- (3-chlorophenyl) piperazine hydrochloride;

5-hydroxytryptamine 2B agonists such as: BW 723C 86;

5-hydroxytryptamine receptor 2C modulators such as: (e.g., BVT933, DPCA37215, IK264, PNU22394, WAY161503, R-1065, YM348, VER-3323 hemifumaric acid, as well as modulators disclosed in U.S. Pat. Nos. 3,914,250, WO 01/66548, WO 02/10169, WO 02/36596, WO 02/40456, and WO02/40457, WO 02/44152, WO 02/48124, WO 02/51844, and WO 03/033479, the disclosures of which are incorporated herein by reference in their entirety);

5-HT 3 agonists such as: phenyl biguanide, O-methyl 5-hydroxytryptamine hydrochloride, SR 57227a, and 1- (3-chlorophenyl) biguanide hydrochloride;

5-HT 4 agonists such as: cisapride, mosapride citrate dihydrate and ML 10302;

5HT7 receptor agonists such as: 4- (2-pyridyl) piperazine, LP 12 hydrochloride hydrate, LP44, and quinoline derivatives;

5-hydroxytryptamine transporter inhibitors such as: imipramine;

5-hydroxytryptamine reuptake inhibitors such as: (e.g., arylpyrrolidine compounds, phenylpiperazine compounds, benzylpiperidine compounds, piperidine compounds, tricyclic gamma-carboline duloxetine compounds, pyrazinoquinoxaline compounds, pyridoindole compounds, piperidinoindole compounds, milnacipran, citalopram, sertraline metabolites, demethylsertraline, norfluoxetine, desmethylcitalopram, escitalopram oxalate, 1-fenfluramine, femoxetine, eformin, lefluxetine, cyanoduloxetine, ritoxetine, dapoxetine, nefazodone, cilazamide, trazodone, mirtazapine, fluvoxamine, indamine, indalazine, milnacipran, paroxetine, sibutramine, zidine, trazodone hydrochloride, dexfenfluramine, biciflumen, vilazone, venlafaxine, duloxetine, demeritiline, butriprine, desipramine, doxepin, duloxetine, and, Doxepin, lofepramin, nortriptyline, protriptyline, trimipramine, amoxapine (amoxaprie), maprotiline, adhyperforin (adhyperforin), brompheniramine, chlorpheniramine, dextromethorphan, diphenhydramine, hyperforin (hyperforin), ketamine, nefazodone, pethidine, phencyclidine, pheniramine, propoxyphene and U.S. Pat. No. 6,365,633, WO01/27060 and WO 01/162341 (the entire disclosures of which are incorporated herein by reference), EPTI, 8-OH-DPAT, Prozac(fluoxetine hydrochloride) and Zolosoft(sertraline hydrochloride);

5-hydroxytryptamine and norepinephrine reuptake inhibitors such as: (e.g., venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, and clomipramine metabolite desmethylclomipramine);

monoamine reuptake inhibitors such as: (e.g., amides);

pyridazinone aldose reductase inhibitors such as: (e.g., pyridazinone compounds);

5-hydroxytryptamine-capable agents (serotonergic agents), which are also 5-hydroxytryptamine receptor stimulators, such as: (e.g., dihydroergotoxine mesylate or pergolide mesylate);

stimulators of 5-hydroxytryptamine synthesis such as: (e.g., vitamin B1, vitamin B3, vitamin B6, biotin, SAMe, folic acid, ascorbic acid, magnesium, coenzyme Q10, or piracetam);

5-hydroxytryptamine receptor agonists such as: rauwolscine (Rauwolscine), yohimbine, alpha-methyl-5-hydroxytryptamine, 1- (1-naphthyl) piperazine, metoclopramide, HTF-919, R-093877, Zolmitriptan (Zolimiptan), 5-methoxy-N, N-dimethyltryptamine, 5-MEO-DIPT hydrochloride hydrate, and lysergic acid diethylamide;

5-hydroxytryptamine precursors such as tryptophan;

agents that promote the release of 5-hydroxytryptamine from nerve endings such as: fenfluramine and desfenfluramine (norfenfluramine);

all of the above compounds are known drugs and are publicly available. Some drugs are commercially available from chemical companies (e.g., Sigma-Aldrich, St. Louis, Mo.). When a drug is not readily available, in certain embodiments, one of ordinary skill in the art will appreciate that the compound can be manufactured and characterized by methods of organic chemistry in accordance with accepted standards (as found, for example, in Merck Index, Remington's pharmaceutical Sciences, USP/NF, and foreign publications). In certain embodiments, the regimen for administering these pharmaceutical compounds is well known and, if necessary, can be readily re-established by a clinician of ordinary skill. It is recognized by those skilled in the art that effective dosages will vary depending upon the following factors: the type and extent of the disease being treated; the subject's physique, weight, age and sex; the route of administration; the use of excipients; a metabolic rate; the rate of excretion, and possible co-administration with other therapeutic treatments. In certain embodiments, co-administration with other drugs may result in faster or slower metabolism or excretion, requiring dose adjustments. In certain other embodiments, when one or more active agents bind to plasma proteins, co-administration of other drugs that affect the degree of binding may also require dose adjustment. The daily dosage of the above compounds may be: the first agent is 5-10,000mg (e.g., 10-5000 or 10-3000mg), the second agent is 1-5000mg (e.g., 2-1000 or 2-3000mg), and the third agent is 0.1-1000mg (e.g., 1-50 mg).

In certain preferred embodiments, the human dose of the composition of the invention is: about 5-5000mg metformin, about 1-5000mg aspirin, and about 0.1-1000mg 5-hydroxytryptamine creatinine sulfate complex. In certain more preferred embodiments, the human dose of the composition is about 1000mg metformin, about 400mg aspirin, and about 4mg 5-hydroxytryptamine sulfate creatinine complex as multiple daily administrations. In certain further preferred embodiments, the dose is administered three times daily.

One aspect of the invention relates to methods of administering to a subject an effective amount of one or more of the above compositions to treat a disease described herein. A healthcare professional (e.g., a clinician) can determine such a subject based on the results of any suitable diagnostic method. An "effective dose" refers to the amount of one or more of the compositions described herein required to achieve a therapeutic effect in the subject being treated.

