US 2011 O158983A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0158983 A1 Bascomb et al. (43) Pub. Date: Jun. 30, 2011

(54) COMPOSITIONS AND METHODS FOR A63L/4045 (2006.01) MUCOSITIS AND ONCOLOGY THERAPES A638/00 (2006.01) A 6LX 3/57 (2006.01) (76) Inventors: Newell Bascomb, Chester Springs, A 6LX 3L/2197 (2006.01) PA (US); John Maki, Mendham, A63L/506 (2006.01) NJ (US); Fredric S. Young, Los A63L/454 (2006.01) Altos, CA (US) A6II 3/69 (2006.01) A63L/352 (2006.01) (21) Appl. No.: 12/921,145 A63L/382 (2006.01) A63L/337 (2006.01) (22) PCT Fled: Mar. 5, 2009 A6II 3/426 (2006.01) A63L/437 (2006.01) A63/675 (2006.01) S371 (c)(1), A63L/4375 2006.O1 (2), (4) Date: Mar. 14, 2011 A63L/435 308: Related U.S. Application Data 3. 7. 308: (60) Provisional application No. 61/034,122, filed on Mar. A638/02 (2006.01) 5, 2008, provisional application No. 61/079,768, filed A6IP35/00 (2006.01) on Jul. 10, 2008, provisional application No. 61/086, A6IPI/00 (2006.01) 437, filed on Aug. 5, 2008, provisional application No. B65D 69/00 (2006.01) 61/144,121, filed on Jan. 12, 2009. (52) U.S. Cl...... 424/133.1: 514/423: 514/165; 514/567; 514/568: 514/411; 514/570; 514/420; Publication Classification 514/413: 514/226.5: 514/682: 514/569; 514/374; (51) Int. Cl. si...","...si...S. St. E. 30: 424/141.1; 514/19.3: 514/266.4: 514/252.18: A6 IK3I/60 (2006.01) 514/234.5; 514/.414: 514/252.19; 514/275; A6 IK3I/I96 (2006.01) 514/323: 514/64; 514/456; 514/437; 514/449; A6 IK3I/92 (2006.01) 514/365: 514/266.24; 514/285; 424/649; A6 IK 3/407 (2006.01) 514/90; 514/283: 514/284: 514/291; 514/29: A6 IK 3/405 (2006.01) 514/2.3; 206/570 A6 IK3I/545 (2006.01) (57) ABSTRACT A6 IK 3L/2 (2006.01) A6 IK 3/42 (2006.01) In alternative embodiments, this invention provides compo A6 IK 3/40 (2006.01) sitions and methods for treating cancer or any condition A6 IK 3L/45 (2006.01) caused by dysfunctional cells, side effects from treatments for A6 IK3I/365 (2006.01) cancer or any condition caused by dysfunctional cells, e.g., A6 IK3I/444 (2006.01) mucositis therapies (e.g., for oral mucositis; digestive A6 IK 3/42 (2006.01) mucositis; esophageal mucositis; intestinal mucositis). In A6 IK3I/35 (2006.01) alternative embodiments, the invention provides cytoprotec A6 IK3I/64 (2006.01) tion products that may be used either alone or in combination A6 IK3I/38 (2006.01) with other medical therapies such as cancer chemotherapies A 6LX 3/5.377 (2006.01) and radiation therapies. US 2011/0158983 A1 Jun. 30, 2011

COMPOSITIONS AND METHODS FOR yphenyl)acetamide (paracetamol or acetaminophen); 2-4- MUCOSITIS AND ONCOLOGY THERAPES (2-methylpropyl)phenylpropanoic acid (ibuprofen); an anticonvulsant orantiseizure drug; an neuropathic pain anal FIELD OF THE INVENTION gesic; an opioid (opiate) painkiller (analgesic); an antibiotic; an antidepressant orantipsychotic; or, further comprising any 0001. This invention relates generally to medicine and pharmaceutical formulations. In alternative embodiments, combination thereof. this invention provides cancer and mucositis therapies (e.g., 0011. The therapeutic combination of claim 1, wherein (i) for oral mucositis; digestive mucositis; esophageal mucositis; the non-steroidal anti-inflammatory drug (a NSAID) com intestinal mucositis) and cytoprotection products that may be prises (a) a cyclooxygenase (COX) (or prostaglandin Syn used either alone or in combination with other medical thera thase) inhibitor; or, (b) the COX inhibitor of (a), wherein the pies, such as cancer chemotherapies and radiation therapies. COX inhibitor comprises or consists of an etodolac or equiva lent; a naproxen or equivalent; a celecoxib or equivalent; a BACKGROUND rofecoxib or equivalent; a etoricoxib or equivalent; a Valde coxib or equivalent; a parecoxib or equivalent; anabumetone 0002 Oral mucositis is an adverse side effect of chemo or equivalent; a diclofenac(2-(2,6-dichloranilino)phenylace therapy and radiation. Current cancer treatment methods commonly include chemotherapy and radiation therapy. tic acid) or equivalent; or, alumiracoxib or equivalent; (ii) the These treatments are associated with adverse effects, even neuropathic pain analgesic comprises or consists of gabapen though they are used with the desire to extend patient survival tin or pregabalin; or (iii) the antisense or siRNA nucleic acid and improve quality of life. For example, the severe adverse comprises or consists of oblimersen or GENASENSETM. reactions to these therapies include increased patient morbid 0012. In alternative embodiments of the therapeutic com ity and mortality. There are approximately 400,000 cases of bination(s) of the invention, the etodolac is LODINETM, treatment-induced damage to the oral cavity worldwide every LODINE SRTM or ECCOXOLACTM; or the celecoxib is year. Cytotoxicity from chemotherapy and radiotherapy often CELEBREXTM or CELEBRATM; or the rofecoxib is results in oral mucositis with associated illness and pain, VIOXXTM, CEOXXTM or CEEOXXTM: or the etoricoxib is including odynophagia (e.g. painful Swallowing), dysgeusia ARCOXIATM, ALGIXTM or TAUXIBTM; or the valdecoxib is (e.g. distortion and/or decrease of the sense of taste) and BEXTRATM; the parecoxib is DYNASTATTM; the naproxen Subsequent dehydration and malnutrition. Clinically, this tox is XENOBIDTM, ALEVETM, ANAPROXTM, MIRANAXTM, icity is ranges from slight erythema (e.g. redness of the skin NAPROGESICTM NAPROSYNTM, NAPRELANTM, associated with capillary congestion) and edema of the oral PROXENTM or SYNFLEXTM: the nabumetone is mucosa (e.g. Swelling due to an increase in interstitial fluid) to RELAFENTM, RELIFEXTM or GAMBARANTM; or, the severe, focal or widespread ulceration, bleeding and exuda diclofenac is FLECTOR PATCHTM, VOLTARENTM, tion (e.g. oozing from Sores). VOLTAROLTM, DICLONTM, DICLOFLEX DIFENTM, SUMMARY OF THE INVENTION DIFENETM, CATAFLAMTM, PENNSAIDTM, PAN AMORTM, RHUMALGANTM, MODIFENACTM, ABI 0003. The invention provides cyto-protection products TRENTM, OLFENTM, VOVERANTM, ARTHROTECTM, and therapies that may be used either alone or in combination DEDOLORTM, DEFLAMATTM, VETAGESICTM or with other medical therapies such as cancer chemotherapies ZOLTEROLTM. and radiation therapies. The products and methods of the 0013. In alternative embodiments of the therapeutic com invention can be used to: treat orameliorate cancer (including bination(s) of the invention, the beta adrenergic receptor any tumor, benign or metastatic), or treat, abolish, ameliorate, antagonist (a beta blocker) comprises propranolol or equiva diminish, improve, and/or inhibit unwanted side effects and lent; or, the propranolol is INDERALTM, AVLOCARDYLTM, disease state symptoms, e.g., of a mucositis, such as an oral DERALINTM, DOCITONTM, INDERALICITM, INNOPRAN mucositis, digestive mucositis, esophageal mucositis, and/or XLTM, or SUMIALTM. intestinal mucositis, or any other side effect resulting from a 0014. In alternative embodiments of the therapeutic com Cancer treatment. bination(s) of the invention, the beta adrenergic receptor 0004. In alternative embodiments, the invention provides antagonist (a beta blocker) comprises propranolol or equiva a therapeutic combination or combinations of drugs for an lent and the non-steroidal anti-inflammatory drug (a NSAID) individual in need thereof comprising or consisting of comprises etodolac or equivalent. 0005 (i) (a) a beta adrenergic receptor antagonist; (b) a 0015. In alternative embodiments of the therapeutic com non-steroidal anti-inflammatory drug (a NSAID); and (c) a bination(s) of the invention, the therapeutic agent for the therapeutic agent for the treatment of cancer, treatment of cancer comprises or consists of a monoclonal 0006 (ii) (a) a macrollide or a composition comprising a antibody, a peptide, a synthetic polypeptide or peptidomi macrollide ring, and (b) a therapeutic agent for the treatment metic, a nucleic acid, a synthetic nucleic acid, a lipid, a of cancer, carbohydrate and/or a small molecule. 0007 (iii)(a) an immunosuppressant composition orphar 0016. In alternative embodiments of the therapeutic com maceutical, and (b) a therapeutic agent for the treatment of bination(s) of the invention, the therapeutic agent for the Cancer, treatment of cancer comprises or consists of a Sorafenib or 0008 (iv) (a) a proton pump inhibitor (a PPI), and (b) a equivalent, or NEXAVARTM; a Sunitinib or equivalent, or therapeutic agent for the treatment of cancer, SUTENTTM; an erlotinib or equivalent, or TARCEVATM; an 0009 (v) any combination of the therapeutic combination imatinib or equivalent, or GLEEVECTM: a lapatinib or of drugs of (i), (ii), (iii) and/or (iv); or equivalent, or TYKERBTM; a bevacizumab or equivalent, or 0010 (vi) the combination of any of (i) to (v) further AVASTINTM: a trastuzumab or equivalent, or HERCEP comprising a proton pump inhibitor (a PPI); a synthetic pros TINTM: a cetuximab or equivalent, or ERBITUXTM: a beva taglandin E (PGE) analogue misoprostol; N-(4-hydrox cizumab or equivalent, or AVASTINTM or BIBW 2992; a US 2011/0158983 A1 Jun. 30, 2011 gefitinib or equivalent, or IRESSATM; a ranibizumab or podophyllotoxin or equivalent; a camptothecin or equivalent; equivalent, or LUCENTISTM; a pegaptainib or equivalent, or an irinotecan or equivalent, or CAMPTOSARTM; or, a com MACUGENTM: a dasatinib or equivalent, or BMS-354825TM; bination thereof. a Sunitinib or equivalent, or SUTENTTM; a pazopanib or 0022. In alternative embodiments of the therapeutic com equivalent; a nilotinib or equivalent, or TASIGNATM; a pani bination(s) of the invention, the therapeutic agent for the tumumab or equivalent, or VECTIBIXTM: a bandetinib or treatment of cancer comprises or consists of an antibiotic, equivalent; a brivanib or equivalent, or E7080TM; thalidomide e.g., a glycopeptide antibiotic; and the glycopeptide antibi or equivalent, or THALOMIDTM; lenalidomide or equivalent, otic can comprise or consist of a bleomycin or equivalent or a or REVLIMIDTM; bortezomib or equivalent, or VEL bleomycin A or B or equivalent; a mitomycin or a mitomy CADETM; disulfiram or equivalent, or ANTABUSETM or cin C or equivalent, a plicamycin (also known as mithramy ANTABUSTM; or epigallocatechingallate (EGCG) or equiva cin) or equivalent, or MITHRACINTM: or, a combination lent; a demecolcine; an etoglucid or elsamitrucin, a thereof. lonidamine, a lucanthone, a mitotane or a mitoguaZone or 0023. In alternative embodiments of the therapeutic com equivalent; or any combination thereof. bination(s) of the invention, the therapeutic agent for the 0017. In alternative embodiments of the therapeutic com treatment of cancer comprises or consists of a steroid receptor bination(s) of the invention, the therapeutic agent for the inhibitor or steroid inhibitor (an anti-steroid); and the steroid treatment of cancer comprises or consists of a protein kinase receptor inhibitor can comprise or consist of an estrogen inhibitor, and the protein kinase inhibitor can comprise or receptor modulator (a SERM), and the estrogen receptor consist of a tyrosine kinase inhibitor or a serine/threonine modulator can comprise or consist of a tamoxifen or equiva kinase inhibitor. lent, or NOLVADEXTM, ISTUBALTM or VALODEXTM. In 0018. In alternative embodiments of the therapeutic com alternative embodiments the steroid inhibitor or an anti-ste bination(s) of the invention, the therapeutic agent for the roid comprises or consists of a finasteride or equivalent, or treatment of cancer comprises or consists of an angiogenesis PROSCARTM, PROPECIATM, FINCARTM, FINPECIATM, inhibitor, and the angiogenesis inhibitor can comprise or FINAXTM, FINASTTM, FINARATM, FINALOTM, PROS consist of a vascular endothelial growth factor (VEGF)-me TERIDETM, GEFINATM, APPECIATM, FINASTERID diated angiogenesis inhibitor. IVAXTM, FINASTERID or ALTERNOVATM. 0019. In alternative embodiments of the therapeutic com 0024. In one embodiment of the therapeutic combination bination(s) of the invention, the therapeutic agent for the (s) of the invention, the therapeutic agent for the treatment of treatment of cancer comprises or consists of an inducer of cancer comprises or consists of a matrix metalloproteinase apoptosis or a mitotic and anti-microtubule inhibitor (inhibi (MMP) inhibitor, or comprises or consists of an inhibitor of a tion of microtubule function); and the inducer of apoptosis or collagenase, a gelatinase and/or a stromelysin enzyme; and mitotic or anti-microtubule inhibitor can comprise or consist the matrix metalloproteinase (MMP) inhibitor can comprise of a raltitrexed or equivalent, or TOMUDEXTM: a doxorubi or consist of batimastat, prinomastat or marimastat. cin or equivalent, or ADRIAMYCINTM: a fluorouracil or 0025. In alternative embodiments of the therapeutic com 5-fluorouracil or equivalent; a paclitaxel or equivalent, or bination(s) of the invention, the macrollide or composition TAXOLTM or ABRAXANETM; a docetaxel or equivalent, or comprising a macrollide ring comprises or consists of a mac TAXOTERETM: a larotaxel, tesetaxel or ortataxel or equiva rolide antibiotic; or the macrollide or composition comprising lent; an epothilone or an epothilone A, B, C, D, E or F or a macrollide ring can comprise or consist of a clarithromycin equivalent; an ixabepilone (also known as azaepothilone B) or equivalent, or BIAXINTM, KLARICIDTM, KLABAXTM, or equivalent, or BMS-247550TM; a vincristine (also known CLARIPENTM, CLARIDARTM, FROMILIDTM or as leurocristine) or equivalent, or ONCOVINTM: a vinblastin, CLACIDTM; an azithromycin or equivalent, or ZITHRO vinblastine, vindesine, Vinflunine, vinorelbine or NAVEL MAXTM, ZITROMAXTM or SUMAMEDTM; a dirithromycin BINETM or equivalent; or, any combination thereof. or equivalent; an erythromycin or equivalent; aroXithromycin 0020. In alternative embodiments of the therapeutic com or equivalent, or ROXOTM, SURLIDTM, RULIDETM, BIAX bination(s) of the invention, the therapeutic agent for the SIGTM, ROXARTM, ROXIMYCINTM or COROXINTM, a treatment of cancer comprises or consists of an alkylating telithromycin or equivalent or KETEKTM; a josamycin or agent; and the alkylating agent can comprise or consist of a equivalent; a kitasamycin or equivalent; a midecamycin or cisplatin or equivalent; a cisplatinum or equivalent; a cis equivalent, oleandomycin or equivalent; a roXithromycin or diamminedichloridoplatinum(II) (CDDP) or equivalent; a equivalent, or ROXOTM, SURLIDTM, RULIDETM, BIAX carboplatin or equivalent; a oxaloplatin or equivalent; a SIGTMROXARTM, ROXIMYCINTM or COROXINTM; atrole cyclophosphamide(cytophosphane) or equivalent, or andomycin or equivalent; or a tylosin or equivalent; or, any ENDOXANTM, CYTOXANTM, NEOSARTM or REVIM combination thereof. MUNETM; a mechlorethamine or equivalent; a chlormethine 0026. In alternative embodiments of the therapeutic com or equivalent; a mustine or equivalent; a nitrogen mustard or bination(s) of the invention, the immunosuppressant compo equivalent; a chlorambucil or equivalent, or LEUKERANTM: sition or pharmaceutical comprises or consists of a sirolimus or, a combination thereof. or equivalent (also known as rapamycin), or RAPAMUNETM: 0021. In alternative embodiments of the therapeutic com a tacrolimus or equivalent, or FK-506TM or FUJIMYCINTM: a bination(s) of the invention, the therapeutic agent for the ciclosporin (or cyclosporine or cyclosporin) or equivalent; or treatment of cancer comprises or consists of a topoisomerase a cortisone or equivalent. inhibitor, and the topoisomerase inhibitor can comprise or 0027. In alternative embodiments of the therapeutic com consist of an etoposide or equivalent, or EPOSINTM, ETO bination(s) of the invention, the proton pump inhibitor (a PPI) POPHOSTM, VEPESIDTM or VP16TM; an amsacrine or comprises or consists of an H-receptor antagonist (HRA); equivalent; a topotecan or equivalent, or HYCAMTINTM: a and the H-receptor antagonist (HRA) can comprise or con teniposide or equivalent, or VUMONTM or VM-26TM; an epi sist of a cimetidine or equivalent, or TAGAMETTM, TAGA US 2011/0158983 A1 Jun. 30, 2011

METHBTM or TAGAMET HB200TM; a ranitidine or equiva 0032. In alternative embodiments of the therapeutic com lent, or TRITECTM or ZANTACTM; a famotidine or bination(s) of the invention, one, two, three, four or five or equivalent, or PEPCIDINETM or PEPCIDTM; anizatidine or more or all of the drugs of the therapeutic combination are equivalent, or TAZACTM or AXIDTM, or the proton pump formulated (e.g., tableted) or manufactured as a parenteral inhibitor (PPI) can comprise or consist of a benzimidazole formulation, an aqueous solution, a liposome, an injectable compound or structure, or an imidazopyridine compound or Solution, a tablet, a pill, a lozenge, a capsule, a caplet, a patch, structure; e.g., the imidazopyridine compound or structure a spray, an inhalant, a powder, a freeze-dried powder, an can comprise or consist of a Zolpidem or equivalent, or inhalant, a patch, a gel, a geltab, a nanosuspension, a nano AMBIENTM, AMBIEN CRTM IVEDALTM, NYTAMELTM, particle, a nanoliposome, a microgel, a pellet, a Suppository STILNOCTTM, STILNOXTM, ZOLDEMTM, ZOLNODTM or or any combination thereof. ZOLPIHEXALTM; an alpidem (also called ananxyl) or 0033. In alternative embodiments of the therapeutic com equivalent; a Saripidem or equivalent, necopidem or equiva bination(s) of the invention, one, two, three, four or five or lent. more or all of the drugs of the therapeutic combination are 0028. In alternative embodiments of the therapeutic com formulated (e.g., tableted) or manufactured together in one bination(s) of the invention, one, two, three, four or five or parenteral formulation, one aqueous solution, one liposome, more drugs of the therapeutic combination are formulated as one injectable solution, one freeze-dried powder, one feed, separate compositions; or one, two, three, four or five or more one food, one food Supplement, one pellet, one lozenge, one drugs of the therapeutic combination are formulated into one liquid, one elixir, one aerosol, one inhalant, one adhesive, one composition or drug formulation (e.g., one, two, three, four or spray, one powder, one freeze-dried powder, one patch, one five or more or more drugs of the therapeutic combination are tablet, one pill, one capsule, one gel, one gel tab, one lozenge, formulated or tableted together). one caplet, one nanosuspension, one nanoparticle, one nano 0029. In alternative embodiments of the therapeutic com liposome, one microgel or one Suppository. bination(s) of the invention, the beta adrenergic receptor antagonist, or a beta blocker or equivalent, or a propranolol or 0034. In alternative embodiments of the therapeutic com equivalent; the non-steroidal anti-inflammatory drug, or a bination(s) of the invention: NSAID or equivalent, or an etodolac or equivalent; and the 0035 (a) the dosage of etodolac ranges from about 200 mg therapeutic agent for the treatment of cancer, are formulated to 400 mga day, or, about 10, 15, 20, 25, 30,35, 40, 45,50, 75, (e.g., tableted) or in different compositions or formulations, 80, 85,90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, or, are formulated in the same composition or formulation, or 700, 800, 900 or 1000 mg or more; or are formulated (e.g., tableted) or together. 0036) (b) the dosage of propranolol ranges from 10 to 320 0030. In alternative embodiments of the therapeutic com mg per day based on heart rate and blood pressure of the bination(s) of the invention, one, two, three, four or five or more or all of the drugs of the therapeutic combination are individual, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, formulated (e.g., tableted) or packaged individually, or are 85,90, 100, 150, 200,250, 300,350, 400, 450, 500, 600, 700, packaged together, or packaged in any combination, in a 800, 900 or 1000 mg or more. single package, a plurality of packages or packettes, or a 0037. In alternative embodiments of the therapeutic com blister packet, lidded blister or blister card or packets, or a bination(s) of the invention: shrink wrap. For example, the beta adrenergic receptor 0038 (a) the dosage of clarithromycin comprises or con antagonist, or a beta blocker or equivalent, or a propranolol or sists of a 250 mg immediate release formulation or tablet equivalent; the non-steroidal anti-inflammatory drug, or a every 12 hours, a 500 mg immediate release formulation or NSAID or equivalent, or an etodolac or equivalent; and the tablet every 12 hours, or a 1000 mg extended release formu therapeutic agent for the treatment of cancer, can be packaged lation or tablet once daily, or any combination thereof; individually in a single package, a plurality of packages or 0039 (b) the dosage of roxithromycin comprises or con packettes, or a blister packet, lidded blister or blister card or packets, or a shrink wrap. sists of a 300 mg formulation or tablet once a day, or a 150 mg 0031. In alternative embodiments of the therapeutic com formulation or tablet twice a day, or any combination thereof; bination(s) of the invention, one, two, three, four or five or 0040 (c) the dosage of rapamycin comprises or consists of more or all of the drugs of the therapeutic combination are 2 mg/day to 20 mg/day, based on tolerability and liver and formulated (e.g., tableted) or packaged together or in any kidney side effects; combination in a single package, a plurality of packages or 0041 (d) the dosage of rapamycin of (c), wherein the dose packettes, or a blister packet, lidded blister or blister card or is increased (doubled) every week; or packets, or a shrinkwrap. In one embodiment, one, two, three, 0042 (e) the dosage of rapamycin of (d), wherein the dose four or five or more or all of the drugs are released upon is doubled every week. opening of the single package, plurality of packages or pack 0043. In alternative embodiments of the therapeutic com ettes, blister packet, lidded blister, blister card or packets or bination(s) of the invention, the drug combination is pack shrink wrap. For example, the beta adrenergic receptor aged in dosages that match a chrono-dosing regimento match antagonist, or a beta blocker or equivalent, or a propranolol or an optimal dose for the time of day, the desired effect, the equivalent; the non-steroidal anti-inflammatory drug, or a patient, the patient's condition, and the like. For example, the NSAID or equivalent, or an etodolac or equivalent; and the beta adrenergic receptor antagonist or a beta blocker or therapeutic agent for the treatment of cancer can be packaged equivalent, or a propranolol or equivalent; the non-steroidal together in a single package, a plurality of packages or pack anti-inflammatory drug or NSAID or equivalent, or etodolac ettes, or a blister packet, lidded blister or blister card or or equivalent; and the therapeutic agent for the treatment of packets, or a shrink wrap, and one, two, three, four or five or cancer, can be packaged in dosages that match a chrono more or all of the drugs can be released upon opening of the dosing regimen to match an optimal dose for the time of day, single package, plurality of packages or packettes, blister the desired effect, the patient, the patient’s condition, and the packet, lidded blister, blister card or packets or shrink wrap. like. US 2011/0158983 A1 Jun. 30, 2011

0044. In alternative embodiments of the therapeutic com digestive mucositis, an esophageal mucositis, an intestinal bination(s) of the invention, the beta adrenergic receptor mucositis and/orananorexia. In alternative embodiments, the antagonist or beta blocker or equivalent or propranolol or therapeutic combination(s) of drugs of the invention are for equivalent; the non-steroidal anti-inflammatory drug or mulated for and/or are used for the treatment, amelioration NSAID or equivalent or etodolac or equivalent; and the thera and/or prevention of a cancer, a cachexia, a cancer cachexia, peutic agent for the treatment of cancer, are packaged in a mucositis, an oral mucositis, a digestive mucositis, an dosages that match a chrono-dosing regimen comprising: esophageal mucositis, an intestinal mucositis and/oran anor 0045 (a) in the AM, 20 mg beta adrenergic receptor CX1a. antagonist (a beta blocker), e.g., a propranolol or equivalent, 0056. In alternative embodiments, the therapeutic combi 200 mg NSAID, e.g., an etodolac or equivalent; in the after nation(s) of drugs of the invention are formulated for and/or noon, 10 mg beta blocker, 200 mg NSAID, e.g., an etodolac or are used for the treatment, amelioration and/or prevention of equivalent; in the PM, 10 mg beta blocker, 400 mg NSAID: a cachexia defined as at least two of the symptoms selected 0046 (b) in the AM 40 mg beta adrenergic receptor from the group consisting of: 1) a hyper-inflammatory state, antagonist (a beta blocker), e.g., a propranolol or equivalent, 2) altered hormone levels and cytokine levels; 3) decreased 200 mg NSAID, e.g., an etodolac or equivalent; in the after heart rate variability; 4) weight loss, and 5) increased heart noon 20 mg beta blocker, 200 mg NSAID; in the evening, 20 rate, wherein optionally the increased heart rate is having a mg propranolol, 400 mg NSAID: sustained elevated heart rate of at least about 6 bpm. The 0047 (c) in the AM 80 mg beta adrenergic receptor cachexia can be defined by an individual having at least a antagonist (a beta blocker), e.g., a propranolol or equivalent, sustained elevated heart rate of at least about 6 bpm and 200 mg NSAID; in the afternoon 40 mg beta blocker, 200 mg weight loss. NSAID, in the evening 40 mg, NSAID; or 0057. In one embodiment, the invention provides pharma 0.048 (d) a dose escalation comprising a regimen of (a) to ceutical compositions or formulations comprising atherapeu (b) to (c). tic combination of drugs of the invention; and the therapeutic 0049. In alternative embodiments of the therapeutic com combination can further comprise or further consist of a phar bination(s) of the invention, the beta adrenergic receptor maceutically acceptable excipient. In alternative embodi antagonist or beta blocker or equivalent or propranolol or ments the pharmaceutical composition(s) or formulation(s) equivalent; the non-steroidal anti-inflammatory drug or are formulated or manufactured as a feed, a food, a food or NSAID or equivalent or etodolac or equivalent; and the thera feed concentrate, a pellet, a lozenge, a liquid, a lotion, an peutic agent for the treatment of cancer, are packaged in implant, a nanoparticle, an elixir, an aerosol, a spray, an dosages that match a chrono-dosing regimen comprising: aerosol, an inhalant, a powder, a tablet, a pill, a capsule, a gel. 0050 Start: AM. 20 mg propranolol, 200 mg etodolac: a geltab, a nanosuspension, a nanoparticle, a patch, a micro afternoon, 10 mg propranolol, 200 mg etodolac: PM 5 mg gel and/or a Suppository. propranolol. 400 mg etodolac, 0058. In alternative embodiments, the invention provides 0051 Dose Escalation 1: AM 40 mg propranolol. 200 mg uses of a therapeutic combination of the invention in the etodolac, afternoon 20 mg propranolol. 200 mg etodolac, manufacture of a medicament orpharmaceutical composition evening, 10 mg propranolol, 400 mg etodolac, for treating, ameliorating or preventing a trauma, condition or 0052 Dose escalation 2: AM 80 mg propranolol, 200 mg disease comprising: a cancer or dysfunctional cell condition; etodolac, afternoon 40 mg propranolol. 200 mg etodolac, any side effect from the treatment of cancer, chronic Systemic evening 20 mg, etodolac. Inflammatory Response State (SIRS); chronic systemic 0053. In alternative embodiments of the therapeutic com inflammatory stress; burns, chronic obstructive pulmonary bination(s) of the invention, the therapeutic drug combination disease; congestive heart failure; chronic kidney disease; Sur is formulated for administration once a day, b.i.d. (twice a gery; sepsis: ageing; acute respiratory distress syndrome; day), t.i.d (three times a day), four times a day, five times a acute lung injury; infection; a CNS disorder or injury; ane day, or hourly, or weekly, or biweekly, or monthly, or in any mia; immunosuppression; insulin resistance; anorexia; anxi desired dosage for any desired administration regimen. For ety; sleep disturbances; weakness; fatigue; gastrointestinal example, the beta adrenergic receptor antagonist (a beta distress; sleep disturbances; wake disturbances; pain; listless blocker) or propranolol or equivalent; the non-steroidal anti ness; shortness of breath; lethargy; depression; malaise; or, a inflammatory drug or NSAID or etodolac or equivalent; and combination thereof. In alternative embodiments, the trauma, the therapeutic agent for the treatment of cancer, can be condition or disease comprises a maladaptive nutritional state formulated for administration once a day, b.i.d. or t.i.d., or secondary to the SIRS, or the maladaptive nutritional state weekly, or biweekly, or monthly. comprises cachexia, and optionally the cachexia comprises 0054. In alternative embodiments, the therapeutic combi cachexia secondary to cancer. In alternative embodiments, nation(s) of drugs are formulated for administration intrave the cancer or dysfunctional cell condition comprises (is) any nously, topically, orally, by inhalation, by infusion, by injec metastatic or benign tumor, and the use is for treating (killing, tion, by inhalation, intraperitoneally, intramuscularly, eliminating, stopping the growth and/or metastasis of) cancer Subcutaneously, intra-aurally, for intra-articular administra stem cells or cancer cells from: lung cancer, bone cancer, tion, for intra-mammary administration, for topical adminis pancreatic cancer, skin cancer, cancer of the head or neck, tration or for absorption through epithelial or mucocutaneous cutaneous or intraocular melanoma, uterine cancer, ovarian linings; or are formulated for administration using any route cancer, rectal cancer, cancer of the anal region, stomach can or combination of routes of administration. cer, colon cancer, breast cancer, carcinoma of the fallopian 0055. In alternative embodiments, the therapeutic combi tubes, carcinoma of the endometrium, carcinoma of the cer nation(s) of drugs further comprise instructions for use, e.g., vix, carcinoma of the vagina, carcinoma of the Vulva, in the treatment, amelioration and/or prevention of a cancer, a Hodgkin's Disease, cancer of the esophagus, cancer of the cachexia, a cancer cachexia, a mucositis, an oral mucositis, a Small intestine, cancer of the endocrine system, cancer of the US 2011/0158983 A1 Jun. 30, 2011

thyroid gland, cancer of the parathyroid gland, cancer of the carcinoma of the renal pelvis, a neoplasm of the central ner adrenal gland, sarcoma of Soft tissue, cancer of the urethra, vous system (CNS), primary CNS lymphoma, spinal axis cancer of the penis, prostate cancer, chronic or acute leuke tumors, brain stem glioma or pituitary adenoma, and any mia, lymphocytic lymphomas, cancer of the bladder, cancer combination thereof. of the kidney or ureter, renal cell carcinoma, carcinoma of the 0065. In alternative embodiments the cachexia is defined renal pelvis, neoplasms of the central nervous system (CNS), as at least two of the symptoms selected from the group primary CNS lymphoma, spinal axis tumors, brain stem consisting of: 1) a hyper-inflammatory state, 2) altered hor glioma or pituitary adenoma, and any combination thereof. mone levels and cytokine levels; 3) decreased heart rate vari 0059. In alternative embodiments of the use(s) of the ability; 4) weight loss, and 5) increased heart rate, wherein invention, wherein the cachexia is defined as at least two of optionally the increased heart rate is having a Sustained the symptoms selected from the group consisting of: 1) a elevated heart rate of at least about 6 bpm; or, the cachexia is hyper-inflammatory state, 2) altered hormone levels and defined by an individual having at least a Sustained elevated cytokine levels; 3) decreased heart rate variability; 4) weight heart rate of at least about 6 bpm and weight loss. loss, and 5) increased heart rate, wherein optionally the 0066. In alternative embodiments the mucositis is a increased heart rate is having a Sustained elevated heart rate of mucositis caused by a chemotherapy and/or a radiation at least about 6 bpm; or, the cachexia is defined by an indi therapy, oran oral mucositis, a digestive mucositis, an esoph vidual having at least a Sustained elevated heart rate of at least ageal mucositis or an intestinal mucositis. about 6 bpm and weight loss. 0067. In alternative embodiments the invention provides 0060. In alternative embodiments of the use(s) of the composition(s) or a product or products of manufacture com invention, the CNS disorder comprises Parkinson's disease or prising a therapeutic combination of the invention, and/or the Alzheimer's disease. pharmaceutical composition or formulation of the invention. 0061. In alternative embodiments the invention provides The pharmaceutical composition or formulation of the inven methods for treating, preventing and/or ameliorating a tion can comprise (e.g., be manufactured as) a blister pack, trauma, condition or disease comprising a cancer or dysfunc clamshell ortray; and in one aspect the therapeutic combina tional cell condition or a mucositis, any side effect from the tion is formulated for unit dosage administration to an indi treatment of a cancer or dysfunctional cell condition, chronic vidual in need thereof at the same time, and each unit dosage Systemic Inflammatory Response State (SIRS), chronic sys is contained within one blister in the blister pack, or compart temic inflammatory stress; burns, chronic obstructive pulmo ment in the clamshell or tray. The pharmaceutical composi nary disease; congestive heart failure; chronic kidney disease; tion or formulation of the invention can comprise (e.g., be Surgery; cancer, sepsis: ageing; acute respiratory distress Syn manufactured as) a caplet, a lozenge, a pill, capsule, tablet, drome; acute lung injury; infection; a CNS disorder or injury; tab, geltab or implant, wherein the therapeutic combination is anemia; immunosuppression; insulin resistance; anorexia; formulated for unit dosage administration to an individual in anxiety; sleep disturbances; weakness; fatigue; gastrointesti need thereof at the same time. nal distress; sleep disturbances; wake disturbances; pain; list 0068. The pharmaceutical composition or formulation of lessness; shortness of breath; lethargy; depression; malaise; the invention can be manufactured in unit dosages, wherein in or, a combination thereof, the method comprising the steps of alternative embodiments each unit dosage is contained within 0062 (a) providing a therapeutic combination of the one, two or three or more caplet(s), lozenge(s), pill(s), capsule invention, or the pharmaceutical composition or formulation (S), tablet(s), tab(s), geltab(s) or implant(s). of the invention; and, 0069. In alternative embodiments the invention provides a 0063 (b) administering a therapeutically effective amount nanoparticle, microparticle, nanoliposome or liposome com of the therapeutic combination or the pharmaceutical compo prising a therapeutic combination of the invention, or the sition or formulation of step (a), thereby treating or amelio pharmaceutical composition or formulation of the invention. rating the side effect, trauma, condition or disease. 0070. In alternative embodiments the invention provides a 0064. In alternative embodiments, the condition or disease kit or kits comprising a therapeutic combination of the inven comprises a maladaptive nutritional State secondary to the tion, or the pharmaceutical composition or formulation of the SIRS; or, the maladaptive nutritional state comprises invention. In alternative embodiments the kits comprise at cachexia or anorexia, or a cachexia secondary to cancer. In least one blister pack, lidded blister or blister card or packets, alternative embodiments the cancer or dysfunctional cell con or a shrink wrap, comprising the therapeutic combination or dition comprises (is) any metastatic or benign tumor, and the the pharmaceutical composition. use is for treating (killing, eliminating, stopping the growth 0071. In alternative embodiments the invention provides a and/or metastasis of) cancer stem cells or cancer cells from: kit or kits for the treatment, amelioration or prevention of a lung cancer, bone cancer, pancreatic cancer, skin cancer, can mucositis, a cancer or any dysfunctional cell condition, a side cer of the head or neck, cutaneous or intraocular melanoma, effect from the treatment of a cancer or dysfunctional cell uterine cancer, ovarian cancer, rectal cancer, cancer of the condition, a chronic Systemic Inflammatory Response State anal region, Stomach cancer, colon cancer, breast cancer, car (SIRS) or a maladaptive nutritional state in a patient popula cinoma of the fallopian tubes, carcinoma of the endometrium, tion, the kit comprising a therapeutic combination of the carcinoma of the cervix, carcinoma of the vagina, carcinoma invention, or the pharmaceutical composition or formulation of the Vulva, Hodgkin's Disease, cancer of the esophagus, of the invention, and instructions for use of the therapeutic cancer of the Small intestine, cancer of the endocrine system, combination or pharmaceutical composition. In alternative cancer of the thyroid gland, cancer of the parathyroid gland, embodiments of the kits the mucositis is a mucositis second cancer of the adrenal gland, sarcoma of soft tissue, cancer of ary to radiotherapy (radiation therapy) and/or chemotherapy, the urethra, cancer of the penis, prostate cancer, chronic or or the mucositis is an oral mucositis, a digestive mucositis, an acute leukemia, lymphocytic lymphomas, cancer of the blad esophageal mucositis, an intestinal mucositis. In alternative der, cancer of the kidney or ureter, renal cell carcinoma, embodiments of the kits the maladaptive nutritional state US 2011/0158983 A1 Jun. 30, 2011

comprises cachexia, and optionally the cachexia comprises 0077. In alternative embodiments, the products of manu cachexia secondary to cancer. In alternative embodiments the facture or formulations of the invention comprise a therapeu cachexia is defined: tic combination of the invention or the pharmaceutical com 0072 (a) as having (being associated with) at least two of position or formulation of the invention, and a nutritional the symptoms selected from the group consisting of: 1) a Supplement, or food Supplement or feed Supplement. 0078. In alternative embodiments the invention provides hyper-inflammatory state, 2) altered hormone levels and/or methods for treating, ameliorating or preventing mucositis, a cytokine levels; 3) decreased heart rate variability; 4) weight cachexia and/or a chronic Systemic Inflammatory Response loss, and 5) Sustained increased heart rate, wherein optionally State (SIRS), wherein a therapeutic combination of the inven the Sustained increased heart rate is having a Sustained tion, or the pharmaceutical composition or formulation of the elevated heart rate of at least about 6 bpm; or invention, is administered to an individual in need thereof. 0073 (b) by an individual having at least a sustained and in alternative embodiments the therapeutic combination elevated heart rate of at least about 6 bpm and weight loss. or the pharmaceutical composition are formulated for mul 0074. In alternative embodiments, the cancer or dysfunc tiple administrations, e.g., at least two administrations, one in tional cell condition comprises (is) any metastatic or benign the morning and one in the evening, wherein the dosage tumor, and the intended use is for treating (killing, eliminat schedule provides a relatively higher dose of beta blocker in ing, stopping the growth and/or metastasis of), ameliorating the morning (the AM) than in the evening, and a relatively and/or preventing the formation (generation) of cancer stem higher dose of an anti-inflammatory medication in the cells or cancer cells from: lung cancer, bone cancer, pancre evening than in the morning. atic cancer, skin cancer, cancer of the head or neck, cutaneous 0079. In alternative embodiments of the methods of the invention, the administration regimen comprises at least two or intraocular melanoma, uterine cancer, ovarian cancer, rec dosages of beta adrenergic receptor antagonist (a beta tal cancer, cancer of the anal region, stomach cancer, colon blocker) drug and at least two dosages of non-steroidal anti cancer, breast cancer, carcinoma of the fallopian tubes, car inflammatory drug (a NSAID), and in alternative embodi cinoma of the endometrium, carcinoma of the cervix, carci ments further comprises administration of an anti-anxiety noma of the vagina, carcinoma of the Vulva, Hodgkin’s Dis drug, a synthetic prostaglandin E (PGE) analogue miso ease, cancer of the esophagus, cancer of the Small intestine, prostol; N-(4-hydroxyphenyl)acetamide(paracetamol or cancer of the endocrine system, cancer of the thyroid gland, acetaminophen); 2-4-(2-methylpropyl)phenylpropanoic cancer of the parathyroid gland, cancer of the adrenal gland, acid (ibuprofen); an anticonvulsant or antiseizure drug; an sarcoma of soft tissue, cancer of the urethra, cancer of the neuropathic pain analgesic; an opioid (opiate) painkiller (an penis, prostate cancer, chronic or acute leukemia, lympho algesic); an antibiotic; an antidepressant or antipsychotic; or, cytic lymphomas, cancer of the bladder, cancer of the kidney further comprising any combination thereof, and in alterna or ureter, renal cell carcinoma, carcinoma of the renal pelvis, tive embodiments the drugs are organized or labeled in one or neoplasms of the central nervous system (CNS), primary more blister packages, one or more lidded blisters or one or CNS lymphoma, spinal axis tumors, brain stem glioma or more blister cards or packets, one or more clamshells, one or pituitary adenoma, and any combination thereof. more trays or one or more shrink wraps for usage by an 0075. In alternative embodiments the invention provides individual for at least two or more administrations, e.g., one in products of manufacture comprising ablister package, a lid the morning and one in the evening; and in one aspect the ded blister or a blister card or packet, a clamshell, a tray or a dosage schedule provides a relatively higher dose of beta shrink wrap comprising a therapeutic combination of the blocker in the morning (the AM) than in the evening, and a invention, or the pharmaceutical composition or formulation relatively higher dose of an anti-anxiety and/or an anti-in of the invention. In alternative embodiments the products of flammatory medication in the evening than in the morning. manufacture can comprise ablister package, a lidded blister 0080. In alternative embodiments of the methods of the or ablister card or packet, a clamshell, a tray or a shrink wrap invention, the administration regimen comprises doses of comprising atherapeutic combination of the invention, or the propranolol given in 20 or 40 mg tablets immediate release on pharmaceutical composition or formulation of the invention, a bid basis, and in the first dose week the doses for propranolol wherein the therapeutic combination or pharmaceutical com are 20 mg in the morning and 20 mg at bedtime, and after 1 position or formulation are manufactured and/or formulated week the dosage is adjusted to 20 mg of the immediate release for at least two, three, four or five or more dosage adminis product in the morning and 60 mg of the extended release at trations; or the therapeutic combination or pharmaceutical bedtime, and optionally if after an additional week the subject composition or formulation are manufactured and/or formu shows no improvement or has not obtained a 20% reduction in lated for once a day, orbid (twice a day), or tid (three times a heart rate, without decreasing heart rate below 60 bpm or day), or four times a day, administration. blood pressure below 90/60, the dose is adjusted to 40 mg of 0076. In alternative embodiments of the products of manu the immediate release propranolol in the morning and 120 mg facture of the invention the therapeutic combination or phar of the extended release propranolol at bedtime. maceutical composition or formulation are formulated (e.g., 0081. In alternative embodiments of the methods of the manufactured) as one dosage administration in the morning invention, the administration regimen comprises doses of and one dosage administration in the evening; or are formu etodolac are given in 200 mg capsules or 500 mg tablets on a lated as one dosage administration in the morning, one dosage bid basis, and doses for etodolac are started at 200 mg in the mid-day and one dosage administration in the evening. In one morning and at bedtime, and after 1 week the dosage are aspect, the dosage schedule provides a relatively higher dose adjusted to 200 mg in the morning and 500 mg at bedtime. of one drug in the morning (the AM) than in the evening, and I0082 In alternative embodiments of the invention pro a relatively higher dose of another medication in the evening vides ablister pack or a plurality of blister packettes, ablister than in the morning. package, a lidded blister or a blister card or packet, a clam US 2011/0158983 A1 Jun. 30, 2011