To practice the methods of the present invention, in certain embodiments, one or more of the above compositions may be administered parenterally, orally, nasally, rectally, topically, or buccally. The term "parenteral" as used herein refers to subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional or intracranial injection, and any suitable infusion or injection technique.

The sterile injectable composition may be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Examples of acceptable carriers and solvents that may be utilized are mannitol, water, ringer's solution and isotonic sodium chloride solution. In addition, fixed oils are conventionally employed as a solvent or suspending base (e.g., synthetic mono-or dioleyl esters). Fatty acids (such as oleic acid and its glyceride derivatives) are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils (such as olive oil or castor oil, especially in their polyethoxylated forms).

These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants (such as tweens or spans) or other similar emulsifying agents or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

The compositions for oral administration may be in any orally administrable dosage form including capsules, tablets, emulsions, as well as aqueous suspensions, dispersions and solutions. In the case of tablets, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When administered orally in the form of an aqueous suspension or emulsion, the active ingredient may be suspended or dissolved in an oily phase together with emulsifying or suspending agents. If desired, certain sweetening, flavoring or coloring agents may be added.

Nasal spray or inhalation compositions may be prepared according to techniques well known in the art of pharmaceutical formulation. For example, such compositions may be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

Compositions for topical application may be prepared as ointments, gels, plasters (platters), emulsions, lotions, creams with mixed phases or amphiphilic emulsion systems (oil/water-water/oil mixed phases), liposomes, transfersomes (transfersomes), pastes or powders.

Any of the compositions described above may also be administered in the form of suppositories for rectal administration of the drug. The composition may also be designed such that it is released in the intestine. For example, the composition may be enclosed within a solid subunit or capsule compartment having a matrix or wall or enclosure, respectively, comprising an enteric polymer which dissolves or disperses at the pH of the small or large intestine to release the drug substance in the intestine. Suitable such polymers have been described above, for example, in U.S. Pat. No. 5,705,189.

In certain embodiments, the carrier in the pharmaceutical composition must be "acceptable" in the sense that it is compatible with (and, preferably, capable of stabilizing) the active ingredients of the composition and not deleterious to the subject being treated. One or more solvents may be used as pharmaceutical excipients for the delivery of the active compound. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D & C Yellow # 10.

Benign tumor

The compounds and methods of the present invention are also suitable for the treatment of a variety of benign tumors. Examples of benign tumors include: adrenal tumors such as adenoma, adrenal pheochromocytoma and adrenal ganglionic neuroma; brain tumors such as meningiomas and adenomas; peripheral nerve tumors such as neurofibroma and schwannoma; liver tumors such as adenoma; thyroid tumors such as follicular adenoma; parathyroid tumors such as adenoma; thymus tumors such as thymoma; salivary gland tumor such as salivary gland mixed tumor; small bowel tumors such as villous adenoma; colon tumors such as villous tubular adenoma, adenomatous polyps of the colon, and Polyposis (Polyposis Coli); pancreatic tumors such as serous cystadenoma, pancreatic islet tumors such as islet cell tumor; nasopharyngeal tumors such as angiofibroma nasalis; ovarian tumors such as atypical proliferative myxoma, ovarian Brenner Tumor (Brenner Tumor), mucinous cystadenoma, papillary cystadenoma, ovarian dermoid cyst, ovarian teratoma, ovarian fibroma, luteal Tumor, and thyroid-like ovarian Tumor; uterine tumors such as uterine cell leiomyoma and leiomyoma; placental tumors such as choriohemangioma, partial hydatidiform mole, complete hydatidiform mole and mole; bone tumors such as cavernous hemangiomas and giant cell tumors; soft tissue tumors such as cavernous hemangioma, desmoid tumor, lipoma, medullary lipoma and osteochondroma; arthromas such as synovial chondromas; lung tumors such as carcinoid tumors, granulomatous tumors and hemangiomas; myocardial tumors such as atrial myxoma; breast tumors such as fibroadenoma, intraductal papillary tumors, and schwannoma; renal tumors such as congenital mesoblastic nephroma; skin tumors such as giant congenital intradermal nevus; renal tumors such as congenital mesoblastic nephroma.

The compositions of the present invention can be administered for the treatment of hyperproliferative disorders. The term "hyperproliferative disorder" refers to a condition of hyperproliferation of cells that is not restricted by the usual limitations of normal growth. The term refers to both malignant and non-malignant cell populations. Excessive cell proliferation can be determined by reference to the general population and/or by reference to a particular patient (e.g., at an earlier time point in the patient's life). Hyperproliferative cell disorders can occur in different species of animals and humans and have different physiological manifestations depending on the infected cells.

Hyperproliferative cell disorders include tumors and non-tumors. "tumor" herein refers to an abnormality in the amount of tissue caused by uncontrolled and progressive excessive cell division, also known as neoplasms (neoplasms).

Examples of tumors include a variety of solid tumors, such as laryngeal tumors, brain tumors, other tumors of the head and neck; colon, rectal and prostate tumors; breast and thymus solid tumors; ovarian and uterine tumors; tumors of the esophagus, stomach, pancreas and liver; bladder and gall bladder tumors; skin tumors such as melanoma, etc.; and fluid tumors such as leukemia.

As used herein, "solid tumor" refers to an abnormal tissue mass, which tissue generally does not include cysts or areas of fluid. Solid tumors can be benign (non-cancerous) or malignant (cancerous). Solid tumors have a well-defined structure similar to normal tissue and comprise two distinct but interdependent portions: parenchymal tissue (neoplastic cells) and stroma (the neoplastic cells are induced and dispersed within). Different types of solid tumors are named for the cell types that form them. Examples of solid tumors are sarcomas, carcinomas and lymphomas.

"solid tumor" refers to the location of tumor cells, wherein the majority of the cells are tumor cells or tumor-associated cells.

More specifically, a tumor referred to herein is a benign (non-cancerous) or malignant tumor.