shell, a tray or a shrink wrap, comprising a therapeutic com tical composition or formulation of the invention. In alterna bination of the invention, or the pharmaceutical composition tive embodiments the invention provides nutraceuticals com or formulation of the invention. In alternative embodiments prising the therapeutic combination of the invention, or the of the blister pack or a plurality of blister packettes, a blister pharmaceutical composition or formulation of the invention. package, a lidded blister or a blister card or packet, a clam I0088. The invention provides compositions or product of shell, a tray or a shrink wrap, the therapeutic combination of manufactures comprising: drugs are arranged or clustered in the blister pack or a plural I0089 (a) a combination of compounds comprising or con ity of blister packettes: (a) in a chrono-dosing arrangement or sisting of pattern; or (b) individually. 0090 (i) at least two different compounds, each 0083. In alternative embodiments of the invention pro Selected from a separate group selected from the group vides a paper, plastic or cellophane package or a plurality of consisting of Group A, Group B. Group C, Group D, packettes comprising a therapeutic combination of the inven Group E, Group F, Group G, Group H, Group I, Group J. tion, or the pharmaceutical composition or formulation of the Group K, Group L and Group M, as set forth in Table 1, invention. In alternative embodiments the invention provides Or, of the paper, plastic or cellophane package or a plurality of 0.091 (ii) at least two different compounds, wherein at packettes the therapeutic combination of drugs are arranged least two of the compounds are selected from the same or clustered in the paper, plastic or cellophane package or a group selected from the group consisting of Group A, plurality of packettes: (a) in a chrono-dosing arrangement or Group B. Group C, Group D, Group E, Group F, Group pattern; or (b) individually. G. Group H, Group I, Group J. Group K, Group L and 0084. In alternative embodiments of the invention a drug Group M, wherein combination of the invention is formulated, packaged or 0092 Group A comprises geranylgeranyl compounds designed for drug regimen compliance of a cancer patient (acyclic polyisoprenoids); population, a pediatric or geriatric population, or a mentally 0093 Group B comprises Angiotensin Converting compromised patient population. Enzyme Inhibitors (ACE Inhibitors or ACE-Is); 0085. In alternative embodiments of the invention drug 0094 Group C comprises Angiotensin Receptor Blockers combination(s) of the invention are formulated, packaged or (ARBs): designed for drug regimen compliance of a cancer patient (0095 Group D comprises Peroxisome Proliferator-Acti population having mild or severe mental retardation, slow vated Receptor (PPAR) ligands; cognition, dementia, senility, Alzheimer's disease, traumatic I0096 Group E comprises Non-Steroidal Anti-Inflamma brain injury, chemical brain damage, mental diseases (e.g., tory Drugs (NSAIDs); dissociative disorder, obsessive-compulsive disorder, delu 0097 Group F comprises compositions for chemotherapy sional disorder, Schizophrenia, mania, panic disorder, depres or radiation therapy (chemotherapy compositions include Sion, dyslexia, any learning disability and the like) post-trau e.g., biologics such as proteins (e.g., peptides, antibodies, matic stress disorder, traumatic war neurosis, post-traumatic cytokines and the like) and Small molecules Such as alkylating stress syndrome (PTSS), physical disability (e.g., blindness). agents); I0086. In alternative embodiments of the blister pack or a (0098 Group G comprises TNF inhibitors; plurality of blisterpackettes, ablisterpackage, a lidded blister 0099 Group H comprises deferrioxamine or deferoxam or ablister card or packet, a clamshell, a tray or a shrink wrap of the invention, or the paper, plastic or cellophane package or ine; a plurality of packettes of the invention, wherein the drug 0100 Group I comprises polyunsaturated fatty acids; combination is formulated, packaged or designed for drug 0101 Group J comprises eflornithine(C-difluoromethy regimen compliance of a cancer patient population, a pediat lornithine or DFMO); ric or geriatric population, or a mentally compromised patient 0102 Group K comprises superoxide dismutases (SOD), population. In alternative embodiments of a blister pack or a catalases, Superoxide dismutase (SOD)-catalase conjugates plurality of blisterpackettes, ablisterpackage, a lidded blister or complexes, peroxiredoxins and peroxidases; or ablister card or packet, a clamshell, a tray or a shrink wrap 0103 Group L comprises activators of a heat shock of the invention, or a paper, plastic or cellophane package or response; a plurality of packettes of the invention, the drug combination 0104 Group M comprises drugs that reduce an inflamma is formulated, packaged or designed for drug regimen com tory response or a progressive tissue damage response; pliance of a cancer patient population having mild or severe 0105 (b) the composition or product of manufacture of (a) mental retardation, slow cognition, dementia, senility, Alzhe comprising or consisting of imer's disease, traumatic brain injury, chemical brain dam 0106 (i) at least three, four, five, six, seven, eight, nine age, mental diseases (e.g., dissociative disorder, obsessive or ten or more different compounds, each selected from compulsive disorder, delusional disorder, Schizophrenia, a separate group selected from the group consisting of mania, panic disorder, depression, dyslexia, any learning dis Group A, Group B. Group C, Group D, Group E, Group ability and the like) post-traumatic stress disorder, traumatic F. Group G, Group H, Group I, Group J. Group K, Group war neurosis, post-traumatic stress syndrome (PTSS), physi L and Group M, as set forth in Table 1, or, cal disability (e.g., blindness). 0.107 (ii) at least three, four, five, six, seven, eight, nine 0087. In alternative embodiments the invention provides a or ten or more different compounds, wherein at least food or food Supplement comprising the therapeutic combi three, four, five, six, seven, eight, nine or ten or more of nation of the invention, or the pharmaceutical composition or the compounds are selected from the same group formulation of the invention. In alternative embodiments the Selected from the group consisting of Group A, Group B, invention provides feed or feed Supplements comprising the Group C, Group D, Group E, Group F, Group G, Group therapeutic combination of the invention, or the pharmaceu H. Group I, Group J. Group K, Group L and Group M. US 2011/0158983 A1 Jun. 30, 2011

0108 (c) the composition or product of manufacture of (a) cam, salsalate, sulindac, tolmetin, a COX2-selective NSAID, or (b), wherein the combination of compounds comprise or celecoxib, rofecoxib, etoricoxib, Valdecoxib, parecoxib, consist of at least one, three, four, five, six, seven, eight, nine meloxicam or lumiracoxib; or ten or more compounds selected from at least one, three, I0123 (g) the composition or product of manufacture of (f), four, five, six, seven, eight, nine, ten, eleven, twelve or all of the following groups: Group A, Group B. Group C, Group D, wherein the combination of compounds comprises or consists Group E, Group F, Group G, Group H, Group I, Group J. of a GGA or an analog of GGA or a teprenone or a SEL Group K, Group L, and/or Group M: BEXTMand: VOLTARENTM, CATAFLAMTM, VOLTAREN 0109 (d) the composition or product of manufacture of XRTM, DOLOBIDTM LODINETM, NALFONTM, ANSAIDTM, (c), wherein the combination of compounds comprises or FROBENTM, MOTRINTM, INDOCINTM, INDOCIN-SRTM, consists of at least one compound from each of ORUDISTM, ORUVAILTM, TORADOLTM, MECLOMENTM, 0110 Group A and Group B. Group A and Group C, Group PONSTELTM, MOBICOXTM, MOBICTM, RELIFEXTM, A and Group D, Group A and Group E, Group A and Group F, RELAFENTM, ALEVETM ANAPROXTM, MIRANNAXTM, Group A and Group G, Group A and Group H, Group A and NAPROGESICTM, NAPROSYNTM, NAPRELANTM SYN Group I, Group A and Group J. Group A and Group K, Group FLEXTM, DAYPROTM or DURAPROXTM, FELDENETM, A and Group L. Group A and Group M. Group B and Group DISALCIDTM SALFLEXTM, CLINORILTM, TOLECTINTM, C CELEBRATM, CELEBREXTM, VIOXXTM CEOXXTM, 0111 Group B and Group C, Group B and Group D, ARCOXIATM, BEXTRATM, DYNASTATTM, MOBICTM or Group B and Group E, Group B and Group F, Group B and PREXIGETM; Group G, Group B and Group H, Group B and Group I, Group 0.124 (h) the composition or product of manufacture of Band Group J. Group B and Group K, Group B and Group L. any of (a) to (d), wherein the combination of compounds Group B and Group M. comprises or consists of a geranylgeranyl acetone (GGA) or 0112 Group C and Group D, Group C and Group E, Group an analog of geranylgeranyl acetone and an angiotensin con E and Group D: Group C and Group E, Group C and Group F, verting enzyme (ACE) inhibitor, or teprenone or SELBEXTM Group C and Group G, Group B and Group H, Group C and and an angiotensin converting enzyme (ACE) inhibitor, Group I, Group C and Group J. Group C and Group K, Group 0.125 (i) the composition or product of manufacture of (h), C and Group L. Group C and Group M. wherein the combination of compounds comprises or consists 0113 Group D and Group E, Group D and Group F, Group of a geranylgeranyl acetone (GGA) or an analog of gera D and Group G, Group D and Group H, Group D and Group nylgeranyl acetone or teprenone or SELBEXTM and: I, Group D and Group J. Group D and Group K, Group D and benazepril; captopril; cilaZapril; enalapril; enalaprilat; fosi Group L. Group D and Group M. nopril, fosinoprilat, imidapril (imidaprilum), lisinopril; 0114 Group E and Group F, Group E and Group G, Group moexipril; perindopril (coversyl); quinapril; ramipril; or, E and Group H, Group E and Group I, Group E and Group J. trandolapril; Group E and Group K, Group E and Group L. Group E and 0.126 (j) the composition or product of manufacture of (i), Group M. wherein the combination of compounds comprises or consists 0115 Group F and Group G, Group F and Group H, Group of a geranylgeranyl acetone (GGA) or an analog of gera F and Group I, Group F and Group J. Group F and Group K, nylgeranyl acetone or teprenone or SELEBEXTM and: Group F and Group L. Group F and Group M, LOTENSINTM, CAPOTINTM, RENITECTM, VASOTECTM, 0116 Group G and Group H, Group G and Group I, Group MONOPRILTM, UNIVASCTM, PERDIXTM, ACCUPRILTM G and Group J. Group G and Group K, Group G and Group L. TRITACETM, RAMACETM, ALTACETM, or MAVIKTM; Group G and Group M. I0127 (k) the composition or product of manufacture of any of (a) to (d), wherein the combination of compounds 0117 Group H and Group I, Group H and Group J. Group comprises or consists of a geranylgeranyl acetone (GGA) or H and Group K, Group H and Group L. Group H and Group an analog of geranylgeranyl acetone and a pentoxifylline, or M 1-(5-oxohexyl)-3,7-dimethylxanthine, or TRENTALTM: 0118 Group I and Group J. Group I and Group K, Group I0128 (1) the composition or product of manufacture of any I and Group L. Group I and Group M, of (a) to (d), wherein the combination of compounds com 0119 Group J and Group K, Group J and Group L. Group prises or consists of a geranylgeranyl acetone (GGA) or an J and Group M, or analog of geranylgeranyl acetone and a desferrioxamine (def 0120 Group K and Group L. Group L and Group M: eroxamine), or DESFERALTM, DESFERANTM, DES 0121 (e) the composition or product of manufacture of FERALTM, DESFEREXTM, DESFERINTM, or DESFER any of (a) to (d), wherein the combination of compounds RINTM, comprises or consists of a geranylgeranyl acetone (GGA) or I0129 (m) the composition or product of manufacture of an analog of geranylgeranyl acetone and a non-steroidal anti any of (a) to (d), wherein the combination of compounds inflammatory drug (NSAID), or teprenone or SELBEXTM comprises or consists of a geranylgeranyl acetone (GGA) or and a non-steroidal anti-inflammatory drug (NSAID); an analog of geranylgeranyl acetone and a polyunsaturated 0122 (f) the composition or product of manufacture of (e), fatty acid; wherein the combination of compounds comprises or consists 0.130 (n) the composition or product of manufacture of of (i) a GGA or an analog of GGA or a teprenone or a (m), wherein the combination of compounds comprises or SELEBEXTM and (ii) etodolac, aspirin, diclofenac, deflunisal, consists of a geranylgeranyl acetone (GGA) or an analog of fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketopro geranylgeranyl acetone and a c)-3 fatty acid or omega-3 fatty fen, ketorolac tromethamine, meclofenamate, mefenamic acid, a (D-6 fatty acid or omega-6 fatty acid, or a as ()-9 fatty acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxi acid or omega-9 fatty acid; US 2011/0158983 A1 Jun. 30, 2011

0131 (o) the composition or product of manufacture of a hydroxypropylmethyl-cellulose, a sodium carboxy-methyl (m), wherein the combination of compounds comprises or cellulose, a gum, an arabic gum, a tragacanth, a gelatin, a consists of a geranylgeranyl acetone (GGA) or an analog of collagen, a disintegrating or Solubilizing agent, a cross-linked geranylgeranyl acetone and O-linolenic acid (ALA), eicosa polyvinyl pyrrolidone, an agar, an alginic acid oralginic salt, pentaenoic acid (EPA), docosahexaenoic acid (DHA), or a sodium alginate; linoleic acid (LA), oleic acid and/or erucic acid; 0141 (y) the composition or product of manufacture of 0132 (p) the composition of any of (a) to (d), wherein the any of (a) through (X), wherein the composition or product of combination of compounds comprises or consists of gera manufacture comprises the combination of geranylgeranyl nylgeranyl acetone (GGA) or an analog of geranylgeranyl acetone (GGA) and captopril; GGA and CAPOTINTM: an acetone and an eflornithine, or C-difluoromethylornithine or analog of GGA and captopril; an analog of and CAPOTINTM: DFMO, or ORNIDYLTM; teprenone (CAS Registry Number 6809-52-5) and captopril; 0.133 (q) the composition or product of manufacture of teprenone and CAPOTINTM: SELBEXTM and CAPOTINTM: any of (a) to (d), wherein the combination of compounds or VT-211TM; or comprises or consists of geranylgeranyl acetone (GGA) or an 0.142 (Z) the composition or product of manufacture of analog of geranylgeranyl acetone and a Superoxide dismutase any of (a) through (X), wherein the composition or product of (SOD); manufacture comprises the combination of geranylgeranyl 0134 (r) the composition or product of manufacture of any acetone (GGA) and etodolac; GGA and LODINETM); an of (a) to (d), wherein the combination of compounds com analog of GGA and etodolac; an analog of GGA and LOD prises or consists of geranylgeranyl acetone (GGA) or an INETM; teprenone (CAS Registry Number 6809-52-5) and analog of geranylgeranyl acetone and an activator of a heat etodolac; teprenone and LODINETM: SELBEXTM and etod shock response; olac: SELBEXTM and LODINETM); or VT-212TM. 0135 (s) the composition or product of manufacture of(r), 0143. One embodiment of the composition or product of wherein the combination of compounds comprises or consists manufacture comprises or consists of ablisterpack, clamshell of geranylgeranyl acetone (GGA) or an analog of gera or tray, wherein the combination of drugs is formulated for nylgeranyl acetone and geranylgeranylacetone or gernate, unit dosage administration to an individual in need thereof at Zinc, tin, Salicylates, dexamethasone, cocaine, nicotine, the same time, and each unit dosage is contained within one alpha-adrenergicagonist, ppar-gamma agonist, a geldanamy blister in the blister pack, or compartment in the clamshell or cin, biomolecular-geldanamycin, cyclopentanone, a pros tray. The composition or product of manufacture can com tanoid, a prostaglandin, a thromboxane, a prostacyclins, prise or consist of a pill, capsule, tablet, tab, geltab or implant, enprostil, paracetamol or acetaminophen(N-(4-hydroxyphe wherein the combination of drugs is formulated for unit dos nyl)-acetamide), ketotiphen, levamisole, diazepam, age administration to an individual in need thereofat the same VALIUMTM, bromocriptine, PARLODELTM, or dopamine(4- time, and each unit dosage is contained within one pill, cap (2-aminoethyl)benzene-1,2-diol); Sule, tablet, tab, geltab or implant. 0.136 (t) the composition or product of manufacture of any 0144. The invention provides nanoparticles or micropar of (a) to (S), wherein the combination of compounds com ticles comprising the composition or product of manufacture prises or consists of at least one compound selected from each of this invention. of three groups selected from the group consisting of Group 0145 The invention provides uses of the composition or A. Group B. Group C, Group D, Group E, Group F, Group G, product of manufacture of this invention, for the manufacture Group H, Group I, Group J. Group K, Group L and Group M: of a medicament. 0.137 (u) the composition or product of manufacture of (t), 0146 The invention provides uses of the composition or wherein the combination of compounds comprises or consists product of manufacture of this invention, for the manufacture of at least one compound selected from Group A, Group B of a medicament for to treat, ameliorate, diminish, improve and Group C; Group A, Group B and Group D: Group A, and/or inhibit unwanted side effects and/or disease state Group B and Group E. Group A, Group D and Group E: symptoms associated with or caused by anger, anemia; anor Group B. Group C and Group D: Group B. Group C and exia; anorexia-cachexia; anxiety; atrophy or muscle atrophy; Group E. Group C, Group E and Group F: cachexia; cancer cachexia; cancer and any conditions caused 0138 (v) the composition or product of manufacture of by dysfunctional cells; cognitive impairment; cytoprotection any of (a) to (u) formulated as a pharmaceutical composition; deficiency; depression or despair; difficulties with activities 0139 (w) the composition or product of manufacture of of daily living; discomfort; emesis; erectile or sexual dys (v) formulated for administration intravenously, topically, function or sexual disinterest; excessive sympathoneural orally, by inhalation, by infusion, by injection, intraperito drive; fatigue; febrile neutropenia; frustration; hair loss; heart neally, intramuscularly, Subcutaneously, intra-aurally, by failure; infection, bacterial infection, viral infection, myco intra-articular administration, by intra-mammary administra bacterium infection, yeast infection, protozoan infection, tion, rectally, by topical administration or by absorption inflammation; intolerance to a medical therapy; lack of appe through epithelial and/or mucocutaneous linings; tite; lack of energy; lack of motivation; mucositis; oral 0140 (x) the composition or product of manufacture of mucositis; digestive mucositis; esophageal mucositis; intes (w) formulated as an aqueous Suspension, a solid, a liquid, a tinal mucositis; myeloprotection deficiency; neutropenia; powder, an emulsion, a lyophilized powder, a spray, a cream, rash; pain; reduced physical activity, wasting; worrying; pru a lotion, a controlled release formulation, a tablet, a pill, a gel. ritis, Xerostomia; cardiotoxicity; ototoxicity; nephrotoxicity; a liposome, on a patch, in an implant, on a tape, a dragee, a peripheral neuropathy and/or stress or anxiety related to any capsule, a lozenge, a gel, a syrup, a slurry and/or a Suspension, of the above. or the composition is formulated with a solid excipient, a 0147 The invention provides methods (therapies) for carbohydrate, a protein filler, a Sugar, a lactose, a Sucrose, a treating or ameliorating a cancer or dysfunctional cell condi mannitol, a Sorbitol, a starch, a cellulose, a methyl cellulose, tion, including any metastatic or benign tumor, including US 2011/0158983 A1 Jun. 30, 2011

cancer stem cells or cancer cells from lung cancer, bone ageal mucositis; intestinal mucositis; myeloprotection cancer, pancreatic cancer, skin cancer, cancer of the head or deficiency; neutropenia; rash; pain; reduced physical neck, cutaneous or intraocular melanoma, uterine cancer, activity; wasting; worrying; pruritis, Xerostomia; car ovarian cancer, rectal cancer, cancer of the anal region, stom diotoxicity; ototoxicity; nephrotoxicity; peripheral neu ach cancer, colon cancer, breast cancer, carcinoma of the ropathy and/or stress or anxiety related to any of the fallopian tubes, carcinoma of the endometrium, carcinoma of above, the cervix, carcinoma of the vagina, carcinoma of the Vulva, 0157 (ii) mucositis or oral mucositis; Hodgkin's Disease, cancer of the esophagus, cancer of the 0158 (iii) radiation therapy or chemotherapy; the Small intestine, cancer of the endocrine system, cancer of the administration can be before, during and/or after the thyroid gland, cancer of the parathyroid gland, cancer of the radiation therapy and/or cancer chemotherapy; or adrenal gland, sarcoma of Soft tissue, cancer of the urethra, 0159 (iv) radiation therapy for cancer or cancer chemo cancer of the penis, prostate cancer, chronic or acute leuke therapy; the administration can be before, during and/or mia, lymphocytic lymphomas, cancer of the bladder, cancer after the radiation therapy and/or cancer chemotherapy: of the kidney or ureter, renal cell carcinoma, carcinoma of the 0160 (b) the method of (a), wherein the administered renal pelvis, neoplasms of the central nervous system (CNS), composition comprises a geranylgeranyl compound, a gera primary CNS lymphoma, spinal axis tumors, brain stem nylgeranyl acetone (GGA) or an analog of geranylgeranyl glioma or pituitary adenoma, and any combination thereof. acetone (GGA), at a dosage regimen of between about 0.10 0148. The invention provides methods (therapies) for mg to about 20.00gm per day, or between about 30 mg to 3 treating, ameliorating, diminishing, improving and/or inhib gm per day; or iting unwanted side effects and/or disease state symptoms 0.161 (c) the method of (a), wherein the administered associated with or caused by composition comprises an angiotensin converting enzyme 0149 (i) anger, anemia; anorexia; anorexia-cachexia; inhibitor at a dosage regimen of between about 0.10 mg to anxiety; atrophy or muscle atrophy, cachexia; cancer about 10.00gm per day, or between about 10 mg to 450 mg cachexia; cancer and any conditions caused by dysfunc per day. tional cells; cognitive impairment; cytoprotection defi 0162 The invention provides methods, treatments, thera ciency; depression or despair; difficulties with activities pies comprising administering to an individual in need of daily living; discomfort; emesis; erectile or sexual thereof an effective amount of at least one composition or dysfunction or sexual disinterest; excessive sympatho product of manufacture of this invention. neural drive; fatigue; febrile neutropenia; frustration; (0163 The invention provides methods, treatments, thera hair loss; heart failure; infection, bacterial infection, pies comprising administering to an individual in need viral infection, mycobacterium infection, yeast infec thereof an effective amount of at least one composition or tion, protozoan infection, inflammation; intolerance to a product of manufacture of this invention, in conjunction (to medical therapy; lack of appetite; lack of energy; lack of gether) with a drug therapy, a chemotherapy or a radiation motivation; oral mucositis; digestive mucositis; esoph therapy. The administration can be before, during and/or after ageal mucositis; intestinal mucositis; myeloprotection the radiation therapy and/or cancer chemotherapy. deficiency; neutropenia; rash; pain; reduced physical 0164. The invention provides kits comprising (a) at least activity; wasting; worrying; pruritis, Xerostomia; car one composition or product of manufacture of this invention; diotoxicity; ototoxicity; nephrotoxicity; peripheral neu or (b) the kit of (a), further comprising instructions to practice ropathy and/or stress or anxiety related to any of the a method, treatment or therapy of this invention. above, 0.165. In alternative embodiments, this invention provides 0150 (ii) mucositis or oral mucositis; products and therapies that comprise use of compositions, 0151 (iii) radiation therapy or chemotherapy; and/or e.g., preparations, formulations, kits and other products of 0152 (iv) radiation therapy for cancer or cancer chemo manufacture (e.g., blisterpacks), comprising combinations of therapy; beneficial ingredients that provide cytoprotection to living 0153 the method comprising cells and tissues, including tissue compartments and/or 0154 (a) administering to an individual in need thereofan organs and/or organ systems; in different embodiments of this effective amount of at least one composition or product of invention said cytoprotection may be measured at the cellular manufacture of this invention, level and/or at a tissue compartment level and/or at the organ 0155 thereby treating, ameliorating, diminishing, level and/or at the organ system level. improving and/or inhibiting the unwanted side effects and/or 0166 The invention provides compositions, e.g., pharma disease state symptoms associated with or caused by ceuticals comprising combinations of drugs, and methods 0156 (i) anger, anemia; anorexia; anorexia-cachexia; comprising use of combinations of drugs, for treating, ame anxiety; atrophy or muscle atrophy, cachexia; cancer liorating, preventing or improving unwanted side effects cachexia; cancer and any conditions caused by dysfunc (e.g., of a treatment, such as a radiotherapy or chemotherapy tional cells; cognitive impairment; cyto-protection defi treatment; the composition can be administered before, dur ciency; depression or despair; difficulties with activities ing and/or after a radiation therapy and/or cancer chemo of daily living; discomfort; emesis; erectile or sexual therapy), unwanted conditions, unwanted States and disease dysfunction or sexual disinterest; excessive sympatho symptoms. In alternative embodiments, this invention pro neural drive; fatigue; febrile neutropenia; frustration; vides products of manufacture, including preparations, prod hair loss; heart failure; infection, bacterial infection, ucts, multi-drug formulations, kits, multi-drug preparations, viral infection, mycobacterium infection, yeast infec and other products of manufacture (e.g., multi-drug blister tion, protozoan infection, inflammation; intolerance to a packs), and methods of using them, comprising use of com medical therapy; lack of appetite; lack of energy; lack of binations of beneficial ingredients for treating, preventing motivation; oral mucositis; digestive mucositis; esoph ameliorating, or improving any unwanted side effects (e.g., of US 2011/0158983 A1 Jun. 30, 2011 a treatment, such as a radiotherapy or chemotherapy treat tion (including pathobiology and treatment problems); ment; the administration can be before, during and/or after the 2/Cyto-toxicity and GI damage secondary to Surgical trauma; radiation therapy and/or cancer chemotherapy), unwanted and 3/acute lung and GI injury secondary to avian influenza, conditions, unwanted States and disease symptoms, as well as other infections and traumas (including from biowarfare any combination of the unwanted side effects, conditions, agents). states and disease symptoms e.g., as presented herein. 0170 The invention provides products of manufacture 0167. In alternative embodiments, unwanted side effects, Such as packages, kits, containers, blister packages, clam conditions, states and disease symptoms treated, ameliorated, shells, trays, shrink wraps and the like, comprising at least prevented or improved by compositions or methods of this two different pharmaceutically active ingredients, where invention include, e.g., 1/anger, 2/anemia; 3/anorexia; 4/an each ingredient is manufactured in a separate pill, tablet, orexia-cachexia; 5/anxiety; 6/atrophy (e.g. muscle atrophy): capsule, package, kit or container; or, all or a Subset of the 7/cachexia, including cancer cachexia; 8/cancer and any con combinations of ingredients are manufactured in a separate ditions caused by dysfunctional cells: 9/cardiotoxicity: package or container. In alternative aspects, the package, kit 10/cognitive impairment; 11/cytoprotection deficiency; or container comprises ablister package, a clamshell, a tray, 12/depression; 13/despair; 14/delayed emesis; 15/diarrhea: a shrink wrap and the like, comprising separate pills, tablets, 16/difficulties with activities of daily living: 17/discomfort; capsules, packages, kits or containers for each of the at least 18/emesis; 19/erectile or sexual dysfunction or sexual disin two different pharmaceutically active ingredients. terest; 20/excessive sympathoneural drive; 2 1/fatigue; 22/fe 0171 In one embodiment, practicing the invention allows brile neutropenia; 23/frustration; 24/hair loss; 25/heart fail use of higher amounts and/or doses and/or longer durations of ure; 26/infection (in different aspects, infection types a medical therapy (e.g., a drug therapy, a cancer therapy or a provided herein include bacterial, viral, mycobacterium, radiation therapy) than the amounts and and/or doses or dura yeast and protozoan infections, and any combination tions of a medical or drug therapy that could be tolerated and thereof); 27/inflammation; 28/intolerance to a medical used without the benefit of this invention. Accordingly, this therapy; 29/lack of appetite; 30/lack of energy: 31/lack or invention provides compositions and methods that can raise motivation: 32/mucositis (e.g., oral, digestive, esophageal or the upper range of the therapeutic window of a medical or a intestinal mucositis); 33/myeloprotection deficiency: 34/my drug treatment. eloSupression (including neutropenia); 35/nausea; 36/neph 0172. The invention provides compositions, products and rotoxicity; 37/neutropenia; 38/oral mucositis; 39/ototoxicity: therapies; and in separate aspects, such a composition or 40/pain; 41/peripheral neuropathy; 42/reduced physical product or therapy may comprise or consist of one or more activity; 43/toxicity (including cyto-toxicity) from any che members selected from any of Group A, Group B. Group C, motherapy or radiation or Surgical trauma (the administration Group D, Group E, Group F, Group G, Group H, Group I, can be before, during and/or after the Surgical trauma, radia Group J. Group K, Group L. and Group M, as shown in Table tion therapy and/or cancer chemotherapy); 44/wasting: 1, where: of Group A comprises or consists of use of gera 45/worrying; 4.6/stress or anxiety related to any of the above. nylgeranyl compounds, including for example, geranylgera 0168 The invention provides compositions, including nyl acetone (GGA) and analogs of geranylgeranyl acetone products of manufacture, preparations, e.g., formulations, (GGA); Group B comprises or consists of use of Angiotensin kits, preparations, and other products of manufacture Such as Converting Enzyme Inhibitors (ACE Inhibitors or ACE-Is); blister packs, and methods of using them, comprising use of Group C comprises or consists of use of Angiotensin Recep combinations of beneficial ingredients for obtaining thera tor Blockers (ARBs); Group D comprises or consists of use of peutic benefits including for example: 1) to allow or enable or Peroxisome Proliferator-Activated Receptor (PPAR) ligands, facilitate the tolerance and use of higher amounts and/or e.g. agonists, such as PPAR alpha agonists, PPARgamma doses and/or longer durations of a medical therapy (e.g. can agonists, PPAR alpha/gamma dual agonists, and other PPAR cer therapies or radiation therapies) than could be used with ligands (e.g. PPAR delta ligands); Group E comprises or out this invention; 2) to allow or enable or facilitate the consists of use of non-steroidal anti-inflammatory drugs tolerance and use of longer durations of a medical therapy (NSAIDs); Group F comprises or consists of NCCN thera (e.g. cancer therapies or radiation therapies) than could be pies; Group G comprises use of or consists of use of TNF used without this invention; 3) to reduce occurrences of inhibitors, e.g. pentoxifylline, or 1-(5-oxohexyl)-3,7-dimeth (drug) resistance to a medical therapy (e.g. cancer chemo ylxanthine (e.g., TRENTALTM); Group H comprises or con therapy or radiation therapy; the administration can be before, sists of use of deferrioxamine; Group I comprises or consists during and/or after the radiation therapy and/or cancer che of polyunsaturated fatty acids, such as e.g. omega-3 fatty motherapy); 4) to enable dosage intensification of a medical acids, including for example eicosapentaenoic acid (EPA), therapy (e.g. cancer chemotherapy or radiation therapy); 5) to and docosahexaenoic acid (DHA); Group J comprises or enable increasing the frequency of a medical therapy (e.g. consists of C-difluoromethylornithine; Group K comprises or cancer chemotherapy or radiation therapy); 6) to enhance consists of superoxide dismutase (SOD) and similar antioxi patient response rates; 7) to increase patient Survival; 8) to dant compounds; Group L comprises or consists of activators induce a tissue protective state; 9) to induce tissue regenera of heat shock response; and Group M comprises or consists of tion; and 10) to induce tissue repair. drugs that reduce the inflammatory/progressive tissue dam 0169. The invention provides compositions and methods age response. for treating, preventing or improving unwanted side effects 0173 The invention provides compositions comprising or (e.g., of a treatment, such as a radiotherapy or chemotherapy consisting of any combination of at least two different drugs treatment), unwanted conditions, unwanted States and disease ortherapeutic combinations, e.g., at least two members as set symptoms arising from cancer or non-cancer medical needs, forth in Table 1, e.g., from two to about one hundred members including non-cancer related indications and problems as set forth in Table 1. In separate embodiments, this inven related to: 1/Host versus graft post bone marrow transplanta tion provides a therapy (e.g. a product or a “method for US 2011/0158983 A1 Jun. 30, 2011 treating) comprising or consisting of all combinations of omega-3 fatty acids, including for example eicosapentaenoic members selected from any of Group A, Group B. Group C, acid (EPA), and docosahexaenoic acid (DHA); Group J com Group D, Group E, Group F, Group G, Group H, Group I, prises or consists of C.-difluoromethylornithine; Group K Group J. Group K, Group L, and/or Group M, as set forth in comprises or consists of Superoxide dismutase (SOD) and Table 1. similar antioxidant compounds; Group L comprises or con 0.174. In alternative embodiments, this invention provides sists of activators of heat shock response; and Group M com therapies (including compositions and methods) comprising prises or consists of drugs that reduce the inflammatory/ or consisting of every possible combination and permutation progressive tissue damage response. of one member, two members, 3 members, 4 members, five 0176). In alternative embodiments, this invention provides members, etc., and up to and including at least 100 (one atherapy (including compositions and methods) (that may be hundred) members selected from any of Group A, Group B, called a “double or 2-member combination therapy') com Group C, Group D, Group E, Group F, Group G, Group H, prising or consisting of all combinations of at least two mem Group I, Group J. Group K, Group L, and Group M, as shown bers selected from any of Group A, Group B. Group C. Group in Table 1, e.g., where: of Group A comprises or consists of D. Group E, Group F, Group G, Group H, Group I, Group J. or Group A comprises use of or consists of use of gera Group K, Group L, and Group M, as shown in Table 1, where: nylgeranyl compounds, including for example, geranylgera of Group A comprises or consists of, or Group A comprises or nyl acetone (GGA) and analogs of geranylgeranyl acetone consists of use of geranylgeranyl compounds, including for (GGA); Group B comprises use of or consists of use of example, geranylgeranyl acetone (GGA) and analogs of gera Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors nylgeranyl acetone (GGA); Group B comprises or consists of or ACE-Is); Group C comprises use of or consists of use of use of Angiotensin Converting Enzyme Inhibitors (ACE Angiotensin Receptor Blockers (ARBs); Group D comprises Inhibitors or ACE-Is); Group C comprises or consists of use use of or consists of use of Peroxisome Proliferator-Activated of Angiotensin Receptor Blockers (ARBs); Group D com Receptor (PPAR) ligands, e.g. agonists, such as PPAR alpha prises or consists of use of Peroxisome Proliferator-Activated agonists, PPARgamma agonists, PPAR alpha/gamma dual Receptor (PPAR) ligands, e.g. agonists, such as PPAR alpha agonists, and other PPAR ligands (e.g. PPAR delta ligands); agonists, PPARgamma agonists, PPAR alpha/gamma dual Group E comprises use of or consists of use of non-steroidal agonists, and other PPAR ligands (e.g. PPAR delta ligands); anti-inflammatory drugs (NSAIDs); Group F consists of Group E comprises or consists of use of non-steroidal anti NCCN therapies; Group G comprises use of or consists ofuse inflammatory drugs (NSAIDs); Group F comprises or con of TNF inhibitors, e.g. pentoxifylline, or 1-(5-oxohexyl)-3,7- sists of NCCN therapies; Group G comprises or consists of dimethylxanthine (e.g., TRENTALTM); Group H comprises use of TNF inhibitors, e.g. pentoxifylline, or 1-(5-oxohexyl)- use of or consists of use of deferrioxamine; Group I comprises 3,7-dimethylxanthine (e.g., TRENTALTM); Group H com polyunsaturated fatty acids, such as e.g. omega-3 fatty acids, prises or consists of use of deferrioxamine; Group I com including for example eicosapentaenoic acid (EPA), and prises or consists of polyunsaturated fatty acids, such as e.g. docosahexaenoic acid (DHA); Group J comprises C.-difluo omega-3 fatty acids, including for example eicosapentaenoic romethylornithine; Group K comprises Superoxide dismutase acid (EPA), and docosahexaenoic acid (DHA); Group J com (SOD) and similar antioxidant compounds; Group L com prises or consists of C.-difluoromethylornithine; Group K prises activators of heat shock response; and Group M com comprises or consists of Superoxide dismutase (SOD) and prises drugs that reduce the inflammatory/progressive tissue similar antioxidant compounds; Group L comprises or con damage response. sists of activators of heat shock response; and Group M com 0.175. In separate embodiments, this invention provides a prises or consists of drugs that reduce the inflammatory/ therapy (including compositions and methods) comprising or progressive tissue damage response, where said members consisting of at least two different members from only one of selected to comprise the “double combination therapy” may Group A, Group B. Group C, Group D, Group E, Group F, all be selected from the same Group (e.g. Group A) or may be Group G, Group H, Group I, Group J. Group K, Group L. and selected from multiple Groups (e.g. Group A and Group B). Group M, as shown in Table 1 (i.e., at least two different 0177. In alternative embodiments, this invention also pro members from a single group), where: of Group A comprises vides a therapy (including compositions and methods) (that or consists of, or Group A comprises or consists of use of may be called a “triple or 3-member combination therapy') geranylgeranyl compounds, including for example, gera comprising or consisting of all combinations of at least three nylgeranyl acetone (GGA) and analogs of geranylgeranyl members selected from any of Group A, Group B. Group C, acetone (GGA); Group B comprises or consists of use of Group D, Group E, Group F, Group G, Group H, Group I, Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors Group J. Group K, Group L. and Group M, as shown in Table or ACE-Is); Group C comprises or consists of use of Angio 1, where: of Group A comprises or consists of, or Group A tensin Receptor Blockers (ARBs); Group D comprises or comprises or consists of use of geranylgeranyl compounds, consists of use of Peroxisome Proliferator-Activated Recep including for example, geranylgeranyl acetone (GGA) and tor (PPAR) ligands, e.g. agonists, such as PPAR alpha ago analogs of geranylgeranyl acetone (GGA); Group B com nists, PPARgamma agonists, PPAR alpha/gamma dual ago prises or consists of use of Angiotensin Converting Enzyme nists, and other PPAR ligands (e.g. PPAR delta ligands); Inhibitors (ACE Inhibitors or ACE-Is); Group C comprises or Group E comprises or consists of use of non-steroidal anti consists of use of Angiotensin Receptor Blockers (ARBs); inflammatory drugs (NSAIDs); Group F comprises or con Group D comprises or consists of use of Peroxisome Prolif sists of NCCN therapies; Group G comprises or consists of erator-Activated Receptor (PPAR) ligands, e.g. agonists, use of TNF inhibitors, e.g. pentoxifylline, or 1-(5-oxohexyl)- such as PPAR alpha agonists, PPARgamma agonists, PPAR 3,7-dimethylxanthine (e.g., TRENTALTM); Group H com alpha/gamma dual agonists, and other PPAR ligands (e.g. prises or consists of use of deferrioxamine; Group I com PPAR delta ligands); Group E comprises or consists of use of prises or consists of polyunsaturated fatty acids, such as e.g. non-steroidal anti-inflammatory drugs (NSAIDs); Group F US 2011/0158983 A1 Jun. 30, 2011 consists of NCCN therapies; Group G comprises or consists (GGA) and analogs of geranylgeranyl acetone (GGA); Group of use of TNF inhibitors, e.g. pentoxifylline, or 1-(5-oxo B comprises or consists of use of Angiotensin Converting hexyl)-3,7-dimethylxanthine (e.g., TRENTALTM); Group H Enzyme Inhibitors (ACE Inhibitors or ACE-Is); Group C comprises or consists of use of deferrioxamine; Group I com comprises or consists of use of Angiotensin Receptor Block prises or consists of polyunsaturated fatty acids, such as e.g. ers (ARBs); Group D comprises or consists of use of Peroxi omega-3 fatty acids, including for example eicosapentaenoic some Proliferator-Activated Receptor (PPAR) ligands, e.g. acid (EPA), and docosahexaenoic acid (DHA); Group J com agonists, such as PPAR alpha agonists, PPARgamma ago prises or consists of C.-difluoromethylornithine; Group K nists, PPAR alpha/gamma dual agonists, and other PPAR comprises or consists of Superoxide dismutase (SOD) and ligands (e.g. PPAR delta ligands); Group E comprises or similar antioxidant compounds; Group L comprises or con consists of use of non-steroidal anti-inflammatory drugs sists of activators of heat shock response; and Group M com (NSAIDs); Group F consists of NCCN therapies; Group G prises or consists of drugs that reduce the inflammatory/ comprises or consists of use of TNF inhibitors, e.g. pentoxi progressive tissue damage response, where said members fylline, or 1-(5-oxohexyl)-3,7-dimethylxanthine (e.g., selected to comprise the “triple combination therapy' may all TRENTALTM); Group H comprises or consists of use of be selected from the same Group (e.g. Group A) or may be deferrioxamine; Group I comprises or consists of polyunsatu selected from multiple Groups (e.g. Group A, Group B, and rated fatty acids, such as e.g. omega-3 fatty acids, including Group E). for example eicosapentaenoic acid (EPA), and docosa 0178. In alternative embodiments, this invention also pro hexaenoic acid (DHA); Group J comprises or consists of vides a therapy (including compositions and methods) (that C.-difluoromethylornithine; Group K comprises or consists of may be called a “quadruple or 4-member combination Superoxide dismutase (SOD) and similar antioxidant com therapy') comprising or consisting of all combinations of at pounds; Group L comprises or consists of activators of heat least four members selected from any of Group A, Group B, shock response; and Group M comprises or consists of drugs Group C, Group D, Group E, Group F, Group G, Group H, that reduce the inflammatory/progressive tissue damage Group I, Group J. Group K, Group L, and Group M, as shown response, where said members selected to comprise the in Table 1, where: of Group A comprises or consists of, or “quintuple combination therapy” may all be selected from the Group A comprises or consists of use of geranylgeranyl same Group (e.g. Group A) or may be selected from multiple compounds, including for example, geranylgeranyl acetone Groups (e.g. Group A, Group B. Group E, and Group F). (GGA) and analogs of geranylgeranyl acetone (GGA); Group 0180. In alternative embodiments, this invention also pro B comprises or consists of use of Angiotensin Converting Vides a therapy (including compositions and methods) (that Enzyme Inhibitors (ACE Inhibitors or ACE-Is); Group C may be called a “sextuple or hextuple or 6-member combi comprises or consists of use of Angiotensin Receptor Block nation therapy') comprising all combinations of at least six ers (ARBs); Group D comprises or consists of use of Peroxi some Proliferator-Activated Receptor (PPAR) ligands, e.g. members selected from any of Group A, Group B. Group C, agonists, such as PPAR alpha agonists, PPARgamma ago Group D, Group E, Group F, Group G, Group H, Group I, nists, PPAR alpha/gamma dual agonists, and other PPAR Group J. Group K, Group L. and Group M, as shown in Table ligands (e.g. PPAR delta ligands); Group E comprises or 1, where: of Group A comprises or consists of, or Group A consists of use of non-steroidal anti-inflammatory drugs comprises or consists of use of geranylgeranyl compounds, (NSAIDs); Group F comprises or consists of use of NCCN including for example, geranylgeranyl acetone (GGA) and therapies; Group G comprises or consists of use of TNF analogs of geranylgeranyl acetone (GGA); Group B com inhibitors, e.g. pentoxifylline, or 1-(5-oxohexyl)-3,7-dimeth prises or consists of use of Angiotensin Converting Enzyme ylxanthine (e.g., TRENTALTM); Group H comprises or con Inhibitors (ACE Inhibitors or ACE-Is); Group C comprises or sists of use of deferrioxamine; Group I comprises or consists consists of use of Angiotensin Receptor Blockers (ARBs); of polyunsaturated fatty acids, such as e.g. omega-3 fatty Group D comprises or consists of use of Peroxisome Prolif acids, including for example eicosapentaenoic acid (EPA), erator-Activated Receptor (PPAR) ligands, e.g. agonists, and docosahexaenoic acid (DHA); Group J comprises or such as PPAR alpha agonists, PPARgamma agonists, PPAR consists of C-difluoromethylornithine; Group K comprises or alpha/gamma dual agonists, and other PPAR ligands (e.g. consists of superoxide dismutase (SOD) and similar antioxi PPAR delta ligands); Group E comprises or consists of use of dant compounds; Group L comprises or consists of activators non-steroidal anti-inflammatory drugs (NSAIDs); Group F of heat shock response; and Group M comprises or consists of comprises or consists of NCCN therapies; Group G com drugs that reduce the inflammatory/progressive tissue dam prises or consists of use of TNF inhibitors, e.g. pentoxifylline, age response, where said members selected to comprise the or 1-(5-oxohexyl)-3,7-dimethylxanthine (e.g., TREN “quadruple combination therapy” may all be selected from TALTM); Group H comprises or consists of use of deferriox the same Group (e.g. Group A) or may be selected from amine; Group I comprises or consists of polyunsaturated fatty multiple Groups (e.g. Group A, Group B. Group E, and Group acids, such as e.g. omega-3 fatty acids, including for example F). eicosapentaenoic acid (EPA), and docosahexaenoic acid 0179. In alternative embodiments, this invention also pro (DHA); Group J comprises or consists of C-difluoromethy vides a therapy (including compositions and methods) (that lornithine; Group K comprises or consists of Superoxide dis may be called a “quintuple or pentuple or 5-member combi mutase (SOD) and similar antioxidant compounds; Group L nation therapy') comprising or consisting of all combinations comprises or consists of activators of heat shock response; of at least five members selected from any of Group A, Group and Group M comprises or consists of drugs that reduce the B. Group C, Group D, Group E, Group F, Group G, Group H, inflammatory/progressive tissue damage response, where Group I, Group J. Group K, Group L, and Group M, as shown said members selected to comprise the 'sextuple combination in Table 1, where: of Group A comprises or consists of, or therapy” may all be selected from the same Group (e.g. Group Group A comprises or consists of use of geranylgeranyl A) or may be selected from multiple Groups (e.g. Group A, compounds, including for example, geranylgeranyl acetone Group B. Group E, and Group F). US 2011/0158983 A1 Jun. 30, 2011

0181. In alternative embodiments, this invention also pro pounds; Group L comprises or consists of activators of heat vides a therapy (including compositions and methods) (that shock response; and Group M comprises or consists of drugs may be called a “septuple or 7-member combination that reduce the inflammatory/progressive tissue damage therapy') comprising or consisting of all combinations of at response, where said members selected to comprise the least seven members selected from any of Group A, Group B, “octuple combination therapy” may all be selected from the Group C, Group D, Group E, Group F, Group G, Group H, same Group (e.g. Group A) or may be selected from multiple Group I, Group J. Group K, Group L, and/or Group M, as Groups (e.g. Group A, Group B. Group E, and Group F). shown in Table 1, where: of Group A comprises or consists of 0183 In alternative embodiments, this invention also pro or Group A comprises or consists of use of geranylgeranyl vides a therapy (including compositions and methods) (that compounds, including for example, geranylgeranyl acetone may be called a “nonuple or 9-member combination (GGA) and analogs of geranylgeranyl acetone (GGA); Group therapy') comprising or consisting of all combinations of at B comprises or consists of use of Angiotensin Converting least nine members selected from any of Group A, Group B, Enzyme Inhibitors (ACE Inhibitors or ACE-Is); Group C Group C, Group D, Group E, Group F, Group G, Group H, comprises or consists of use of Angiotensin Receptor Block Group I, Group J. Group K, Group L, and/or Group M, as ers (ARBs); Group D comprises or consists of use of Peroxi shown in Table 1, where: of Group A comprises or consists of, some Proliferator-Activated Receptor (PPAR) ligands, e.g. or Group A comprises or consists of use of geranylgeranyl agonists, such as PPAR alpha agonists, PPARgamma ago compounds, including for example, geranylgeranyl acetone nists, PPAR alpha/gamma dual agonists, and other PPAR (GGA) and analogs of geranylgeranyl acetone (GGA); Group ligands (e.g. PPAR delta ligands); Group E comprises or B comprises or consists of use of Angiotensin Converting consists of use of non-steroidal anti-inflammatory drugs Enzyme Inhibitors (ACE Inhibitors or ACE-Is); Group C (NSAIDs); Group F comprises or consists of NCCN thera comprises or consists of use of Angiotensin Receptor Block pies; Group G comprises or consists of use of TNF inhibitors, ers (ARBs); Group D comprises or consists of use of Peroxi e.g. pentoxifylline, or 1-(5-oxohexyl)-3,7-dimethylxanthine some Proliferator-Activated Receptor (PPAR) ligands, e.g. (e.g., TRENTALTM); Group H comprises or consists of use of agonists, such as PPAR alpha agonists, PPARgamma ago deferrioxamine; Group I comprises or consists of polyunsatu nists, PPAR alpha/gamma dual agonists, and other PPAR rated fatty acids, such as e.g. omega-3 fatty acids, including ligands (e.g. PPAR delta ligands); Group E comprises or for example eicosapentaenoic acid (EPA), and docosa consists of use of non-steroidal anti-inflammatory drugs hexaenoic acid (DHA); Group J comprises or consists of (NSAIDs); Group F comprises or consists of NCCN thera C.-difluoromethylornithine; Group K comprises or consists of pies; Group G comprises or consists of use of TNF inhibitors, superoxide dismutase (SOD) and similar antioxidant com e.g. pentoxifylline, or 1-(5-oxohexyl)-3,7-dimethylxanthine pounds; Group L comprises or consists of activators of heat (e.g., TRENTALTM); Group H comprises or consists of use of shock response; and Group M comprises or consists of drugs deferrioxamine; Group I comprises or consists of polyunsatu that reduce the inflammatory/progressive tissue damage rated fatty acids, such as e.g. omega-3 fatty acids, including response, where said members selected to comprise the “sep for example eicosapentaenoic acid (EPA), and docosa tuple combination therapy may all be selected from the same hexaenoic acid (DHA); Group J comprises or consists of Group (e.g. Group A) or may be selected from multiple C.-difluoromethylornithine; Group K comprises or consists of Groups (e.g. Group A, Group B. Group E, and Group F). Superoxide dismutase (SOD) and similar antioxidant com 0182. In alternative embodiments, this invention also pro pounds; Group L comprises or consists of activators of heat vides a therapy (including compositions and methods) (that shock response; and Group M comprises or consists of drugs may be called an "octuple or 8-member combination that reduce the inflammatory/progressive tissue damage therapy') comprising or consisting of all combinations of at response, where said members selected to comprise the least eight members selected from any of Group A, Group B, “nonuple combination therapy” may all be selected from the Group C, Group D, Group E, Group F, Group G, Group H, same Group (e.g. Group A) or may be selected from multiple Group I, Group J. Group K, Group L, and/or Group M, as Groups (e.g. Group A, Group B. Group E, and Group F). shown in Table 1, where: of Group A comprises or consists of 0184. In alternative embodiments, this invention also pro or Group A comprises or consists of use of geranylgeranyl vides a therapy (including compositions and methods) (that compounds, including for example, geranylgeranyl acetone may be called a “decuple or 10-member combination (GGA) and analogs of geranylgeranyl acetone (GGA); Group therapy') comprising or consisting of all combinations of at B comprises or consists of use of Angiotensin Converting least ten members selected from any of Group A, Group B, Enzyme Inhibitors (ACE Inhibitors or ACE-Is); Group C Group C, Group D, Group E, Group F, Group G, Group H, comprises or consists of use of Angiotensin Receptor Block Group I, Group J. Group K, Group L, and/or Group M, as ers (ARBs); Group D comprises or consists of use of Peroxi shown in Table 1, where: of Group A comprises or consists of, some Proliferator-Activated Receptor (PPAR) ligands, e.g. or Group A comprises or consists of use of geranylgeranyl agonists, such as PPAR alpha agonists, PPARgamma ago compounds, including for example, geranylgeranyl acetone nists, PPAR alpha/gamma dual agonists, and other PPAR (GGA) and analogs of geranylgeranyl acetone (GGA); Group ligands (e.g. PPAR delta ligands); Group E comprises or B comprises or consists of use of Angiotensin Converting consists of use of non-steroidal anti-inflammatory drugs Enzyme Inhibitors (ACE Inhibitors or ACE-Is); Group C (NSAIDs); Group F comprises or consists of NCCN thera comprises or consists of use of Angiotensin Receptor Block pies; Group G comprises or consists of use of TNF inhibitors, ers (ARBs); Group D comprises or consists of use of Peroxi e.g. pentoxifylline, or 1-(5-oxohexyl)-3,7-dimethylxanthine some Proliferator-Activated Receptor (PPAR) ligands, e.g. (e.g., TRENTALTM); Group H comprises or consists of use of agonists, such as PPAR alpha agonists, PPARgamma ago deferrioxamine; Group I comprises or consists of polyunsatu nists, PPAR alpha/gamma dual agonists, and other PPAR rated fatty acids, such as e.g. omega-3 fatty acids, including ligands (e.g. PPAR delta ligands); Group E comprises or for example eicosapentaenoic acid (EPA), and docosa consists of use of non-steroidal anti-inflammatory drugs hexaenoic acid (DHA); Group J comprises or consists of (NSAIDs); Group F comprises or consists of NCCN thera C.-difluoromethylornithine; Group K comprise or consists of pies; Group G comprises or consists of use of TNF inhibitors, S Superoxide dismutase (SOD) and similar antioxidant com e.g. pentoxifylline, or 1-(5-oxohexyl)-3,7-dimethylxanthine US 2011/0158983 A1 Jun. 30, 2011

(e.g., TRENTALTM); Group H comprises or consists of use of EXAMPLE 2-4 deferrioxamine; Group I comprises or consists of polyunsatu rated fatty acids, such as e.g. omega-3 fatty acids, including 0189 Any combination comprising or consisting of One for example eicosapentaenoic acid (EPA), and docosa Member of Group A and One Member of Group E (see Table hexaenoic acid (DHA); Group J comprises or consists of 1). In alternative aspects, atherapy provided herein comprises C.-difluoromethylornithine; Group K comprise or consists of or consists at least one member selected from Group A, and at S Superoxide dismutase (SOD) and similar antioxidant com least one member selected from Group E, as shown in Table pounds; Group L comprises or consists of activators of heat 1, where: of Group A comprises or consists of, or Group A shock response; and Group M comprises or consists of drugs comprises or consists use of geranylgeranyl compounds, that reduce the inflammatory/progressive tissue damage including for example, geranylgeranyl acetone (GGA) and response, where said members selected to comprise the analogs of geranylgeranyl acetone (GGA); and Group E com “decuple combination therapy” may all be selected from the same Group (e.g. Group A) or may be selected from multiple prises or consists use of non-steroidal anti-inflammatory Groups (e.g. Group A, Group B. Group E, and Group F). drugs (NSAIDs). “Double Combinations Therapies” (All “Combination Pos EXAMPLE 2-5 sibilities’) 0190. Any combination comprising or consisting of One 0185. The invention provides compositions and therapies Member of Group A and One Member of Group F (see Table (methods) comprising or consisting of use of any combina 1). In alternative aspects, atherapy provided herein comprises tion of at least one compound from at least two Groups (from or consists of at least one member selected from Group A, and Table 1), and below are 78 non-limiting exemplary combina at least one member selected from Group F, as shown in Table tions of this invention. 1, where: of Group A comprises or consists of, or Group A comprises use of or consists of use of geranylgeranyl com EXAMPLE 2-1 pounds, including for example, geranylgeranyl acetone 0186. Any combination comprising or consisting of One (GGA) and analogs of geranylgeranyl acetone (GGA); and Member of Group A and One Member of Group B (see Table Group F consists of NCCN therapies. 1). In alternative aspects, atherapy provided herein comprises or consists of or consists of at least one member selected from EXAMPLE 2-6 Group A, and at least one member selected from Group B, as shown in Table 1, where: of Group A comprises or consists of 0191) Any combination comprising or consisting of One or Group A comprises or consists of use of geranylgeranyl Member of Group A and One Member of Group G (see Table compounds, including for example, geranylgeranyl acetone 1). In alternative aspects, atherapy provided herein comprises (GGA) and analogs of geranylgeranyl acetone (GGA); and or consists of at least one member selected from Group A, and Group B comprises or consists of use of Angiotensin Con at least one member selected from Group G, as shown in Table verting Enzyme Inhibitors (ACE Inhibitors or ACE-Is). 1, where: of Group A comprises or consists of, or Group A comprises use of or consists of use of geranylgeranyl com EXAMPLE 2-2 pounds, including for example, geranylgeranyl acetone (GGA) and analogs of geranylgeranyl acetone (GGA); and 0187. Any combination comprising or consisting of One Group G comprises use of or consists of use of TNF inhibi Member of Group A and One Member of Group C (see Table tors, e.g. pentoxifylline, or 1-(5-oxohexyl)-3,7-dimethylxan 1). In alternative aspects, atherapy provided herein comprises thine (e.g., TRENTALTM). or consists of at least one member selected from Group A, and at least one member selected from Group C, as shown in Table 1, where: of Group A comprises or consists of, or Group A EXAMPLE 2-7 comprises or consists use of geranylgeranyl compounds, 0.192 Any combination comprising or consisting of One including for example, geranylgeranyl acetone (GGA) and Member of Group A and One Member of Group H (see Table analogs of geranylgeranyl acetone (GGA); and Group C com 1). In alternative aspects, atherapy provided herein comprises prises or consists use of Angiotensin Receptor Blockers or consists of at least one member selected from Group A, and (ARBs). at least one member selected from Group H, as shown in Table 1, where: of Group A comprises or consists of, or Group A EXAMPLE 2-3 comprises use of or consists of use of geranylgeranyl com 0188 Any combination comprising or consisting of One pounds, including for example, geranylgeranyl acetone Member of Group A and One Member of Group D (see Table (GGA) and analogs of geranylgeranyl acetone (GGA); and 1). In alternative aspects, atherapy provided herein comprises Group H comprises use of or consists of use of deferrioxam or consists at least one member selected from Group A, and at 1C. least one member selected from Group D, as shown in Table 1, where: of Group A comprises or consists of, or Group A EXAMPLE 2-8 comprises or consists use of geranylgeranyl compounds, including for example, geranylgeranyl acetone (GGA) and 0193 Any combination comprising or consisting of One analogs of geranylgeranylacetone (GGA); and Group D com Member of Group A and One Member of Group I (see Table prises or consists use of Peroxisome Proliferator-Activated 1). In alternative aspects, atherapy provided herein comprises Receptor (PPAR) ligands, e.g. agonists, such as PPAR alpha or consists of at least one member selected from Group A, and agonists, PPARgamma agonists, PPAR alpha/gamma dual at least one member selected from Group I, as shown in Table agonists, and other PPAR ligands (e.g. PPAR delta ligands). 1, where: of Group A comprises or consists of, or Group A US 2011/0158983 A1 Jun. 30, 2011

comprises use of or consists of use of geranylgeranyl com at least one member selected from Group C, as shown in Table pounds, including for example, geranylgeranyl acetone 1, where: Group B comprises use of or consists of use of (GGA) and analogs of geranylgeranyl acetone (GGA); and Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors Group I comprises polyunsaturated fatty acids, Such as e.g. or ACE-Is); and Group C comprises use of or consists of use omega-3 fatty acids, including for example eicosapentaenoic of Angiotensin Receptor Blockers (ARBs). acid (EPA), and docosahexaenoic acid (DHA). EXAMPLE 2-14 EXAMPLE 2-9 0199 Any combination comprising or consisting of One 0194 Any combination comprising or consisting of One Member of Group B and One Member of Group D (see Table Member of Group A and One Member of Group J (see Table 1). In alternative aspects, atherapy provided herein comprises 1). In alternative aspects, atherapy provided herein comprises or consists of at least one member selected from Group B, and or consists of at least one member selected from Group A, and at least one member selected from Group D, as shown in Table at least one member selected from Group J, as shown in Table 1, where: Group B comprises use of or consists of use of 1, where: of Group A comprises or consists of, or Group A Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors comprises use of or consists of use of geranylgeranyl com or ACE-Is); and Group D comprises use of or consists of use pounds, including for example, geranylgeranyl acetone of Peroxisome Proliferator-Activated Receptor (PPAR) (GGA) and analogs of geranylgeranyl acetone (GGA); and ligands, e.g. agonists, such as PPAR alpha agonists, PPAR Group J comprises C.-difluoromethylornithine. gamma agonists, PPAR alpha/gamma dual agonists, and other PPAR ligands (e.g. PPAR delta ligands). EXAMPLE 2-10 EXAMPLE 2-15 0.195 Any combination comprising or consisting of One Member of Group A and One Member of Group K (see Table 0200 Any combination comprising or consisting of One 1). In alternative aspects, atherapy provided herein comprises Member of Group B and One Member of Group E (see Table or consists of at least one member selected from Group A, and 1). In alternative aspects, atherapy provided herein comprises at least one member selected from Group K, as shown in Table or consists of at least one member selected from Group B, and 1, where: of Group A comprises or consists of, or Group A at least one member selected from Group E, as shown in Table comprises use of or consists of use of geranylgeranyl com 1, where: Group B comprises use of or consists of use of pounds, including for example, geranylgeranyl acetone Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors (GGA) and analogs of geranylgeranyl acetone (GGA); and or ACE-Is); and Group E comprises use of or consists of use Group K comprises superoxide dismutase (SOD) and similar of non-steroidal anti-inflammatory drugs (NSAIDs). antioxidant compounds. EXAMPLE 2-16 EXAMPLE 2-11 0201 Any combination comprising or consisting of One 0196. Any combination comprising or consisting of One Member of Group B and One Member of Group F (see Table Member of Group A and One Member of Group L (see Table 1). In alternative aspects, atherapy provided herein comprises 1). In alternative aspects, atherapy provided herein comprises or consists of at least one member selected from Group B, and or consists of at least one member selected from Group A, and at least one member selected from Group F, as shown in Table at least one member selected from Group L, as shown in Table 1, where: Group B comprises use of or consists of use of 1, where: of Group A comprises or consists of, or Group A Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors comprises use of or consists of use of geranylgeranyl com or ACE-Is); and Group F consists of NCCN therapies. pounds, including for example, geranylgeranyl acetone (GGA) and analogs of geranylgeranyl acetone (GGA); and EXAMPLE 2-17 Group L comprises activators of heat shock response. 0202 Any combination comprising or consisting of One Member of Group B and One Member of Group G (see Table EXAMPLE 2-12 1). In alternative aspects, atherapy provided herein comprises or consists of at least one member selected from Group B, and 0.197 Any combination comprising or consisting of One at least one member selected from Group G, as shown in Table Member of Group A and One Member of Group M (see Table 1, where: Group B comprises use of or consists of use of 1). In alternative aspects, atherapy provided herein comprises Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors or consists of at least one member selected from Group A, and or ACE-Is); and Group G comprises use of or consists of use at least one member selected from Group M, as shown in of TNF inhibitors, e.g. pentoxifylline, or 1-(5-oxohexyl)-3,7- Table 1, where: of Group A comprises or consists of, or Group dimethylxanthine (e.g., TRENTALTM). A comprises use of or consists of use of geranylgeranyl compounds, including for example, geranylgeranyl acetone EXAMPLE 2-18 (GGA) and analogs of geranylgeranyl acetone (GGA); and Group M comprises drugs that reduce the inflammatory/pro 0203) Any combination comprising or consisting of One gressive tissue damage response. Member of Group B and One Member of Group H (see Table 1). In alternative aspects, atherapy provided herein comprises EXAMPLE 2-13 or consists of at least one member selected from Group B, and at least one member selected from Group H, as shown in Table 0198 Any combination comprising or consisting of One 1, where: Group B comprises use of or consists of use of Member of Group B and One Member of Group C (see Table Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors 1). In alternative aspects, atherapy provided herein comprises or ACE-Is); and Group H comprises use of or consists of use or consists of at least one member selected from Group B, and of deferrioxamine. US 2011/0158983 A1 Jun. 30, 2011

EXAMPLE 2-19 at least one member selected from Group D, as shown in Table 1, where: Group C comprises use of or consists of use of 0204 Any combination comprising or consisting of One Angiotensin Receptor Blockers (ARBs); and Group D com Member of Group B and One Member of Group I (see Table prises use of or consists of use of Peroxisome Proliferator 1). In alternative aspects, atherapy provided herein comprises Activated Receptor (PPAR) ligands, e.g. agonists, such as or consists of at least one member selected from Group B, and PPAR alpha agonists, PPARgamma agonists, PPAR alpha/ at least one member selected from Group I, as shown in Table 1, where: Group B comprises use of or consists of use of gamma dual agonists, and other PPAR ligands (e.g. PPAR Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors delta ligands). or ACE-Is); and Group I comprises polyunsaturated fatty acids, such as e.g. omega-3 fatty acids, including for example EXAMPLE 2-25 eicosapentaenoic acid (EPA), and docosahexaenoic acid 0210 Any combination comprising or consisting of One (DHA). Member of Group C and One Member of Group E (see Table 1). In alternative aspects, atherapy provided herein comprises EXAMPLE 2-2O or consists of at least one member selected from Group C, and at least one member selected from Group E, as shown in Table 0205 Any combination comprising or consisting of One 1, where: Group C comprises use of or consists of use of Member of Group B and One Member of Group J (see Table Angiotensin Receptor Blockers (ARBs); and Group E com 1). In alternative aspects, atherapy provided herein comprises prises use of or consists of use of non-steroidal anti-inflam or consists of at least one member selected from Group B, and matory drugs (NSAIDs). at least one member selected from Group J, as shown in Table 1, where: Group B comprises use of or consists of use of EXAMPLE 2-26 Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors or ACE-Is); and Group J comprises C.-difluoromethylorni 0211 Any combination comprising or consisting of One thine. Member of Group C and One Member of Group F (see Table 1). In alternative aspects, atherapy provided herein comprises EXAMPLE 2-21 or consists of at least one member selected from Group C, and at least one member selected from Group F, as shown in Table 0206. Any combination comprising or consisting of One 1, where: Group C comprises use of or consists of use of Member of Group B and One Member of Group K (see Table Angiotensin Receptor Blockers (ARBs); and Group F con 1). In alternative aspects, atherapy provided herein comprises sists of NCCN therapies. or consists of at least one member selected from Group B, and at least one member selected from Group K, as shown in Table EXAMPLE 2-27 1, where: Group B comprises use of or consists of use of Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors 0212 Any combination comprising or consisting of One or ACE-Is); and Group K comprises Superoxide dismutase Member of Group C and One Member of Group G (see Table (SOD) and similar antioxidant compounds. 1). In alternative aspects, atherapy provided herein comprises or consists of at least one member selected from Group C, and EXAMPLE 2-22 at least one member selected from Group G, as shown in Table 1, where: Group C comprises use of or consists of use of 0207 Any combination comprising or consisting of One Angiotensin Receptor Blockers (ARBs); and Group G com Member of Group B and One Member of Group L (see Table prises use of or consists of use of TNF inhibitors, e.g. pen 1). In alternative aspects, atherapy provided herein comprises toxifylline, or 145-oxohexyl)-3,7-dimethylxanthine (e.g., or consists of at least one member selected from Group B, and TRENTALTM). at least one member selected from Group L, as shown in Table 1, where: Group B comprises use of or consists of use of EXAMPLE 2-28 Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors or ACE-Is); and Group L comprises activators of heat shock 0213 Any combination comprising or consisting of One Member of Group C and One Member of Group H (see Table response. 1). In alternative aspects, atherapy provided herein comprises EXAMPLE 2-23 or consists of at least one member selected from Group C, and at least one member selected from Group H, as shown in Table 0208 Any combination comprising or consisting of One 1, where: Group C comprises use of or consists of use of Member of Group B and One Member of Group M (see Table Angiotensin Receptor Blockers (ARBs); and Group H com 1). In alternative aspects, atherapy provided herein comprises prises use of or consists of use of deferrioxamine. or consists of at least one member selected from Group B, and at least one member selected from Group M, as shown in EXAMPLE 2-29 Table 1, where: Group B comprises use of or consists of use of Angiotensin Converting Enzyme Inhibitors (ACE Inhibi 0214. Any combination comprising or consisting of One tors or ACE-Is); and Group M comprises drugs that reduce the Member of Group C and One Member of Group I (see Table inflammatory/progressive tissue damage response. 1). In alternative aspects, atherapy provided herein comprises or consists of at least one member selected from Group C, and at least one member selected from Group I, as shown in Table EXAMPLE 2-24 1, where: Group C comprises use of or consists of use of 0209 Any combination comprising or consisting of One Angiotensin Receptor Blockers (ARBs); and Group I com Member of Group C and One Member of Group D (see Table prises polyunsaturated fatty acids, such as e.g. omega-3 fatty 1). In alternative aspects, atherapy provided herein comprises acids, including for example eicosapentaenoic acid (EPA), or consists of at least one member selected from Group C, and and docosahexaenoic acid (DHA). US 2011/0158983 A1 Jun. 30, 2011

EXAMPLE 2-30 1, where: Group D comprises use of or consists of use of 0215. Any combination comprising or consisting of One Peroxisome Proliferator-Activated Receptor (PPAR) ligands, Member of Group C and One Member of Group J (see Table e.g. agonists, such as PPAR alpha agonists, PPARgamma 1). In alternative aspects, atherapy provided herein comprises agonists, PPAR alpha/gamma dual agonists, and other PPAR or consists of at least one member selected from Group C, and ligands (e.g. PPAR delta ligands); and Group F consists of at least one member selected from Group J, as shown in Table NCCN therapies. 1, where: Group C comprises use of or consists of use of Angiotensin Receptor Blockers (ARBs); and Group J com EXAMPLE 2-36 prises C.-difluoromethylornithine. 0221) Any combination comprising or consisting of One Member of Group D and One Member of Group G (see Table EXAMPLE 2-31 1). In alternative aspects, atherapy provided herein comprises 0216. Any combination comprising or consisting of One or consists of at least one member selected from Group D, and Member of Group C and One Member of Group K (see Table at least one member selected from Group G, as shown in Table 1). In alternative aspects, atherapy provided herein comprises 1, where: Group D comprises use of or consists of use of or consists of at least one member selected from Group C, and Peroxisome Proliferator-Activated Receptor (PPAR) ligands, at least one member selected from Group K, as shown in Table e.g. agonists, such as PPAR alpha agonists, PPARgamma 1, where: Group C comprises use of or consists of use of agonists, PPAR alpha/gamma dual agonists, and other PPAR Angiotensin Receptor Blockers (ARBs); and Group K com ligands (e.g. PPAR delta ligands); and Group G comprises use prises Superoxide dismutase (SOD) and similar antioxidant of or consists of use of TNF inhibitors, e.g. pentoxifylline, or compounds. 1-(5-oxohexyl)-3,7-dimethylxanthine (e.g., TRENTALTM).

EXAMPLE 2-32 EXAMPLE 2-37 0217. Any combination comprising or consisting of One 0222 Any combination comprising or consisting of One Member of Group C and One Member of Group L (see Table Member of Group D and One Member of Group H (see Table 1). In alternative aspects, atherapy provided herein comprises 1). In alternative aspects, atherapy provided herein comprises or consists of at least one member selected from Group C, and or consists of at least one member selected from Group D, and at least one member selected from Group L, as shown in Table at least one member selected from Group H, as shown in Table 1, where: Group C comprises use of or consists of use of 1, where: Group D comprises use of or consists of use of Angiotensin Receptor Blockers (ARBs); and Group L com Peroxisome Proliferator-Activated Receptor (PPAR) ligands, prises activators of heat shock response. e.g. agonists, such as PPAR alpha agonists, PPARgamma agonists, PPAR alpha/gamma dual agonists, and other PPAR EXAMPLE 2-33 ligands (e.g. PPAR delta ligands); and Group H comprises use 0218. Any combination comprising or consisting of One of or consists of use of deferrioxamine. Member of Group C and One Member of Group M (see Table 1). In alternative aspects, atherapy provided herein comprises EXAMPLE 2-38 or consists of at least one member selected from Group C, and at least one member selected from Group M, as shown in 0223) Any combination comprising or consisting of One Table 1, where: Group C comprises use of or consists of use Member of Group D and One Member of Group I (see Table of Angiotensin Receptor Blockers (ARBs); and Group M 1). In alternative aspects, atherapy provided herein comprises comprises drugs that reduce the inflammatory/progressive or consists of at least one member selected from Group D, and tissue damage response. at least one member selected from Group I, as shown in Table 1, where: Group D comprises use of or consists of use of EXAMPLE 2-34 Peroxisome Proliferator-Activated Receptor (PPAR) ligands, 0219. Any combination comprising or consisting of One e.g. agonists, such as PPAR alpha agonists, PPARgamma Member of Group D and One Member of Group E (see Table agonists, PPAR alpha/gamma dual agonists, and other PPAR 1). In alternative aspects, atherapy provided herein comprises ligands (e.g. PPAR delta ligands); and Group I comprises or consists of at least one member selected from Group D, and polyunsaturated fatty acids, such as e.g. omega-3 fatty acids, at least one member selected from Group E, as shown in Table including for example eicosapentaenoic acid (EPA), and 1, where: Group D comprises use of or consists of use of docosahexaenoic acid (DHA). Peroxisome Proliferator-Activated Receptor (PPAR) ligands, e.g. agonists, such as PPAR alpha agonists, PPARgamma EXAMPLE 2-39 agonists, PPAR alpha/gamma dual agonists, and other PPAR 0224. Any combination comprising or consisting of One ligands (e.g. PPAR delta ligands); and Group E comprises use Member of Group D and One Member of Group J (see Table of or consists of use of non-steroidal anti-inflammatory drugs 1). In alternative aspects, atherapy provided herein comprises (NSAIDs). or consists of at least one member selected from Group D, and at least one member selected from Group J, as shown in Table EXAMPLE 2-35 1, where: Group D comprises use of or consists of use of 0220 Any combination comprising or consisting of One Peroxisome Proliferator-Activated Receptor (PPAR) ligands, Member of Group D and One Member of Group F (see Table e.g. agonists, such as PPAR alpha agonists, PPARgamma 1). In alternative aspects, atherapy provided herein comprises agonists, PPAR alpha/gamma dual agonists, and other PPAR or consists of at least one member selected from Group D, and ligands (e.g. PPAR delta ligands); and Group J comprises at least one member selected from Group F, as shown in Table C.-difluoromethylornithine. US 2011/0158983 A1 Jun. 30, 2011

EXAMPLE 2-40 G comprises use of or consists of use of TNF inhibitors, e.g. pentoxifylline, or 1-(5-oxohexyl)-3,7-dimethylxanthine 0225. Any combination comprising or consisting of One (e.g., TRENTALTM). Member of Group D and One Member of Group K (see Table 1). In alternative aspects, atherapy provided herein comprises EXAMPLE 2-45 or consists of at least one member selected from Group D, and at least one member selected from Group K, as shown in Table 0230. Any combination comprising or consisting of One 1, where: Group D comprises use of or consists of use of Member of Group E and One Member of Group H (see Table Peroxisome Proliferator-Activated Receptor (PPAR) ligands, 1). In alternative aspects, atherapy provided herein comprises e.g. agonists, such as PPAR alpha agonists, PPARgamma or consists of at least one member selected from Group E, and agonists, PPAR alpha/gamma dual agonists, and other PPAR at least one member selected from Group H, as shown in Table ligands (e.g. PPAR delta ligands); and Group K comprises 1, where: Group E comprises use of or consists of use of Superoxide dismutase (SOD) and similar antioxidant com non-steroidal anti-inflammatory drugs (NSAIDs); and Group pounds. H comprises use of or consists of use of deferrioxamine EXAMPLE 2-46 EXAMPLE 2-41 0231. Any combination comprising or consisting of One 0226. Any combination comprising or consisting of One Member of Group E and One Member of Group I (see Table Member of Group D and One Member of Group L (see Table 1). In alternative aspects, atherapy provided herein comprises 1). In alternative aspects, atherapy provided herein comprises or consists of at least one member selected from Group E, and or consists of at least one member selected from Group D, and at least one member selected from Group I, as shown in Table at least one member selected from Group L, as shown in Table 1, where: Group E comprises use of or consists of use of 1, where: Group D comprises use of or consists of use of non-steroidal anti-inflammatory drugs (NSAIDs); and Group Peroxisome Proliferator-Activated Receptor (PPAR) ligands, I comprises polyunsaturated fatty acids, such as e.g. omega-3 e.g. agonists, such as PPAR alpha agonists, PPARgamma fatty acids, including for example eicosapentaenoic acid agonists, PPAR alpha/gamma dual agonists, and other PPAR (EPA), and docosahexaenoic acid (DHA). ligands (e.g. PPAR delta ligands); and Group L comprises activators of heat shock response. EXAMPLE 2-47 0232 Any combination comprising or consisting of One EXAMPLE 2-42 Member of Group E and One Member of Group J (see Table 1). In alternative aspects, atherapy provided herein comprises 0227. Any combination comprising or consisting of One or consists of at least one member selected from Group E, and Member of Group D and One Member of GroupM (see Table at least one member selected from Group J, as shown in Table 1). In alternative aspects, atherapy provided herein comprises 1, where: Group E comprises use of or consists of use of or consists of at least one member selected from Group D, and non-steroidal anti-inflammatory drugs (NSAIDs); and Group at least one member selected from Group M, as shown in J comprises C.-difluoromethylornithine. Table 1, where: Group D comprises use of or consists of use of Peroxisome Proliferator-Activated Receptor (PPAR) EXAMPLE 2-48 ligands, e.g. agonists, such as PPAR alpha agonists, PPAR 0233. Any combination comprising or consisting of One gamma agonists, PPAR alpha/gamma dual agonists, and Member of Group E and One Member of Group K (see Table other PPAR ligands (e.g. PPAR delta ligands); and Group M 1). In alternative aspects, atherapy provided herein comprises comprises drugs that reduce the inflammatory/progressive or consists of at least one member selected from Group E, and tissue damage response. at least one member selected from Group K, as shown in Table 1, where: Group E comprises use of or consists of use of EXAMPLE 2-43 non-steroidal anti-inflammatory drugs (NSAIDs); and Group K comprises Superoxide dismutase (SOD) and similar anti 0228. Any combination comprising or consisting of One oxidant compounds. Member of Group E and One Member of Group F (see Table 1). In alternative aspects, atherapy provided herein comprises EXAMPLE 2-49 or consists of at least one member selected from Group E, and at least one member selected from Group F, as shown in Table 0234 Any combination comprising or consisting of One 1, where: Group E comprises use of or consists of use of Member of Group E and One Member of Group L (see Table non-steroidal anti-inflammatory drugs (NSAIDs); and Group 1). In alternative aspects, atherapy provided herein comprises F consists of NCCN therapies. or consists of at least one member selected from Group E, and at least one member selected from Group L, as shown in Table 1, where: Group E comprises use of or consists of use of EXAMPLE 2-44 non-steroidal anti-inflammatory drugs (NSAIDs); and Group 0229. Any combination comprising or consisting of One L comprises activators of heat shock response. Member of Group E and One Member of Group G (see Table 1). In alternative aspects, atherapy provided herein comprises EXAMPLE 2-50 or consists of at least one member selected from Group E, and 0235 Any combination comprising or consisting of One at least one member selected from Group G, as shown in Table Member of Group E and One Member of Group M (see Table 1, where: Group E comprises use of or consists of use of 1). In alternative aspects, atherapy provided herein comprises non-steroidal anti-inflammatory drugs (NSAIDs); and Group or consists of at least one member selected from Group E, and US 2011/0158983 A1 Jun. 30, 2011 20 at least one member selected from Group M, as shown in EXAMPLE 2-57 Table 1, where: Group E comprises use of or consists ofuse of non-steroidal anti-inflammatory drugs (NSAIDs); and Group 0242 Any combination comprising or consisting of One M comprises drugs that reduce the inflammatory/progressive Member of Group F and One Member of Group M (see Table tissue damage response. 1). In alternative aspects, atherapy provided herein comprises or consists of at least one member selected from Group F, and EXAMPLE 2-51 at least one member selected from Group M, as shown in Table 1, where: Group F consists of NCCN therapies; and 0236 Any combination comprising or consisting of One Group M comprises drugs that reduce the inflammatory/pro Member of Group F and One Member of Group G (see Table 1). In alternative aspects, atherapy provided herein comprises gressive tissue damage response. or consists of at least one member selected from Group F, and at least one member selected from Group G, as shown in Table EXAMPLE 2-58 1, where: Group F consists of NCCN therapies; and Group G 0243 Any combination comprising or consisting of One comprises use of or consists of use of TNF inhibitors, e.g. Member of Group G and One Member of Group H (see Table pentoxifylline, or 1-(5-oxohexyl)-3,7-dimethylxanthine 1). In alternative aspects, atherapy provided herein comprises (e.g., TRENTALTM). or consists of at least one member selected from Group G, and at least one member selected from Group H, as shown in Table EXAMPLE 2-52 1, where: Group G comprises use of or consists of use of TNF 0237 Any combination comprising or consisting of One inhibitors, e.g. pentoxifylline; and Group H comprises use of Member of Group F and One Member of Group H (see Table or consists of use of deferrioxamine. 1). In alternative aspects, atherapy provided herein comprises or consists of at least one member selected from Group F, and EXAMPLE 2-59 at least one member selected from Group H, as shown in Table 0244 Any combination comprising or consisting of One 1, where: Group F consists of NCCN therapies; and Group H Member of Group G and One Member of Group I (see Table comprises use of or consists of use of deferrioxamine. 1). In alternative aspects, atherapy provided herein comprises EXAMPLE 2-53 or consists of at least one member selected from Group G, and at least one member selected from Group I, as shown in Table 0238 Any combination comprising or consisting of One 1, where: Group G comprises use of or consists of use of TNF Member of Group F and One Member of Group I (see Table inhibitors, e.g. pentoxifylline; and Group I comprises poly 1). In alternative aspects, atherapy provided herein comprises unsaturated fatty acids, such as e.g. omega-3 fatty acids, or consists of at least one member selected from Group F, and including for example eicosapentaenoic acid (EPA), and at least one member selected from Group I, as shown in Table 1, where: Group F consists of NCCN therapies; and Group I docosahexaenoic acid (DHA). comprises polyunsaturated fatty acids, Such as e.g. omega-3 fatty acids, including for example eicosapentaenoic acid EXAMPLE 2-60 (EPA), and docosahexaenoic acid (DHA). 0245 Any combination comprising or consisting of One Member of Group G and One Member of Group J (see Table EXAMPLE 2-54 1). In alternative aspects, atherapy provided herein comprises 0239. Any combination comprising or consisting of One or consists of at least one member selected from Group G, and Member of Group F and One Member of Group J (see Table at least one member selected from Group J, as shown in Table 1). In alternative aspects, atherapy provided herein comprises 1, where: Group G comprises use of or consists of use of TNF or consists of at least one member selected from Group F, and inhibitors, e.g. pentoxifylline; and Group J comprises C.-dif at least one member selected from Group J, as shown in Table luoromethylornithine. 1, where: Group F consists of NCCN therapies; and Group J comprises C.-difluoromethylornithine. EXAMPLE 2-61 EXAMPLE 2-55 0246. Any combination comprising or consisting of One Member of Group G and One Member of Group K (see Table 0240 Any combination comprising or consisting of One 1). In alternative aspects, atherapy provided herein comprises Member of Group F and One Member of Group K (see Table or consists of at least one member selected from Group G, and 1). In alternative aspects, atherapy provided herein comprises at least one member selected from Group K, as shown in Table or consists of at least one member selected from Group F, and 1, where: Group G comprises use of or consists of use of TNF at least one member selected from Group K, as shown in Table inhibitors, e.g. pentoxifylline; and Group K comprises Super 1, where: Group F consists of NCCN therapies; and Group K comprises Superoxide dismutase (SOD) and similar antioxi oxide dismutase (SOD) and similar antioxidant compounds. dant compounds. EXAMPLE 2-62 EXAMPLE 2-56 0247 Any combination comprising or consisting of One 0241 Any combination comprising or consisting of One Member of Group G and One Member of Group L (see Table Member of Group F and One Member of Group L (see Table 1). In alternative aspects, atherapy provided herein comprises 1). In alternative aspects, atherapy provided herein comprises or consists of at least one member selected from Group G, and or consists of at least one member selected from Group F, and at least one member selected from Group L, as shown in Table at least one member selected from Group L, as shown in Table 1, where: Group G comprises use of or consists of use of TNF 1, where: Group F consists of NCCN therapies; and Group L inhibitors, e.g. pentoxifylline; and Group L comprises acti comprises activators of heat shock response. vators of heat shock response. US 2011/0158983 A1 Jun. 30, 2011