Malignant tumor

Examples of malignancies include, but are not limited to: breast cancer:

1. ductal carcinoma: A1. ductal Carcinoma In Situ (DCIS): breast acne cancer, ethmoid cancer, papillary carcinoma, and papillary carcinoma; A2. invasive Ductal Carcinoma (IDC): tubular carcinoma, mucinous (glial) carcinoma, medullary carcinoma, papillary carcinoma, metaplastic carcinoma, inflammatory carcinoma;

2. lobular carcinoma: B1. lobular Carcinoma In Situ (LCIS); B2. invasive lobular carcinoma;

3. paget's disease of the nipple.

Female reproductive system

Cervix: cervical intraepithelial neoplasia (grade I), cervical intraepithelial neoplasia (grade II), cervical intraepithelial neoplasia (grade III) (squamous cell carcinoma in situ), keratinized squamous cell carcinoma, non-keratinized squamous cell carcinoma, verrucous carcinoma, adenocarcinoma in situ (exo-cervix), endometrioid adenocarcinoma, clear cell adenocarcinoma, adenosquamous carcinoma, adenoid cystic carcinoma, small cell carcinoma, undifferentiated carcinoma.

Uterus body: endometrioid carcinoma, adenocarcinoma, adenoacanthoma (adenocarcinoma with squamous metaplasia), adenosquamous carcinoma (mixed adenocarcinoma and squamous cell carcinoma, mucinous adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, squamous cell adenocarcinoma, undifferentiated adenocarcinoma.

Ovary: serous cystadenoma, serous cystadenocarcinoma, mucinous cystadenoma, mucinous cystadenocarcinoma, endometrioid tumor, endometrioid adenocarcinoma, clear cell tumor, clear cell cystadenocarcinoma, unclassified tumor.

Vagina: squamous cell carcinoma, adenocarcinoma.

Vulva: vulvar intraepithelial neoplasia (grade I), vulvar intraepithelial neoplasia (grade II), vulvar intraepithelial neoplasia (grade III) (squamous cell carcinoma in situ), squamous cell carcinoma, verrucous carcinoma, vulvar paget's disease, adenocarcinoma, NOS, basal cell carcinoma, NOS, vestibular adenocarcinoma.

Male reproductive system

Penis: squamous cell carcinoma.

Prostate gland: adenocarcinoma, sarcoma, transitional cell carcinoma of prostate.

Testis: seminoma, non-seminoma, teratoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma.

Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma.

Respiratory system

Throat: squamous cell carcinoma.

Pleural mesothelioma: primary pleural mesothelioma.

Pharynx: squamous cell carcinoma.

Lung (lung)

1. Squamous cell carcinoma (epidermoid carcinoma), variant: a fusiform cell;

2. small cell carcinoma, other cell carcinoma, intermediate cell type, combined oat cell tumor;

3. adenocarcinoma: acinar adenocarcinoma, papillary adenocarcinoma, bronchioloalveolar carcinoma, solid cancer with mucus formation;

4. large cell carcinoma: giant cell carcinoma, clear cell carcinoma, sarcoma.

Gastrointestinal tract

Hepatopancreatic duct ampulla: primary adenocarcinoma, carcinoid tumor, lymphoma.

Anal canal: adenocarcinoma, squamous cell carcinoma, melanoma.

Extrahepatic bile duct: carcinoma in situ, adenocarcinoma, papillary adenocarcinoma, enterotype, mucinous adenocarcinoma, clear cell adenocarcinoma, signet-ring cell carcinoma (Segnet-ring cell carcinoma), adenosquamous carcinoma, squamous cell carcinoma, small cell (oat) carcinoma, undifferentiated carcinoma, NOS, sarcoma, carcinoid tumor.

Colon and rectum: adenocarcinoma in situ, adenocarcinoma, mucinous adenocarcinoma (colloid type; more than 50% of mucinous adenocarcinomas), Signet ring cell carcinoma (more than 50% of Signet-ring cell carcinomas), squamous cell (epidermoid) carcinoma, adenosquamous carcinoma, small cell (oat cell) carcinoma, undifferentiated carcinoma, NOS, sarcoma, lymphoma, carcinoid tumor.

Esophagus: squamous cell carcinoma, adenocarcinoma, leiomyosarcoma lymphoma.

Gallbladder: adenocarcinoma, intestinal adenocarcinoma, adenosquamous carcinoma, carcinoma in situ, carcinoma, NOS, clear cell adenocarcinoma, mucinous adenocarcinoma, papillary adenocarcinoma, signet ring cell carcinoma, small cell (oat cell) carcinoma, squamous cell carcinoma, undifferentiated carcinoma.

Lips and mouth: squamous cell carcinoma.

Liver: liver cancer (hepatocellular carcinoma), extrahepatic cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma.

Pancreatic exocrine gland: ductal cell carcinoma, giant cell carcinoma of pleomorphic type, giant cell carcinoma of osteoclastic type, adenocarcinoma, adenosquamous carcinoma, mucinous (colloid) carcinoma, cystadenocarcinoma, acinar cell carcinoma, papillary carcinoma, small cell (oat cell) carcinoma, mixed cell type, carcinoma, NOS, undifferentiated carcinoma, endocrine cell tumor derived from pancreatic islets, carcinoid.

Salivary glands: acinar cell carcinoma, adenoid cystic carcinoma (cylindroma), adenocarcinoma, squamous cell carcinoma, polymorphic adenocarcinoma (malignant mixed tumor), mucoepidermoid carcinoma, well-differentiated (low grade), well-differentiated (high grade).

Stomach: adenocarcinoma, papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma, Signet-ring cell carcinoma, adenosquamous carcinoma, squamous cell carcinoma, small cell carcinoma, undifferentiated carcinoma, lymphoma, sarcoma, carcinoid tumor.

Small intestine: adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma.

Urinary system

Kidney: renal cell carcinoma, Bellini's collecting duct carcinoma, papillary adenocarcinoma, tubular carcinoma, granular cell carcinoma, clear cell carcinoma (adenoid tumor on kidney), renal sarcoma, nephroblastoma.

Renal pelvis and ureter: transitional cell carcinoma, papillary transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma (adenocarcinoma).

Urethra: transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma.

Bladder: carcinoma of the orthotopic urethra, transitional urethral cell carcinoma, papillary transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, undifferentiated.