EXAMPLE 2-63 EXAMPLE 2-69 0248 Any combination comprising or consisting of One Member of Group G and One Member of GroupM (see Table 0254 Any combination comprising or consisting of One 1). In alternative aspects, atherapy provided herein comprises Member of Group I and One Member of Group J (see Table or consists of at least one member selected from Group G, and 1). In alternative aspects, atherapy provided herein comprises at least one member selected from Group M, as shown in or consists of at least one member selected from Group I, and Table 1, where: Group G comprises use of or consists of use at least one member selected from Group J, as shown in Table of TNF inhibitors, e.g. pentoxifylline; and Group M com 1, where: Group I comprises polyunsaturated fatty acids, such prises drugs that reduce the inflammatory/progressive tissue as e.g. omega-3 fatty acids, including for example eicosap damage response. entaenoic acid (EPA), and docosahexaenoic acid (DHA); and EXAMPLE 2-64 Group J comprises C.-difluoromethylornithine. 0249 Any combination comprising or consisting of One Member of Group H and One Member of Group I (see Table EXAMPLE 2-70 1). In alternative aspects, atherapy provided herein comprises or consists of at least one member selected from Group H, and 0255 Any combination comprising or consisting of One at least one member selected from Group I, as shown in Table Member of Group I and One Member of Group K (see Table 1, where: Group H comprises use of or consists of use of 1). In alternative aspects, atherapy provided herein comprises deferrioxamine; and Group I comprises polyunsaturated fatty or consists of at least one member selected from Group I, and acids, such as e.g. omega-3 fatty acids, including for example at least one member selected from Group K, as shown in Table eicosapentaenoic acid (EPA), and docosahexaenoic acid 1, where: Group I comprises polyunsaturated fatty acids, such (DHA). as e.g. omega-3 fatty acids, including for example eicosap entaenoic acid (EPA), and docosahexaenoic acid (DHA); and EXAMPLE 2-65 Group K comprises superoxide dismutase (SOD) and similar 0250) Any combination comprising or consisting of One antioxidant compounds. Member of Group H and One Member of Group J (see Table 1). In alternative aspects, atherapy provided herein comprises EXAMPLE 2-71 or consists of at least one member selected from Group H, and at least one member selected from Group J, as shown in Table 0256 Any combination comprising or consisting of One 1, where: Group H comprises use of or consists of use of Member of Group I and One Member of Group L (see Table deferrioxamine; and Group J comprises C.-difluoromethylor 1). In alternative aspects, atherapy provided herein comprises nithine. or consists of at least one member selected from Group I, and at least one member selected from Group L, as shown in Table EXAMPLE 2-66 1, where: Group I comprises polyunsaturated fatty acids, such 0251 Any combination comprising or consisting of One as e.g. omega-3 fatty acids, including for example eicosap Member of Group H and One Member of Group K (see Table entaenoic acid (EPA), and docosahexaenoic acid (DHA); and 1). In alternative aspects, atherapy provided herein comprises Group L comprises activators of heat shock response. or consists of at least one member selected from Group H, and at least one member selected from Group K, as shown in Table 1, where: Group H comprises use of or consists of use of EXAMPLE 2-72 deferrioxamine; and Group K comprises Superoxide dismu tase (SOD) and similar antioxidant compounds. 0257 Any combination comprising or consisting of One Member of Group I and One Member of Group M (see Table EXAMPLE 2-67 1). In alternative aspects, atherapy provided herein comprises 0252) Any combination comprising or consisting of One or consists of at least one member selected from Group I, and Member of Group H and One Member of Group L (see Table at least one member selected from Group M, as shown in 1). In alternative aspects, atherapy provided herein comprises Table 1, where: Group I comprises polyunsaturated fatty or consists of at least one member selected from Group H, and acids, such as e.g. omega-3 fatty acids, including for example at least one member selected from Group L, as shown in Table eicosapentaenoic acid (EPA), and docosahexaenoic acid 1, where: Group H comprises use of or consists of use of (DHA); and Group M comprises drugs that reduce the inflam deferrioxamine; and Group L comprises activators of heat matory/progressive tissue damage response. shock response. EXAMPLE 2-73 EXAMPLE 2-68 0253) Any combination comprising or consisting of One 0258 Any combination comprising or consisting of One Member of Group H and One Member of GroupM (see Table Member of Group J and One Member of Group K (see Table 1). In alternative aspects, atherapy provided herein comprises 1). In alternative aspects, atherapy provided herein comprises or consists of at least one member selected from Group H, and or consists of at least one member selected from Group J, and at least one member selected from Group M, as shown in at least one member selected from Group K, as shown in Table Table 1, where: Group H comprises use of or consists of use 1, where: Group J comprises C.-difluoromethylornithine; and of deferrioxamine; and Group M comprises drugs that reduce Group K comprises superoxide dismutase (SOD) and similar the inflammatory/progressive tissue damage response. antioxidant compounds. US 2011/0158983 A1 Jun. 30, 2011 22

EXAMPLE 2-74 Group (e.g. Group A) or may be multiple Groups (e.g. Group A. Group B, and Group E). Thus, this invention also provides 0259 Any combination comprising or consisting of One in separate embodiments, a therapy comprising every pos Member of Group J and One Member of Group L (see Table sible combination and permutation of three members selected 1). In alternative aspects, atherapy provided herein comprises from any of Group A, Group B. Group C, Group D, Group E, or consists of at least one member selected from Group J, and Group F, Group G, Group H, Group I, Group J. Group K, at least one member selected from Group L, as shown in Table Group L, and/or Group M, as shown in Table 1, where: of 1, where: Group J comprises C.-difluoromethylornithine; and Group A comprises or consists of, or Group A comprises use Group L comprises activators of heat shock response. ofor consists of use of geranylgeranyl compounds, including for example, geranylgeranyl acetone (GGA) and analogs of EXAMPLE 2-75 geranylgeranyl acetone (GGA); Group B comprises use of or 0260 Any combination comprising or consisting of One consists of use of Angiotensin Converting Enzyme Inhibitors Member of Group J and One Member of Group M (see Table (ACE Inhibitors or ACE-Is); Group C comprises use of or 1). In alternative aspects, atherapy provided herein comprises consists of use of Angiotensin Receptor Blockers (ARBs); or consists of at least one member selected from Group J, and Group D comprises use of or consists of use of Peroxisome at least one member selected from Group M, as shown in Proliferator-Activated Receptor (PPAR) ligands, e.g. ago Table 1, where: Group J comprises C.-difluoromethylorni nists, such as PPAR alpha agonists, PPARgamma agonists, thine; and Group M comprises drugs that reduce the inflam PPAR alpha/gamma dual agonists, and other PPAR ligands matory/progressive tissue damage response. (e.g. PPAR delta ligands); Group E comprises use of or con sists of use of non-steroidal anti-inflammatory drugs EXAMPLE 2-76 (NSAIDs); Group F consists of NCCN therapies; Group G 0261 Any combination comprising or consisting of One comprises use of or consists of use of TNF inhibitors, e.g. Member of Group K and One Member of Group L (see Table pentoxifylline; Group H comprises use of or consists of use of 1). In alternative aspects, atherapy provided herein comprises deferrioxamine; Group I comprises polyunsaturated fatty or consists of at least one member selected from Group K, and acids, such as e.g. omega-3 fatty acids, including for example at least one member selected from Group L, as shown in Table eicosapentaenoic acid (EPA), and docosahexaenoic acid 1, where: Group K comprises superoxide dismutase (SOD) (DHA); Group J comprises C.-difluoromethylornithine; and similar antioxidant compounds; and Group L comprises Group K comprises superoxide dismutase (SOD) and similar activators of heat shock response. antioxidant compounds; Group L comprises activators of heat shock response; and Group M comprises drugs that reduce EXAMPLE 2-77 the inflammatory/progressive tissue damage response, where said members selected to comprise the “triple combination 0262 Any combination comprising or consisting of One therapy” may all be selected from the same Group (e.g. Group Member of Group Kand One Member of GroupM (see Table A) or may be selected from multiple Groups (e.g. Group A, 1). In alternative aspects, atherapy provided herein comprises Group B, and Group E). or consists of at least one member selected from Group K, and at least one member selected from Group M, as shown in Examples: “Ouadruple Combination Therapies” (All “Com Table 1, where: Group K comprises superoxide dismutase bination Possibilities’) (SOD) and similar antioxidant compounds; and Group M comprises drugs that reduce the inflammatory/progressive 0265. The invention provides compositions and therapies tissue damage response. (methods) comprising use of any combination of at least one compound from at least four Groups (from Table 1). In addi EXAMPLE 2-78 tional embodiments, this invention comprises all possible quadruple combinations comprising a first member selected 0263. Any combination comprising or consisting of One from a first Group, a second member selected from a second Member of Group L and One Member of Group M (see Table Group, a third member selected from third Group, and a 1). In alternative aspects, atherapy provided herein comprises fourth member selected from a fourth Group (the Groups are or consists of at least one member selected from Group L. and described in Table 1). Thus, this invention also provides, in at least one member selected from Group M, as shown in separate embodiments, a therapy comprising all combina Table 1, where: Group L comprises activators of heat shock tions of four members selected from any of Group A, Group response; and Group M comprises drugs that reduce the B. Group C, Group D, Group E, Group F, Group G, Group H, inflammatory/progressive tissue damage response. Group I, Group J. Group K, Group L, and/or Group M, as shown in Table 1, where: of Group A comprises or consists of, Examples: “Triple Combination Therapies’ (All “Combina or Group A comprises use of or consists of use of gera tion Possibilities’) nylgeranyl compounds, including for example, geranylgera 0264. The invention provides compositions and therapies nyl acetone (GGA) and analogs of geranylgeranyl acetone (methods) comprising use of any combination of at least one (GGA); Group B comprises use of or consists of use of compound from at least three Groups (from Table 1). In Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors additional embodiments, this invention comprises all pos or ACE-Is); Group C comprises use of or consists of use of sible “triple combination therapies' comprising a first mem Angiotensin Receptor Blockers (ARBs); Group D comprises ber selected from a first Group as listed herein, a second use of or consists of use of Peroxisome Proliferator-Activated member selected from a second Group as listed herein, and a Receptor (PPAR) ligands, e.g. agonists, such as PPAR alpha third member selected from third Group as listed herein (the agonists, PPARgamma agonists, PPAR alpha/gamma dual Groups are described in Table 1), where said first Group, said agonists, and other PPAR ligands (e.g. PPAR delta ligands); second Group, and said third Group may all be the same Group E comprises use of or consists of use of non-steroidal US 2011/0158983 A1 Jun. 30, 2011

anti-inflammatory drugs (NSAIDs); Group F consists of 0267 Additional aspects of the invention include benefits, NCCN therapies; Group G comprises use of or consists ofuse goals, purposes, and utilities provided herein, and include any of TNF inhibitors, e.g. pentoxifylline; Group H comprises use combination and and/or permutation of the following ben of or consists of use of deferrioxamine; Group I comprises efits, goals, purposes, and utilities: polyunsaturated fatty acids, such as e.g. omega-3 fatty acids, 0268. 1) to allow or enable or facilitate the tolerance and including for example eicosapentaenoic acid (EPA), and use of higher amounts and/or doses and/or longer dura docosahexaenoic acid (DHA); Group J comprises C.-difluo tions of a medical therapy (e.g. cancer therapies or radia romethylornithine; Group K comprises Superoxide dismutase tion therapies) than could be used without this invention; (SOD) and similar antioxidant compounds; Group L com 0269. 2) to allow or enable or facilitate the tolerance and prises activators of heat shock response; and Group M com use of longer durations of a medical therapy (e.g. cancer prises drugs that reduce the inflammatory/progressive tissue therapies or radiation therapies) than could be used with damage response, where said members selected to comprise out this invention; the “quadruple combination therapy” may all be selected 0270 3) to reduce occurrences of (drug) resistance to a from the same Group (e.g. Group A) or may be selected from medical therapy (e.g. cancer chemotherapy or radiation multiple Groups (e.g. Group A, Group B. Group D, and therapy; administration can be before, during and/or Group E). after the radiation therapy and/or cancer chemotherapy): 0271 4) to enable dosage intensification of a medical therapy (e.g. cancer chemotherapy or radiation therapy; Examples’ “Quintuple Combination Therapies’ (All “Com administration can be before, during and/or after the bination Possibilities’) medical therapy); 0266 The invention provides compositions and therapies 0272 5) to enable increasing the frequency of a medical (methods) comprising use of any combination of at least one therapy (e.g. cancer chemotherapy or radiation therapy; compound from at least five Groups (from Table 1). In similar administration can be before, during and/or after the fashion, this invention comprises all possible quintuple com medical therapy); binations comprising a first member selected from a first 0273 6) to enhance patient response rates: Group, a second member selected from a second Group, a 0274 7) to increase patient survival; third member selected from third Group, a fourth member 0275 8) to induce a tissue protective state; selected from a fourth Group, and a fifth member selected 0276 9) to induce tissue regeneration; and from a fifth Group (the Groups are described in Table 1). (0277 10) to induce tissue repair. Thus, this invention also provides, in separate embodiments, 0278. Other conditions, states and disease symptoms atherapy comprising every possible combination and permu treated, prevented and/or ameliorated by the compositions tation of five members selected from any of Group A, Group and methods of the invention are exemplified by any combi B. Group C, Group D, Group E, Group F, Group G, Group H, nation of the following examples: intolerance to cancer Group I, Group J. Group K, Group L, and/or Group M, as therapy (e.g. chemotherapy or radiation therapy), wasting, shown in Table 1, where: of Group A comprises or consists of and/or atrophy, such as muscle atrophy. or Group A comprises use of or consists of use of gera 0279. The invention provides any combination and/or per nylgeranyl compounds, including for example, geranylgera mutation of the following: treating, preventing and/or ame nyl acetone (GGA) and analogs of geranylgeranyl acetone liorating conditions, diseases, symptoms and/or disease (GGA); Group B comprises use of or consists of use of states comprising or caused by, or as a side effect of cancer Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors and any conditions caused by dysfunctional cells, inflamma or ACE-Is); Group C comprises use of or consists of use of tion, excessive sympathoneural drive (sympathetic nerve Angiotensin Receptor Blockers (ARBs); Group D comprises activity), cachexia, anorexia, and anorexia-cachexia, and use of or consists of use of Peroxisome Proliferator-Activated stress or anxiety related thereto for the purpose of improving Receptor (PPAR) ligands, e.g. agonists, such as PPAR alpha one or more undesirable symptoms associated with these agonists, PPARgamma agonists, PPAR alpha/gamma dual conditions, diseases, symptoms and/or disease States, or for agonists, and other PPAR ligands (e.g. PPAR delta ligands); slowing the progression (worsening) of one or more symp Group E comprises use of or consists of use of non-steroidal toms associated with these conditions, diseases, symptoms anti-inflammatory drugs (NSAIDs); Group F consists of and/or disease states. NCCN therapies; Group G comprises use of or consists ofuse 0280. In one aspect, this invention provides a product (e.g. of TNF inhibitors, e.g. pentoxifylline; Group H comprises use a cytoprotection product) and/or a therapy (e.g. a cytoprotec of or consists of use of deferrioxamine; Group I comprises tion therapy), that is selective for (e.g. selectively affects) polyunsaturated fatty acids, such as e.g. omega-3 fatty acids, normal tissue, e.g. non-cancer tissue that is not the intended including for example eicosapentaenoic acid (EPA), and target of cancer therapy (Such as chemotherapy or radiation docosahexaenoic acid (DHA); Group J comprises C.-difluo therapy). In one embodiment, the cytoprotection provided by romethylornithine; Group K comprises Superoxide dismutase this invention includes the protection of tissues at the cellular (SOD) and similar antioxidant compounds; Group L com level; and in another embodiment, the cytoprotection pro prises activators of heat shock response; and Group M com vided by this invention includes the protection of tissues at the prises drugs that reduce the inflammatory/progressive tissue organ system level. damage response, where said members selected to comprise 0281. In one aspect this invention provides a cytoprotec the “triple combination therapy” may all be selected from the tion product and a cytoprotection therapy that can preferen same Group (e.g. Group A) or may be selected from multiple tially target tissue compartment and/or a cell type that are in Groups (e.g. Group A, Group B. Group C, Group D, and a normal or unstressed state over tissue compartments and Group E). cell types that are in a stressed physiological state. US 2011/0158983 A1 Jun. 30, 2011 24

0282. This invention provides a product (e.g. a cytopro neally, intramuscularly, Subcutaneously, intra-aurally, by tection therapy) and/or a therapy (e.g. a cytoprotection intra-articular administration, by intra-mammary administra therapy), that will induce a protective state in normal host tion, by topical administration or by absorption through epi tissue (e.g. non-cancer tissue) compartments and cells (in thelial or mucocutaneous linings. cluding, in different embodiments, mucosal tissue compart 0289. The invention provides kits comprising the thera ment(s), bone marrow, brain, heart, lung, kidney, liver, GI peutic combination of the invention, or the pharmaceutical track, auditory compartment(s), dermal/scalp compartment composition of the invention. The kit can comprise at least (S), etc.) preferentially over abnormal stressed tissue com one package, e.g., a blister pack, containing any one or more partments and stressed cancer cells. As used herein, this of a therapeutic combination of any of the invention, or the invention provides that stressed cancer cells and associated pharmaceutical composition of the invention. tissue compartment(s) have already undergone a stress 0290. In alternative aspects, the therapeutic combination response and are not (or not as) responsive to a therapy or of the invention, or the pharmaceutical composition of the composition intended to provide prophylactic cytoprotection invention, is formulated for administration intravenously, to non-cancerous and and/or normal cells. topically, orally, by inhalation, by infusion, by injection, 0283. This invention provides combination preparations intraperitoneally, intramuscularly, Subcutaneously, intra-au and formulations, kits and other products of manufacture rally, for intra-articular administration, for intra-mammary (e.g., blister packs, tablets, capsules, pills and the like) that administration, for topical administration or for absorption can be used as cytoprotective Supportive care therapies and through epithelial or mucocutaneous linings. can be furthermore used as adjunct therapies for multi-drug 0291. The therapeutic combination of the invention, or the resistant cases. pharmaceutical composition of the invention, can be pack 0284. In alternative embodiments of this invention, a cyto aged for administration intravenously, topically, orally, by protection product or a cytoprotection therapy is exemplified inhalation, by infusion, by injection, intraperitoneally, intra by a therapeutic combination comprising at least one member muscularly, Subcutaneously, intra-aurally, for intra-articular of a first group and at least one member of a second group; administration, for intra-mammary administration, for topi wherein members of the first group are selected from the group consisting of angiotensin-converting enzyme (ACE) cal administration or for absorption through epithelial or inhibitors, and angiotensin receptor blockers (ARBs). In one mucocutaneous linings. aspect, the therapeutic combination comprises: at least one 0292. In one aspect, therapeutic combinations of the angiotensin-converting enzyme (ACE) inhibitors; and at least invention, or pharmaceutical compositions of the invention one angiotensin receptor blocker (ARB). (e.g., the multi-ingredient combinations of drugs of the inven 0285. In one aspect, the therapeutic combinations com tion), are formulated for chrono-dosing, or the methods of the prise at least one member of the first group and the at least one invention comprise use of chrono-dosing or escalating dosage member of the second group are formulated as separate com regimens. For example, in one aspect the therapeutic combi positions. In one aspect, the therapeutic combinations com nations of the invention, or pharmaceutical compositions of prise at least one member of the first group and the at least one the invention, are formulated for administration once a day, member of the group are formulated in the same composition. b.i.d. ort.i.d or more often, or for continuous administration. In one aspect, each member of each selected group is formu In one aspect, therapeutic combinations of the invention, or lated as a separate composition, or, all selected members are pharmaceutical compositions of the invention, are formulated formulated in the same composition, or, a combination and dosaged as set forth in any one of exemplary ingredient thereof. In one aspect, each member of each selected group is combinations. manufactured in a separate package or container (e.g., a “blis 0293. The invention provides methods wherein a formu ter package'), or, all selected members are manufactured in lation or preparation is administered by oral means, inhala the same package or container, or, any combination thereof. tion, infusion or injection, topical application or by absorp 0286 The invention provides pharmaceutical composi tion through epithelial or mucocutaneous linings. tions comprising a therapeutic combination of the invention; 0294 The invention provides liquids comprising the or, therapeutic combination of the invention can be singly or preparation of the invention, or formulation of the invention. multiply formulated or packaged as one or more pharmaceu The invention provides capsules, sprays, powders, lotions, tical compositions. The pharmaceutical compositions can tablets or pills comprising a preparation of the invention or further comprise any pharmaceutically acceptable excipient. formulation of the invention. Compositions used in the therapeutic combinations of the 0295 The invention provides foods or food supplements invention, e.g., the pharmaceutical compositions of the inven comprising a preparation of the invention or a formulation of tion, can be formulated in or as a feed, a food, a liquid, an the invention. The food or food Supplement can comprise a elixir, an aerosol, a spray, a powder, a tablet, a pill, a capsule, flavored bar, a power bar, a diet bar, an energy bar or a a gel, a gel tab, a nanosuspension, a nanoparticle, a microgel nutritional bar. or a Suppository. 0296. The invention provides methods for maintaining the 0287. In one aspect of the methods, the therapeutic com health of a tissue comprising administering an effective bination of the invention, or the pharmaceutical composition amount of a preparation of the invention or a formulation of of the invention, is administered in single or multiple doses, the invention. The tissue can be skeletal muscle tissue, fat and optionally the pharmaceutical compositions are pack tissue, or more than one body tissue type, including the major aged in a single or a plurality of packages or packets. ity of the body. The invention provides methods for amelio 0288. In one aspect of the methods, the therapeutic com rating a disease or condition in an individual comprising bination of the invention, or the pharmaceutical composition administering an effective amount of a preparation of the of the invention, is administered intravenously, topically, invention or a formulation of the invention. The disease or orally, by inhalation, by infusion, by injection, intraperito condition can affect skeletal muscle tissue or fat tissue. US 2011/0158983 A1 Jun. 30, 2011

0297. In separate embodiments, the product this invention inhibitors, e.g. pentoxifylline; Group H comprises use of or provides different products that comprise (contain at least), or consists of use of deferrioxamine; Group I comprises poly methods that use, all the combinations and permutations of unsaturated fatty acids, such as e.g. omega-3 fatty acids, any ingredients provided herein by specific mention. This including for example eicosapentaenoic acid (EPA), and invention also provides different products that comprise (con docosahexaenoic acid (DHA); Group J comprises C.-difluo tain at least) all the combinations and permutations of any romethylornithine; Group K comprises Superoxide dismutase ingredients provided herein, if not by specific mention of said (SOD) and similar antioxidant compounds; Group L com ingredients, then by knowledge in the art that said ingredients prises activators of heat shock response; and Group M com are part of one or more category or group of ingredients prises drugs that reduce the inflammatory/progressive tissue provided herein. damage response. 0298. In separate embodiments, this invention provides 0300. In one aspect, the term “at least one member” in different products that comprise (contain at least), or methods reference to exemplary alternative embodiments comprises that use, all the combinations and permutations of ingredients minimally every integer value from one to about 20 or more, selected from members of Group A, Group B. Group C, inclusive; i.e. in one aspect “at least one member” in this Group D, Group E, Group F, Group G, Group H, Group I, context means at least one member, in another aspect “at least Group J. Group K, Group L, and/or Group M, as shown in one member” in this context means at least two members, in Table 1, where: of Group A comprises or consists of, or Group another aspect “at least one member in this context means at A comprises use of or consists of use of geranylgeranyl least three members, ..., etc., and in another aspect “at least compounds, including for example, geranylgeranyl acetone one member” in this context means at least 20 members. In (GGA) and analogs of geranylgeranyl acetone (GGA); Group further alternative embodiments “at least one member in this B comprises use of or consists of use of Angiotensin Convert context can comprise more than 20 members. ing Enzyme Inhibitors (ACE Inhibitors or ACE-Is); Group C 0301 In one embodiment, this invention provides every comprises use of or consists of use of Angiotensin Receptor combination and permutation of ingredients exemplified in Blockers (ARBs); Group D comprises use of or consists of Table 1 (i.e. from members of Group A, Group B. Group C, use of Peroxisome Proliferator-Activated Receptor (PPAR) Group D, Group E, Group F, Group G, Group H, Group I, ligands, e.g. agonists, such as PPAR alpha agonists, PPAR Group J. Group K, Group L, and/or Group M, as shown in gamma agonists, PPAR alpha/gamma dual agonists, and Table 1, for example). Exemplary combinations and permu other PPAR ligands (e.g. PPAR delta ligands); Group E com tations provided herein comprise ingredients selected from at prises use of or consists of use of non-steroidal anti-inflam least 1 group, where the at least 1 group is selected from any matory drugs (NSAIDs); Group F consists of NCCN thera of Group A, Group B. Group C, Group D, Group E, Group F, pies; Group G comprises use of or consists of use of TNF Group G, Group H, Group I, Group J. Group K, Group L. inhibitors, e.g. pentoxifylline; Group H comprises use of or and/or Group M, as shown in Table 1. In alternative embodi consists of use of deferrioxamine; Group I comprises poly ments there may be at least one, at least 2, at least 3, at least 4, unsaturated fatty acids, such as e.g. omega-3 fatty acids, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, including for example eicosapentaenoic acid (EPA), and at least 11, at least 12, at least 13, at least 14, at least 15, at least docosahexaenoic acid (DHA); Group J comprises C.-difluo 16, at least 17, at least 18, at least 19, and at least 20 different romethylornithine; Group K comprises Superoxide dismutase members selected from any to each of members of Group A, (SOD) and similar antioxidant compounds; Group L com Group B. Group C, Group D, Group E, Group F, Group G, prises activators of heat shock response; and Group M com Group H, Group I, Group J. Group K, Group L. and/or Group prises drugs that reduce the inflammatory/progressive tissue M, as shown in Table 1. damage response. 0302) Exemplary combinations and permutations pro 0299. By way of illustration, in separate embodiments, vided herein comprise ingredients selected from at least 2 this invention provides kits and packages containing thera groups, where the at least 2 groups are selected from any of peutic preparations, which therapeutic preparations that com members of Group A, Group B. Group C, Group D, Group E, prise (contain at least) all the combinations and permutations Group F, Group G, Group H, Group I, Group J. Group K, of from any one ingredient to any 100 ingredients selected Group L, and/or Group M, as shown in Table 1. In alternative from members of Group A, Group B. Group C, Group D, embodiments there may be at least one, at least 2, at least 3, at Group E, Group F, Group G, Group H, Group I, Group J. least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at Group K, Group L, and/or Group M, as shown in Table 1, least 10, at least 11, at least 12, at least 13, at least 14, at least where: of Group A comprises or consists of, or Group A 15, at least 16, at least 17, at least 18, at least 19, and at least comprises use of or consists of use of geranylgeranyl com 20 different members selected from any to each of members pounds, including for example, geranylgeranyl acetone of Group A, Group B. Group C, Group D, Group E, Group F, (GGA) and analogs of geranylgeranyl acetone (GGA); Group Group G, Group H, Group I, Group J. Group K, Group L. and B comprises use of or consists of use of Angiotensin Convert Group M, as shown in Table 1. ing Enzyme Inhibitors (ACE Inhibitors or ACE-Is); Group C 0303 Exemplary combinations and permutations pro comprises use of or consists of use of Angiotensin Receptor vided herein comprise ingredients selected from at least 3 Blockers (ARBs); Group D comprises use of or consists of groups, where the at least 3 groups are selected from any of use of Peroxisome Proliferator-Activated Receptor (PPAR) members of Group A, Group B. Group C, Group D, Group E, ligands, e.g. agonists, such as PPAR alpha agonists, PPAR Group F, Group G, Group H, Group I, Group J. Group K, gamma agonists, PPAR alpha/gamma dual agonists, and Group L, and/or Group M, as shown in Table 1. In alternative other PPAR ligands (e.g. PPAR delta ligands); Group E com embodiments there may be at least one, at least 2, at least 3, at prises use of or consists of use of non-steroidal anti-inflam least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at matory drugs (NSAIDs); Group F consists of NCCN thera least 10, at least 11, at least 12, at least 13, at least 14, at least pies; Group G comprises use of or consists of use of TNF 15, at least 16, at least 17, at least 18, at least 19, and at least US 2011/0158983 A1 Jun. 30, 2011 26

20 different members selected from any to each of Groups 1-5 (e.g., BMS-354825TM), sunitinib (e.g., SUTENT)TM, pazo members of Group A, Group B. Group C, Group D, Group E, panib, nilotinib (e.g., TASIGNATM), panitumumab (e.g., Group F, Group G, Group H, Group I, Group J. Group K, VECTIBIXTM), bandetinib, brivanib, E7080TM or a combina Group L, and Group M, as shown in Table 1. tion thereof. 0304 Exemplary combinations and permutations pro 0310. In alternative embodiments, the therapeutic agent vided herein comprise ingredients selected from at least 4 for the treatment of cancer can comprise or consist of a groups, where the at least 4 groups are selected from any of members of Group A, Group B. Group C, Group D, Group E, tyrosine kinase inhibitor or a serine/threonine kinase inhibi Group F, Group G, Group H, Group I, Group J. Group K, tor; or a histone deacetylase inhibitor, e.g., comprising or Group L, and/or Group M, as shown in Table 1. In alternative consisting of avorinostat (rINN) or ZOLINZATM, or suberoy embodiments there may be at least one, at least 2, at least 3, at lanilide hydroxamic acid (SAHA). least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at 0311. In alternative embodiments, the therapeutic agent least 10, at least 11, at least 12, at least 13, at least 14, at least for the treatment of cancer can comprise or consist of an 15, at least 16, at least 17, at least 18, at least 19, and at least angiogenesis inhibitor, e.g., a vascular endothelial growth 20 different members selected from any to each of members factor (VEGF)-mediated angiogenesis inhibitor. of Group A, Group B. Group C, 0312. In alternative embodiments, the therapeutic agent 0305 Group D, Group E, Group F, Group G, Group H, for the treatment of cancer can comprise or consist of an Group I, Group J. Group K, Group L, and Group M, as shown inducer of apoptosis or a mitotic and anti-microtubule inhibi in Table 1. tor (inhibition of microtubule function), e.g., a raltitrexed 0306 Exemplary combinations and permutations pro (e.g., TOMUDEXTM), doxorubicin (e.g., ADRIAMY vided herein comprise ingredients selected from at least 5 CINTM), fluorouracil (e.g., 5-fluorouracil), paclitaxel (e.g., groups, where the at least 5 groups are selected from any of TAXOLTM or ABRAXANETM) docetaxel (e.g., TAXO members of Group A, Group B. Group C, Group D, Group E, TERETM), vinblastin, vindesine, vinorelbine (NAVEL Group F, Group G, Group H, Group I, Group J. Group K, BINETM); an epothilone (e.g., epothilone A, B, C, D, E or F), Group L, and/or Group M, as shown in Table 1. In alternative ixabepilone (also known as azaepothilone B, e.g., BMS embodiments there may be at least one, at least 2, at least 3, at 247550TM) or a combination thereof. least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at 0313. In alternative embodiments, the therapeutic agent least 10, at least 11, at least 12, at least 13, at least 14, at least for the treatment of cancer can comprise or consist of an 15, at least 16, at least 17, at least 18, at least 19, and at least alkylating agent, e.g., a cisplatin, cisplatinum or cis-diam 20 different members selected from any to each of members of Group A, Group B. Group C, Group D, Group E, Group F, minedichloridoplatinum(II) (CDDP), carboplatin, oxalopl Group G, Group H, Group I, Group J. Group K, Group L. atin, cyclophosphamide (cytophosphane) (e.g., and/or Group M, as shown in Table 1. ENDOXANTM, CYTOXANTM, NEOSARTM, REVIM 0307 The invention also provides computer program MUNETM), mechlorethamine (chlormethine, mustine, nitro products for implementing the computer implemented meth gen mustard), chlorambucil (e.g., LEUKERANTM) or a com ods of the invention, and computers comprising the computer bination thereof. program products of the invention. 0314. In alternative embodiments, a topoisomerase inhibi 0308 The invention provides therapeutic combination of tor, e.g., an etoposide (e.g., EPOSINTM, ETOPOPHOSTM, drugs for an individual in need thereof comprising or consist VEPESIDTM, VP-16TM), amsacrine, topotecan (e.g., ing of: (a) a beta adrenergic receptor antagonist (a beta HYCAMTINTM), teniposide (e.g., VUMONTM, VM-26TM), blocker), e.g., a propranolol or equivalent; (b) a non-steroidal an epipodophyllotoxin, a camptothecin, irinotecan (e.g., anti-inflammatory drug (a NSAID), e.g., an etodolac or CAMPTOSARTM), or a combination thereof. equivalent; and (c) a therapeutic agent for the treatment of 0315. In alternative embodiments, the therapeutic agent cancer. In one embodiment, the non-steroidal anti-inflamma for the treatment of cancer can comprise or consist of a tory drug (a NSAID) comprises etodolac, e.g., the etodolac glycopeptide antibiotic, e.g., a bleomycin (e.g., bleomycin A can be LODINET.M. In one embodiment, the beta adrenergic or B.), mitomycin (e.g., mitomycin C), plicamycin (also receptor antagonist (a beta blocker) comprises propranolol. known as mithramycin; e.g., MITHRACINTM), or a combi e.g., the propranolol can be INDERALTM. In one embodi nation thereof. ment, the beta adrenergic receptor antagonist (a beta blocker) 0316. In alternative embodiments, the therapeutic agent comprises propranolol and the non-steroidal anti-inflamma for the treatment of cancer can comprise or consist of a steroid tory drug (a NSAID) comprises etodolac. receptor inhibitor or steroid inhibitor (an anti-steroid), e.g., an 0309. In alternative embodiments, the therapeutic agent estrogen receptor modulator (a SERM), such as a tamoxifen for the treatment of cancer can comprise or consist of a (e.g., NOLVADEXTM, ISTUBALTM, VALODEXTM); or, the monoclonal antibody, a peptide, a synthetic polypeptide or steroid inhibitor or an anti-steroid can comprise or consist of peptidomimetic, a nucleic acid, a synthetic nucleic acid, a a finasteride (e.g., PROSCARTM, PROPECIATM, FIN lipid, a carbohydrate and/or a small molecule. The therapeutic CARTM, FINPECIATM, FINAXTM, FINASTTM, FINARATM, agent for the treatment of cancer can comprise or consist of FINALOTM, PROSTERIDETM, GEFINATM, APPECIATM, Sorafenib (NEXAVARTM), sunitinib (e.g., SUTENT)TM, erlo FINASTERIDIVAXTM, FINASTERIDALTERNOVATM). tinib (e.g., TARCEVATM), imatinib (e.g., GLEEVECTM), 0317. In alternative embodiments, the therapeutic agent lapatinib (e.g., TYKERBTM), bevacizumab (e.g., AVAS for the treatment of cancer can comprise or consist of (a) a TINTM), trastuzumab (e.g., HERCEPTINTM), cetuximab matrix metalloproteinase (MMP) inhibitor; (b) an mTOR (e.g., ERBITUXTM), bevacizumab (e.g., AVASTINTM), (mammalian target of rapamycin) inhibitor, or (c) an mTOR BIBW 2992, gefitinib (e.g., IRESSATM), ranibizumab (e.g., inhibitor comprising or consisting of a temsirolimus or LUCENTISTM), pegaptainib (e.g., MACUGENTM), dasatinib equivalent, or TORISELTM. US 2011/0158983 A1 Jun. 30, 2011 27

0318. In alternative embodiments, the beta adrenergic 0324. In alternative embodiments, the dosage of etodolac receptor antagonist (a beta blocker), the non-steroidal anti ranges from about 200 mg to 400 mg a day, or, about 10, 15, inflammatory drug (a NSAID), and the therapeutic agent for 20, 25, 30, 35, 40, 45, 50, 75, 80, 85,90, 100, 150, 200, 250, the treatment of cancer are formulated, are all formulated as 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or separate compositions; or, the beta adrenergic receptor more. In alternative embodiments, the dosage of propranolol antagonist (a beta blocker), e.g., propranolol or equivalent; ranges from 10 to 320 mg per day based on heart rate and the non-steroidal anti-inflammatory drug (a NSAID), e.g., an blood pressure of the individual, or, about 10, 15, 20, 25, 30, etodolac or equivalent; and the therapeutic agent for the treat 35, 40, 45, 50, 75, 80, 85,90, 100, 150, 200, 250, 300,350, ment of cancer are formulated in the same composition (they 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more. are formulated together). 0325 In alternative embodiments, the beta adrenergic 0319. In alternative embodiments, the beta adrenergic receptor antagonist (a beta blocker), e.g., a propranolol or receptor antagonist (a beta blocker), e.g., a propranolol or equivalent; the non-steroidal anti-inflammatory drug (a equivalent; the non-steroidal anti-inflammatory drug (a NSAID), e.g., an etodolac or equivalent; and the therapeutic NSAID), e.g., an etodolac or equivalent; and the therapeutic agent for the treatment of cancer are packaged individually in agent for the treatment of cancer are packaged in dosages that a single package, a plurality of packages or packettes, or a match a chrono-dosing regimen to match an optimal dose for blister packet, lidded blister or blister card or packets, or a the time of day. In alternative embodiments, the beta adren shrink wrap. ergic receptor antagonist (a beta blocker), e.g., a propranolol 0320 In alternative embodiments, the beta adrenergic or equivalent; the non-steroidal anti-inflammatory drug (a receptor antagonist (a beta blocker), e.g., propranolol or NSAID), e.g., an etodolac or equivalent; and the therapeutic equivalent; the non-steroidal anti-inflammatory drug (a agent for the treatment of cancer are packaged in dosages that NSAID), e.g., an etodolac or equivalent; and the therapeutic matcha chrono-dosing regimen comprising: (a) in the AM. 20 agent for the treatment of cancer are packaged together in a mg propranolol, 200 mg etodolac, in the afternoon, 10 mg single package, a plurality of packages or packettes, or a propranolol, 200 mg etodolac; in the PM, 10 mg propranolol, blister packet, lidded blister or blister card or packets, or a 400 mg etodolac; (b) in the AM 40 mg propranolol. 200 mg shrink wrap. etodolac, in the afternoon 20 mg propranolol. 200 mg etod 0321. In alternative embodiments, the beta adrenergic olac; in the evening, 20 mg propranolol, 400 mg etodolac.; (c) receptor antagonist (a beta blocker), e.g., a propranolol or in the AM 80 mg propranolol, 200 mg etodolac; in the after equivalent; the non-steroidal anti-inflammatory drug (a noon 40 mg propranolol. 200 mg etodolac, in the evening 40 NSAID), e.g., an etodolac or equivalent; and the therapeutic mg, etodolac, or (d) a dose escalation comprising a regimen agent for the treatment of cancer are packaged together in a of (a) to (b) to (c). In alternative embodiments, the beta single package, a plurality of packages or packettes, or a adrenergic receptor antagonist (a beta blocker), e.g., a pro blister packet, lidded blister or blister card or packets, or a pranolol or equivalent; the non-steroidal anti-inflammatory shrink wrap, and with both drugs released upon opening of drug (a NSAID), e.g., an etodolac or equivalent; and the the single package, plurality of packages or packettes, blister therapeutic agent for the treatment of cancer are packaged in packet, lidded blister, blister card or packets or shrink wrap. dosages that match a chrono-dosing regimen comprising: 0322. In alternative embodiments, the beta adrenergic Start: AM. 20 mg propranolol, 200 mg etodolac; afternoon, receptor antagonist (a beta blocker), e.g., a propranolol or 10 mg propranolol, 200 mg etodolac; PM 5 mg propranolol, equivalent; the non-steroidal anti-inflammatory drug (a 400 mg etodolac.; Dose Escalation 1: AM 40 mg propranolol, NSAID), e.g., an etodolac or equivalent; and the therapeutic 200 mg etodolac; afternoon 20 mg propranolol, 200 mg etod agent for the treatment of cancer are packaged together in a olac, evening, 10 mg propranolol. 400 mg etodolac, Dose single package, a plurality of packages or packettes, or a escalation 2: AM 80 mg propranolol, 200 mg etodolac; after blister packet, lidded blister or blister card or packets, or a noon 40 mg propranolol, 200 mg etodolac, evening 20 mg. shrink wrap, and with both drugs are formulated as a tablet, a pill, a lozenge, a capsule, a caplet, a patch, a spray, an inhal etodolac. ant, a gel, a geltab, a nanosuspension, a nanoparticle, a micro 0326 In alternative embodiments, the beta adrenergic gel and/or a pellet, and the tablet, pill, lozenge, capsule, gel. receptor antagonist (a beta blocker), e.g., a propranolol or geltab, nanosuspension, nanoparticle, microgel and/or a pel equivalent; the non-steroidal anti-inflammatory drug (a let are released upon opening of the single package, plurality NSAID), e.g., an etodolac or equivalent; and the therapeutic of packages or packettes, blister packet, lidded blister, blister agent for the treatment of cancer are formulated for adminis card or packet, or shrink wrap. tration once a day, b.i.d. or t.i.d., or weekly, or biweekly, or 0323. In alternative embodiments, the beta adrenergic monthly. receptor antagonist (a beta blocker), e.g., propranolol or 0327. In alternative embodiments, the beta adrenergic equivalent; the non-steroidal anti-inflammatory drug (a receptor antagonist (a beta blocker), e.g., a propranolol or NSAID), e.g., an etodolac or equivalent; and the therapeutic equivalent; the non-steroidal anti-inflammatory drug (a agent for the treatment of cancer are formulated or manufac NSAID), e.g., an etodolac or equivalent; and the therapeutic tured as a feed, a food, a pellet, a lozenge, a liquid, an elixir, agent for the treatment of cancer are formulated for adminis an aerosol, an inhalant, a spray, a powder, a tablet, a pill, a tration intravenously, topically, orally, by inhalation, by infu capsule, a gel, a gel tab, a nanosuspension, a nanoparticle, a Sion, by injection, by inhalation, intraperitoneally, intramus microgel or a Suppository. In alternative embodiments, the cularly, Subcutaneously, intra-aurally, for intra-articular beta adrenergic receptor antagonist (a beta blocker), e.g., a administration, for intra-mammary administration, for topi propranolol or equivalent; the non-steroidal anti-inflamma cal administration or for absorption through epithelial or tory drug (a NSAID), e.g., an etodolac or equivalent; and the mucocutaneous linings therapeutic agent for the treatment of cancer are packaged as 0328. In alternative embodiments, the therapeutic combi ablister pack or plurality of blister packettes, or lidded blister nation of the invention further comprises instructions for use or blister card or packets, or a shrink wrap. in the treatment of cancer, cachexia, cancer cachexia, mucosi US 2011/0158983 A1 Jun. 30, 2011 28 tis and/oranorexia. The cachexia can be defined as at least two rate is having a Sustained elevated heart rate of at least about of the symptoms selected from the group consisting of: 1) a 6 bpm. The cachexia can be defined by an individual having at hyper-inflammatory state, 2) altered hormone levels and least a sustained elevated heart rate of at least about 6 bpm and cytokine levels; 3) decreased heart rate variability; 4) weight weight loss. The CNS disorder can comprise (be) Parkinson's loss, and 5) increased heart rate, wherein optionally the disease or Alzheimer's disease. increased heart rate is having a Sustained elevated heart rate of 0331. The invention provides methods for treating orame at least about 6 bpm. The cachexia can be defined by an liorating a trauma, condition or disease comprising a cancer individual having at least a Sustained elevated heart rate of at or dysfunctional cell condition mucositis, any side effect least about 6 bpm and weight loss. from the treatment of a cancer or dysfunctional cell condition, 0329. The invention provides pharmaceutical composi chronic Systemic Inflammatory Response State (SIRS), tions or formulations comprising the therapeutic combination chronic systemic inflammatory stress; burns, chronic of the invention. The pharmaceutical compositions or formu lations can further comprise a pharmaceutically acceptable obstructive pulmonary disease; congestive heart failure; excipient. The pharmaceutical composition or formulation chronic kidney disease; can beformulated or manufactured as a feed, a food, a food or 0332 Surgery; cancer; sepsis: ageing; acute respiratory feed concentrate, a pellet, a lozenge, a liquid, a lotion, an distress syndrome; acute lung injury; infection; a CNS disor implant, a nanoparticle, an elixir, an aerosol, a spray, an der or injury; anemia; immunosuppression; insulin resis aerosol, an inhalant, a powder, a tablet, a pill, a capsule, a gel. tance; anorexia; anxiety; sleep disturbances; weakness; a geltab, a nanosuspension, a nanoparticle, a patch, a micro fatigue; gastrointestinal distress; sleep disturbances; wake gel or a Suppository. disturbances; pain; listlessness; shortness of breath; lethargy; 0330. The invention provides uses of the therapeutic com depression; malaise; or, a combination thereof, the method bination of the invention in the manufacture of a medicament comprising the steps of or pharmaceutical composition for treating, ameliorating or 0333 (a) providing the therapeutic combination of the preventing a trauma, condition or disease comprising: a can invention, or the pharmaceutical composition or formulation cer or dysfunctional cell condition; any side effect from the of the invention; and, treatment of cancer, chronic Systemic Inflammatory Response State (SIRS); chronic systemic inflammatory 0334 (b) administering a therapeutically effective amount stress; burns, chronic obstructive pulmonary disease; conges of the therapeutic combination or the pharmaceutical compo tive heart failure; chronic kidney disease; surgery; sepsis: sition or formulation of step (a), thereby treating or amelio ageing; acute respiratory distress syndrome; acute lung rating the side effect, trauma, condition or disease. injury; infection; a CNS disorder or injury; anemia; immu 0335. In alternative embodiments of the methods, the con nosuppression; insulin resistance; anorexia; anxiety; sleep dition or disease comprises a maladaptive nutritional state disturbances; weakness; fatigue; gastrointestinal distress; secondary to the SIRS; or, the maladaptive nutritional state sleep disturbances; wake disturbances; pain; listlessness; comprises cachexia or anorexia, or a cachexia secondary to shortness of breath; lethargy; depression; malaise; or, a com cancer. The cancer or dysfunctional cell condition can com bination thereof. The trauma, condition or disease can com prises (be) any metastatic or benign tumor, and the use is for prise a maladaptive nutritional state secondary to the SIRS, or treating (killing, eliminating, stopping the growth and/or the maladaptive nutritional state comprises cachexia, and metastasis of) cancer stem cells or cancer cells from: lung optionally the cachexia comprises cachexia secondary to can cancer, bone cancer, pancreatic cancer, skin cancer, cancer of cer. The cancer or dysfunctional cell condition can comprise the head or neck, cutaneous or intraocular melanoma, uterine (be) any metastatic or benign tumor, and the use is for treating cancer, ovarian cancer, rectal cancer, cancer of the anal (killing, eliminating, stopping the growth and/or metastasis region, stomach cancer, colon cancer, breast cancer, carci of) cancer stem cells or cancer cells from: lung cancer, bone noma of the fallopian tubes, carcinoma of the endometrium, cancer, pancreatic cancer, skin cancer, cancer of the head or carcinoma of the cervix, carcinoma of the vagina, carcinoma neck, cutaneous or intraocular melanoma, uterine cancer, of the Vulva, Hodgkin's Disease, cancer of the esophagus, ovarian cancer, rectal cancer, cancer of the anal region, stom cancer of the Small intestine, cancer of the endocrine system, ach cancer, colon cancer, breast cancer, carcinoma of the cancer of the thyroid gland, cancer of the parathyroid gland, fallopian tubes, carcinoma of the endometrium, carcinoma of cancer of the adrenal gland, sarcoma of soft tissue, cancer of the cervix, carcinoma of the vagina, carcinoma of the Vulva, the urethra, cancer of the penis, prostate cancer, chronic or Hodgkin's Disease, cancer of the esophagus, cancer of the acute leukemia, lymphocytic lymphomas, cancer of the blad Small intestine, cancer of the endocrine system, cancer of the der, cancer of the kidney or ureter, renal cell carcinoma, thyroid gland, cancer of the parathyroid gland, cancer of the carcinoma of the renal pelvis, neoplasms of the central ner adrenal gland, sarcoma of Soft tissue, cancer of the urethra, vous system (CNS), primary CNS lymphoma, spinal axis cancer of the penis, prostate cancer, chronic or acute leuke tumors, brain stem glioma or pituitary adenoma, and any mia, lymphocytic lymphomas, cancer of the bladder, cancer combination thereof. of the kidney or ureter, renal cell carcinoma, carcinoma of the 0336. In alternative embodiments of the methods, the renal pelvis, neoplasms of the central nervous system (CNS), cachexia is defined as at least two of the symptoms selected primary CNS lymphoma, spinal axis tumors, brain stem from the group consisting of: 1) a hyper-inflammatory state, glioma or pituitary adenoma, and any combination thereof. 2) altered hormone levels and cytokine levels; 3) decreased The cachexia can be defined as at least two of the symptoms heart rate variability; 4) weight loss, and 5) increased heart selected from the group consisting of: 1) a hyper-inflamma rate, wherein optionally the increased heart rate is having a tory state, 2) altered hormone levels and cytokine levels; 3) sustained elevated heart rate of at least about 6 bpm; or, the decreased heart rate variability; 4) weight loss, and 5) cachexia is defined by an individual having at leasta Sustained increased heart rate, wherein optionally the increased heart elevated heart rate of at least about 6 bpm and weight loss. US 2011/0158983 A1 Jun. 30, 2011 29

0337 The invention provides compositions or products of vous system (CNS), primary CNS lymphoma, spinal axis manufacture comprising the therapeutic combination of the tumors, brain stem glioma or pituitary adenoma, and any invention, or the pharmaceutical composition or formulation combination thereof. of the invention. The composition or product of manufacture 0340. The invention provides products of manufacture can comprise (can be formulated, manufactured or fabricated comprising ablister package, a lidded blister or ablister card as) a blister pack, clamshell or tray, wherein the therapeutic or packet, a clamshell, a tray or a shrink wrap comprising the combination is formulated for unit dosage administration to therapeutic combination of the invention, or the pharmaceu an individual in need thereof at the same time, and each unit tical composition or formulation of the invention. The inven dosage is contained within one blister in the blister pack, or tion provides products of manufacture comprising a blister compartment in the clamshell or tray; or, can comprise (can package, a lidded blister or a blister card or packet, a clam be formulated, manufactured or fabricated as) a pill, capsule, shell, a tray or a shrink wrap comprising the therapeutic tablet, tab, gel tab or implant, wherein the therapeutic combi combination of the invention, or the pharmaceutical compo nation is formulated for unit dosage administration to an sition or formulation of the invention, wherein the therapeutic individual in need thereof at the same time, and each unit combination or pharmaceutical composition or formulation dosage is contained within one pill, capsule, tablet, tab, geltab are manufactured and/or formulated for at least two dosage or implant. administrations. The therapeutic combination or pharmaceu 0338. The invention provides nanoparticles, micropar tical composition or formulation can be formulated as one ticles or liposomes comprising the therapeutic combination dosage administration in the morning and one dosage admin of the invention, or the pharmaceutical composition or for istration in the evening. The dosage schedule can provide a mulation of the invention. relatively higher dose of one drug in the morning (the AM) 0339. The invention provides kits comprising the thera than in the evening, and a relatively higher dose of another peutic combination of the invention, or the pharmaceutical medication in the evening than in the morning. composition or formulation of the invention. In alternative 0341 The invention provides products of manufacture or embodiments, the kits comprise at least one blister pack, formulations comprising the therapeutic combination of the lidded blister or blister card or packets, or a shrink wrap, invention, or the pharmaceutical composition or formulation comprising the therapeutic combination or the pharmaceuti of the invention, and a nutritional Supplement. cal composition. The invention provides kits for the treat 0342. The invention provides methods for treating, ame ment, amelioration or prevention of a cancer or any dysfunc liorating or preventing a cachexia and/or a chronic Systemic tional cell condition, a side effect from the treatment of a Inflammatory Response State (SIRS), wherein the therapeu cancer or dysfunctional cell condition, a chronic Systemic tic combination of the invention, or the pharmaceutical com Inflammatory Response State (SIRS) or a maladaptive nutri position or formulation of the invention, is administered to an tional state in a patient population, the kit comprising the individual in need thereof, and the therapeutic combination or therapeutic combination of the invention, or the pharmaceu the pharmaceutical composition are formulated for at least tical composition or formulation of the invention, and instruc two administrations, one in the morning and one in the tions for use of the therapeutic combination or pharmaceuti evening, wherein the dosage schedule provides a relatively cal composition. The maladaptive nutritional state can higher dose of beta blocker in the morning (the AM) than in comprise cachexia, and optionally the cachexia comprises the evening, and a relatively higher dose of an anti-inflam cachexia secondary to cancer. The cachexia can be defined: matory medication in the evening than in the morning. The (a) as having (being associated with) at least two of the administration regimen can comprise at least two dosages of symptoms selected from the group consisting of: 1) a hyper beta adrenergic receptor antagonist (a beta blocker) drug and inflammatory state, 2) altered hormone levels and/or cytokine at least two dosages of non-steroidal anti-inflammatory drug levels; 3) decreased heart rate variability; 4) weight loss, and (a NSAID), and further comprising administration of an anti 5) Sustained increased heart rate, wherein optionally the Sus anxiety drug, and the drugs are organized or labeled in a tained increased heart rate is having a Sustained elevated heart blister package, a lidded blister or a blister card or packet, a rate of at least about 6 bpm, or (b) by an individual having at clamshell, a tray or a shrink wrap for usage by an individual least a sustained elevated heart rate of at least about 6 bpm and for at least two administrations, one in the morning and one in weight loss. The cancer or dysfunctional cell condition can the evening, wherein the dosage schedule provides a rela comprise (be) any metastatic or benign tumor, and the use is tively higher dose of beta blocker in the morning (the AM) for treating (killing, eliminating, stopping the growth and/or than in the evening, and a relatively higher dose of an anti metastasis of) cancer stem cells or cancer cells from: lung anxiety and/or an anti-inflammatory medication in the cancer, bone cancer, pancreatic cancer, skin cancer, cancer of evening than in the morning. The administration regimen can the head or neck, cutaneous or intraocular melanoma, uterine comprise doses of beta adrenergic receptor antagonist (e.g., cancer, ovarian cancer, rectal cancer, cancer of the anal propranolol) given in 20 or 40 mg tablets immediate release region, stomach cancer, colon cancer, breast cancer, carci on a bid basis, and in the first dose week the doses for beta noma of the fallopian tubes, carcinoma of the endometrium, adrenergic receptor antagonist are 20 mg in the morning and carcinoma of the cervix, carcinoma of the vagina, carcinoma 20 mg at bedtime, and after 1 week the dosage is adjusted to of the Vulva, Hodgkin's Disease, cancer of the esophagus, 20 mg of the immediate release product in the morning and 60 cancer of the Small intestine, cancer of the endocrine system, mg of the extended release at bedtime, and optionally if after cancer of the thyroid gland, cancer of the parathyroid gland, an additional week the Subject shows no improvement or has cancer of the adrenal gland, sarcoma of soft tissue, cancer of not obtained a 20% reduction inheart rate, without decreasing the urethra, cancer of the penis, prostate cancer, chronic or heart rate below 60 bpm or blood pressure below 90/60, the acute leukemia, lymphocytic lymphomas, cancer of the blad dose is adjusted to 40 mg of the immediate release propra der, cancer of the kidney or ureter, renal cell carcinoma, nolol in the morning and 120 mg of the extended release beta carcinoma of the renal pelvis, neoplasms of the central ner adrenergic receptorantagonist at bedtime. The administration US 2011/0158983 A1 Jun. 30, 2011 30 regimen can comprise doses of non-steroidal anti-inflamma slow cognition, dementia, senility, Alzheimer's disease, trau tory drug (a NSAID) (e.g., etodolac) given in 200 mg capsules matic brain injury, chemical brain damage or a mental dis or 500 mg tablets on a bid basis, and doses for the NSAID ease; or post-traumatic stress disorder, traumatic war neuro (e.g., etodolac) are started at 200 mg in the morning and at sis, post-traumatic stress syndrome (PTSS) or a physical bedtime, and after 1 week the dosage are adjusted to 200 mg disability or blindness. In one embodiment of the uses, the in the morning and 500 mg at bedtime. mental disease comprises a dissociative disorder, an obses 0343. The invention provides blister packs or a plurality of sive-compulsive disorder, a delusional disorder, a schizo blister packettes, ablister package, a lidded blister or ablister phrenia, a mania, a panic disorder, depression, dyslexia or a card or packet, a clamshell, a tray or a shrink wrap, compris learning disability. ing the therapeutic combination of the invention, or the phar maceutical composition or formulation of the invention, 0348. The details of one or more aspects of the invention wherein the beta adrenergic receptor antagonist (e.g., propra are set forth in the description below. Other features, objects, nolol or equivalent), NSAID (e.g., etodolac or equivalent) and and advantages of the invention will be apparent from the the therapeutic agent for the treatment of cancer are arranged description and from the claims. or clustered in the blister pack or a plurality of blister pack 0349 All publications, patents and patent applications ettes: (a) in a chrono-dosing arrangement or pattern; or (b) cited herein are hereby expressly incorporated by reference individually. for all purposes. 0344) The invention provides papers, plastics or cello phane packages or a plurality of packettes comprising the therapeutic combination of the invention, or the pharmaceu DETAILED DESCRIPTION tical composition or formulation of the invention, wherein the beta adrenergic receptor antagonist (e.g., propranolol or 0350. In alternative embodiments, this invention provides equivalent), NSAID (e.g., etodolac or equivalent) and the cancer and mucositis therapies, and cytoprotection products therapeutic agent for the treatment of cancer are arranged or and methods, foruse either alone or incombination with other clustered in the paper, plastic or cellophane package or a medical therapies, such as cancer chemotherapies and radia plurality of packettes: (a) in a chrono-dosing arrangement or tion therapies for e.g., cancer. The invention provides com pattern; or (b) individually. positions and methods for treating, ameliorating (e.g., delay 0345. In alternative embodiments, the blister pack or a ing the onset of or diminishing the severity of) or preventing plurality of blister packettes, a blister packages, a lidded oral mucositis; digestive mucositis; esophageal mucositis; blisters or blister cards or packets, clamshells, trays or shrink intestinal mucositis; or any side effect of a cancer chemo wraps of the invention, or the paper, plastic or cellophane therapy or radiation therapy for e.g., cancer. package or a plurality of packettes of the invention, can be 0351. In alternative embodiments the invention provides formulated or designed for drug regimen compliance of a compositions, e.g., formulations and products of manufac cancer patient population, a pediatric or geriatric population, ture, formulated or designed for drug regimen compliance of or a mentally compromised patient population, which in vari a “challenged patient population, e.g., a population of ous embodiments includes patients having mild or severe patients where drug regimen compliance is difficult, e.g., a mental retardation, slow cognition, dementia, senility, Alzhe stressed population Such as a cancer patient population, a imer's disease, traumatic brain injury, chemical brain dam pediatric or geriatric population, or a mentally compromised age, mental diseases (e.g., dissociative disorder, obsessive patient population; or a patient population having mild or compulsive disorder, delusional disorder, Schizophrenia, mania, panic disorder, depression, dyslexia, any learning dis severe mental retardation, slow cognition, dementia, senility, ability and the like) post-traumatic stress disorder, traumatic Alzheimer's disease, traumatic brain injury, chemical brain war neurosis, post-traumatic stress syndrome (PTSS), physi damage, a mental disease, e.g., a dissociative disorder, an cal disability (e.g., blindness). obsessive-compulsive disorder, delusional disorder, Schizo 0346. The invention provides foods or food supplements phrenia, mania, panic disorder, depression, dyslexia, any comprising the therapeutic combination of the invention, or learning disability and the like; or a patient population having the pharmaceutical composition or formulation of the inven post-traumatic stress disorder, traumatic war neurosis, post tion. traumatic stress syndrome (PTSS), physical disability, e.g., 0347 The invention provides uses of the therapeutic com blindness and the like. bination of the invention; the pharmaceutical composition or 0352. In one embodiment, the invention provides compo formulation of the invention; the composition or product of sitions and methods for using them as a cytoprotection prod manufacture of the invention; the nanoparticle, microparticle, uct, e.g., as a product that provides cytoprotection. In one nanoliposome or liposome of the invention; at least one com embodiment, the invention provides compositions and meth position or product of manufacture of the invention; or a ods that are cytoprotection therapies, e.g., as compositions blister pack or a plurality of blister packettes, a blister pack and therapies that provide cytoprotection. age, a lidded blister or a blister card or packet, a clamshell, a 0353. In alternative embodiments, the invention provides tray or a shrink wrap of the invention, or the paper, plastic or compositions and methods that provide cytoprotection, cellophane package or a plurality of packettes of the inven includes providing or aiding in providing an acquired cellular tion, the kit of the invention; for making a deliverable package tolerance to a normally lethal stress or toxicant by pre-expo for increasing drug regimen compliance of a stressed, chal sure to a sub-lethalamount of the same or a different stress or lenged or non-compliant patient population. In one embodi toxicant (cross-tolerance). In one exemplification the Suc ment of the uses, the stressed, challenged or non-compliant cessful manifestation of cytoprotection may be detected in a patient population comprises a cancer patient population; or a targeted cell or tissue by the appearance of molecules called patient population having mild or severe mental retardation, “heat shock proteins’ (HSPs) and/or other related molecules. US 2011/0158983 A1 Jun. 30, 2011

0354. In one embodiment, the invention provides compo positions and methods of this invention; thus, the invention sitions for use with medical treatments associated with or provides the appropriate therapy to restore flux to within the causing one or more detrimental or unwanted side effects, cells adaptive ranges to treat the disease or condition, for e.g., cancer chemotherapy or radiation therapy, or any drug example, to delay or prevent mucositis (e.g., an oral mucosi therapy. tis, digestive mucositis, esophageal mucositis and/or intesti 0355 An exemplary therapy of this invention is a combi nal mucositis) onset and reduce its severity. nation of ingredients that may be administered (a) prior to a 0362. While the invention not directed to any particular cancer therapy, a radiation therapy and/or a drug therapy, (b) mechanism of action, compositions and methods of the inven at about the same time or during a cancer therapy, a radiation tion manipulate and/or augment or enhance the normal cycle therapy and/or a drug therapy, (c) after a cancer therapy, a of wound healing for a cell and/or tissue compartment that radiation therapy and/or a drug therapy, or (d) any combina Suffers an injury oran unwanted side effect, e.g., as a mucosi tion thereof, for treating, preventing, ameliorating or abating tis, e.g., an oral or a digestive mucositis. In one embodiment, an unwanted side effect; wherein the cancer therapy, a radia the invention identifies when, where and how to intervene to tion therapy and/or a drug therapy causes the unwanted side treat a disease or condition, e.g., a mucositis (e.g., an oral effect(s); for example, the compositions and/or therapies mucositis, digestive mucositis, esophageal mucositis and/or (methods) of this invention are used for treating, preventing, intestinal mucositis); for example, the invention identifies ameliorating or abating a drug-induced, a chemotherapy-in what the specific macro fluxes (tissue or cellular) and micro duced, and/or a radiation therapy-induced mucositis, includ fluxes (protein/DNA/other molecules) are to place a cell or ing oral or a digestive mucositis. tissue in an adaptive, or healing, range particularly when it 0356. In one embodiment, compositions and therapies is outside an adaptive or healing range, e.g., because of the (methods) of this invention also provide cytoprotection, e.g., injury, disease or condition. This invention provides drug as a myelo-protection therapy. An exemplary therapy of this combinations to attenuate the signals and cellular environ invention can be used with a cancer therapy that causes mental conditions that are outside the cells or the tissues unwanted side effects, such as a drug therapy, a chemotherapy adaptive range to lead a benign range of signals and cellular and/or a radiation therapy, e.g., that causes mucositis, includ environmental conditions needed for a healing, remodeling ing an oral mucositis, digestive mucositis, esophageal response. mucositis and/or intestinal mucositis. In alternative embodi 0363 The compositions (e.g., drug combinations) and ments, compositions and therapies (methods) of this inven methods of this invention treat and ameliorate disease and tion are used for treating, preventing, ameliorating or abating injury by understanding and directly addressing the clinical any mucositis, including an oral mucositis, digestive mucosi manifestations of disease pathology and when the molecular tis, esophageal mucositis and/or intestinal mucositis. signals of damage and inflammation exceed the capacity of a 0357 The invention provides compositions and methods cell or a tissue. While the invention not directed to any par for treating, preventing or ameliorating an unwanted side ticular mechanism of action, compositions and methods of effect or disease state symptom, e.g., the invention provides the invention are a therapeutic intervention that does not compositions and methods to abolish, to ameliorate, to dimin interfere with the normal wound healing process, but rather ish, to improve, and/or to inhibit, the unwanted side effects of prevents or reduces damage. a drug therapy, a chemotherapy and/or a radiation therapy, 0364. Initiation and Ulcer Formation. Compositions and e.g., wherein the unwanted side effect is a mucositis, includ methods of the invention can treat, ameliorate (which ing an oral mucositis, digestive mucositis, esophageal includes delaying the onset or severity of) or prevent adverse mucositis and/or intestinal mucositis. side effects of a medical therapy, e.g., a cancer therapy, that 0358. In alternative embodiments, the invention provides are commonly observed in the oral cavity, e.g., changes in the combinations of active agents (ingredients) comprising one epithelium as a result of damage to proliferating and differ or a plurality of (multiple) member, including only one mem entiating cells and signals associated with the insult. While ber, or two members, three members, four members, five the invention not directed to any particular mechanism of members, six members, or more; e.g., a composition com action, in one embodiment compositions and methods of the prising a combination of between about two and twenty or invention act to treat, ameliorate (which includes delaying the more members, i.e., active agents, such as a drug or a treat onset or severity of) or prevent pathology in the more rapidly ment composition. proliferating tissues where atrophy and ulceration can repre 0359. In alternative embodiments, the invention provides sent a dose-limiting and potentially serious complication of therapies, which can comprise us of a composition, a method, treatment; e.g., damage to normally rapidly proliferating tis a product, or any tool that is serviceable for that particular Sues by a drug, e.g., a cancer drug, many times requires therapy of the invention, e.g. a therapy that is serviceable for limitation on the dosage of that drug, e.g., the cancer drug. treating (“to treat') a patient. 0365 Compositions and methods of the invention can 0360. In alternative embodiments, the invention provides treat, ameliorate (which includes delaying the onset or sever therapies for use in any individual, which can include the ity of) or prevent the lesions first observed on the soft palate, animals (e.g., farm animals, Zoo or research animals, or tongue, and cheeks caused by a drug or a medical treatment, domestics, e.g., dogs, cats). e.g., a chemotherapy or radiotherapy, e.g., for a cancer. Com 0361. While the invention not directed to any particular positions and methods of the invention can treat, ameliorate mechanism of action, compositions and methods of the inven or prevent these lesions and prevent or delay their forming or tion for treating a mucositis, e.g., an oral or a digestive their enlargement, and thus decrease associated pain and dys mucositis and related maladies and conditions, are designed phagia (e.g. difficulty with Swallowing or inability to Swal to treat key stages of the mucositis by identifying pathways low, often associated with pain), and coincident dehydration, activated in the disease process. Imbalances of flux that are poor nutritional status (because of painful chewing), and a outside adaptive ranges of the tissue are addressed by com decreased quality of life. US 2011/0158983 A1 Jun. 30, 2011 32

0366 Compositions and methods of the invention can be tions and methods of the invention will decrease or eliminate administered with, or for a prophylactic effect, before, or these negative effects. Compositions and methods of the after, any medical therapy, e.g., a chemotherapy and/or a invention can be used to decrease the harmful effects of ROS, radiation therapy, e.g., a medical therapy which can lower cell which can effectively activate a number of central biological proliferation and turnover in connective tissue. Compositions control mechanisms, including a select group of transcription and methods of the invention can be used to ameliorate or factors, pro-inflammatory cytokines and adhesion molecules. Compositions and methods of the invention can be used to prevent the harmful effects of ionizing radiation (from radia decrease or dampen the self-amplification of this process that tion therapy), including tissue matrix damage, which causes results in induction of other effector proteins and tissue increased vascular permeability, tissue edema, and an infil injury. Compositions and methods of the invention can be tration of inflammatory cells; the invention can be practiced used to decrease the tissue damage that leads to activation of before, during and/or after the therapy. Compositions and additional transcription factors, each being associated with an methods of the invention can be used to ameliorate damage to expression of genes and their biologically active proteins that fibroblasts, which can result in cell loss and fibrosis, and have a harmful effect. ameliorate damage to blood vessels, which can lead to 0369 Thus, in some embodiment, the compositions and hypovascularity and tissue ischemia. Together, these changes methods of the invention augment, mimic or reproduce “nor will reduce the ability of the tissue to heal and resist infection; mal' responses to injury, allowing downstream elements in thus, practicing the compositions and methods of the inven the injury response (e.g., wound healing) process to proceed tion will increase the ability of tissue to heal and resist infec normally, or closer to normal. Therefore, in alternative tion. Indirect effects of radiation therapy, such as damage to embodiments, compositions and methods of the invention the salivary glands, which will reduce salivary production and provide an effective therapy for reducing the impact of an impair barrier efficiency, resulting in a reduction in immuno injury, whether that injury be from drug administration (in competence (especially when associated with a myeloabla cluding chemotherapy), toxin exposure (including allergens tive therapy, e.g. a therapy that severely damages a patient's or poisons), radiation administration or radiation exposure bone marrow function and ability to make blood cells), also (including workplace exposure), or trauma; thus attenuating can be ameliorated using the compositions and methods of the response to that injury and not negatively impacting the the invention. Because this damage will increase the risk of wound healing process. local infection from oral organisms; thus, practicing the com 0370 Wound Healing. Compositions and methods of the positions and methods of the invention will increase the abil invention are used to treat wounds, whether that wound be ity to resist or recover from local, pathological infection from from drug administration (including chemotherapy), toxin oral organisms, including viruses, yeast, fungi and/or bacte exposure (including allergens or poisons), radiation adminis 18. tration or radiation exposure, workplace exposure or trauma. 0367 Compositions and methods of the invention can be In alternative embodiments, compositions and methods of the used to decrease both DNA and non-DNA (e.g., cellular or invention are used to mimic or reproduce an acute wound tissue) damage, which occur almost immediately after expo healing process, e.g., reproduce the specific manner or Sure to a medical therapy, e.g., radiation or chemotherapy, or approximate a wound healing process; which can be charac exposure to a poison or radiation (e.g., as an accident, a terized by four distinct, but overlapping phases: 1/hemosta workplace exposure or in warfare or terrorist attacks). Com sis; 2/inflammation; 3/proliferation (3a/granulation and positions and methods of the invention can be used to 3b/tissue restitution); and 4/remodeling, as described below. decrease DNA strand breaks in the epithelium as well as in the Compositions and methods of the invention can augment, cells of the Submucosa, thus preventing cells from dying, or trigger, or replace, the specific biological markers that char from dying quickly, and preventing or ameliorating a cascade acterize the healing of acute wounds, or wounds or injuries of biological events that occurs as a sequelae to radiation from drug administration (including chemotherapy), toxin exposure or to chemotherapy. exposure (including allergens or poisons), radiation adminis 0368 Compositions and methods of the invention can be tration or radiation exposure, or trauma. In one embodiment, used to decrease events mediated by the generation of reactive compositions and methods of the invention can ameliorate or oxygen species (ROS), which occurs shortly after radiation decrease the biologic markers that characterize pathologic exposure or chemotherapy. ROS have a far-ranging and broad responses that result in fibrosis and chronic non-healing biological downstream impact; thus, practicing the composi ulcers. US 2011/0158983 A1 Jun. 30, 2011 33

Hemostasis • Activation of coagulation • vasoconstriction

Inflammation • Increased vascular permeability e Vasodilation • Leukocyte infiltration

Granulation tissue formation Influx of neutrophils/macrophages • Activation of macrophages/fibroblasts • Fibrogenesis Angiogenesis

Tissue restitution Cessation of fibrogenesis and angiogenesis oWound contraction Re-epithelialization

Remodeling Remodeling of the wound matrix Chart 1: The 4 Phases of Wound Healing US 2011/0158983 A1 Jun. 30, 2011 34

0371. In one embodiment, compositions and methods of sis as well as releasing more PDGF and TGF-B. Once the the invention are used to augment or initiate, or mimic, a wound site is cleaned out, fibroblasts migrate in to begin a normal healing response, which can begin the moment the proliferative phase and deposit new extracellular matrix. The tissue is injured. For example, compositions and methods of new collagen matrix then becomes cross-linked and orga nized during the final remodeling phase. Compositions and the invention are used to augment or initiate, or mimic the methods of the invention are used to augment or initiate, or injury healing response where blood components enter the mimic, this efficient and highly controlled repair process. site of injury, and platelets come into contact with exposed 0372 Although the oral mucosa heals faster than skin does collagen and other elements of the extracellular matrix. The and is more resistant to initial damage, compositions and platelet contact triggers the platelets to release clotting factors methods of the invention can be used to augment this process (that promote hemostasis) as well as essential growth factors and to ameliorate the tissue injury caused by radiotherapy, and cytokines such as platelet-derived growth factor (PDGF) e.g., fractionated radiotherapy, and many types of chemo and transforming growth factor beta (TGF-B). Following therapy, most of which are Sufficient to cause wound forma hemostasis, the neutrophils then enter the wound site and tion. Compositions and methods of the invention can be used begin the task of phagocytosis to remove foreign materials, to decrease the injury seen in a mucositis, e.g., an oral or a bacteria and damaged tissue, and these processes promote an digestive mucositis, and/or to augment or initiate the healing inflammation phase. As part of this inflammatory phase, the process, e.g., as illustrated in the five steps of the traditional macrophages appear and continue the process of phagocyto pathobiology model of mucositis, see Chart 2, below. US 2011/0158983 A1 Jun. 30, 2011 35 Chart 2: The 5 Steps in the Traditional Pathobiology Model of Mucositis

Radiation Therapy/Chemotherapy

Initiation ROS generation, direct cell and tissue damage, initiate downstream signaling

Upregulation Activation of transcription factors (p53, NK KB), pro-inflammatory cytokine induction, pro-apoptosis pathway

Amplification Positive feedback loops initiate "vicus", basal membrane and submucosal tissue damage

Ulceration Loss of barrier, bacterial Colonization, inflammation, angiogenesis

Wound Healing Cytokine, chemokine and growth factor induction, influx of epithelial cells to rebuild tissue US 2011/0158983 A1 Jun. 30, 2011 36

0373 Compositions and methods of the invention can be 0384 Compositions and methods of the invention also can used with or in place of existing mucositis treatment products, be used with superoxide dismutase (SOD) to treat radiation e.g., to augment a productor a method of treatment, including induced fibrosis. e.g. any products already approved and available for mucosi 0385 Compositions and methods of the invention can be tis, such as an oral or a digestive mucositis, treatment or used in wound generation and healing, and as an adjunctive prevention, including e.g. the following. treatment to minimize ulcer formation. 0374 1. Palifermin (e.g., KEPIVANCETM), a recombi 0386 While the invention is not limited by any particular nant protein mimic of Keratinocyte Growth Factor mechanism of action, compositions and methods of the inven (KGF), may impact prevention, upregulation/amplifica tion can be used to treat mucositis, such as an oral or a tion and facilitate the start of normal healing. digestive mucositis, by affecting at least five relevant points 0375 2. Amifostine (commonly known as WR-1065 in of intervention: its active form) (e.g., ETHYOLTM), which scavenges 0387 1. Compositions and methods of the invention oxygen free-radicals that are produced by ionizing can be used to prevent initiation of the damage response radiation. state—by e.g., increasing the tissue compartment's 0376 3. Products that target the mucositis and are capacity to tolerate radiation and chemotherapy-in administered locally, thereby eliminating side-effects duced damage, (includes the endothelial, fibroblast, epi from systemic delivery. These products include the tet thelial as well as tissue resident macrophages, stem cells racycline class of antibiotics which reduce inflammation etc.). and promote wound healing (similar to KGF), and food 0388 2. Compositions and methods of the invention additives, antioxidants and gels/barrier to reduce can be used attenuate the inflammatory response and mechanical trauma and infiltration of bacteria. These minimize damage response state of adjacent tissues—by interventions administered alone can be less effective reducing the influx of inflammatory cells and the because they are typically applied after the initiating degranulation and creation of reactive oxygen species to event and amplification stage. within the tissue compartment’s ability to clear. This 0377 Compositions and methods of the invention can be protective step attenuates the buildup of damaging used with or in place of other known pharmacological treat breakdown products and inflammatory signaling that ments for mucositis, such as an oral or a digestive mucositis; may lead to further inflammation outside the adaptive including non steroidal anti-inflammatory drugs (NSAIDs), range. angiotensin converting enzyme inhibitors (ACE inhibitors), 0389) 3. Compositions and methods of the invention angiotensin receptor blockers (ARBs), pentoxifylline, defer can be used provide appropriate signaling during the rioxamine, polyunsaturated fatty acids, C.-difluoromethylor damage response State to facilitate healthy wound heal nithine, and Superoxide dismutase. ing—once the cycle has been initiated, appropriate nor 0378 For example, compositions and methods of the mal processes need to be activated and extrinsic damag invention can be used with NSAIDS to augment their anti ing signaling needs to be offset. For example, use of inflammatory effect in the prophylaxis or treatment of radia corticosteroids alone might undermine normal wound tion-induced normal tissue injury. In some aspects, use of healing process and would be contraindicated. compositions and methods of the invention can mitigate the 0390 4. Compositions and methods of the invention injury caused by Some anti-inflammatory agents in some can be used to prevent or decrease tertiary damage or Organs. interference with wound healing—to prevent or treat 0379 Compositions and methods of the invention also can any secondary infection or further trauma to the tissue be used with ACE inhibitors or ARBS for the effective treat compartment that may increase damage or blockhealthy ment and prophylaxis of radiation nephropathy. Composi healing response. tions and methods of the invention also can be used with ACE 0391 5. Compositions and methods of the invention inhibitors or ARBs for a prophylaxis effect to reduce pulmo can be used to provide or augment an appropriate nutri nary fibrosis and block radiation-induced rises in pulmonary ent and healthy body response—including providing a arterial pressure. Compositions and methods of the invention nutrient and an oxygen rich environment, and circulat also can be used with ACE inhibitors or ARBs for prophylaxis ing and tissue resident stem cells, immune cells, sys of radiation pneumonitis. temic hormones that Sustain a healthy wound healing 0380 Compositions and methods of the invention also can cycle. be used with pentoxifylline for all types of radiation injuries, including for the treatment of radiation-induced fibrosis and 0392 Compositions and methods of the invention can be radiation-induced soft-tissue necrosis. used to treat and/or ameliorate other diseases that may be 0381 Compositions and methods of the invention also can caused by different assaults but which cause the same imbal be used with deferrioxamine: the iron chelator, deferrioxam ances of flux and therefore result in similar pathology as a ine, has shown efficacy against experimental radiation mucositis, such as an oral or a digestive mucositis. Compo induced spinal cord injury when combined with a low-iron sitions and methods of the invention can be used to lesson or diet. abrogate the primary drivers of an eventual lesion, are signals 0382 Compositions and methods of the invention also can generated directly or indirectly by DNA and cell damage. For be used with polyunsaturated fatty acids to reduce radiation example, compositions and methods of the invention can be induced skin and spinal cord injury in animals and humans. used to treat or ameliorate ischemia/reperfusion (I/R) injury. 0383 Compositions and methods of the invention also can Although the cause of tissue injury in I/R is very different be used with C-difluoromethylornithine, a polyamine-syn from mucositis caused by chemo- or radiotherapy, the under thesis inhibitor for, e.g., reducing brain injury after cranial lying disease progression is highly similar. Therefore, com irradiation. positions and methods of the invention effective for mucositis US 2011/0158983 A1 Jun. 30, 2011 37 also can be used in I/R protection, which is a complex patho tion is within the adaptive range of the tissue. In one embodi physiological event associated with significant impairment of ment, the compositions and methods of this invention prevent multiple vascular and cellular responses. Compositions and accumulation of toxic products during the initial beneficial methods of the invention can be used to lesson or abrogate inflammatory response and do not cause excess damaging oxidative damage due to the presence of radical oxygen spe (runaway) inflammation. cies, which is an essential step that initiates a wide range of 04.04. In one embodiment, the compositions and methods intracellular stress signaling processes that culminate in of this invention induce a protective Heat Shock Response. In excessive cytokine and chemokine response, adhesion mol response to stress, mammalian cells produce stress or heat ecule upregulation and nitric oxide overproduction. Compo shock proteins (HSPs). Stress or heat shock proteins are sitions and methods of the invention can be used to lesson or among the most conserved proteins present in both prokary abrogate gut ischemia, which is frequently encountered in otes and eukaryotes. HSPs comprise molecular chaperones trauma, shock, cardiovascular Surgery, and organ transplan that are essential for the quality control of intracellular pro tation has the same pathophysiology. teins. Intracellular HSP have been shown to have an anti 0393. In one embodiment, the invention provides a treat inflammatory role in various conditions. HSP induction by a ment for mucositis, such as an oral or a digestive mucositis, composition or method of this invention before a pro-inflam comprising a combination of geranylgeranyl acetone (GGA) matory stimulus can be beneficial; however, HSP induction and analogs of GGA, or teprenone (CAS Registry Number after a pro-inflammatory stimulus is cytotoxic. 6809-52-5) (SELBEXTM), and captopril (e.g., CAPOTINTM), 0405. In one embodiment, the compositions (the drug e.g., an exemplary combination in the form of Vicus Thera combinations) and methods of this invention comprise the peutics (Morristown N.J.) product VT-211TM. acyclic isoprenoid, geranylgeranylacetone (teprenone), 0394. In one embodiment, the invention provides a treat which is a non-toxic Hsp70 inducer. Teprenone-comprising ment for mucositis, such as an oral or a digestive mucositis, compositions (the drug combinations) and methods of this comprising a combination of a drug approved for GI indica invention can block insult-induced apoptosis at multiple lev tions, such asteprenone or teprenone (SELEBEXTM) or geranyl els; for example, they can inhibit activation of c-Jun N-termi geranyl acetone (GGA) and analogs of GGA; and, the second nal kinases, decline of mitochondrial membrane potential, drug approved for use to treat inflammation, e.g., the NSAID and formation of apoptosome by binding with Apaf-1. etodolac (e.g., LODINETM). In one aspect, this drug combi 0406. In one embodiment, the compositions (the drug nation is provided in the form of Vicus Therapeutics (Morris combinations) and methods of this invention comprising town N.J.) product VT-212TM (i.e., a formulation comprising geranylgeranylacetone (teprenone) have a cytoprotective active agents consisting of NSAID etodolac and geranylgera function by altering the membrane signaling cascade that nyl acetone (GGA)). leads to DNA damage. The prophylactic administration of 0395. In one aspect, the drug combinations of this inven compositions (the drug combinations) and methods of this tion, e.g., VT-212TM and/or VT-211TM, are used to target the invention comprising geranylgeranylacetone (teprenone) initial stage of a maladaptive response to prevent, delay, and/ before radiation can promote an accumulation of protective or reduce the severity of ulceration that is often seen about 7 HSPs in non-cancer cells in advance of radiation treatment to 10 days after mucotoxic therapies. and potential damage. 0396. In alternative embodiments, compositions (the drug 0407 Compositions (the drug combinations) and methods combinations) and methods of the invention: of this invention can comprise, or be used in conjunction with, 0397) 1. Are administered orally. other heat shock protein inducers such as Zinc, Salicylates, 0398 2. Are administered such that they will not interfere nicotine, alcohol, C.-adrenergic agonists, PPAR-Y agonists, with the patient's ongoing oncologic therapy and will not bimoclomol, geldanamycin, teprenone, and cyclopentenone adversely affect the treatment outcome. Thus, in this embodi prostanoids. ment, the ongoing therapy is not compromised, and this 0408. In one embodiment, the compositions (the drug invention's treatment for mucositis should not compromise combinations) and methods of this invention comprise the safety of the patient. In one aspect, the drug combination Angiotensin Converting Enzyme (ACE) inhibitors. The of this invention also has anti-cancer activity. renin-angiotensin System (RAS) is an important determinant 0399. Accordingly, alternative embodiments of the inven of vascular and fluid homeostasis as well as blood pressure tion, including the compositions (the drug combinations) and regulation. Thus, compositions (the drug combinations) and methods of the invention for treating mucositis. Such as an methods of this invention can be used to regulate cellular oral or a digestive mucositis, provide a safe oral regimen of growth in a variety of tissues through the principal effector of pre-approved drugs that are able to act synergistically to: an ACE inhibitor, angiotensin II, and its two receptors, AT1 0400 1. Provide prophylactic protection to the oral cavity. and AT2. 04.01 2. Reduce signals that could lead to ulceration (run 04.09. In one embodiment, the compositions (the drug away inflammation). combinations) and methods of this invention comprise 0402. 3. Facilitate wound healing/repair. N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP or AcS 0403. Alternative embodiments of the invention have two DKP), a tetrapeptide that has been reported to inhibit endot aspects: First is to induce a protective response in the normal helin 1 (ET-1)-induced cell proliferation and collagen synthe tissue by, e.g., inducing the tissue's natural "heat shock” sis in cultured rat cardiac fibroblasts (CFs) and to reduce left protective response. Second is to attenuate excess inflamma Ventricle collagen deposition in rats with aldosterone-salt tory reaction by, e.g., inhibiting lymphocyte influx so that rate and angiotensin II (Ang II)-induced hypertension. By com of debridement and reactive oxygen species (ROS) genera prising ACE inhibitors, the compositions (the drug combina US 2011/0158983 A1 Jun. 30, 2011