Muscle, bone and soft tissue

Bone: A. bone formation: osteosarcoma; B. cartilage formation: chondrosarcoma, interstitial chondrosarcoma, c. giant cell tumor, malignant, d. ewing's sarcoma, e. hemangioma: angioendothelioma, hemangiopericytoma, angiosarcoma; F. connective tissue tumors: fibrosarcoma, liposarcoma, malignant stromal tumor, undifferentiated sarcoma; G. other tumors: chordoma, long enamel tumor.

Soft tissue: alveolar soft tissue sarcoma, angiosarcoma, epithelioid sarcoma, extraosseous chondrosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, malignant perithecoma, malignant interstitial tumor, malignant schwannoma, rhabdomyosarcoma, synovial sarcoma, and NOS.

The nervous system: cranium (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pilealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma).

Blood system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma (malignant lymphoma).

Endocrine system

Thyroid gland: papillary carcinomas (including follicular lesions), follicular carcinomas, medullary carcinomas, undifferentiated (anaplastic) carcinomas;

neuroblastoma: sympathetic neuroblastoma, sympathetic neurogenic cytoma, malignant ganglioneuroma, ganglionic sympathetic neuroblastoma, ganglionic cytoma.

Skin(s)

Squamous cell carcinoma, spindle cell variant of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma derived from sweat gland or sebaceous gland, malignant melanoma.

Eye (A)

And (3) forming a conjunctiva: conjunctival cancer.

Eyelid: basal cell carcinoma, squamous cell carcinoma, sebaceous gland carcinoma.

Lacrimal gland: adenocarcinoma, adenoid cystic carcinoma, carcinoma among polymorphic adenomas, mucoepidermoid carcinoma, squamous cell carcinoma.

Eyelid: eyelid melanoma.

Pigment layer: fusiform melanoma, mixed cell melanoma, epithelial cell melanoma.

Orbital sarcoma: soft tissue tumors, osteosarcomas.

Retinal neuroblastoma: neuroblastoma of the retina.

Examples of non-neoplastic hyperproliferative diseases include, but are not limited to, myelodysplastic disorders; carcinoma of the cervix in situ; familial intestinal polyps such as Gardner syndrome; oral leukoplakia; (ii) a histiocytic disease; keloid; hemangioma; inflammatory arthritis; hyperkeratosis and papulosquamous eruptions including arthritis. Also included are virus-induced hyperproliferative diseases such as warts and EBV-induced diseases (i.e. infectious mononucleosis), scar formation, vascular proliferative diseases such as restenosis, atherosclerosis, in-stent stenosis, in-stent restenosis and the like; fibrotic diseases; psoriasis; glomerulonephritis; macular degenerative diseases; benign growth diseases such as prostate enlargement and lipoma; autoimmune diseases, and the like.

Compositions of the invention may also be administered for the treatment of cardiac arrhythmias including, but not limited to, Wolff-Parkinson-White syndrome and atrioventricular nodal reentry tachycardia Ventricular Tachycardia (VT), atrial tachycardia, atrial flutter and atrioventricular fibrillation tachycardia.

The compositions of the present invention may also be administered for the treatment of endometriosis, uterine fibroids (uterine leiomyoma) menorrhagia, cervical erosion, cervical polyps, and the like.

The compositions of the present invention may also be administered for the treatment of intervertebral disc defects or conditions, including but not limited to annular fissures, nucleus pulposus fractures, and herniated disc containing projections, disc degeneration.

The compositions described above can be pre-screened for efficacy in treating the above-mentioned diseases by in vitro assays and then confirmed by animal experiments (see examples 1-9 below) and clinical trials. Other methods will be apparent to those of ordinary skill in the art in view of the information provided herein.

The following specific examples are intended to be illustrative only and are not intended to be limiting in any way to the remainder of this disclosure. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are incorporated by reference in their entirety.

Description of The Preferred Embodiment

Cells may be present at different stages of the cell cycle, such as: g1 phase cells, S phase cells (indicating DNA synthesis and doubling), and G2 phase cells. In comparison of tumor cells with normal cells, it was found that the proportion of cells in the G1 phase is reduced in cancer, the proportion of cells undergoing synthesis in cancer is increased, and the proportion of cells in the G2 and S phases is increased.

Example 1

In example 1, B20L (metformin 1mM + aspirin 0.4mM + 5-hydroxytryptamine creatinine sulfate complex 0.002mM) and B20H (metformin 10mM + aspirin 4mM + 5-hydroxytryptamine creatinine sulfate complex 0.02mM) were tested to determine their effect on the cell cycle of pancreatic cancer cells after 24 hours. Each cell sample is then tested in a flow cytometer. The test methods and apparatus are described below. Cells were harvested and washed twice with Phosphate Buffered Saline (PBS) and fixed with 70% cold ethanol overnight at 4 ℃. Before analysis, cells were washed twice with PBS containing 1% Bovine Serum Albumin (BSA), then resuspended in 400. mu.l PBS and treated with 100. mu.l/ml RNase (Roche Diagnostics) and 50. mu.g/ml Propidium Iodide (PI) (Sigma). After incubation at 37 ℃ for 30 minutes, the cells were subjected to DNA content analysis. Propidium Iodide (PI) fluorescence was analyzed by FACSCalibur flow cytometer (Becton Dickinson). Data for at least 10,000 cells were analyzed with the software. The results for the control and two active treatment groups are given in table 1 below.

Table 1: effect of B20L metformin + aspirin + 5-hydroxytryptamine creatinine sulfate Complex and B20H metformin + aspirin + 5-hydroxytryptamine creatinine sulfate Complex on pancreatic cancer cells after 24 hours

The results show that metformin + aspirin + 5-hydroxytryptamine creatinine sulfate complex blocks the progression of pancreatic cancer cells in stage G1 to stage S and stage G2 after 24 hours, because both treatment groups have a higher proportion of cancer cells in stage G1.

Example 2

In example 2, the test steps according to example 1 above were carried out for 48 and 72 hours, comparing the control group with the B20L treated group. The results are provided in table 2 below.