tions) and methods of this invention can increase plasma 0415 2. ACE inhibitors increase the flux of bradykinins Ac-SDKP, which in turn inhibits LV inflammatory cell infil as well as AcSDKP, both of which have anti-inflamma tration, interstitial cell proliferation (most likely fibroblasts), tory and cytoprotective impact. In particular, AcSDKP TGF-B, Smad3 activation, and collagen deposition. By com has a direct impact on inducing the Go phase of the prising ACE inhibitors, the compositions (the drug combina hematopoietic tissue (and possibly other tissue compart ments) that further protects those compartments from tions) and methods of this invention can increase plasma and radiotherapy or chemotherapy induced toxicity. tissue Ac-SDKP and decrease cardiac and renal fibrosis. By 0416) 3. ARBs increase flux through the AT receptor 2 comprising Ac-SDKP, the compositions (the drug combina signaling pathway that has anti-inflammatory effects. tions) and methods of this invention can mediate the anti The increase in Ang II also increases the creation of inflammatory and antifibrotic effects of ACE inhibitors. Angiotensin 1-7 which has additional hematopoietic 0410. In one embodiment, the compositions (the drug protective as well as growth stimulating effects. combinations) and methods of this invention comprise angio 0417. Impact of Teprenone, ARBS/ACE Inhibitors, and tensin II (ang II). By comprising Ang II, the compositions (the NSAIDs. There are many years of experience with respect to drug combinations) and methods of this invention can cause use and safety for all these classes of drugs, and no evidence neutrophil recruitment, which can be mediated through the of significant adverse effects on chemotherapy or radiation release of CXC chemokines such as CINC/KC and MIP-2 in therapy has been shown to date. An area of possible concern rats and IL-8 inhumans, and may contribute to the infiltration is with hematological cancers with myeloablative therapy of neutrophils. because ACE inhibitors in particular may prevent the virtually total ablation of the bone marrow when this virtually total 0411. In one aspect of this invention, a mucositis therapy ablation is in fact desired. Therefore, in a particular non (e.g., for oral or digestive mucositis) will begin at least about limiting embodiment of this invention, a mucositis therapy three days in advance of a chemotherapy dose and, in one (e.g. comprising ACE inhibitors), as provided herein, is to be aspect, will end the evening before the chemotherapy or used for Solid tumors (rather than to protect against mucositis radiation therapy. In one embodiment of this invention, dos from myeloablation therapy). ing with a composition of this invention (a drug combination) 0418. As noted above, cancer cells often have an already highly activated stress response (including, e.g. a near maxi comprising an ACE inhibitor will start at the same time as the mal or maximal heat shock response); in particular in cancer teprenone but will continue for two days after chemotherapy tissue environments characterized by the typical hypoxic, treatment. In one aspect of this invention, to address any acidic and non-physiological conditions of a cancer tissue. safety concerns the first dose of ACE inhibitor can be admin Therefore adding an HSP inducer should have little or no istered in the physician office so blood pressure can be moni effect on the tumor whereas it will increase the level of pro tored during the first few hours when a hypotensive event tection of the healthy tissue. would be most likely. In one embodiment of this invention, 0419. Therapies Provided and Intended for Protection. the dosing of the teprenone is tid (three times daily) using the The instant invention provides therapies comprising one or highest safe dose (current label is for 150 mg per day total). In more members selected from the following Groups: as shown in Table 1, where: of Group A comprises or consists of, or an alternative embodiment of this invention, the dosing for Group A comprises use of or consists of use of geranylgera captopril is the lowest recommended dose (6.25 mg/dose) nyl compounds, including for example, geranylgeranyl administered tid (three times daily). acetone (GGA) and analogs of geranylgeranyl acetone 0412. In alternative embodiments, further benefits of com (GGA); Group B comprises use of or consists of use of positions of this invention comprising teprenone and ARBS/ Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors ACE inhibitors of this invention are: a number of additional or ACE-Is); Group C comprises use of or consists of use of potential benefits of both teprenone and ARBs/ACE inhibi Angiotensin Receptor Blockers (ARBs); Group D comprises tors beyond the mucosal (oral and intestinal) tissue, espe use of or consists of use of Peroxisome Proliferator-Activated Receptor (PPAR) ligands, e.g. agonists, such as PPAR alpha cially in the hematopoietic tissue compartment, auditory agonists, PPARgamma agonists, PPAR alpha/gamma dual compartment, eye, lung and central nervous system that Sug agonists, and other PPAR ligands (e.g. PPAR delta ligands); gest these products may have much broader protection. In Group E comprises use of or consists of use of non-steroidal addition, the systemic cytoprotection may have a positive anti-inflammatory drugs (NSAIDs); Group F consists of impact on the underlying cause of cancer fatigue and impair NCCN therapies; Group G comprises use of or consists ofuse ment of cognitive and physical function. of TNF inhibitors, e.g. pentoxifylline; Group H comprises use 0413 While the invention is not limited by any particular of or consists of use of deferrioxamine; Group I comprises polyunsaturated fatty acids, such as e.g. omega-3 fatty acids, mechanism of action, additional modes of actions by which a including for example eicosapentaenoic acid (EPA), and product and methods of this invention, e.g., using VT-212TM docosahexaenoic acid (DHA); Group J comprises C.-difluo and/or VT-211TM, may provide benefit include: romethylornithine; Group K comprises Superoxide dismutase 0414 1. Teprenone may systemically damp tissue turn (SOD) and similar antioxidant compounds; Group L com over via inhibition of prenylation through other means prises activators of heat shock response; and Group M com that in turn block Rab, Ras and Rho signaling. This can prises drugs that reduce the inflammatory/progressive tissue have both system anti-inflammatory effects as well as damage response. causing a greater percentage of cells to be in Go or 0420. This invention provides compositions, e.g., pharma stationary phase. Tissues are more protected in Gothan ceutical compounds, preparations, formulations, kits and in other phases of the cell cycle. In addition, teprenone products of manufacture (e.g., blisterpackages, shrinkwraps, modulates fluidity of membranes and there is evidence etc.), comprising combinations of beneficial ingredients for that this increases the ability of the tissue to heal or deal the primary treatment of cancer and any conditions caused by with trauma to the mucosal membranes. dysfunctional cells. The invention provides compositions, US 2011/0158983 A1 Jun. 30, 2011 39 e.g., pharmaceutical compounds, preparations, formulations, 0421 Table 1 provides exemplary combinations of drugs kits and products of manufacture (e.g., blister packages, and/or pharmaceuticals of the invention. These components shrink wraps, etc.), comprising combinations of beneficial (e.g., exemplary combinations of drugs) are presented as members of groups with non-limiting examples provided that ingredients that are serviceable as therapies for improving, can be used in the compositions (e.g., pharmaceutical com treating, ameliorating and/or preventing conditions, states pounds, preparations, formulations, kits and products of and/or disease symptoms involving mucositis, such as oral manufacture) and methods of the invention. mucositis. Relevant symptoms improved, treated, amelio 0422 Table 1 sets forth ingredients and combinations of rated and/or prevented by the compositions and methods of active ingredients, e.g., drugs, of this invention. By way of the invention further include, e.g., inflammation, excessive non-limiting exemplification, any heat shock protein inducer sympathoneural drive, cachexia, anorexia, anorexia can be used, including all possible permutations and combi cachexia, stress, anxiety related thereto, wasting and/or atro nations of ingredients as provided herein. phy, Such as muscle atrophy, or anorexia-cachexia, e.g., as 0423. The following Table 1 describes exemplary ingredi cachexia related to chronic and/or wasting diseases, such as ents of compositions of this invention, and compositions used cancer, and method of using them. in methods of this invention:

Group Gro up Members

A. Geranyl compounds: acyclic polyisoprenoids: Inc uding, e.g., geranylgeranyl acetone (GGA) and analogs of geranylgeranyl 800 one (GGA). Geranylgeranoic acid; and 4,5-didehydrogeranylgeranoic acid. Additional compounds that can be used to practice this invention are described in: U.S. Pat. No. (USPN) 7,1258.52; U.S. Patent Application No. 2OO 6 O135623. Teprenone, e.g., SELBEXTM (CAS Registry Number 6809-52-5 Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors, ACE-I's, ACEi): Inc uding,8, e.g.,6.9. benazeprilp (e.g.,9. LOTENSINTM);; captopcaptopril (e.g.9. CAPOTINTM); cilazapril; enalapril (e.g., RENITECTM, VASOTECTM); (8. aprilat; fosinopril (e.g., MONOPRILTM), fosinoprilat, imidapril (or imida prilum), lisinopril: moexipril (e.g., UNIVASCTM, PERDIXTM); periindopril (or coversyl); quinapril (e.g., ACCUPRILTM); ramipril (e.g., TR TACETM, RAMACETM, ALTACETM); trandolapril (e.g., MAVIKTM). Angiotensin Receptor Blockers (ARBs) Inc uding, e.g., Candesartan; Eprosartan; Irbesartan; Losartan; Olmesartan; Telmisartan; Valsartan. Peroxisome Proliferator-Activated Receptor (PPAR) ligands, e.g. agonists Inc uding, e.g., PPAR alpha agonists, PPARgamma agonists; PPAR alpha gamma dual agonists, and other PPAR ligands (e.g. PPAR delta ligan s). Examples include rosiglitaZone (e.g., AVANDIATM), pioglitazone (e.g., ACTOSTM), trogilitazone (e.g., REZULINTM), Muraglitzar, naveglitazar, netOg itaZone, rivog itaZone, and tesaglitazar. Additional compounds that can be used to practice this invention are described in: U.S. Pat. No. (USPN) 6,756,399. Additional examples are provided in . Pat. No. 6,869,967. Non-Steroidal Anti inflammatory Drugs (NSAIDs) including, e.g., NSAIDs, e.g. aspirin, diclofenac (e.g., VOLTARENTM, CATAFLAMTM, VOLTAREN-XRTM); diflunisal (e.g., DOLOBIDTM); etodolac (e.g., LOD NETM); fenoprofen (e.g., NALFONTM); flurbiprofen (e.g., AN SAIDTM, FROBENTM); ibuprofen (e.g., MOTRINTM); indomethacin (e.g., NDOC (NTM, INDOCIN-SRTM); ketoprofen, or (RS)2-(3-benzoylphenyl)- O pionic acid (e.g., ORUDISTM, ORUVAILTM); ketorolac or ketorolac romethamine (e.g., TORADOLTM); Meclofenamate (e.g., MECLOMENTM); le enamic acid, or 2 (2,3-dimethylphenyl)aminobenzoic acid (e.g., PONST ELTM); meloxicam (e.g., MOBICOXTM, MOBICTM): nabumetone (e.g., RELIFEXTM, RELAFENTM); Naproxen (e.g., ALEVETM, ANAPROXTM, MI RANNAXTM, NAPROGESICTM, NAPROSYNTM, NAPRELANTM, SYNFLEXTM); oxaprozinum or oxaprozin (e.g., DAYPROTM or DU RAPROXTM); piroxicam (e.g., FELDENETM); salsalate (e.g., DISALCIDTM, SALFLEXTM), sulindac (e.g., CLINORILTM); tolmetin (e.g., TO LECTINTM); and, COX-2-selective NSAIDs, e.g. celecoxib (e.g., CE LEBRATM, CELEBREXTM); rofecoxib (e.g., VIOXXTM, CEOXXTM); etoricoxib (e.g., ARCOXIATM); valdecoxib (e.g., BEXTRATM); parecoxib (e.g., DYNASTATTM); meloxicam (e.g., MOBICTM); Lumiracoxib (e.g., PR EXIGETM). US 2011/0158983 A1 Jun. 30, 2011 40

TABLE 1. Group Group Members Section 2 “Cidal/Static Ingredients F Any Chemotherapy or Radiation Therapy Including, e.g., any chemotherapy or radiation therapy, that is listed in the current NCCN Clinical Practice Guidelines in Oncology TM. Section 3 “Complementary Ingredients

G TNF inhibitors Including, e.g., anti-TNF agents, anti-TNF mAbs, pentoxifylline, or 1-(5- oxohexyl)-3,7-dimethylxanthine (e.g., TRENTALTM), thalidomide or 2-(2,6- dioxopiperidin-3-yl) isoindoline-1,3-dione (e.g., THALOMIDTM). NOTE: Pentoxifylline is a PDE4 inhibitor that increases intracellular cAMP and stimulates PKA activity. Pentoxifylline is also an inhibitor of tumor necrosis factor-alpha. H Deferrioxamine or deferoxamine synonyms: deferoxamine meSylate; deferoxaminum; deferrioxamine; deferoxamin; DFO; N-benzoylferrioxamine B: DFB; DFOA: DFOM; desferrioxamine; desferrioxamine B: deferrioxamine B: deferoxamide B: deferoxamine B; brand names containing deferoxamine: DESFERALTM, DESFERANTM, DESFERALTM, DESFEREXTM, DESFERINTM, DESFERRINTM. NOTE: Deferrioxamine is a chelator that has been used for than 20 years in treatment of severe ion poisoning, of disturbances in iron storage and of diseases which lead to increased iron values. It may have other activities. I Polyunsaturated fatty acids Including, e.g., polyunsaturated fatty acid; e.g., a co-3 fatty acid or omega-3 fatty acid, Such as C-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA); or a (O-6 fatty acid or omega-6 fatty acid, such as linoleic acid (LA); or a as co-9 fatty acid or omega-9 fatty acid, such as oleic acid and erucic acid. In non-limiting examples, these fatty acids may be administered orally or intravenously. J eflornithine (C-difluoromethylornithine or DFMO) (e.g., ORNIDYLTM) Note: C-Difluoromethylornithine is an inhibitor of ornithine decarboxylase (an enzyme involved in polyamine synthesis), by reducing the polyamine content of mucosa. K Superoxide dismutase (SOD) (EC 1.15.1.1) Including, e.g., Group K comprises Superoxide dismutase (SOD), catalase, Superoxide dismutase (SOD)-catalase conjugates or complexes, peroxiredoxins, and peroxidases (e.g. glutathione peroxidase), and enzymes of similar activity. Superoxide dismutase (SOD), and similar antioxidant compounds, can include: a? enzymes with the ability to catalyze the conversion of hydrogen peroxide into other compounds; blenzymes with the ability to catalyze the decomposition of peroxides; cfcompounds that have antioxidant activity; and di compounds that promote antioxidant activity, such as co-factors, precursors and/or subunits and other enzymes in a shared biochemical reaction pathway, including, e.g. selenium, cysteine, glutamine, tryptophan, and glutathione reductase. L Activators of heat shock response including, e.g. geranylgeranylacetone or gernate, zinc, tin, Salicylates, dexamethasone, cocaine, nicotine, alpha-adrenergic agonist, ppar-gamma agonist, a geldanamycin (which is a benzoquinone ansamycin antibiotic that binds to Hsp90, or Heat Shock Protein 90), biomolecular-geldanamycin, cyclopentanone, a prostanoid (a Subclass of eicosanoid consisting of the prostaglandins, thromboxanes, prostacyclins), emprostill (a synthetic prostaglandin), paracetamol or acetaminophen (N-(4-hydroxyphenyl)- acetamide), ketotiphen, levamisole, diazepam (e.g., VALIUMTM), bromocriptine (e.g., PARLODELTM), dopamine (4-(2-aminoethyl)benzene-1,2- diol). M Drugs that reduce the inflammatory progressive tissue damage response including including, e.g. ACE inhibitors, ARBs, phenylbutry rate or PPARgamma (insulin sensitizer) and/or probucol, calcitriol as alternative combinations to further stimulate protective vascular response, NSAIDs to reduce inflammation, peptide-containing compounds, inhibitors of macrophage migration inhibitory factor (MIF), inhibitors of lipoxin biosynthesis, natural alternatives to the synthetic COX inhibitors and LOX inhibitors, and other natural products (including existing, novel and yet to be discovered products) Such as lipids, oils (e.g. mussel oil), peptides, and Small molecules, and products derived and/or extracted from lipids or oils or peptides or Small molecules. US 2011/0158983 A1 Jun. 30, 2011

0424. In alternative aspects, subgroups (categories within mechanism of action, Such analogues may derive their anti each Group) in Table 1 are not necessarily mutually exclusive. oxidant activity from increasing the expression of thioredoxin 0425 The followingTable 2 describes exemplary amounts or other genes involved in the protection of cells and tissues of ingredients used to formulate and/or administer composi from oxidative stress. Non-limiting Exemplary GGA ana tions of this invention: logues are shown below.

Group (with example of a Example 1 Exemplary amounts of both individually and group member) Dose collectively as a group) Group A. 30 mg to 3 gm From about 0.10 mg to about 20.00000 gm per day Geranylgeranylacetones per day inclusively, including for example each daily amount E.g. GGA within this range separated by an increment of about 0.01 mg (e.g. 0.10 mg, 0.11 mg, 0.12 mg, 0.13 mg, etc.). Group B. 10 mg to From about 0.10 mg to about 10.00000gm per day ACE Inhibitors 450 mg per inclusively, including for example each daily amount E.g. Captopril day within this range separated by an increment of about 0.01 mg (e.g. 0.10 mg, 0.11 mg, 0.12 mg, 0.13 mg, etc.). Group C. 10 to 100 mg From about 0.10 mg to about 10.00000gm per day Angiotensin II receptor per day inclusively, including for example each daily amount Blockers within this range separated by an increment of about E.g. Lovartab 0.01 mg (e.g. 0.10 mg, 0.11 mg, 0.12 mg, 0.13 mg, etc.). Group D. 1 mg to 8 mg From about 0.10 mg to about 10.00000 gm per day PPARgamma (and alpha) per day inclusively, including for example each daily amount agonists within this range separated by an increment of about E.g. 0.01 mg (e.g. 0.10 mg, 0.11 mg, 0.12 mg, 0.13 mg, RosiglitaZone etc.). Group E. Various From about 0.10 mg to about 10.00000gm per day Non-steroidal anti- inclusively, including for example each daily amount inflammatory drugs within this range separated by an increment of about (NSAIDs) 0.01 mg (e.g. 0.10 mg, 0.11 mg, 0.12 mg, 0.13 mg, E.g. etodolac (e.g., etc.). LODINETM) Group F. Various Various (including the ranges recommended by NCCN therapies NCCN, but also including up to 10x higher limits).

0426 Group A: The invention provides compositions 0429 Class I: One class of GGA analogues (Class I) used comprising geranylgeranyl compounds, including for to practice this invention, e.g., in the methods, formulations, example geranylgeranyl acetone (GGA) and analogs of gera dosages, combinations, and routes of administration of this nylgeranyl acetone (GGA). invention, comprises compounds of the formula: 0427 GGA: The ingredients serviceable for the current invention include the GGA analogues named in U.S. Patent 0430. In alternative embodiments, Class I compounds Application Pub. No. 20060135623; specifically they include used to practice this invention can have n=8 or 9 and R1 can members that are categorized by U.S. Patent Application Pub. be any of the following functional groups: 1) acetone, 2) No. 20060135623 into categories as exemplified by catego ethyl, 3) hydroxyalkyl 4) amine 5) hydroxyl 6) pivaloyl ries termed Class I, Class II, Class IIIa, Class IIIb, Class IIIc, 7)formyl 8) propionyl 9) butryl) 10) valleryl 11) isovaleryl 12) Class IIId, IVa, IVb, IVc, IVd, V, VIa, VIb, VIc, VId, VIe, VIf, stearoyl 13) myristoyl 14) palmitoyl 15) oleoyl 16) benzoyl VIg, VIIa, VIIb, VIIc, VIId, VIIIa, VIIIb, VIIIc, VIIId, IXa, 17) lauroyl. IXb, Xa, Xb, Xc, XIa, XIb, XII, XIIIa, XIIIb, XIV, XVa, XVb, 0431. These compounds may be synthesized using chemi XVc, XVIa, XVIb, XVIc, XVIIa, XVIIb, and XVIIc, as fol cal synthesis methods familiar to one of ordinary skill in the lows: art. General methods for chemical synthesis may be found in, 0428 The invention provides compositions comprising among other sources, “Comprehensive Organic Transforma GGA analogues, including GGA-like molecules with GGA tions: A Guide to Functional Group Preparations'. Richard C. antioxidantactivity. Compositions and methods of this inven tion comprising geranylgeranyl acetone can have anti-ulcer Larock, Wiley-VCH: 1999 and in “March's Advanced activity and can induce heat-shock protein upregulation. Organic Chemistry: Reactions, Mechanisms and Structure'. Compositions and methods of this invention comprising Jerry March and Michael Smith, John Wiley and Sons Inc.: GGA can be used as an antioxidant, or to induce thioredoxin, 2001. a protein which plays an important protective role against 0432 Class II: Compositions and methods of this inven oxidative stress. Compositions and methods of this invention tion can comprise another class of GGA analogues (Class II) can comprise derivatives of GGA with varying numbers and including compounds of formula (I) in which n=8 or 9 and R1 configurations of double bonds and differing attached func can be any of the following functional groups: 1) 2-oxopropyl tional groups, and these compositions can have antioxidant 2) 2-oxopentyl 3) 3-methyl-2-oxobutyl 4) amino 5) carbe activity. While the invention is not limited by any particular thoxyl amino 6) 2-hydroxypropyl 7) retinol acetate. US 2011/0158983 A1 Jun. 30, 2011 42

0433. These compounds may be synthesized using chemi 2-oxopentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) cal synthesis methods familiar to one of ordinary skill in the Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl art. General methods for chemical synthesis may be found in, 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe among other sources, “Comprehensive Organic Transforma thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. tions: A Guide to Functional Group Preparations”. Richard C. 0442. These compounds may be synthesized using chemi Larock, Wiley-VCH: 1999 and in “March's Advanced cal synthesis methods familiar to one of ordinary skill in the Organic Chemistry: Reactions, Mechanisms and Structure'. Jerry March and Michael Smith, John Wiley and Sons Inc.: art. General methods for chemical synthesis may be found in, 2001. among other sources, “Comprehensive Organic Transforma 0434 Class IIIa: Compositions and methods of this inven tions: A Guide to Functional Group Preparations'. Richard C. tion can comprise another class of GGA analogues (Class Larock, Wiley-VCH: 1999 and in “March's Advanced IIIa), which can include derivatives of the geranylgeranyl Organic Chemistry: Reactions, Mechanisms and Structure'. family that have 5 instead of 4 double bonds with an addi Jerry March and Michael Smith, John Wiley and Sons Inc.: tional double bond as illustrated below: 2001. 0435 Compositions and methods of this invention can 0443 Class IIId: Compositions and methods of this inven comprise use of Class Ma compounds, which can be in all tion can comprise another class of GGA analogues (Class trans or a 5-cis form or can be a mixture of these two isomers. Ind) which includes derivatives of the geranylgeranyl family R can be any one of the following functional groups: 1) that have 8 instead of 4 double bonds with additional double acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) hydroxyl bonds as illustrated below: 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) 2-oxo 0444. In alternative embodiments, Class Ind compounds pentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) can be in all-trans or a 5-cis form or can be a mixture of these Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl two isomers. Rs can be any one of the following functional 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe groups: 1) acetone, 2) ethyl, 3) hydroalkyl. 4) amine, 5) thoxyl amino: 23) 3-methyl-2-oxobutyl; 24)2-hydroxypro hydroxyl 6) formyl, 7) propionyl, 8) butryl) 9) 2-oxopropyl, pyl. 0436 These compounds may be synthesized using chemi 10) 2-oxopentyl, 11) retinol acetate 12) stearoyl 12) myristoyl cal synthesis methods familiar to one of ordinary skill in the 13) Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) ole art. General methods for chemical synthesis may be found in, oyl 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) car among other sources, “Comprehensive Organic Transforma bethoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypro tions: A Guide to Functional Group Preparations”. Richard C. pyl. Larock, Wiley-VCH: 1999 and in “March's Advanced 0445. These compounds may be synthesized using chemi Organic Chemistry: Reactions, Mechanisms and Structure'. cal synthesis methods familiar to one of ordinary skill in the Jerry March and Michael Smith, John Wiley and Sons Inc.: art. General methods for chemical synthesis may be found in, 2001. among other sources, “Comprehensive Organic Transforma 0437 Class IIIb: Compositions and methods of this inven tions: A Guide to Functional Group Preparations'. Richard C. tion can comprise another class of GGA analogues (Class Larock, Wiley-VCH: 1999 and in “March's Advanced IIIb), which can include derivatives of the geranylgeranyl Organic Chemistry: Reactions, Mechanisms and Structure'. family that have 6 instead of 4 double bonds with additional Jerry March and Michael Smith, John Wiley and Sons Inc.: double bonds as illustrated below: 2001. 0438. In alternative embodiments, Class Mb compounds 0446 Class IVa: Compositions and methods of this inven can be in all-trans or a 5-cis form or can be a mixture of these tion can comprise another class of GGA analogues (Class two isomers. R can be any one of the following functional IVa) which includes derivatives of the geranylgeranyl family groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) that have 3 instead of 4 double bonds, with the double bonds 2-oxopentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) at positions C13 and C17 being saturated and with an addi Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl tional double bond at the CI position as illustrated below: 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe 0447. In alternative embodiments, Class IVa compounds thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. can be in all-trans or a 5-cis form or can be a mixture of these 0439. These compounds may be synthesized using chemi two isomers. R can be any one of the following functional cal synthesis methods familiar to those of ordinary skill in the groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) art. General methods for chemical synthesis may be found in, hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) among other sources, “Comprehensive Organic Transforma 2-oxopentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) tions: A Guide to Functional Group Preparations”. Richard C. Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl Larock, Wiley-VCH: 1999 and in “March's Advanced 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe Organic Chemistry: Reactions, Mechanisms and Structure'. thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. Jerry March and Michael Smith, John Wiley and Sons Inc.: 0448. These compounds may be synthesized using chemi 2001. cal synthesis methods familiar to one of ordinary skill in the 0440 Class IIIc: Compositions and methods of this inven art. General methods for chemical synthesis may be found in, tion can comprise another class of GGA analogues (Class among other sources, “Comprehensive Organic Transforma IIIc) includes derivatives of the geranylgeranyl family that tions: A Guide to Functional Group Preparations'. Richard C. have 7 instead of 4 double bonds with additional double Larock, Wiley-VCH: 1999 and in “March's Advanced bonds as illustrated below: Organic Chemistry: Reactions, Mechanisms and Structure'. 0441. In alternative embodiments, Class IIIc compounds Jerry March and can be in all-trans or a 5-cis form or can be a mixture of these 0449 Michael Smith, John Wiley and Sons Inc.: 2001. two isomers. R can be any one of the following functional 0450 Class IVb: Compositions and methods of this inven groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) tion can comprise another class of GGA analogues (Class hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) IVb) which includes derivatives of the geranylgeranyl family US 2011/0158983 A1 Jun. 30, 2011

that have 2 instead of 4 double bonds with some double bonds Organic Chemistry: Reactions, Mechanisms and Structure'. being saturated and with a new double bond as illustrated Jerry March and Michael Smith, John Wiley and Sons Inc.: below: 2001. 0451. In alternative embodiments, Class IVb compounds 0459 Class V: Compositions and methods of this inven can be in all-trans or a 5-cis form or can be a mixture of these tion can comprise another class of GGA analogues (Class V) two isomers. R, can be any one of the following functional which includes a 5-cis-geranylgeranyl compound as shown groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) below: hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) 0460. In alternative embodiments, R.Sub.10 can be any 2-oxopentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) one of the following functional groups: 1)acetone, 2) ethyl, 3) Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl hydroxyalkyl 4) amine 5) hydroxyl 6) formyl 7) propionyl 8) 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe butryl)9) 2-oxopropyl 10) 2-oxopenty111) retinol acetate 12) thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. stearoyl 12) myristoyl 13) Valeryl 14) isovaleryl 15) pivaloyl 0452. These compounds may be synthesized using chemi 16) palmitoyl 17) oleoyl 18) benzoyl 19) lauroyl 20) stearoyl cal synthesis methods familiar to one of ordinary skill in the 21) amino 22) carbethoxyl amino 23) 3-methyl-2-oxobutyl art. General methods for chemical synthesis may be found in, 24)2-hydroxypropyl. among other sources, “Comprehensive Organic Transforma 0461 These compounds may be synthesized using chemi tions: A Guide to Functional Group Preparations”. Richard C. cal synthesis methods familiar to one of ordinary skill in the Larock, Wiley-VCH: 1999 and in “March's Advanced art. General methods for chemical synthesis may be found in, Organic Chemistry: Reactions, Mechanisms and Structure'. among other sources, “Comprehensive Organic Transforma Jerry March and Michael Smith, John Wiley and Sons Inc.: tions: A Guide to Functional Group Preparations'. Richard C. 2001. Larock, Wiley-VCH: 1999 and in “March's Advanced 0453 Class IVc: Compositions and methods of this inven Organic Chemistry: Reactions, Mechanisms and Structure'. tion can comprise another class of GGA analogues (Class Jerry March and Michael Smith, John Wiley and Sons Inc.: IVc) which includes derivatives of the geranylgeranyl family 2001. that have 1 instead of 4 double bonds with some double bonds 0462 Class VIa: Compositions and methods of this inven saturated and with a single double bond as illustrated below: tion can comprise another class of GGA analogues (Class 0454. In alternative embodiments, Class IVc compounds VIa) which includes derivatives of alpha.-carotene, as illus can be in all-trans or a 5-cis form or can be a mixture of these trated below, where n=2-4 and the isoprenoid units can exist two isomers. Rs can be any one of the following functional in any reduced or form. groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) 0463. These compounds may be synthesized using chemi hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) cal synthesis methods familiar to one of ordinary skill in the 2-oxopentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) art. General methods for chemical synthesis may be found in, Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl among other sources, “Comprehensive Organic Transforma 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe tions: A Guide to Functional Group Preparations'. Richard C. thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. Larock, Wiley-VCH: 1999 and in “March's Advanced 0455 These compounds may be synthesized using chemi Organic Chemistry: Reactions, Mechanisms and Structure'. cal synthesis methods familiar to one of ordinary skill in the Jerry March and Michael Smith, John Wiley and Sons Inc.: art. General methods for chemical synthesis may be found in, 2001. among other sources, “Comprehensive Organic Transforma 0464 Class VIb: Compositions and methods of this inven tions: A Guide to Functional Group Preparations”. Richard C. tion can comprise another class of GGA analogues (Class Larock, Wiley-VCH: 1999 and in “March's Advanced VIb) which includes derivatives of beta-carotene, as illus Organic Chemistry: Reactions, Mechanisms and Structure'. trated below, where n=2-4 and the isoprenoid units can exist Jerry March and Michael Smith, John Wiley and Sons Inc.: in any reduced or oxidized form. 2001. 0465. These compounds may be synthesized using chemi 0456 Class IVd: Compositions and methods of this inven cal synthesis methods familiar to one of ordinary skill in the tion can comprise another class of GGA analogues (Class art. General methods for chemical synthesis may be found in, IVd) which includes derivatives of the geranylgeranyl family among other sources, “Comprehensive Organic Transforma that have no double bonds as illustrated below: tions: A Guide to Functional Group Preparations'. Richard C. 0457. In alternative embodiments, R can be any one of the Larock, Wiley-VCH: 1999 and in “March's Advanced following functional groups: 1) acetone, 2) ethyl, 3) hydroxy Organic Chemistry: Reactions, Mechanisms and Structure'. alkyl 4) amine 5) hydroxyl 6) formyl 7) propionyl 8) butryl) 9) Jerry March and Michael Smith, John Wiley and Sons Inc.: 2-oxopropyl 10) 2-oxopentyl 11) retinol acetate 12) stearoyl 2001 12) myristoyl 13) Valeryl 14) isovaleryl 15) pivaloyl 16) 0466 Class VIc: Another class of GGA analogues (Class palmitoyl 17) oleoyl 18) benzoyl 19) lauroyl 20) stearoyl 21) VIc) includes derivatives of gamma-carotene, as illustrated amino 22) carbethoxyl amino 23) 3-methyl-2-oxobutyl 24) below, where n=2-4 and the isoprenoid units can exist in any 2-hydroxypropyl. reduced or oxidized form. 0458. These compounds may be synthesized using chemi 0467. These compounds may be synthesized using chemi cal synthesis methods familiar to one of ordinary skill in the cal synthesis methods familiar to one of ordinary skill in the art. General methods for chemical synthesis may be found in, art. General methods for chemical synthesis may be found in, among other sources, “Comprehensive Organic Transforma among other sources, “Comprehensive Organic Transforma tions: A Guide to Functional Group Preparations”. Richard C. tions: A Guide to Functional Group Preparations'. Richard C. Larock, Wiley-VCH: 1999 and in “March's Advanced Larock, Wiley-VCH: 1999 and in “March's Advanced US 2011/0158983 A1 Jun. 30, 2011 44

Organic Chemistry: Reactions, Mechanisms and Structure'. 0477 These compounds may be synthesized using chemi Jerry March and Michael Smith, John Wiley and Sons Inc.: cal synthesis methods familiar to one of ordinary skill in the 2001 art. General methods for chemical synthesis may be found in, 0468 Class VId: Compositions and methods of this inven among other sources, “Comprehensive Organic Transforma tion can comprise another class of GGA analogues (Class tions: A Guide to Functional Group Preparations'. Richard C. VId) which includes derivatives of lycopene, as illustrated Larock, Wiley-VCH: 1999 and in “March's Advanced below, where n=24 and the isoprenoid units can exist in any Organic Chemistry: Reactions, Mechanisms and Structure'. reduced or oxidized form. Jerry March and Michael Smith, John Wiley and Sons Inc.: 0469. These compounds may be synthesized using chemi 2001. cal synthesis methods familiar to one of ordinary skill in the art. General methods for chemical synthesis may be found in, 0478 Class VIIb: Compositions and methods of this among other sources, “Comprehensive Organic Transforma invention can comprise another class of GGA analogues tions: A Guide to Functional Group Preparations”. Richard C. (Class VIIb) which includes derivatives of tocopherol, as Larock, Wiley-VCH: 1999 and in “March's Advanced illustrated below, where n=2-4 and the isoprenoid units can Organic Chemistry: Reactions, Mechanisms and Structure'. exist in any reduced or oxidized form. Jerry March and Michael Smith, John Wiley and Sons Inc.: 0479. These compounds may be synthesized using chemi 2001. cal synthesis methods familiar to one of ordinary skill in the 0470 Class VIe: Compositions and methods of this inven art. General methods for chemical synthesis may be found in, tion can comprise another class of GGA analogues (Class among other sources, “Comprehensive Organic Transforma VIe) which includes derivatives of phytoene, as illustrated tions: A Guide to Functional Group Preparations'. Richard C. below, where n=2-6, 8, or 9 and the compound is either in a Larock, Wiley-VCH: 1999 and in “March's Advanced reduced or oxidized form Organic Chemistry: Reactions, Mechanisms and Structure'. 0471. These compounds may be synthesized using chemi Jerry March and Michael Smith, John Wiley and Sons Inc.: cal synthesis methods familiar to one of ordinary skill in the 2001. art. General methods for chemical synthesis may be found in, among other sources, “Comprehensive Organic Transforma 0480 Class VIIc: Compositions and methods of this tions: A Guide to Functional Group Preparations”. Richard C. invention can comprise another class of GGA analogues Larock, Wiley-VCH: 1999 and in “March's Advanced (Class VIc) which includes derivatives of delta-tocopherol, as Organic Chemistry: Reactions, Mechanisms and Structure'. illustrated below, where n=2-4 and the isoprenoid units can Jerry March and Michael Smith, John Wiley and Sons Inc.: exist in any reduced or oxidized form. 2001. 0481. These compounds may be synthesized using chemi 0472 Class VIf: Compositions and methods of this inven cal synthesis methods familiar to one of ordinary skill in the tion can comprise another class of GGA analogues (Class art. General methods for chemical synthesis may be found in, VIf) which includes derivatives of lutein, as illustrated below, among other sources, “Comprehensive Organic Transforma where n=2-4 and the isoprenoid units can exist in any reduced tions: A Guide to Functional Group Preparations'. Richard C. or oxidized form. Larock, Wiley-VCH: 1999 and in “March's Advanced 0473. These compounds may be synthesized using chemi Organic Chemistry: Reactions, Mechanisms and Structure'. cal synthesis methods familiar to one of ordinary skill in the Jerry March and Michael Smith, John Wiley and Sons Inc.: art. General methods for chemical synthesis may be found in, 2001. among other sources, “Comprehensive Organic Transforma 0482 Class VIId: Compositions and methods of this tions: A Guide to Functional Group Preparations”. Richard C. invention can comprise another class of GGA analogues Larock, Wiley-VCH: 1999 and in “March's Advanced (Class VIId) which includes derivatives of gamma.-toco Organic Chemistry: Reactions, Mechanisms and Structure'. pherol, as illustrated below, where n=2-4 and the isoprenoid Jerry March and Michael Smith, John Wiley and Sons Inc.: units can exist in any reduced or oxidized form. 2001. 0483 These compounds may be synthesized using chemi 0474 Class VIg: Compositions and methods of this inven cal synthesis methods familiar to one of ordinary skill in the tion can comprise another class of GGA analogues (Class art. General methods for chemical synthesis may be found in, VIg) which includes derivatives of zeaxanthin, as illustrated among other sources, “Comprehensive Organic Transforma below, where n=24 and the isoprenoid units can exist in any tions: A Guide to Functional Group Preparations'. Richard C. reduced or oxidized form. Larock, Wiley-VCH: 1999 and in “March's Advanced 0475. These compounds may be synthesized using chemi Organic Chemistry: Reactions, Mechanisms and Structure'. cal synthesis methods familiar to one of ordinary skill in the Jerry March and Michael Smith, John Wiley and Sons Inc.: art. General methods for chemical synthesis may be found in, 2001. among other sources, “Comprehensive Organic Transforma 0484 Class VIIIa: Compositions and methods of this tions: A Guide to Functional Group Preparations”. Richard C. invention can comprise another class of GGA analogues Larock, Wiley-VCH: 1999 and in “March's Advanced (Class VIIIa) which includes derivatives of alpha-tocotrienol, Organic Chemistry: Reactions, Mechanisms and Structure'. as illustrated below, where n=1, 2, 4, 5, 6, 8, or 9, and the Jerry March and Michael Smith, John Wiley and Sons Inc.: isoprenoid chain existing in any reduced or oxidized form. 2001. 0485 These compounds may be synthesized using chemi 0476 Class VIIa: Compositions and methods of this cal synthesis methods familiar to one of ordinary skill in the invention can comprise another class of GGA analogues art. General methods for chemical synthesis may be found in, (Class VIIa) which includes derivatives of alpha-tocopherol among other sources, “Comprehensive Organic Transforma (Vitamin E), as illustrated below, where n=24 and the iso tions: A Guide to Functional Group Preparations'. Richard C. prenoid units can exist in any reduced or oxidized form Larock, Wiley-VCH: 1999 and in “March's Advanced US 2011/0158983 A1 Jun. 30, 2011