Table 2: B20L action of metformin + Aspirin + 5-hydroxytryptamine sulphate Complex on pancreatic cancer cells after 48 and 72 hours

The results show that metformin + aspirin + 5-hydroxytryptamine creatinine sulfate complex blocks the progression of pancreatic cancer cells in G1 stage to S stage and G2 stage after 24, 48, and 72 hours, because both treatment groups have a higher proportion of G1 stage cancer cells.

Example 3

In example 3, different doses of metformin + aspirin + 5-hydroxytryptamine creatinine complex were tested to determine its effect on the cell cycle of breast cancer cells after 24 hours. Each cell sample was then examined in a flow cytometer according to the procedure described in example 1 above. The results for the control group and the two active treatment groups are given in table 3 below.

Table 3: effect of metformin + aspirin + 5-hydroxytryptamine creatinine sulfate complexes at various doses on breast cancer cells after 24 hours

The results indicate that different doses of the B20 metformin + aspirin + 5-hydroxytryptamine creatinine sulfate complex blocked progression of breast cancer cells in G1 to S phase after 24 hours because there was a lower proportion of S phase cancer cells in both treatment groups.

Example 4

In example 4, different doses of metformin + aspirin + 5-hydroxytryptamine creatinine complex were tested to determine their effect on the rate of pancreatic cancer cell proliferation after 24, 48 and 72 hours. The test methods and instruments used are described below. Pancreatic cancer cells were sub-cultured in 96-well plates (approximately 4X 10 per ml)⁴Cells) were allowed to attach at 37 ℃ for 24 hours prior to drug treatment. Cell viability was assessed using Dojindo cell counting kit-8. Cell viability is directly proportional to absorbance at 450 nm.Thus, cell viability was expressed as absorbance at 450 nm. All experiments were performed in triplicate on three different occasions. The results for the control group and the two active treatment groups are given in table 4 below.

Table 4: effect of metformin + aspirin + 5-hydroxytryptamine-sulfate creatinine complexes at different doses on pancreatic cancer cell proliferation Rate after 24, 48 and 72 hours

^*p＜0.05，^**p＜0.01

The results show that metformin + aspirin + 5-hydroxytryptamine creatinine sulfate complex at different doses can inhibit the proliferation of pancreatic cancer cells, and the effect is time and dose dependent.

Example 5

In example 5, metformin was tested at 5 mM; metformin 5mM + aspirin 2 mM; metformin 5mM + aspirin 2mM + 5-hydroxytryptamine-creatinine sulfate complex 0.001mM to determine its effect on the cell cycle of B16 (mouse melanoma cells) at the G1, S and G2 cell stages. The test procedure as described in example 1 above was carried out in a flow cytometer. The results are given in table 5 below.

Table 5: effect of metformin 5mM, metformin 5mM + aspirin 2mM, and metformin 5mM + aspirin 2mM + 5-hydroxytryptamine creatinine sulfate Complex 0.01mM on melanoma cells of B16 mice at the G1, S and G2 cell stages

The results indicate that metformin is effective. Metformin + aspirin worked better than metformin alone; however, the metformin + aspirin + 5-hydroxytryptamine creatinine sulfate complex acts better than metformin + aspirin.

Example 6

In example 6, metformin was tested at 50 mM; 100mM of metformin; metformin 150mM and metformin 200mM to determine its killing effect on breast cancer cells after 3, 12 and 24 hours. The test methods and instruments used are described below. Pancreatic cancer cells were sub-cultured in 96-well plates (approximately 4X 10 per ml)⁴Cells) were allowed to attach at 37 ℃ for 24 hours prior to drug treatment. Cell viability was assessed using Dojindo cell counting kit-8. Cell viability is directly proportional to absorbance at 450 nm. Thus, cell viability was expressed as absorbance at 450 nm. All experiments were performed in triplicate on three different occasions. The results are given in table 6 below, which shows the killing rate (compared to the control) at different concentrations and different time of action of metformin on MCF-7 cells (breast cancer cells).

Table 6: effect of metformin on the killing Rate of MCF-7 against Breast cancer cells after 3, 12 and 24 hours

^*p＜0.05，^**p＜0.01

The results indicate that metformin is effective, killing breast cancer cells, and that the effect is time and dose dependent.

Example 7

In example 7, metformin + 5-hydroxytryptamine creatinine sulfate complex + different compounds with anti-inflammatory activity or acetaminophen or tramadol (different first agents) were tested to determine their killing effect on hepatocytes after 24 and 48 hours. The test methods and apparatus were performed as described above in example 6. The results are given in table 7 below, which shows the effect of different compositions and different action times on the killing rate of HepG-2 cells (hepatoma cells) compared to the control group.

Table 7: killing rate of HepG-2 cells with different compositions and different duration of action

(^*p＜0.05，^**p＜0.01)

The results show that metformin + 5-hydroxytryptamine creatinine sulfate complex + different compounds with anti-inflammatory activity, acetaminophen and tramadol (different first agents) can kill liver cancer cells well and have stronger effects than metformin alone.

Example 8

In example 8, phenformin (a different second agent) + 5-hydroxytryptamine creatinine sulfate complex + a different compound with anti-inflammatory activity or acetaminophen or tramadol was tested to determine its killing effect on hepatocytes after 24 and 48 hours. The test methods and apparatus were performed as described above in example 6. The results are given in Table 8 below, showing the killing rate of HepG-2 cells by different compositions and different action times (compared to the control).

Table 8: killing rate of HepG-2 cells with different compositions and different action times

(^*p＜0.05，^**p＜0.01)

The results show that phenformin (a different second medicament), 5-hydroxytryptamine creatinine sulfate complex, different compounds with anti-inflammatory activity or acetaminophen and tramadol can kill liver cancer cells well, and the effect is stronger than that of metformin alone.

Example 9

In example 9, B10 (metformin 50mg/kg + aspirin 40mg/kg + 5-hydroxytryptamine sulfate creatinine complex 0.4mg/kg) was tested to determine its effect on the hepatoma volume of Kunming strain mice (KM) (relative to the 10% Glucose Saline (GS) group). The drug was administered by intratumoral injection for 3 days, twice daily. Each group measured volume before and after treatment. The results, including the volume change, are given in table 9 below.

Table 9: b10 metformin 50mg/kg + aspirin 40mg/kg

Effect of + 5-hydroxytryptamine Creatinine sulfate Complex 0.4mg/kg on volume of hepatocellular carcinoma in KM mice

(n＝4，^*p＜0.05，^**p＜0.01)

The results show that B10 (metformin 50mg/kg + aspirin 40mg/kg + 5-hydroxytryptamine creatinine sulfate complex 0.4mg/kg) eliminated hepatoma volume in KM mice at a rate of 94.1%.

Example 10

In example 10, B10 (metformin 50mg/kg + aspirin 40mg/kg + 5-hydroxytryptamine-creatinine sulfate complex 0.4mg/kg) was tested to determine its effect on human hepatoma transplanted in nude miceInfluence of weight and volume of (relative to 10% GS group and anhydrous ethanol group). The procedure for performing this test is as follows. Preparation 25X 10⁶Cells/ml HepG2 cells, and 0.2ml of this cell suspension (5 x 10)⁶Cells) were injected into the exposed mouse mammary fat pad. When the tumor reached the desired size (0.5 cm)³) In this case, the treatment was carried out once a day for 6 days with 50. mu. l B10, dehydrated ethanol or 10% glucose solution. On day 12 after the last injection, tumor size was measured (long (L) and short (S)) and measured with V0.52L S²Estimation to estimate tumor volume. 12 days after the last injection, mice were sacrificed and tumors were excised, weighed, and stored in formalin solution for further evaluation. The volume of each group was measured before and after treatment. The results, including the volume change, are given in table 10 below.

Table 10: effect of B10 on the weight and volume of hepatoma in KM mice

(n＝4，^*p＜0.05，^**p＜0.01)

The results show that B10 eliminated the volume of hepatoma in nude mice at a rate of 99.4% compared to the rate of 52.7% for anhydrous ethanol group.

Example 11

In example 11, B3 (metformin 50mg/kg + celecoxib 10mg/kg + 5-hydroxytryptamine creatinine sulfate complex 0.4mg/kg) was tested to determine its effect on hepatocellular carcinoma H22 cell metastasis. 5 ten thousand (50,000) mouse hepatocellular carcinoma H22 cells were injected into the abdominal cavity of KM mice, followed by administration of 10% G.S. to the control group, or metformin 50mg/kg + celecoxib 10mg/kg + 5-hydroxytryptamine-creatinine sulfate complex 0.4mg/kg twice daily for the active treatment group for the first 30 days only. After the treatment was completed, the survival time was observed. The results for the active treatment group and the 10% g.s. group are given in table 11 below.

Table 11: days of survival of KM mice treated (30 days, 3 times per day) with metformin 50mg/kg + celecoxib 10mg/kg + 5-hydroxytryptamine creatinine sulfate complex 0.4mg/kg

(n＝12，^*p＜0.05，^**p＜0.01)

The results showed that 9 mice survived 120 days in the group of 50mg/kg metformin + 10mg/kg celecoxib + 0.4mg/kg 5-hydroxytryptamine creatinine sulfate complex, and only 2 mice survived 120 days in the control group. The survival time of the active drug group was also longer than the control group, indicating that the drug treatment can prolong the survival time of mice and reduce the cancer cell transplantation rate.

Example 12

In example 12, the effects of B3 and B10 were tested to determine their effects on the tumor incidence of hepatoma H22 cancer cells in KM mice. 5 ten thousand (50000) mouse liver cancer H22 cells were injected subcutaneously into KM mice. Treatment groups included B3 and B10, 3 times daily for 30 days. After the drug administration was completed, the mice were observed for the presence of tumor tissue to determine whether tumors had occurred. The results of the B10 and B3 treated groups and the g.s. treated group are given in table 12 below.

Table 12: tumor incidence at 1, 2, 3, 4, 6 and 8 weeks after vaccination and treatment with B10 (metformin 50mg/kg + aspirin 40mg/kg + 5-hydroxytryptamine creatinine sulfate complex 0.4mg/g) and B3 (metformin 50mg/kg + celecoxib 10mg/kg + 5-hydroxytryptamine creatinine sulfate complex 0.4mg/kg)

The results show that at 8 weeks after drug administration, metformin 50mg/kg + aspirin 40mg/kg + 5-hydroxytryptamine creatinine sulfate complex 0.4mg/kg group had only a 20% tumor incidence. The 50mg/kg metformin, 10mg/kg celecoxib and 0.4mg/kg sulfuric acid 5-hydroxytryptamine creatinine complex group have only 50% tumor incidence. The tumor incidence was lower in both active drug groups than in the control group (90%). Thus, these drugs can reduce the rate of tumor cell transplantation.

Other embodiments

All features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Accordingly, other embodiments are within the scope of the following claims.

Claims (88)

1. A composition for treating a hyperproliferative disease, comprising:

a first agent selected from: (i) an agent having anti-inflammatory activity, (ii) acetaminophen, (iii) phenacetin, (iv) tramadol, and pharmaceutically acceptable salts, prodrugs and solvates thereof; and

a second agent selected from the group consisting of an oxidative phosphorylation inhibitor, an ionophore, and an adenosine 5-monophosphate-activated protein kinase (AMPK) activator.

2. The composition of claim 1, wherein the hyperproliferative disease is a benign tumor.

3. The composition of claim 1, wherein the hyperproliferative disease is cancerous.

4. The composition of claim 1, wherein the composition reduces proliferation of hyperproliferative cells.

5. The composition of claim 1, further comprising a third agent that has or maintains 5-hydroxytryptamine activity.

6. The composition of claim 5, wherein the hyperproliferative disorder is a tumor and the composition kills a portion of the tumor.

7. The composition of claim 5, wherein the hyperproliferative disease is a tumor and the composition inhibits metastasis of the tumor.

8. A method of treating a hyperproliferative disorder comprising administering to a patient in need thereof an effective amount of a composition comprising aspirin or celecoxib, and pharmaceutically acceptable salts, prodrugs, and solvates thereof, and metformin or phenformin, and pharmaceutically acceptable salts, prodrugs, and solvates thereof.

9. The method of claim 8, wherein the composition further comprises a third agent that has or maintains 5-hydroxytryptamine activity.

10. The method of claim 8 or 9, wherein the composition is administered parenterally or orally.

11. The method of claim 8 or 9, wherein the hyperproliferative disease is a solid tumor and the composition is injected directly into the tumor.

12. The method of claim 8 or 9, wherein the composition reduces proliferation.

13. The method of claim 8 or 9, wherein the composition kills cells causing the hyperproliferative disease.

14. The method of claim 8 or 9, wherein the composition inhibits metastasis of hyperproliferative cells.

15. The method of claim 8 or 9, wherein the hyperproliferative disease is benign.

16. The method of claim 8 or 9, wherein the hyperproliferative disease is cancer.

17. A method of treating a hyperproliferative disorder comprising administering to a patient in need thereof an effective amount of a composition comprising metformin or phenformin, and pharmaceutically acceptable salts, prodrugs and solvates thereof; aspirin or celecoxib, and pharmaceutically acceptable salts, prodrugs and solvates thereof, and carrier materials useful for delivery of the compositions to the site of intended action.

18. The method of claim 17, wherein the metformin is linked to an antibody.

19. The method of claim 17, wherein metformin, phenformin, aspirin, or celecoxib is covalently bonded to an immunoglobulin specific for a marker found on hyperproliferative cells of the patient targeted for treatment.

20. The method of claim 19, wherein the immunoglobulin is IgG.

21. The method of any one of claims 17-20, wherein the composition is administered intravenously.

22. The method of any one of claims 17-20, wherein the composition is administered orally.

23. The method of any of claims 17-20, wherein the amount of the composition required to provide a therapeutic effect is less than the amount of the composition required to provide a therapeutic effect when administered without a carrier substance.

24. The method of any one of claims 17-20, wherein the healthy cells of the patient experience less toxicity than when the composition is administered without a carrier substance.

25. The method of any one of claims 17-20, wherein the patient experiences less side effects than when the composition is administered without a carrier substance.

26. The method of any of claims 17-20, wherein the amount of the composition required to provide a therapeutic effect is less than the amount of the composition required to provide a therapeutic effect when administered without a carrier substance, and wherein the composition is administered intravenously or orally.

27. The method of any one of claims 17-20, wherein the healthy cells of the patient experience less toxicity than the composition does when administered without a carrier substance, and wherein the composition is administered intravenously or orally.

28. The method of any one of claims 17-20, wherein the patient experiences fewer side effects than the side effects experienced when the composition is administered without a carrier substance, and wherein the composition is administered intravenously or orally.

29. A composition, comprising:

a first agent selected from: (i) an agent having anti-inflammatory activity, (ii) acetaminophen, (iii) phenacetin, and (iv) tramadol; and

a second agent selected from the group consisting of an oxidative phosphorylation inhibitor, an ionophore, and an adenosine 5-monophosphate-activated protein kinase (AMPK) activator.

30. A composition, comprising:

a first agent selected from: (i) an agent having anti-inflammatory activity, (ii) acetaminophen, (iii) phenacetin, and (iv) tramadol; and

a second agent selected from the group consisting of an oxidative phosphorylation inhibitor, an ionophore, and an adenosine 5-monophosphate-activated protein kinase (AMPK) activator; and

a third agent that has or maintains 5-hydroxytryptamine activity.

31. The composition of claim 29 or 30, wherein the second agent is selected from the group consisting of metformin, phenformin, and buformin, and pharmaceutically acceptable salts, prodrugs, and solvates thereof.

32. The composition of claim 29 or 30, wherein the first agent is a non-steroidal anti-inflammatory compound.

33. The composition of claim 29 or 30, wherein the first agent is aspirin, diclofenac, ibuprofen, indomethacin, acetaminophen, nimesulide, and pharmaceutically acceptable salts, prodrugs and solvates thereof, or is a COX-2 inhibitor.

34. The composition of claim 29 or 30, wherein the first agent is aspirin, aspirin-arginine, L-arginine acetylsalicylic acid, aspirin-DL-lysine, or celecoxib.

35. The composition of claim 30, wherein the third agent is 5-hydroxytryptamine or a 5-hydroxytryptamine reuptake inhibitor.

36. The composition of claim 35, wherein the third agent is 5-hydroxytryptamine sulfate, 5-hydroxytryptamine creatinine sulfate complex, or 5-hydroxytryptamine hydrochloride.

37. The composition of claim 29 or 30, wherein the composition comprises 1-5000mg of the first agent, 5-5000mg of the second agent, and when a third agent is present, 0.1-1000mg of the third agent; or with the same proportional amounts.

38. The composition of claim 29 or 30, wherein the composition comprises 1-3000mg of the first agent, 5-1500mg of the second agent, and when a third agent is present, 0.1-500mg of the third agent; or with the same proportional amounts.

39. The composition of claim 29 or 30, wherein the composition comprises 1-1000mg of the first agent, 5-1000mg of the second agent, and when a third agent is present, 0.1-100mg of the third agent; or with the same proportional amounts.

40. The composition of claim 30, wherein the composition comprises metformin hydrochloride, aspirin or aspirin-arginine, L-arginine acetylsalicylic acid; aspirin-DL-lysine, and 5-hydroxytryptamine creatinine sulfate complex or 5-hydroxytryptamine hydrochloride.

41. The composition of claim 29 or 30, wherein the composition comprises 1 to 5000mg aspirin, 5 to 5000mg metformin hydrochloride, and when the third agent is present, 0.1 to 1000mg 5-hydroxytryptamine creatinine sulfate complex; or with the same proportional amounts.

42. The composition of claim 29 or 30, wherein the composition comprises 1 to 3000mg aspirin, 5 to 1500mg metformin hydrochloride, and when the third agent is present, 0.1 to 100mg 5-hydroxytryptamine creatinine sulfate complex; or with the same proportional amounts.

43. The composition of claim 29 or 30, wherein the composition comprises 1-1000mg aspirin, 5-1000mg metformin hydrochloride, and when the third agent is present, 0.1-50mg of the third agent; or with the same proportional amounts.

44. The composition of claim 29 or 30, wherein the composition further comprises a pharmaceutically acceptable carrier.

45. The composition of claim 30, wherein the composition consists essentially of the first, second, and third agents.

46. The composition of claim 29 or 30, wherein the second agent is an AMPK activator.

47. The composition of claim 46, wherein the composition consists essentially of the first, second, and third agents.

48. The composition of claim 46, wherein the AMPK activator is selected from the group consisting of metformin, phenformin, buformin, AICAR, thienopyridones, resveratrol, nootkatone, thiazole, adiponectin, thiazolidinediones, rosiglitazone, pioglitazone, and dithiolethione.

49. The composition of claim 29 or 30, wherein the second agent is an oxidative phosphorylation inhibitor or an ionophore.

50. A composition, comprising:

a first agent selected from: (i) an agent having anti-inflammatory activity, (ii) acetaminophen, (iii) phenacetin, and (iv) tramadol;

a second agent selected from metformin, phenformin or buformin, and pharmaceutically acceptable salts, prodrugs and solvates thereof; and

a third agent that has or maintains 5-hydroxytryptamine activity.

51. The composition of claim 50, wherein said second agent is selected from the group consisting of metformin and phenformin, and pharmaceutically acceptable salts, prodrugs and solvates thereof.

52. The composition of claim 50, wherein the first agent is a non-steroidal anti-inflammatory compound.

53. The composition of claim 50, wherein said first agent is aspirin or a COX-2 inhibitor.

54. The composition of claim 50, wherein the third agent is 5-hydroxytryptamine and pharmaceutically acceptable salts, prodrugs, and solvates thereof.

55. The composition of claim 50, wherein the composition comprises metformin hydrochloride, aspirin or aspirin-arginine, L-arginine acetylsalicylic acid; aspirin-DL-lysine, and 5-hydroxytryptamine creatinine sulfate complex or 5-hydroxytryptamine hydrochloride.

56. The composition of claim 50, wherein the composition consists essentially of the first, second, and third agents.

57. A method of treating a hyperproliferative disease comprising administering to a subject in need thereof an effective amount of a composition comprising a first agent selected from the group consisting of: (i) an agent having anti-inflammatory activity, (ii) acetaminophen, (iii) phenacetin, and (iv) tramadol; the second agent is selected from the group consisting of an oxidative phosphorylation inhibitor, an ionophore, and an AMPK activator; the third agent has or maintains 5-hydroxytryptamine activity.

58. The method of claim 57, wherein the composition consists essentially of the first, second, and third agents.

59. The composition of claim 57, wherein the second agent is an AMPK activator.

60. The composition of claim 57, wherein the second agent is an oxidative phosphorylation inhibitor or an ionophore.

61. The composition of claims 57-60, wherein the hyperproliferative disease is a benign tumor.

62. The composition of claims 57-60, wherein the hyperproliferative disease is a malignancy.

63. The composition of claims 57-60, wherein the hyperproliferative disease is a solid tumor.

64. A method of treating a hyperproliferative disease comprising administering to a subject in need thereof an effective amount of a composition comprising a first agent selected from the group consisting of: (i) an agent having anti-inflammatory activity, (ii) acetaminophen, (iii) phenacetin, and (iv) tramadol; the second agent is selected from the group consisting of an oxidative phosphorylation inhibitor, an ionophore, and an AMPK activator; the third agent possesses or maintains 5-hydroxytryptamine activity, wherein the first, second, and third agents are associated with their respective carrier substances that facilitate transport of the active agents to the target site of action.

65. A method of treating a hyperproliferative disease comprising administering to a subject in need thereof an effective amount of a composition comprising a first agent selected from the group consisting of: (i) an agent having anti-inflammatory activity, (ii) acetaminophen, (iii) phenacetin, and (iv) tramadol; the second agent is selected from the group consisting of an oxidative phosphorylation inhibitor, an ionophore, and an AMPK activator; the third agent possesses or maintains 5-hydroxytryptamine activity, wherein the first and second agents are associated with their respective carrier substances that facilitate transport of the active agents to the target site of action.

66. The method of claim 64, wherein said composition consists essentially of said first, second and third agents and a carrier substance.

67. The method of claim 64 or 65, wherein the second agent is an AMPK activator.

68. The method of claim 64 or 65, wherein the second agent is an oxidative phosphorylation inhibitor or an ionophore.

69. The method of claim 64 or 65 wherein the carrier substance is an antibody.

70. The method of claim 64 or 65, wherein the antibody is specific for a marker of the hyperproliferative disease cell.

71. The method of claim 70, wherein the disease is a benign tumor.

72. The method of claim 70, wherein the disease is a malignancy.

73. The method of any of claims 64-70, wherein the subject experiences less side effects than treatment with an effective amount of the composition without the carrier substance.

74. A method of inhibiting metastasis, comprising administering to a subject in need thereof the composition of any one of claims 29-56.

75. A method of treating a hyperproliferative disease comprising administering to a subject in need thereof an effective amount of a composition comprising an active agent selected from the group consisting of an oxidative phosphorylation inhibitor, an ionophore, and an AMPK activator; wherein the active agent is associated with a carrier substance that facilitates transport of the active agent to the target site of action.

76. The method of claim 75 wherein said active agent is selected from the group consisting of metformin and phenformin, and pharmaceutically acceptable salts, prodrugs and solvates thereof, and said carrier substance is an antibody specific for a marker on cells of said hyperproliferative disease.

77. The method of claim 75, wherein the active agent is an AMPK activator.

78. The method of claim 75, wherein the active agent is an oxidative phosphorylation inhibitor or an ionophore.

79. The method of claim 75, wherein the hyperproliferative disease is colon cancer.

80. The method of claims 75-79, wherein said active agent is administered orally.

81. The method of claims 75-79, wherein the active agent is administered parenterally.

82. The method of claims 75-79, wherein the disease is a benign tumor.

83. The method of claims 75-79, wherein the disease is a malignant tumor.

84. The method of claims 75-79, wherein the subject experiences less side effects than treatment with an effective amount of the active agent without a carrier substance.

85. The method of claim 84, wherein said active agent is administered orally.

86. The method of claim 84, wherein the active agent is administered parenterally.

87. The method of claim 84, wherein the disease is a benign tumor.

88. The method of claim 84, wherein the disease is a malignancy.