Organic Chemistry: Reactions, Mechanisms and Structure'. 0495. These compounds may be synthesized using chemi Jerry March and Michael Smith, John Wiley and Sons Inc.: cal synthesis methods familiar to one of ordinary skill in the 2001. art. General methods for chemical synthesis may be found in, 0486 Class VIIIb: Compositions and methods of this among other sources, “Comprehensive Organic Transforma invention can comprise another class of GGA analogues tions: A Guide to Functional Group Preparations'. Richard C. (Class VIIIb) which includes derivatives of beta-tocotrienol, Larock, Wiley-VCH: 1999 and in “March's Advanced as illustrated below, where n=1, 2, 4, 5, 6, 8, or 9, and the Organic Chemistry: Reactions, Mechanisms and Structure'. isoprenoid chain existing in any reduced or oxidized form. Jerry March and Michael Smith, John Wiley and Sons Inc.: 0487. These compounds may be synthesized using chemi 2001 cal synthesis methods familiar to one of ordinary skill in the 0496 Class Xa: Compositions and methods of this inven art. General methods for chemical synthesis may be found in, tion can comprise another class of GGA analogues (Class Xa) among other sources, “Comprehensive Organic Transforma which includes derivatives of semiquinone (Coenzyme Q10) tions: A Guide to Functional Group Preparations”. Richard C. radical, as illustrated below, where n=2-6, 8, or 9 Larock, Wiley-VCH: 1999 and in “March's Advanced 0497. These compounds may be synthesized using chemi Organic Chemistry: Reactions, Mechanisms and Structure'. cal synthesis methods familiar to one of ordinary skill in the Jerry March and Michael Smith, John Wiley and Sons Inc.: art. General methods for chemical synthesis may be found in, 2001 among other sources, “Comprehensive Organic Transforma 0488 Class VIIIc: Compositions and methods of this tions: A Guide to Functional Group Preparations'. Richard C. invention can comprise another class of GGA analogues Larock, Wiley-VCH: 1999 and in “March's Advanced (Class VIIIc) which includes derivatives of delta-tocotrienol, Organic Chemistry: Reactions, Mechanisms and Structure'. as illustrated below, where n=1, 2, 4, 5, 6, 8, or 9, and the Jerry March and Michael Smith, John Wiley and Sons Inc.: isoprenoid chain existing in any reduced or oxidized form. 2001 0489. These compounds may be synthesized using chemi 0498 Class Xb: Compositions and methods of this inven cal synthesis methods familiar to one of ordinary skill in the tion can comprise another class of GGA analogues (Class Xb) art. General methods for chemical synthesis may be found in, which includes derivatives of the reduced form of Coenzyme among other sources, “Comprehensive Organic Transforma Q10, as illustrated below, where n=2-6, 8, or 9. tions: A Guide to Functional Group Preparations”. Richard C. 0499. These compounds may be synthesized using chemi Larock, Wiley-VCH: 1999 and in “March's Advanced cal synthesis methods familiar to one of ordinary skill in the Organic Chemistry: Reactions, Mechanisms and Structure'. art. General methods for chemical synthesis may be found in, Jerry March and Michael Smith, John Wiley and Sons Inc.: among other sources, “Comprehensive Organic Transforma 2001 tions: A Guide to Functional Group Preparations'. Richard C. 0490 Class VIIId: Compositions and methods of this Larock, Wiley-VCH: 1999 and in “March's Advanced invention can comprise another class of GGA analogues Organic Chemistry: Reactions, Mechanisms and Structure'. (Class VIIId) which includes derivatives of gamma-tocot Jerry March and Michael Smith, John Wiley and Sons Inc.: rienol, as illustrated below, where n=1, 2, 4, 5, 6, 8, or 9, and 2001. the isoprenoid chain existing in any reduced or oxidized form. 0500 Class Xc: Compositions and methods of this inven 0491. These compounds may be synthesized using chemi tion can comprise another class of GGA analogues (Class Xc) cal synthesis methods familiar to one of ordinary skill in the which includes derivatives of the oxidized form of Coenzyme art. General methods for chemical synthesis may be found in, Q10, as illustrated below, where n=2-6, 8, or 9. among other sources, “Comprehensive Organic Transforma 0501. These compounds may be synthesized using chemi tions: A Guide to Functional Group Preparations”. Richard C. cal synthesis methods familiar to one of ordinary skill in the Larock, Wiley-VCH: 1999 and in “March's Advanced art. General methods for chemical synthesis may be found in, Organic Chemistry: Reactions, Mechanisms and Structure'. among other sources, “Comprehensive Organic Transforma Jerry March and Michael Smith, John Wiley and Sons Inc.: tions: A Guide to Functional Group Preparations'. Richard C. 2001. Larock, Wiley-VCH: 1999 and in “March's Advanced 0492 Class IXa: Compositions and methods of this inven Organic Chemistry: Reactions, Mechanisms and Structure'. tion can comprise another class of GGA analogues (Class Jerry March and Michael Smith, John Wiley and Sons Inc.: IXa) which includes derivatives of phylloquinone (Vitamin 2001. K), as illustrated below, where n=2-4, and the isoprenoid 0502 Class XIa: Compositions and methods of this inven chain exists in any reduced or oxidized form. tion can comprise another class of GGA analogues (Class 0493. These compounds may be synthesized using chemi XIa) which includes derivatives of plaunotol, as illustrated cal synthesis methods familiar to one of ordinary skill in the below. art. General methods for chemical synthesis may be found in, 0503 Class XIa compounds can be in all-trans or a 5-cis among other sources, “Comprehensive Organic Transforma form or can be a mixture of these two isomers. R can be any tions: A Guide to Functional Group Preparations”. Richard C. one of the following functional groups: 1)acetone, 2) ethyl, 3) Larock, Wiley-VCH: 1999 and in “March's Advanced hydroxyalkyl 4) amine 5) hydroxyl 6) formyl 7) propionyl 8) Organic Chemistry: Reactions, Mechanisms and Structure'. butryl)9) 2-oxopropyl 10) 2-oxopenty111) retinol acetate 12) Jerry March and Michael Smith, John Wiley and Sons Inc.: stearoyl 12) myristoyl 13) Valeryl 14) isovaleryl 15) pivaloyl 2001. 16) palmitoyl 17) oleoyl 18) benzoyl 19) lauroyl 20) stearoyl 0494 Class IXb: Compositions and methods of this inven 21) amino 22) carbethoxyl amino 23) 3-methyl-2-oxobutyl tion can comprise another class of GGA analogues (Class 24)2-hydroxypropyl. IXb) which includes derivatives of menaquinone (Vitamin 0504 These compounds may be synthesized using chemi K), as illustrated below, where n=2-4, and the isoprenoid cal synthesis methods familiar to one of ordinary skill in the chain exists in any reduced or oxidized form. art. General methods for chemical synthesis may be found in, US 2011/0158983 A1 Jun. 30, 2011 46 among other sources, “Comprehensive Organic Transforma trophiles, also known as avicins, as illustrated below. The R2 tions: A Guide to Functional Group Preparations”. Richard C. to 15 groups of the Class XIV compositions shown below can Larock, Wiley-VCH: 1999 and in “March's Advanced be either hydrogen or a hydroxyl group. Organic Chemistry: Reactions, Mechanisms and Structure'. 0514. These compounds may be synthesized using chemi Jerry March and Michael Smith, John Wiley and Sons Inc.: cal synthesis methods familiar to one of ordinary skill in the 2001. art. General methods for chemical synthesis may be found in, 0505 Class XIb: Compositions and methods of this inven among other sources, “Comprehensive Organic Transforma tion can comprise another class of GGA analogues (Class tions: A Guide to Functional Group Preparations'. Richard C. XIb) which includes derivatives of gefarnate, as illustrated Larock, Wiley-VCH: 1999 and in “March's Advanced below, where n=2-4, and the isoprenoid units can exist in any Organic Chemistry: Reactions, Mechanisms and Structure'. reduced or oxidized form. Jerry March and Michael Smith, John Wiley and Sons Inc.: 0506. These compounds may be synthesized using chemi 2001. cal synthesis methods familiar to one of ordinary skill in the art. General methods for chemical synthesis may be found in, 0515 Class XVa: Compositions and methods of this among other sources, “Comprehensive Organic Transforma invention can comprise another class of analogues (Class tions: A Guide to Functional Group Preparations”. Richard C. XVa) which includes derivatives of docosahexaenoic acid, as Larock, Wiley-VCH: 1999 and in “March's Advanced illustrated below, where the structure may contain between Organic Chemistry: Reactions, Mechanisms and Structure'. 0-8 methyl groups. Jerry March and Michael Smith, John Wiley and Sons Inc.: 0516 R.Sub. 16 can be any one of the following functional 2001. groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) 0507 Class XII: Compositions and methods of this inven hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) tion can comprise another class of GGA analogues (Class 2-oxopentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) XII) which includes derivatives of cholesterol glucoside, as Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl illustrated below, where n=1-4, and the isoprenoid units can 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe exist in any reduced or oxidized form. thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. 0508. These compounds may be synthesized using chemi 0517. These compounds may be synthesized using chemi cal synthesis methods familiar to one of ordinary skill in the cal synthesis methods familiar to one of ordinary skill in the art. General methods for chemical synthesis may be found in, art. General methods for chemical synthesis may be found in, among other sources, “Comprehensive Organic Transforma among other sources, “Comprehensive Organic Transforma tions: A Guide to Functional Group Preparations”. Richard C. tions: A Guide to Functional Group Preparations', Richard C. Larock, Wiley-VCH: 1999 and in “March's Advanced Larock, Wiley-VCH: 1999 and in “March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure'. Organic Chemistry: Reactions, Mechanisms and Structure'. Jerry March and Michael Smith, John Wiley and Sons Inc.: Jerry March and Michael Smith, John Wiley and Sons Inc.: 2001. 2001. 0509 Class XIIIa: Compositions and methods of this invention can comprise another class of GGA analogues 0518 Class XVb: Compositions and methods of this (Class XIIIa) which includes derivatives of diferuloyl invention can comprise another class of analogues (Class methane (curcumin), as illustrated below, where n=1-4, and XVb) which includes derivatives of eicosapentaenoic acid, as the isoprenoid units can existin any reduced or oxidized form. illustrated below, where the structure may contain between 0510. These compounds may be synthesized using chemi 0-8 methyl groups. cal synthesis methods familiar to one of ordinary skill in the 0519 R, can be any one of the following functional art. General methods for chemical synthesis may be found in, groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) among other sources, “Comprehensive Organic Transforma hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) tions: A Guide to Functional Group Preparations”. Richard C. 2-oxopentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) Larock, Wiley-VCH: 1999 and in “March's Advanced Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl Organic Chemistry: Reactions, Mechanisms and Structure'. 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe Jerry March and Michael Smith, John Wiley and Sons Inc.: thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. 2001. 0520. These compounds may be synthesized using chemi 0511 Class XIIIb: Compositions and methods of this cal synthesis methods familiar to one of ordinary skill in the invention can comprise another class of GGA analogues art. General methods for chemical synthesis may be found in, (Class XIIIb) which includes derivatives of sulforaphane, as among other sources, “Comprehensive Organic Transforma illustrated below, where n=1-4, and the isoprenoid units can tions: A Guide to Functional Group Preparations'. Richard C. exist in any reduced or oxidized form. Larock, Wiley-VCH: 1999 and in “March's Advanced 0512. These compounds may be synthesized using chemi Organic Chemistry: Reactions, Mechanisms and Structure'. cal synthesis methods familiar to one of ordinary skill in the Jerry March and Michael Smith, John Wiley and Sons Inc.: art. General methods for chemical synthesis may be found in, 2001. among other sources, “Comprehensive Organic Transforma 0521 Class XVc: Compositions and methods of this tions: A Guide to Functional Group Preparations”. Richard C. invention can comprise another class of analogues (Class Larock, Wiley-VCH: 1999 and in “March's Advanced XVc) which includes derivatives of alpha linolenic acid, as Organic Chemistry: Reactions, Mechanisms and Structure'. illustrated below, where the structure may contain between Jerry March and Michael Smith, John Wiley and Sons Inc.: 0-8 methyl groups. 2001. 0522 Rs can be any one of the following functional 0513 Class XIV: Compositions and methods of this groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) invention can comprise another class of GGA analogues hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) (Class XIV) which includes derivatives of triterpenoid elec 2-oxopentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) US 2011/0158983 A1 Jun. 30, 2011 47

Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl 0532. These compounds may be synthesized using chemi 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe cal synthesis methods familiar to one of ordinary skill in the thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. art. General methods for chemical synthesis may be found in, 0523 These compounds may be synthesized using chemi among other sources, “Comprehensive Organic Transforma cal synthesis methods familiar to one of ordinary skill in the tions: A Guide to Functional Group Preparations'. Richard C. art. General methods for chemical synthesis may be found in, Larock, Wiley-VCH: 1999 and in “March's Advanced among other sources, “Comprehensive Organic Transforma Organic Chemistry: Reactions, Mechanisms and Structure'. tions: A Guide to Functional Group Preparations”. Richard C. Jerry March and Michael Smith, John Wiley and Sons Inc.: Larock, Wiley-VCH: 1999 and in “March's Advanced 2001. Organic Chemistry: Reactions, Mechanisms and Structure'. Jerry March and Michael Smith, John Wiley and Sons Inc.: 0533 Class XVIIa: Compositions and methods of this 2001. invention can comprise another class of analogues (Class 0524 Class XVIa: Compositions and methods of this XVIIa) which includes derivatives of erucic acid, as illus invention can comprise another class of analogues (Class trated below, where the structure may contain between 0-8 XVIa) which includes derivatives of arachidonic acid, as methyl groups. illustrated below, where the structure may contain between 0534 R can be any one of the following functional 0-8 methyl groups. groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) 0525 R can be any one of the following functional hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) 2-oxopentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl 2-oxopentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. 0535 These compounds may be synthesized using chemi 0526. These compounds may be synthesized using chemi cal synthesis methods familiar to one of ordinary skill in the cal synthesis methods familiar to one of ordinary skill in the art. General methods for chemical synthesis may be found in, art. General methods for chemical synthesis may be found in, among other sources, “Comprehensive Organic Transforma among other sources, “Comprehensive Organic Transforma tions: A Guide to Functional Group Preparations'. Richard C. tions: A Guide to Functional Group Preparations”. Richard C. Larock, Wiley-VCH: 1999 and in “March's Advanced Larock, Wiley-VCH: 1999 and in “March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure'. Organic Chemistry: Reactions, Mechanisms and Structure’, Jerry March and Michael Smith, John Wiley and Sons Inc.: Jerry March and Michael Smith, John Wiley and Sons Inc.: 2001. 2001. 0536 Class XVIIb: Compositions and methods of this 0527 Class XVIb: Compositions and methods of this invention can comprise another class of analogues (Class invention can comprise another class of analogues (Class XVIIb) which includes derivatives of 11-docosenoic acid, as XVIb) which includes derivatives of linoleic acid, as illus illustrated below, where the structure may contain between trated below, where the structure may contain between 0-8 0-8 methyl groups. methyl groups. 0528 Ro can be any one of the following functional 0537 R can be any one of the following functional groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) 2-oxopenty11) retinol acetate 12) stearoyl 12) myristoyl 13) 2-oxopentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. 0529. These compounds may be synthesized using chemi 0538. These compounds may be synthesized using chemi cal synthesis methods familiar to one of ordinary skill in the cal synthesis methods familiar to one of ordinary skill in the art. General methods for chemical synthesis may be found in, art. General methods for chemical synthesis may be found in, among other sources, “Comprehensive Organic Transforma among other sources, “Comprehensive Organic Transforma tions: A Guide to Functional Group Preparations”. Richard C. tions: A Guide to Functional Group Preparations'. Richard C. Larock, Wiley-VCH: 1999 and in “March's Advanced Larock, Wiley-VCH: 1999 and in “March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure'. Organic Chemistry: Reactions, Mechanisms and Structure'. Jerry March and Michael Smith, John Wiley and Sons Inc.: Jerry March and Michael Smith, John Wiley and Sons Inc.: 2001. 2001. 0530 Class XVIc: Compositions and methods of this 0539 Class XVIIc: Compositions and methods of this invention can comprise another class of analogues (Class invention can comprise another class of analogues (Class XVIc) which includes derivatives of gammalinolenic acid, as XVIIc) which includes derivatives of 5-docosenoic acid, as illustrated below, where the structure may contain between illustrated below, where the structure may contain between 0-8 methyl groups. 0-8 methyl groups. 0531 R can be any one of the following functional (0540 R can be any one of the following functional groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) groups: 1) acetone, 2) ethyl, 3) hydroxyalkyl 4) amine 5) hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) hydroxyl 6)formyl 7) propionyl 8) butryl) 9) 2-oxopropyl 10) 2-oxopentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) 2-oxopentyl 11) retinol acetate 12) stearoyl 12) myristoyl 13) Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl Valeryl 14) isovaleryl 15) pivaloyl 16) palmitoyl 17) oleoyl 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe 18) benzoyl 19) lauroyl 20) stearoyl 21) amino 22) carbe thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. thoxylamino 23) 3-methyl-2-oxobutyl 24)2-hydroxypropyl. US 2011/0158983 A1 Jun. 30, 2011 48

0541. These compounds may be synthesized using chemi tromethamine (e.g., TOR ADOLTM); Meclofenamate (e.g., cal synthesis methods familiar to one of ordinary skill in the MECLOMENTM); mefenamic acid, or (2,3-dimethylphenyl) art. General methods for chemical synthesis may be found in, aminobenzoic acid (e.g., PONSTELTM); meloxicam (e.g., among other sources, “Comprehensive Organic Transforma MOBICOXTM, MOBICTM): nabumetone (e.g., RELIFEXTM, tions: A Guide to Functional Group Preparations”. Richard C. RELAFENTM); Naproxen (e.g., ALEVETM, ANAPROXTM, Larock, Wiley-VCH: 1999 and in “March's Advanced MIRANNAXTM, NAPROGESICTM, NAPROSYNTM, Organic Chemistry: Reactions, Mechanisms and Structure'. NAPRELANTM, SYNFLEXTM); oxaprozinum or oxaprozin Jerry March and Michael Smith, John Wiley and Sons Inc.: (e.g., DAYPROTM or DURAPROXTM); piroxicam (e.g., 2001. FELDENETM); salsalate (e.g., DISALCIDTM, SALFLEXTM), 0542. In the classes of compounds described herein, if a sulindac (e.g., CLINORILTM); tolmetin (e.g., TOLEC GGA analogue or related analogue contains Stereochemistry, TINTM); and, COX-2-selective NSAIDs, e.g. celecoxib (e.g., all enantiomeric and diastereomeric forms of the GGA ana CELEBRATM, CELEBREXTM); rofecoxib (e.g., VIOXXTM, logues or related analogue are intended. Pure Stereoisomers, CEOXXTM): etoricoxib (e.g., ARCOXIATM); Valdecoxib mixtures of enantiomers and/or diastereomers, and mixtures (e.g., BEXTRATM); parecoxib (e.g., DYNASTATTM); of different GGA analogues or related analogue are meloxicam (e.g., MOBICTM); or Lumiracoxib (e.g., PREX described. Thus, the GGA analogues or related analogues IGETM). may occur as racemates, racemic mixtures and as individual 0547. The invention provides compositions and methods diastereomers, or enantiomers with all isomeric forms being using steroids. In additional aspects, invention also provides included. A racemate or racemic mixture does not necessarily therapeutic combinations, e.g., pharmaceutical compositions imply a 50:50 mixture of stereoisomers. of the invention, comprising steroids (including those shown 0543. Where a given structural formula or chemical name in Table 1, above), e.g., anabolic steroids, such as andarine, is presented for a GGA analogue or related analogues, it is ethylestrenol, mesterolone, methandrostenolone, meth intended that all possible solvates, pharmaceutically accept enolone, methyltestosterone, Oxandrolone, oxymetholone able salts, esters, amides, complexes, chelates, Stereoisomers, stanozolol, boldenone, hexoxymestrolum, methandros geometric isomers, crystalline or amorphous forms, metabo tenolone, methenolone enanthate, nandrolone decanoate, lites, metabolic precursors or prodrugs of the compound are nandrolone phenproprionate, stanozolol, Stenbolone, test also separately described by the chemical structural formula osterone cypionate, testosterone enanthate, testosterone, tes or chemical name.” tosterone nicotinate, therobolin, trenbolone, trenbolone, tro phobolene or a combination thereof. Alternative Group B: Angiotensin Converting Enzyme Inhibitors (ACE embodiments comprise all possible combinations of ingredi Inhibitors or ACE-Is). Group C. Angiotensin Receptor Block ents provided herein (e.g. members of Group A, Group B, ers (ARBs). Group C, Group D, Group E, Group F, Group G, Group H, 0544 Compositions and methods of this invention can Group I, Group J. Group K, Group L, and Group M in Table comprise ACE inhibitor drugs that effect the renin-angio 1), including those in Table 1, and these ingredients include tensin System, which has a large degree of overlap with the steroids and steroid combinations as provided herein. effects of beta blockers. Compositions and methods of this invention can comprise compounds that inhibit the enzyme Group F: NCCN Therapies. that converts angiotensin I to angiotensin II for controlling blood pressure, including ACE inhibitors e.g., angiotensin 0548. The invention provides compositions and methods converting enzyme inhibitors), e.g., structurally related com using NCCN Therapies: Exemplary chemotherapy or radia pounds. tion therapies that can be used to practice this invention Group D: Peroxisome Proliferator-Activated Receptor include therapies that are listed in the current NCCN Clinical (PPAR) ligands, e.g. agonists, such as PPAR alpha agonists, Practice Guidelines in OncologyTM (NCCN therapies), and PPARgamma agonists, PPAR alpha/gamma dual agonists, are exemplified by NCCN therapies in the category of A) and other PPAR ligands (e.g. PPAR delta ligands), or equiva NCCN“Treatment Of Cancer By Site” and in the category of lents thereof. B) NCCN “Supportive Care”. The current NCCN therapies 0545. The invention provides compositions and methods are published and available online, in print, and by request. using rosiglitaZone (e.g., AVANDIATM), pioglitaZone (e.g., (0549. Exemplary NCCN therapies that can be used to ACTOSTM), troglitazone (e.g., REZULINTM), muraglitazar, practice this invention can be categorized under “Treatment naveglitazar, netoglitaZone, rivoglitaZone, and/or tesagli by Site” include treatments for: 1) Acute Myeloid Leukemia; tazar, or equivalents thereof. Additional examples are pro 2) Bladder Cancer (incl. Bladder Cancer, Upper Tract vided in U.S. Pat. No. 6,756,399, and U.S. Pat. No. 6,869,967. Tumors, Urothelial Carcinoma of the Prostate); 3) Bone Can cer (including Chondrosarcoma, Ewing's Sarcoma, Osteosa Group E: Non-Steroidal Anti-Inflammatory Drugs rcoma); 4) Breast Cancer (incl. Noninvasive, Invasive, Phyl (NSAIDs). lodes Tumor, Paget's Disease, Breast Cancer During 0546. The invention provides compositions and methods Pregnancy); 5) Central Nervous System Cancers (incl. Adult using NSAIDs. Exemplary non-steroidal anti-inflammatory Low-Grade Infiltrative Supratentorial Astrocytoma/Oligo drugs (NSAIDs) that can be used to practice this invention dendroglioma, Adult Intracranial Ependymoma, Anaplastic include, e.g., comprising aspirin, diclofenac (e.g., Astrocytoma/Anaplastic Oligodendroglioma/Glioblastoma VOLTARENTM, CATAFLAMTM, VOLTAREN-XRTM); Multiforme, Limited (1-3) Metastatic Lesions, Multiple (>3) diflunisal (e.g., DOLOBIDTM): etodolac (e.g., LODINETM); Metastatic Lesions, Carcinomatous Lymphomatous Menin fenoprofen (e.g., NALFONTM); flurbiprofen (e.g., gitis, Non-immunosuppressed Primary CNS Lymphoma, ANSAIDTM, FROBENTM); ibuprofen (e.g., MOTRINTM); Metastatic Spine Tumors, Principles of Brain Tumor indomethacin (e.g., INDOCINTM, INDOCIN-SRTM); keto Therapy); 6) Cervical Cancer; 7) Chronic Myelogenous Leu profen, or (RS)2-(3-benzoylphenyl)-propionic acid (e.g., kemia; 8) Colon/Rectal Cancer (incl. Colon Cancer, Rectal ORUDISTM, ORUVAILTM); ketorolac or ketorolac Cancer, Anal Carcinoma); 9) Esophageal Cancer; 10) Gastric US 2011/0158983 A1 Jun. 30, 2011 49

Cancer; 11) Head and Neck Cancers (incl. Ethmoid Sinus Group I: comprises or consists of polyunsaturated fatty acids, Tumors, Maxillary Sinus Tumors, Salivary Gland Tumors, Such as e.g. omega-3 fatty acids, including for example Cancer of the Lip, Cancer of the Oral Cavity, Cancer of the eicosapentaenoic acid (EPA), and docosahexaenoic acid Oropharynx, Cancer of the Hypopharynx, Occult Primary, (DHA). Cancer of the Glottic Larynx, Cancer of the Supraglottic 0552. In one aspect, invention provides therapeutic com Larynx, Cancer of the Nasopharynx. Advanced Head and binations, e.g., pharmaceutical compositions of the invention, Neck Cancer); 12) Hepatobiliary Cancers (incl. Hepatocellu comprising a natural oil or fatty acid, e.g., comprising an lar Carcinoma, Gallbladder Cancer, Intrahepatic Cholangio omega-3 fatty acid, a fish oil, a long-chain polyunsaturated carcinoma, Extrahepatic Cholangiocarcinoma); 13) Hodgkin fatty acid, an n-3 and/or n-6 highly unsaturated fatty acid, Disease/Lymphoma; 14) Kidney Cancer, 15) Melanoma; 16) eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) Multiple Myeloma (incl. Multiple Myeloma, Waldenström’s or a combination thereof. In non-limiting examples, these Macroglobulinemia); 17) Myelodysplastic Syndromes: 18) fatty acids may be administered orally or intravenously. Neuroendocrine Tumors (incl. Multiple Endocrine Neopla Group J: comprises or consists of C-difluoromethylornithine. sia: Type 1, Multiple Endocrine Neoplasia: Type 2, Carcinoid 0553 C.-Difluoromethylornithine is an inhibitor of orni Tumors, Islet Cell Tumors, Pheochromocytoma, Poorly Dif thine decarboxylase (an enzyme involved in polyamine Syn ferentiated/Small Cell/Atypical Lung Carcinoids); 19) Non thesis), by reducing the polyamine content of mucosa. Group Hodgkin's Lymphoma (incl. Chronic Lymphocytic Leuke J also includes (comprises or consists of) all inhibitors of mia/Small Lymphocytic Lymphoma, Follicular Lymphoma, ornithine decarboxylase. Marginal Zone Lymphoma, Mantle Cell Lymphoma, Diffuse Group K: comprises or consists of Superoxide dismutase Large B-Cell Lymphoma, Burkitt's Lymphoma, Lympho (SOD) and similar antioxidant compounds. blastic Lymphoma, AIDS-Related B-Cell Lymphoma); 20) 0554 Group K comprises or consists of Superoxide dis Non-Melanoma Skin Cancers(incl. Basal and Squamous Cell mutase (SOD), catalase, superoxide dismutase (SOD)-cata Skin Cancers, Dermatofibrosarcoma Protuberans, Merkel lase conjugates or complexes, peroxiredoxins, and peroxi Cell Carcinoma); 21) Non-Small Cell Lung Cancer: 22) dases (e.g. glutathione peroxidase). Occult Primary; 23) Ovarian Cancer (incl. Epithelial Ovarian 0555 Superoxide dismutase (SOD), and similar antioxi Cancer, Borderline Epithelial Ovarian Cancer (Low Malig dant compounds, includes specifically: nant Potential), Less Common Ovarian Histologies); 24) Pan 0556 a? enzymes with the ability to catalyze the conver creatic Adenocarcinoma; 25) Prostate Cancer; 26) Small Cell sion of hydrogen peroxide into other compounds; Lung Cancer (incl. Small Cell Lung Cancer, Lung Neuroen 0557 b/enzymes with the ability to catalyze the decom docrine Tumors): 27) Soft Tissue Sarcoma (incl. Soft-tissue position of peroxides; Extremity, Retroperitoneal, Intra-abdominal Sarcoma, Des 0558 c/compounds that have antioxidant activity; and moid); 28) Testicular Cancer; 29) Thyroid Carcinoma (incl. 0559 d/compounds that promote antioxidant activity, Nodule Evaluation, Papillary Carcinoma, Follicular Carci Such as co-factors, precursors and/or subunits and other noma, Hirthle Cell Neoplasm, Medullary Carcinoma, Ana enzymes in a shared biochemical reaction pathway, includ plastic Carcinoma); and 30) Uterine Cancers (incl. Endome ing, e.g. Selenium, cysteine, glutamine, tryptophan, and glu trial Cancer, Uterine Sarcoma); and all these therapies are tathione reductase. provided herein for protection as part of this invention. Group L: comprises or consists of activators of heat shock 0550 Exemplary NCCN therapies that can be used to response. practice this invention are categorized under “Supportive 0560 Group L comprises or consists of activators of heat Care” include treatments for: 1) Adult Cancer Pain, 2) anti shock response, e.g. Geranylgeranylacetone or gernate, Zinc, emesis; 3) Cancer- and Treatment-Related Anemia; 4) Can tin, Salicylates, dexamethasone, cocaine, nicotine, alpha-adr cer-Related Fatigue; 5) Distress Management; 6) Fever and energic agonist, ppar-gamma agonist, biomolecular-geldana Neutropenia; 7) Myeloid Growth Factors; 8) Palliative Care: mycin, cyclopentanone, prostanoids enprostil, paracetamol. 9) Pediatric Cancer Pain; 10) Senior Adult Oncology; and 11) ketotiphen, levamisole, diazepam, bromocriptine, dopamine. Venous Thromboembolic Disease; and all these therapies are Group M: comprises or consists of drugs that reduce the provided herein for protection as part of this invention. Sup inflammatory/progressive tissue damage response. portive care, as provided herein for protection in this inven 0561 Group M comprises or consists of ACE inhibitors, tion, includes G-CSF therapy, and erythropoietin therapy. ARBs, phenylbutry rate or PPARgamma (insulin sensitizer) Group F: comprises use of or consists of use of TNF inhibi and/or probucol, calcitriol as alternative combinations to fur tors, e.g. pentoxifylline. ther stimulate protective vascular response, NSAIDs to Group G: comprises use of or consists of use of TNF inhibi reduce inflammation, peptide-containing compounds, inhibi tors, e.g. anti-TNF agents, anti-TNF mAbs, pentoxifylline, tors of macrophage migration inhibitory factor (MIF), inhibi thalidomide. Pentoxifylline is a PDE4 inhibitor that increases tors of lipoxin biosynthesis, natural alternatives to the Syn intracellular cAMP and stimulates PKA activity. Pentoxifyl thetic COX inhibitors and LOX inhibitors, and other natural line is also an inhibitor of tumor necrosis factor-alpha (TNF products (including existing, novel and yet to be discovered alpha or TNF-C.). Group G also includes (comprises or con products) such as lipids, oils (e.g. mussel oil), peptides, and sists of) all phosphodiesterase inhibitors and TNF inhibitors. Small molecules, and products derived and/or extracted from Group H: comprises use of or consists of use of deferrioxam lipids or oils or peptides or Small molecules. 1. 0562 Treating, Ameliorating, Reducing, and/or Improv 0551 Deferrioxamine is a chelator that has been used for ing Conditions, States and Disease Symptoms. The instant than 20 years in treatment of severe ion poisoning, of distur invention may be used to treat all possible combination and bances in iron storage and of diseases which lead to increased permutations of conditions, states and disease symptoms as iron values. Group H also includes all chelators, such as provided herein for protection, including by way of non DMSA, EDTA, and EDTA. limiting exemplification, those shown in Table 3, below. In US 2011/0158983 A1 Jun. 30, 2011 50 alternative embodiments, the products and compositions of amounts or doses and/or longer durations of a medical this invention can be used to treat, ameliorate, reduce, and/or therapy (e.g. cancer therapies or radiation therapies) than improve, by way of non-limiting exemplification, the condi could be used without this invention; 2) to allow or enable or tions, states and symptoms listed in Table 3, below. In alter facilitate the tolerance and use of longer durations of a medi native embodiments of this invention, the products and com cal therapy (e.g. cancer therapies or radiation therapies) than positions of this invention may be used to treat ameliorate, could be used without this invention; 3) to reduce occurrences reduce, and/or improve, all possible combinations and per of (drug) resistance to a medical therapy (e.g. cancer chemo therapy or radiation therapy); 4) to enable dosage intensifi mutations of the conditions, states and symptoms listed in cation of a medical therapy (e.g. cancer chemotherapy or Table 3, below. radiation therapy); 5) to enable increasing the frequency of a medical therapy (e.g. cancer chemotherapy or radiation TABLE 3 therapy); 6) to enhance patient response rates; 7) to increase Exemplary conditions, states and disease symptoms ameliorate, patient survival; 8) to induce a tissue protective state; 9) to reduce, and/or improved by compositions and methods of this invention. induce tissue regeneration; and/or 10) to induce tissue repair. 1 anger 2 anemia TABLE 4 3 anorexia 4 anorexia-cachexia Exemplary uses of compositions and/or methods of the invention. 5 anxiety 6 atrophy (e.g. muscle atrophy) 1 to allow or enable or facilitate the tolerance and use of higher 7 cachexia amounts and/or doses and/or longer durations of a medical therapy 8 cancer cachexia (e.g. cancer therapies or radiation therapies) than could be used 9 cardiotoxicity without this invention 10 cognitive impairment 2 to allow or enable or facilitate the tolerance and use of longer 11 cytoprotection deficiency durations of a medical therapy (e.g. cancer therapies or radiation 12 depression herapies) than could be used without this invention 13 despair 3 to reduce occurrences of (drug) resistance to a medical therapy (e.g. 14 delayed emesis cancer chemotherapy or radiation therapy) 15 diarrhea 4 to enable dosage intensification of a medical therapy (e.g. cancer 16 difficulties with activities of daily living chemotherapy or radiation therapy) 17 discomfort 5 o enable increasing the frequency of a medical therapy (e.g. cancer 18 emesis chemotherapy or radiation therapy) 19 erectile or sexual dysfunction or sexual o enhance patient response rates disinterest o increase patient Survival 2O excessive sympathoneural drive o induce a tissue protective state 21 fatigue o induce tissue regeneration 22 febrile neutropenia o induce tissue repair 23 frustration 24 hair loss 25 heart failure 0564. In alternative aspects, some ingredients of the inven 26 infection (in different aspects, infection tion (e.g., exemplary combinations of drugs) provided herein types provided herein include bacterial, viral, mycobacterium, yeast and protozoan can be administered by more than one route. infections, and any combination thereof) 0565. By non-limiting exemplification, in alternative 27 inflammation aspects a number of steroids can be administered by more 28 intolerance to a medical therapy 29 lack of appetite than one route, and their mention herein under one list of 30 lack of energy examples with a common route of administration (e.g. oral 31 lack or motivation administration) does not preclude the understanding that said 32 mucositis (e.g. oral or digestive, including ingredient may also be administered by a different route; this esophageal or intestinal mucositis) 33 myeloprotection deficiency invention provides that, for each ingredient provided herein, 34 myeloSupression (including neutropenia) that all possible routes of administration are provided herein; 35 8Se.8 the invention also provides kits comprising the combinations 36 nephrotoxicity of compounds (e.g., drugs, ingredients) of the invention, 37 neutropenia 38 oral mucositis including ingredient forms suitable for different modes of 39 ototoxicity administration (e.g., a form of a compound that can be admin 40 pain istered orally, a form of a compound that can be administered 41 peripheral neuropathy topically, etc.). In separate aspects, this invention provides 42 reduced physical activity 43 toxicity (including cyto-toxicity) from any protection for each subgroup, and each subgroup may include chemotherapy or radiation or Surgical members of another Subgroup. trauma 0566. The invention provides alternative embodiments 44 wasting 45 worrying wherein the preparations of the invention comprise ingredi 46 stress or anxiety related to any of the ents of the invention (e.g., exemplary combinations of drugs above of the invention) as exemplified in Table 1, and, in one aspect, are orally ingestible. In a non-limiting exemplification these preparations can be liquids (e.g. that can be orally ingested 0563. Additional Benefits in the Context of the Adverse with the help of a spoon), or powders, capsules, tablets, and Effects of Chemotherapy and Radiation. This invention pro pills. In non-limiting exemplifications, they can also be vides compositions (e.g., products of manufacture) and meth formed into flavored bars (e.g. similar to what bars that are ods (e.g., therapies), in non-limiting exemplifications: 1) to marketed as “power bars”, “diet bars”, “energy bars’, and allow or enable or facilitate the tolerance and use of higher “nutritional bars). US 2011/0158983 A1 Jun. 30, 2011

0567 This invention provides that the ingredients of the propranolol-etodolac-chemo drug combination of the inven invention (e.g., exemplary combinations of drugs of the tion comprises use of a tyrosine kinase inhibitor (TKI) as the invention), such as the ingredients exemplified in Table 1 (for chemotherapeutic agent. Another exemplary propranolol making the preparations of the invention) are ingredients that etodolac-chemo drug combination of the invention comprises are available commercially (and thus can be purchased or use of any compound that inhibits and/or prevents vascular manufactured). endothelial growth factor (VEGF)-mediated angiogenesis. 0568. In alternative aspects, ingredients used to practice 0571 For example, in one embodiment the invention pro this invention (e.g., for use in the exemplary combinations of vides a composition comprising (1) a propranolol (e.g., drugs of the invention), and in one aspect, methods and com INDERALTM) or equivalents, a non selective antagonist that positions of the invention used to treat, prevent and/or ame inhibits beta1, beta2 and beta3 subclasses of beta adrenergic liorate wasting and/or atrophy, such as muscle atrophy, or receptors; (2) etodolac (e.g., LODINETM) or equivalents, an methods and compositions of the invention used for protec NSAID that inhibits both Cox-1 and Cox-2 enzymes, with tion against oxidants (e.g., used as an antioxidant), as dis Some preference towards Cox-2 causing less gastrointestinal cussed herein, include any single known or groups of ingre problems; and (3) a cancer chemotherapy agent. An exem dients that have a measurable positive ORAC value (or plary embodiment is VT-122TM and a cancer chemotherapy similar value using another comparable test, see below for agent. As with any composition of the invention, this embodi explanation: ORAC assays and ORAC values discussed in ment can be administered by several routes, including intra detail, below) of at least about 1 ORAC unit/gram, or, at least venous, topical and oral, and the like. This embodiment can about 5 ORAC units/gram, or, at least about 10 ORAC units/ be used in the treatment of a cachexia, for example, a cancer gram, or, at least about 20 ORAC units/gram, or, at least about cachexia, including administration to patients before, during 30 ORAC units/gram, or, at least about 40 ORAC units/gram, and/or after chemotherapy, radiation therapy or a combina or, at least about 50 ORAC units/gram, or, at least about 60 tion thereof. The compositions of the invention can also be ORAC units/gram, or, at least about 70 ORAC units/gram, or, administered to treat, ameliorate or prevent inflammation, at least about 80 ORAC units/gram, or, at least about 90 excessive sympathoneural drive, cachexia, anorexia, anor ORAC units/gram, or, at least about 100 ORAC units/gram, exia-cachexia or stress or anxiety related to any of these. or, at least about 200 ORAC units/gram, or, at least about 300 0572. In alternative embodiments, this combination is ORAC units/gram, or, at least about 400 ORAC units/gram, used in defined regimens with approved chemotherapies, and or, at least about 500 ORAC units/gram, or, at least about 600 can increase tolerability, increase efficacy and/or reduce cost ORAC units/gram, or, at least about 700 ORAC units/gram, of a cancer treatment. or, at least about 800 ORAC units/gram, or, at least about 900 0573 While the invention is not limited by any particular ORAC units/gram, or, at least about 1000 ORAC units/gram, mechanism of action: a composition of the invention (e.g., or, at least about 1000 ORAC units/gram, or, at least about comprising the propranolol-etodolac-chemo drug combina 1500 ORAC units/gram, or, at least about 2000 ORAC units/ tion) can work by directly by reducing systemic inflammation gram, or, at least about 2500 ORAC units/gram, or, at least and autonomic dysfunction the patient feels better and is able about 3000 ORAC units/gram, or, at least about 3500 ORAC and willing to tolerate more cycles of a drug, e.g., a chemo units/gram, or, at least about 4000 ORAC units/gram, or, at therapy drug. In one embodiment, it is possible to reduce the least about 4500 ORAC units/gram, and or, at least about dose of the chemotherapy and maintain high efficacy of the 5000 ORAC units/gram. chemotherapy because the composition of the invention (e.g., 0569. Oxygen Radical Absorbance Capacity (ORAC) is a the propranolol-etodolac-chemo drug combination of exem method of measuring antioxidant capacities of different plary pharmaceuticals of the invention) has multiple mecha foods; correlation between the high antioxidant capacity of nisms of action; this can allow reduction of the amount of the fruits and vegetables, and the positive impact of diets high in chemotherapy drug administered to the patient in need fruits and vegetables, is believed to play an important role in thereof. This can also result in reduced cost of the treatment the free-radical theory of aging. An exemplary ORAC assay for the patient. is: measure the oxidative degradation of a fluorescent mol ecule (e.g., a beta-phycoerythrin or fluorescein) after being Tyrosine Kinase Inhibitors mixed with free radical generators such as azo-initiator com pounds. AZO-initiators are considered to produce peroxyl free 0574. A drug combination of the invention (e.g., the exem radical by heating, which damages the fluorescent molecule, plary propranolol-etodolac-chemo drug combination) com resulting in the loss of fluorescence. Antioxidant is able to prises use of a tyrosine kinase inhibitor (TKI) as the chemo protect the fluorescent molecule from the oxidative degenera therapeutic agent. In one embodiment, a drug combination of tion. The degree of protection can be quantified using a fluo the invention of the invention comprises VT-122TM with tar rometer. Equipment that can automatically measure and cal geted therapy Such as a protein kinase inhibitor, e.g., a culate the capacity is commercially available; see e.g., Ou tyrosine kinase inhibitor (TKI). In alternative embodiment, (2001) Development and validation of an improved oxygen TKIs that are specific for certain kinases are used, or, TKIs radical absorbance capacity assay using fluorescein as the that are broad protein kinase inhibitors, e.g., are multi-kinase fluorescent probe. JAgric Food Chem 49(10):4619-4626. inhibitors, are used. In alternative embodiments, TKIs that can interfere epidermal growth factor receptor (EGFR) activ Propranolol, Etodolac and a Cancer Chemotherapy Agent ity are used; e.g., monoclonal antibodies and Small-molecule 0570. This invention provides compositions (e.g., drugs, inhibitors of protein kinases, including EGFR. pharmaceutical compositions, formulations, preparations, 0575. Use of a drug combination of the invention will kits and the like) comprising a propranolol, an etodolac (e.g., allow a decreased amount of EGFR inhibitor be used; this will VT-122TM, Vicus Therapeutics, Morristown, N.J.), and a can decrease, ameliorate or eliminate the rash that occurs upon cer chemotherapy agent or compositions; chemotherapy use of protein kinase inhibitors (it is estimated that rash agents or compositions include e.g., biologics such as pro occurs in 60% to 80% of patients, with the majority experi teins (e.g., peptides, antibodies, cytokines and the like) and encing a mild to moderate rash; severe symptoms can neces Small molecules Such as alkylating agents. An exemplary sitate dose alterations occur in up to 20% of the patients with US 2011/0158983 A1 Jun. 30, 2011 52 rash). Use of a drug combination of the invention, e.g., an exemplary propranolol-etodolac-chemo drug combination, -continued will allow high clinical benefit with reduced toxicity. 0576. In alternative embodiments, because expression of Name Target Company Class EGFR is detected in many human cancers including those of imatinib Bcr-Abl Novartis Sma the head and neck, colon, and rectum, compositions of the (e.g., GLEEVECTM) OleClic invention (e.g., comprising the propranolol-etodolac-chemo trastuzumab (e.g., Erb2 Genentech Monoclonal HERCEPTINTM) Roche antibody drug combination) are used to treat head and neck, colon, and gefitinib EGFR AstraZeneca Sma rectum cancers. (e.g., IRESSATM) OleClic ranibizumab (e.g., VEGF Genentech Monoclonal 0577. In alternative embodiments, because vascular LUCENTISTM) antibody endothelial growth factor (VEGF)-mediated angiogenesis is pegaptainib (e.g., VEGF OSISPfizer Sma thought to play a critical role in tumor growth and metastasis, MACUGENTM) OleClic compositions of the invention (e.g., comprising the propra Sorafenib (e.g., TKI Onyx/Bayer Sma NEXAVARTM) OleClic nolol-etodolac-chemo drug combination) are used in con dasatinib (e.g., BMS- TKI BMS Sma junction with anti-VEGF therapies, e.g., either as an alterna 354825 TM) OleClic tive or as an adjunct to conventional chemo or radiation Sunitinib (e.g., TKI Pfizer Sma therapy. Compositions of the invention can be used with any SUTENT) TM OleClic technique that can block the VEGF pathway, including neu erlotinib Erb.1 Genentech Sma (e.g., TARCEVATM) Roche OleClic tralizing monoclonal antibodies against VEGF or its receptor, paZopanib TKI GSK Sma small molecule tyrosine kinase inhibitors of VEGF receptors; OleClic or soluble VEGF receptors which act as decoy receptors for nilotinib (e.g., Bcl-Abir Novartis Sma TASIGNATM) OleClic VEGF. Compositions of the invention can be used with any lapatinib Erb.1 Erb2 GSK Sma tyrosine kinase inhibitor to treat cancer, for example: (e.g., TYKERBTM) OleClic panitumumab EGFR Amgen Monoclonal (e.g., VECTIBIXTM) antibody bandetinib RETIVEGFR AstraZeneca Sma Name Target Company Class OleClic briwanib VEGF, FGF BMS Sma bevacizumab (e.g., VEGF Genentech Monoclonal Molecule AVASTINTM) antibody E7080 TM Multiple targets: Esai Sma BIBW 2992 EGFR and Erb2 Boehringer Small RETIVEGFR OleClic Ingelheim molecule cetuximab (e.g., Erb1 Imclone. BMS Monoclonal ERBITUXTM) antibody Compositions of the invention can be used with any protein kinase inhibitor, for example:

Drug (Trade name) Class Target Indication Dose

cetuximab mAb EGFR In combination with radiation Intravenous (e.g., therapy for locally or regionally 400 mg/m ERBITUXTM) advanced HNSCC initial dose ImClone, Bristol Recurrent or metastatic HNSCC then 250 mg/m. Myers Squibb progressing after platinum-based weekly therapy Single agent in metastatic CRC (EGFR-expressing) after failure ofirinotecan- and Oxaliplatin based regimens Metastatic CRC (EGFR expressing) in combination with irinotecan for irinotecan refractory patients erotinib TKI EGFR Second-line therapy in locally Oral (e.g., advanced or metastatic non-Small 150 mg daily TARCEVATM) cell lung cancer (NSCLC) Genentech, OSI First line, in combination with Pharmaceuticals gemcitabine in locally advanced or metastatic pancreatic cancer gefitinib TKI EGFR Monotherapy for the treatment of Oral (e.g., IRESSATM) patients with advanced or 250 mg daily AstraZeneca metastatic NSCLC who are benefiting or have benefited from gefitinib US 2011/0158983 A1 Jun. 30, 2011 53

-continued Drug (Trade name) Class Target Indication Dose lapatinib TKI EGFR/HER2 In combination with capecitabine Oral (e.g., for the treatment of patients with 1250 mg daily TYKERBTM) advanced or metastatic HER2 for 21 days GSK overexpressing breast cancer then 1 week who have received prior Off treatment with an anthracycline, a taxane, and trastuzumab panitumumab mAb EGFR Metastatic colorectal carcinoma Intravenous (e.g., (EGFR-expressing) after 6 mg/kg every VECTIBIXTM) treatment with fluoropyrimidine-, 14 days Amgen Oxaliplatin-, and irinotecan containing chemotherapy regimens

0578) Effect on Cancer tion), by combined use of beta-blockers and NSAIDs, can 0579. In alternative embodiments, compositions, uses and modulate a dysregulated neuroendocrine-immune system methods of the invention (including e.g., compositions com and its associated clinical manifestations of cachexia, thus prising the propranolol-etodolac-chemo drug combination), being beneficial for cancer patients. are used in the treatment or amelioration of (including the 0584. In alternative embodiments, compositions of the primary treatment or amelioration of) any cancer or disease or invention (including e.g., compositions comprising the pro conditions caused by dysfunctional cells. In alternative pranolol-etodolac-chemo drug combination), are used in the embodiments, compositions, uses and methods of the inven treatment oramelioration of (including the primary treatment tion are used prophylactically (as a preventative treatment). or amelioration of): 1) Acute Myeloid Leukemia; 2) Bladder 0580 While the invention is not limited by any particular Cancer (incl. Bladder Cancer, Upper Tract Tumors, Urothe mechanism of action: a composition of the invention (e.g., lial Carcinoma of the Prostate); 3) Bone Cancer (including comprising the propranolol-etodolac-chemo drug combina Chondrosarcoma, Ewing's Sarcoma, Osteosarcoma); 4) tion) can work by: Switching the tumor from a state of auto Breast Cancer (incl. Noninvasive, Invasive, Phyllodes Tumor, promotion (malignancy) to a state of wound healing, or Paget's Disease, Breast Cancer During Pregnancy); 5) Cen Switching the tumor from a developmental state to a normal tral Nervous System Cancers (incl. Adult Low-Grade Infil tissue regulated State. A composition or method of the inven trative Supratentorial Astrocytoma/Oligodendroglioma, tion also can ameliorate a cachexia, thereby allowing exten Adult Intracranial Ependymoma, Anaplastic Astrocytoma/ sion of the duration of treatment. While the invention is not Anaplastic Oligodendroglioma/Glioblastoma Multiforme, limited by any particular mechanism of action: a composition Limited (1-3) Metastatic Lesions, Multiple (>3) Metastatic or method of the invention also can Switch tumor-associated Lesions, Carcinomatous Lymphomatous Meningitis, Non cells from wound healing and developmental states to infec immunosuppressed Primary CNS Lymphoma, Metastatic tion and tissue maintenance states, this 'switching leading to Spine Tumors, Principles of Brain Tumor Therapy); 6) Cer further eradication of the tumor by the patient’s immune vical Cancer; 7) Chronic Myelogenous Leukemia; 8) Colon/ system. Rectal Cancer (incl. Colon Cancer, Rectal Cancer, Anal Car 0581. While the invention is not limited by any particular cinoma); 9) Esophageal Cancer; 10) Gastric Cancer; 11) mechanism of action: a composition or method of the inven Head and Neck Cancers (incl. Ethmoid Sinus Tumors, Max tion (e.g., comprising the propranolol-etodolac-chemo drug illary Sinus Tumors, Salivary Gland Tumors, Cancer of the combination) also can reduce catecholamine levels; an Lip, Cancer of the Oral Cavity, Cancer of the Oropharynx, increase in catecholamine levels can increase VEGF secretion Cancer of the Hypopharynx, Occult Primary, Cancer of the by human cancer cells and enhance tumor cell invasion. Cat Glottic Larynx, Cancer of the Supraglottic Larynx, Cancer of echolamine levels are reduced by beta adrenergic blockade. the Nasopharynx. Advanced Head and Neck Cancer); 12) 0582. While the invention is not limited by any particular Hepatobiliary Cancers (incl. Hepatocellular Carcinoma, mechanism of action: a composition of the invention (e.g., Gallbladder Cancer, Intrahepatic Cholangiocarcinoma, comprising the propranolol-etodolac-chemo drug combina Extrahepatic Cholangiocarcinoma); 13) Hodgkin Diseasef tion) also can have a direct impact on the cancer through its Lymphoma; 14) Kidney Cancer; 15) Melanoma; 16) Multiple NSAID, e.g., etodolac, component by regulating angiogen Myeloma (incl. Multiple Myeloma, Waldenström's Macro esis, inducing apoptosis, prevention of metastases, reprioriti globulinemia); 17) Myelodysplastic Syndromes: 18) Neu Zation of energy utilization, reactivation of the immune sys roendocrine Tumors (incl. Multiple Endocrine Neoplasia: tem, cancer chemoprevention, radiosensitivity and/or Type 1, Multiple Endocrine Neoplasia: Type 2, Carcinoid repression of catenin function (catenin is central to the inva Tumors, Islet Cell Tumors, Pheochromocytoma, Poorly Dif sive cellular phenotype). In one embodiment, the specific ferentiated/Small Cell/Atypical Lung Carcinoids); 19) Non NSAID etodolac may induce apoptosis, prevent metastases or Hodgkin's Lymphoma (incl. Chronic Lymphocytic Leuke act as a cytotoxic anticancer agent. mia/Small Lymphocytic Lymphoma, Follicular Lymphoma, 0583. While the invention is not limited by any particular Marginal Zone Lymphoma, Mantle Cell Lymphoma, Diffuse mechanism of action: a composition of the invention (e.g., Large B-Cell Lymphoma, Burkitt's Lymphoma, Lympho comprising the propranolol-etodolac-chemo drug combina blastic Lymphoma, AIDS-Related B-Cell Lymphoma); 20) US 2011/0158983 A1 Jun. 30, 2011 54

Non-Melanoma Skin Cancers(incl. Basal and Squamous Cell 0589. In alternative embodiments, a multi-ingredient kit Skin Cancers, Dermatofibrosarcoma Protuberans, Merkel of the invention may contain comprises two, three, four or five Cell Carcinoma); 21) Non-Small Cell Lung Cancer: 22) or more ingredients in approximately equimolar amounts. In Occult Primary; 23) Ovarian Cancer (incl. Epithelial Ovarian alternative embodiments, a multi-ingredient kit comprises Cancer, Borderline Epithelial Ovarian Cancer (Low Malig two, three, four or five or more ingredients that are not in nant Potential), Less Common Ovarian Histologies); 24) Pan equimolar amounts. In alternative embodiments, a multi-in creatic Adenocarcinoma; 25) Prostate Cancer; 26) Small Cell gredient kit comprises two, three, four or five or more ingre Lung Cancer (incl. Small Cell Lung Cancer, Lung Neuroen dients that are inapproximately equimolar amounts as well as docrine Tumors): 27) Soft Tissue Sarcoma (incl. Soft-tissue Extremity, Retroperitoneal, Intra-abdominal Sarcoma, Des one or more ingredients that are not in equimolar amounts. moid); 28) Testicular Cancer; 29) Thyroid Carcinoma (incl. 0590. In alternative embodiments, a multi-ingredient kit Nodule Evaluation, Papillary Carcinoma, Follicular Carci comprises two, three, four or five or more ingredients that are noma, Hirthle Cell Neoplasm, Medullary Carcinoma, Ana admixed. In alternative embodiments, a multi-ingredient kit plastic Carcinoma); and 30) Uterine Cancers (incl. Endome comprises two, three, four or five or more ingredients that are trial Cancer, Uterine Sarcoma). not admixed. In alternative embodiments, a multi-ingredient kit comprises two, three, four or five or more ingredients that Methods of Administration are partially admixed. In alternative embodiments, a multi ingredient kit comprises two, three, four or five or more 0585. This invention provides compositions (e.g., the ingredients that are at least partially admixed, as well as one exemplary combinations of drugs of the invention), e.g., phar or more ingredients that are not admixed. In alternative maceutical compositions, formulations, products of manu embodiments, an ingredient in a multi-ingredient kit of the facture, preparations and kits, that can be administered by invention can beformulated or manufactured in a liquid form, several routes, including intravenous, topical and oral, and the e.g., a form that can be administered orally or parenterally. methods for administering them. In separate embodiments, this invention provides forms of compositions, preparations 0591 An ingredient or ingredients (e.g., a drug or a thera and kits that can be administered by inhalation, infusion or peutic combination of drugs of this invention) in a multi injection, (e.g., intraperitoneal, intramuscular, Subcutaneous, ingredient kit of the invention can be formulated or manufac intra-aural, intra-articular, intra-mammary, etc.), topical tured in any delivery form, e.g., as capsules, tablets, powders, application (e.g., on areas. Such as eyes, ears, skin or on sprays, aerosols, pellets (e.g. for animal consumption), Sup afflictions such as wounds, burns, etc.), and by absorption positories, or creams and ointments. An ingredient or ingre through epithelial or mucocutaneous linings (e.g. vaginal and dients also can be formulated or manufactured in delivery other epithelial linings, gastrointestinal mucosa, etc.). Meth forms such as physiological (e.g., Saline) solutions Suitable ods are known for making the compositions of the invention for I.V. administration or other parenteral administration. (e.g., the pharmaceutical compositions, formulations, prod 0592 An ingredient or ingredients (e.g., a drug or a thera ucts of manufacture, preparations, kits and the like compris peutic combination of drugs of this invention) in a multi ing the therapeutic combinations of drugs of the invention) ingredient kit of the invention can be separated by physical that are suitable for each of these methods of administration compartmentalization; e.g. in separate compartments that are as well as other methods of administration that are know in part of said kit, where said kit is a multi-compartment kit. the art. Alternatively, separate compartments, e.g., as found in a 0586 For example, in alternative embodiments, this “blisterpack” type of packaging, may contain different ingre invention provides compositions, preparations and kits in dients (e.g., a therapeutic combination of drugs of this inven liquid forms that can be administered orally. The composi tion), as discussed below. In one embodiment, the composi tions, preparations and kits can be also prepared as capsules, tion or product of manufacture is contained in a gels, geltabs, tablets, powders, sprays, aerosols, pellets (e.g. multiparticulate and/or a solid dispersion formulation, e.g., as for animal consumption), Suppositories, or creams and oint described in, e.g., U.S. Patent App. Pub. No. 20080118560, ments. The compositions, preparations and kits can be also e.g., comprising a hydrophobic matrix former which is a prepared as physiological Solutions suitable for I.V. adminis water-insoluble, non-Swelling amphiphilic lipid; and a hydro tration or other parenteral administration. philic matrix former which is a meltable, water-soluble 0587. In alternative embodiments, this invention also pro excipient. vides all the possible combinations of component quantities 0593. In one embodiment, the composition or product of that are possible (e.g. the total of all the components does not manufacture is contained in tablets, pills, capsules, troches, Surpass 100% of the relevant total dosage compositions, and the like comprising any combination of a binder, e.g., as preparations and kits, and admixing or solubility limitations a starch, polyvinyl pyrrolidone, gum tragacanth or gelatin; a are not exceeded). filler, such as microcrystalline cellulose or lactose; a disinte 0588. In alternative embodiments, a multi-ingredient kit, grating agent, such as crospovidone, sodium starch glycolate, as provided herein (see e.g., section on packaging, below) corn starch, and the like; a lubricant, Such as magnesium comprises two, three, four or five or more ingredients in Stearate, Stearic acid, glyceryl behenate; a glidant, Such as approximately equal amounts. An amount may be deter colloidal silicon dioxide and talc, a Sweetening agent, such as mined, e.g. by mass or by weight or by molar amount. In Sucrose or saccharin, aspartame, acesulfame-K; and/or fla alternative embodiments, a multi-ingredient kit comprises Voring agent, such as peppermint, methyl salicylate, or two, three, four or five or more ingredients in unequal orange flavoring. When the dosage unit form is a capsule, it amounts. In alternative embodiments, a multi-ingredient kit also can comprise a liquid carrier, Such as a fatty oil. comprises two, three, four or five or more ingredients in 0594. In one aspect, a composition or product of manufac approximately equal amounts as well as one or more ingre ture of the invention comprises (or is contained or packaged dients that are not in unequal amounts. in) unit dosage formulations having a coating, e.g., a coat US 2011/0158983 A1 Jun. 30, 2011

comprising a Sugar, shellac, Sustained and/or other enteric Steroid Biochem. Mol. Biol. 58:611-617: Groning (1996) coating agents, or any pharmaceutically pure and/or nontoxic Pharmazie 51:337-341; Fotherby (1996) Contraception agents. 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; 0595. In one aspect, a composition or product of manufac Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. ture of the invention comprises (or is contained or packaged J. Clin. Pharmacol. 24:103-108. Details on techniques for in) unit dosage formulations, wherein each different com formulation and administration are well described in the sci pound of the composition or product of manufacture is con entific and patent literature, see, e.g., the latest edition of tained in a different layer of a pill, tablet or capsule, e.g., as Remington's Pharmaceutical Sciences, Maack Publishing described in U.S. Pat. No. 7,384,653, e.g., having an outer Co., Easton Pa. (“Remington's'). The state of the art allows base-soluble layer and an inner acid-soluble layer. the clinician to determine the dosage regimen for each indi 0596. In one aspect, a composition or product of manufac vidual patient, active agent and disease or condition treated. ture of the invention comprises (or is contained or packaged Guidelines provided for similar compositions used as phar in) unit dosage formulations, wherein each different com maceuticals can be used as guidance to determine the dosage pound of the composition or product of manufacture is con regiment, i.e., dose schedule and dosage levels, administered tained in a liquid or a gel of different viscosity, e.g., described practicing the methods of the invention are correct and appro in U.S. Patent App. Pub. No. 20050214223. priate. 0597. In one aspect, a composition or product of manufac 0602 Single or multiple administrations of formulations ture of the invention comprises (or is contained or packaged can be given depending on the dosage and frequency as in) unit dosage formulations having reduced abuse potential, required and tolerated by the patient. The formulations should e.g., as described in U.S. Patent App. Pub. No. 20040228802, provide a sufficient quantity of active agent to effectively e.g., comprising a bittering agent, a bright deterrent/indicator treat, prevent or ameliorate a conditions, diseases or symp dye, or a fine insoluble particulate matter. toms as described herein. For example, an exemplary phar 0598. In alternative embodiments, the invention provides maceutical formulation for oral administration is in a daily methods and compositions to treat, ameliorate, reduce, and/or amount of between about 0.1 to 0.5 to about 20, 50, 100 or improve a conditions, state and/or disease symptom. This 1000 or more ug per kilogram of body weight per day. In an invention further provides myelo-protective and/or cyto-pro alternative embodiment, dosages are from about 1 mg to tective therapies that are serviceable for treating, ameliorat about 4 mg per kg of body weight per patient per day are used. ing, reducing, and/or improving a condition, a state and/or a Lower dosages can be used, in contrast to administration disease symptom coincident with mucositis and/or present in orally, into the blood stream, into a body cavity or into a patient who experiences mucositis or in a patient who is lumen of an organ. Substantially higher dosages can be used expected to experience mucositis. in topical or oral administration or administering by powders, 0599 Dosaging spray or inhalation. Actual methods for preparing parenter 0600 The compositions (e.g., pharmaceuticals, formula ally or non-parenterally administrable formulations will be tions) of the invention can be administered for prophylactic known or apparent to those skilled. and/or therapeutic treatments. In therapeutic applications, 0603. In one aspect the therapeutic combinations of the compositions are administered to a Subject already suffering invention comprise formulations having the dosage of etod from a condition, infection or disease (e.g., cancer) in an olac ranges from about 200 mg to 400 mg a day, or, about 10, amount sufficient to cure, alleviate or partially arrest the 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85,90, 100, 150, 200, clinical manifestations of the condition (e.g., cachexia), 250, 300,350, 400, 450, 500, 600, 700, 800,900 or 1000 mg infection or disease and its complications (a “therapeutically or more. In alternative embodiments, the dosage of propra effective amount'). For example, in alternative embodiments, nolol can range from 10 to 320 mg per day based on heart rate compositions of the invention (e.g., pharmaceuticals) are and blood pressure of the individual; or, can be about 10, 15, administered in an amount Sufficient to treat, prevent and/or 20, 25, 30, 35, 40, 45, 50, 75, 80, 85,90, 100, 150, 200, 250, ameliorate normal, dysfunction (e.g., abnormally proliferat 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or ing) blood vessels, including endothelial and/or capillary cell more; wherein the invention includes all combinations of growth; including neovasculature related to (within, provid these exemplary dosages. In one aspect, the methods of the ing a blood Supply to) hyperplastic tissue, a granuloma or a invention comprise administration of these therapeutic com tumor. In alternative embodiments, compositions of the binations of the invention; wherein practicing the methods of invention (e.g., pharmaceuticals) are administered in an the invention can include use of any or all combinations of amount Sufficient to treat, prevent and/or ameliorate mucosi these exemplary dosages. tis and/or cachexia. The amount of composition, e.g., as a 0604 For example, therapeutic combinations of the inven pharmaceutical, adequate to accomplish this is defined as a tion can be packaged in dosages that match a chrono-dosing “therapeutically effective dose.” The dosage schedule and regimen to match an optimal dose for the time of day, or the amounts effective for this use, i.e., the "dosing regimen.” will day or month (as any therapeutic drug combination of the depend upon a variety of factors, including the stage of the invention can be applied once, twice, three or four times, or disease or condition, the severity of the disease or condition, more, a day or a week or a month, depending on the patient the general state of the patient's health, the patient's physical and the indication the for which the drugs are being admin status, age and the like. In calculating the dosage regimen for istered). a patient, the mode of administration also is taken into con 0605 For example, in one aspect the therapeutic combi sideration. nations of the invention are packaged in dosages that match a 0601 The dosage regimen also takes into consideration chrono-dosing regimen comprising: (a) in the AM. 20 mg pharmacokinetics parameters well known in the art, i.e., the propranolol. 200 mg etodolac, in the afternoon, 10 mg pro active agents’ rate of absorption, bioavailability, metabolism, pranolol, 200 mg etodolac; in the PM, 10 mg propranolol, 400 clearance, and the like (see, e.g., Hidalgo-Aragones (1996).J. mg etodolac; (b) in the AM 40 mg propranolol, 200 mg US 2011/0158983 A1 Jun. 30, 2011 56 etodolac, in the afternoon 20 mg propranolol. 200 mg etod etodolac in the morning and higher levels of etodolacat night. olac; in the evening, 20 mg propranolol, 400 mg etodolac.; (c) For each of the above exemplary embodiments, there would in the AM 80 mg propranolol, 200 mg etodolac; in the after be multiple dose levels; for example: noon 40 mg propranolol. 200 mg etodolac, in the evening 40 mg, etodolac, or (d) a dose escalation comprising a regimen EXAMPLE 1. of (a) to (b) to (c); or any equivalents. Level Dose Propranolol and Etodolac 0606 For example, in one aspect the drugs are packaged in dosages that match a chrono-dosing regimen comprising: 0615 0607 Start: AM. 20 mg propranolol, 200 mg etodolac: afternoon, 10 mg propranolol, 200 mg etodolac: PM 5 mg propranolol. 400 mg etodolac, Propranolol Etodolac 0608 Dose Escalation 1: AM 40 mg propranolol. 200 mg AM 60 mg LA 1200 mg XR Noon etodolac, afternoon 20 mg propranolol. 200 mg etodolac, PM evening, 10 mg propranolol, 400 mg etodolac, Bed

0609 Dose escalation 2: AM 80 mg propranolol, 200 mg R = immediate release etodolac, afternoon 40 mg propranolol. 200 mg etodolac, LA = extended release formulation (LA, XL, XR, etc. . . ) evening 20 mg, etodolac. 0610 For example, in one aspect of the invention the drugs are formulated for administration once a day, b.i.d.ort.i.d., or EXAMPLE 2 four times a day, or more, or for weekly, or biweekly, or Level Dose Propranolol and Etodolac monthly administration (in any combination, as described herein, particularly to accommodate chronodosaging). 0616 0611. In one aspect of the invention the drugs are dosaged as set forth in any one of exemplary ingredient combinations 1 to 90. Propranolol Etodolac 0612. In one aspect of the therapeutic combination of the AM 20 mg IR 200 mg IR invention the drugs are formulated for administration intra Noon 20 mg IR 200 mg IR venously, topically, orally, by inhalation, by infusion, by PM 20 mg IR 200 mg IR injection, by inhalation, intraperitoneally, intramuscularly, Bed 20 mg IR 200 mg IR Subcutaneously, intra-aurally, for intra-articular administra R = immediate release tion, for intra-mammary administration, for topical adminis LA = extended release formulation (LA, XL, XR, etc. . . ) tration or for absorption through epithelial or mucocutaneous linings. EXAMPLE 3 0613. In one aspect the therapeutic combinations of the invention, including the compositions and products of manu High Propranolol AM, Level Etodolac Concentra facture of the invention, further comprise instructions for use, tions e.g., in the treatment of cachexia, the treatment of anorexia or 0617 anorexia-cachexia, and stress or anxiety related thereto. In one aspect the cachexia is defined as at least two of the symptoms selected from the group consisting of: 1) a hyper inflammatory state, 2) altered hormone levels and cytokine Propranolol Etodolac levels; 3) decreased heart rate variability; 4) weight loss, and AM 20 mg IR + 60 mg 1200 mg XR 5) increased heart rate, wherein optionally the increased heart LA rate is having a Sustained elevated heart rate of at least about Noon 6 bpm, or, the cachexia is defined by an individual having at PM least a sustained elevated heart rate of at least about 6 bpm and Bed weight loss. 0.614. In one embodiment, an extended release formula tion (e.g., of propranolol and/or etodolac) is used (e.g., both EXAMPLE 4 extended release etodolac and propranolol can be used). In High Propranolol AM, Increasing Etodolac Concen one embodiment, a simple dosage regimen is used: an trations extended release formulation used once a day; e.g., an extended release propranolol and extended release etodolac 0618 given once/day. In one embodiment, a more complex dosage regimen is used: for example, high dosage of one drug in the combination in the morning with progressively lower dosages Propranolol Etodolac administered during the day; for example, an exemplary dos age regimen comprises administration of high propranolol in AM 40 mg IR 200 mg IR Noon 20 mg IR 200 mg IR the morning and lower at night, but with steady levels of PM 10 mg IR 200 mg IR etodolac throughout the day. In one embodiment, high dos Bed 10 mg IR 200 mg IR ages of propranolol are given in the morning and lower dos ages of propranolol are given at night, with low dosages of US 2011/0158983 A1 Jun. 30, 2011 57

EXAMPLE 5 34/myeloSupression (including neutropenia); 35/nausea; 36/nephrotoxicity; 37/neutropenia; 38/oral mucositis; High Propranolol AM, Increasing Etodolac Concen 39/ototoxicity; 40/pain; 41/peripheral neuropathy; 42/re trations duced physical activity; 43/toxicity (including cyto-toxicity) from any chemotherapy or radiation or Surgical trauma; 0619 44/wasting; 45/worrying; 4.6/stress or anxiety related to any of the above. 0623. In alternative embodiment, the packaging is a criti Propranolol Etodolac cal component for the Success of the drug treatment because AM 20 mg IR + 60 mg 1200 mg XR the therapeutic combination of drugs of the invention cannot LA be successfully administered to a stressed, challenged or non Noon compliant patient population in a conventional formal or for PM 200 mg IR mulation combination. However, in alternative embodiments Bed a stressed, challenged or non-compliant patient population can be properly administered a combination of drugs by using 0620. All of the above can have dose increased 50% and compositions of this invention, e.g., therapeutic combination 100%. Alternatively, the combinations can be used at a lower of drugs of the invention packaged for usage compliance by a (10% less, 20% less, 30% less, 40% less, 50% less, or 60% or stressed, challenged or non-compliant patient population. more less) dosage. 0624. In alternative embodiments, the stressed, chal 0621 For example, exemplary dosages that can be used lenged or non-compliant patient population comprises a can when practicing the compositions and/or methods of this cer patient population; or a patient population having mild or invention include: severe mental retardation, slow cognition, dementia, senility, Alzheimer's disease, traumatic brain injury, chemical brain damage or a mental disease; or post-traumatic stress disorder, traumatic war neurosis, post-traumatic stress syndrome Oncology Drug Standard Dose Low Dose (PTSS) or a physical disability or blindness. The mental dis Sorafenib (NEXAVARTM) 800 mg bid 400 mg qd ease can be a dissociative disorder, an obsessive-compulsive Sunitinib (e.g., 50 mg qd 37.5 mg or 25 mg disorder, a delusional disorder, a schizophrenia, a mania, a SUTENT) TM qd erlotinib 100 or 150 mg qd 75 or 100 mg qd panic disorder, depression, dyslexia or a learning disability. (e.g., TARCEVATM) 0625. In alternative embodiments, each member of the imatinib 400 mg qd or 800 mg 200 mg to 400 mg combination of ingredients is manufactured in a separate (e.g., GLEEVECTM) bid qd lapatinib 1250 mg qd 750 mg qd package, kit or container; or, all or a Subset of the combina (e.g., TYKERBTM) tions of ingredients are manufactured in a separate package or bevacizumab (e.g., 5-15 mg/kg IV 5-10 mg/kg IV container. In alternative aspects, the package, kit or container AVASTINTM) comprises ablisterpackage, a clamshell, a tray, a shrink wrap trastuzumab (e.g., 4-8 mg/kg IV 4 mg/kg IV and the like. HERCEPTINTM) cetuximab (e.g., 400 mg/m2 IV 200 mg/m2 IV 0626. In alternative embodiments, the invention provides ERBITUXTM) ablister package, a clamshell, a tray or a shrink wrap; and in separate exemplifications, said blister package, clamshell, tray or shrink wrap may comprise every possible combination Packaging Combinations of Compounds of the Invention and permutation of two members, three members, four mem bers, five members, etc and up to and including at least 100 0622. The invention provides compositions, including (one hundred) members selected from any of Group A, Group preparations, formulations and/or kits, comprising combina B. Group C, and Group D (as shown in Table 1), where: of tions of ingredients (e.g., the combinations of drugs of the Group A comprises or consists of, or Group A comprises use invention), for use, e.g., as therapies for treating, preventing, ofor consists of use of geranylgeranyl compounds, including ameliorating or improving conditions, states, disease symp for example, geranylgeranyl acetone (GGA) and analogs of toms, and unwanted side effects including e.g.: 1/anger; geranylgeranyl acetone (GGA); Group B comprises use of or 2/anemia; 3/anorexia; 4/anorexia-cachexia; 5/anxiety; 6/atro consists of use of Angiotensin Converting Enzyme Inhibitors phy (e.g. muscle atrophy): 7/cachexia, including cancer (ACE Inhibitors or ACE-Is); Group C comprises use of or cachexia; 8/cancer and any conditions caused by dysfunc consists of use of Angiotensin Receptor Blockers (ARBs); tional cells; 9/cardiotoxicity; 10/cognitive impairment; Group D comprises use of or consists of use of Peroxisome 11/cytoprotection deficiency: 12/depression: 13/despair; Proliferator-Activated Receptor (PPAR) ligands, e.g. ago 14/delayed emesis; 15/diarrhea: 16/difficulties with activities nists, such as PPAR alpha agonists, PPARgamma agonists, of daily living: 17/discomfort; 18/emesis; 19/erectile or PPAR alpha/gamma dual agonists, and other PPAR ligands sexual dysfunction or sexual disinterest, 20/excessive sym (e.g. PPAR delta ligands); Group E comprises use of or con pathoneural drive; 2 1/fatigue; 22/febrile neutropenia; sists of use of non-steroidal anti-inflammatory drugs 23/frustration; 24/hair loss; 25/heart failure: 26/infection (in (NSAIDs); Group F consists of NCCN therapies; Group G different aspects, infection types provided herein include bac comprises use of or consists of use of TNF inhibitors, e.g. terial, viral, mycobacterium, yeast and protozoan infections, pentoxifylline; Group H comprises use of or consists of use of and any combination thereof); 27/inflammation; 28/intoler deferrioxamine; Group I comprises polyunsaturated fatty ance to a medical therapy; 29/lack of appetite; 30/lack of acids, such as e.g. omega-3 fatty acids, including for example energy; 31/lack or motivation; 32/mucositis (e.g. esophageal eicosapentaenoic acid (EPA), and docosahexaenoic acid or intestinal mucositis); 33/myeloprotection deficiency; (DHA); Group J comprises C.-difluoromethylornithine; US 2011/0158983 A1 Jun. 30, 2011

Group K comprises superoxide dismutase (SOD) and similar 0630. In one aspect, blister packaging comprises at least antioxidant compounds; Group L comprises activators of heat two, three, four or five or more components (e.g., is a multi shock response; and Group M comprises drugs that reduce ingredient combination of drugs of the invention): a thermo the inflammatory/progressive tissue damage response. formed “blister” which houses the product (e.g., a pharma ceutical combination of the invention), and then a “blister 0627. In alternative embodiments, the package, kit or con card” that is a printed card with an adhesive coating on the tainer comprises a “blister package' (also called a blister front Surface. During the assembly process, the blister com pack, or bubble pack). In one aspect, the blister package is ponent, which is most commonly made out of PVC, can be made up of two separate elements: a transparent plastic cavity attached to the blister card using a blister machine. This shaped to the product and its blister board backing. These two machine introduces heat to the flange area of the blister which elements are then joined together with a heat sealing process activates the glue on the card in that specific area and ulti which allows the product to be hung or displayed. Exemplary mately secures the PVG blister to the printed blister card. The types of “blister packages” include: Face seal blister pack thermoformed PVG blister and the printed blister card can be ages, gang run blister packages, mockblister packages, inter as Small or as large as you would like, but there are limitations active blister packages, slide blister packages. and cost considerations in going to an oversized blister card. 0628. In alternative embodiments, blister packs, clam Conventional blister packs can also be sealed (e.g., using an shells or trays or any equivalent form of packaging used for AERGO 8 DUOTM, SCA Consumer Packaging, Inc., DeKalb goods is used to practice this invention, e.g., to package and Ill.) using regular heat seal tooling. This alternative aspect, deliver the therapeutic combination of drugs of this invention. using heat seal tooling, can seal common types of thermo In alternative embodiments, the invention provides for blister formed packaging. packs, clamshells or trays comprising a composition; e.g., a 0631. In one aspect, a composition or product of manufac multi-ingredient combination of drugs of the invention, or a ture of the invention comprises (or is contained or packaged combination of active ingredients of the invention. In alter in) ablister pack, wherein the combination of drugs is formu native embodiments, blisterpacks, clamshells ortrays used to lated for unit dosage administration to an individual in need practice this invention are designed to be non-reclosable, so thereof at the same time, and each unit dosage is contained consumers can tell if a package has already opened. In alter within one blister in the blister pack. In one embodiment, the native aspects, these embodiments are used to package drugs composition or product of manufacture is contained in a where product tampering is a consideration, Such as the pub child-resistant blister card package, e.g., as in U.S. Pat. No. lic sale of pharmaceuticals, including the therapeutic combi 7.395,928, e.g., having a plurality of unit package regions for nations of this invention. In alternative aspects, these embodi enclosing one unit dosage form, each comprising a cavity and ments are used to package drugs (e.g., therapeutic a closure sheet to seal the cavity. In one embodiment, once a combinations of this invention) where child-resistant tamper unit package region is detached, the corner defined by lines of ing is desired or required. In one aspect, a blister pack of the weakening with perforations can be detached to expose an invention comprises a moulded PVC base, with raised areas unsealed area and easily access the content of each unit pack (the “blisters') to contain the tablets, pills, etc. comprising the age region. combinations of the invention, covered by a foil laminate. 0632. In one embodiment, a composition or product of Tablets, pills, etc. can be removed from the pack either by manufacture of the invention comprises (or is contained or peeling the foil back or by pushing the blister to force the packaged in) a packages, e.g., as in U.S. Patent App. Pub. No. tablet to break the foil. In one aspect, a specialized form of a 20060138016, e.g., having a base web comprising a poly blister pack that is a strip pack is used. In one aspect, in the meric film or sheet having at least one recess containing a United Kingdom, blister packs adhere to British Standard packaged item, i.e., the composition or product of manufac 8404. ture of the invention, and a sealing web, which can be sealed 0629. In one aspect, a blister pack of the invention also to a base web and covering the recess. The sealing web can comprises a method of packaging where the compositions have a strength which Substantially prevents the packaged comprising combinations of ingredients of the invention are item from being pushed through it, unless on applying suffi contained in-between a card and a clear PVC. The PVC can be cient force to the recess in the base web. A portion of the transparent so the item (pill, tablet, geltab, etc.) can be seen package where the base web is sealed to the sealing web can and examined easily; and in one aspect, can be vacuum have multiple lines of weakness positioned so that the portion formed around a mould so it can contain the item Snugly and can be folded towards a portion of the sealing web, and a have room to be opened upon purchase. In one aspect, the card corner of the package can be used to puncture the sealing web is brightly colored and designed depending on the item (pill, so that the packaged item can then be pushed through the tablet, gel tab, etc.) inside, and the PVC is affixed to the card sealing web. using pre-formed tabs where the adhesive is placed. The 0633. In one embodiment, the composition or product of adhesive can be strong enough so that the pack may hang on manufacture is contained in a child-resistant blister card a peg, but weak enough so that this way one can tear open the package, e.g., as in U.S. Patent App. Pub. No. 20020008046, join and access the item. Sometimes with large items or e.g., a package having a non-through score line in an exposed multiple enclosed pills, tablets, geltabs, etc., the card has a surface of a blister sheet of the blister package. The non perforated window for access. In one aspect, more secure through score line can extend from one edge of an individual blister packs, e.g., for items such as pills, tablets, geltabs, etc. blister unit to an opposite or adjacent edge, e.g., across the of the invention are used, and they can comprise of two corner of the blister unit. When the blister unit is angulated or vacuum-formed PVC sheets meshed together at the edges, flexed back at the non-through score line, the blister sheet can with the informative card inside. These can be hard to open by fracture. The smaller portion of the fractured blister sheet, hand, so a pair of Scissors or a sharp knife may be required to still bonded to a backing sheet, can act as a tab for peeling the open. backing sheet from the blister sheet exposing the blister con US 2011/0158983 A1 Jun. 30, 2011 59 tents. Camouflage lines on the blister sheet can help hide the 0638. The following examples are offered to illustrate, but score line, thereby rendering the package highly child-resis not to limit the claimed invention. tant. 0634. In one embodiment, the composition or product of EXAMPLES manufacture is contained in a child-resistant blister card package, e.g., as in U.S. Pat. No. 6,830,153, e.g., a child Example: Therapy for Cellular Self-Defense Enhancement. resistant blister pack for unit dosage forms having a blister 0639. An exemplary therapy of this invention comprises film sheet with depressions therein, where unit dosage forms use of or consists of use of a combination of compounds are contained within the depressions and a lidding sheet over (ingredients); e.g., as in one embodiment, comprising or con lies the depressions, which is secured to a film sheet So as to sisting of drugs, that will enhance the ability of a cell to seal the unit dosage forms within the depressions. A network defend against stress-induced damage and trauma, and this of lines of weakness in the pack can define a plurality of “stress-defense enhancement' is achieved through the acti dosage units. Each dosage unit can include one of said dosage vation of a “heat shock response' (including the production of forms and a peel region where part of the lidding sheet is not heat shock proteins) and through increasing a cells’ ability to secured to the blister film sheet. Each peel region can be process (and thus defend against and/or tolerate) reactive disposed adjacent a respective one of the lines of weakness oxygen species; this 'stress-defense enhancement may also 0635. In one embodiment, the composition or product of beachieved using other defense systems prior to or during, or manufacture is contained in a package as described in, e.g., after, chemotherapy. U.S. Pat. No. 5,046,618, e.g., a child-resistant blister package 0640. Upon start of chemotherapy or radiation therapy, wherein each individual package is defined by lines of weak further tissue protection (and an aid for recovery) may be ening terminating short of the edge of the blisterpackage and achieved by administering a combination of compounds of is provided with a tear strip defined by an additional line of this invention, thereby reducing excessive or unwanted lym weakening. After removal of the tear Strip an unsealed corner phocyte tracking that can lead to excess inflammation, as well region is exposed, which can be grasped and pulled allowing as progressive and self-propagating tissue damage. the separation of the closure sheet from the container sheet and the access to the formulation dosage. Example: Pre-Chemotherapy and Pre-Radiation Therapy. 0636. In one embodiment, the composition or product of manufacture is contained in a package as described in, e.g., 0641 An exemplary therapy of this invention comprises U.S. Pat. No. 5,557,505, e.g., a blister card package with cut use of or consists of use of a combination of compounds out areas exposing an area of the closure sheet at the inter (ingredients); e.g., as in one embodiment, comprising or con section of the lines of weakening. After detachment of one sisting of drugs, that may be administered prior to, or at about individual dosage blister the area of exposed closure sheet the same time as, or at the same time as, or after, or a combi forms a finger tab that when pulled separates the closure sheet nation thereof a therapy (Such as a drug therapy, chemo from the container sheet allowing access to the content of the therapy and/or radiation therapy that causes mucositis) that blister cavity. causes an unwanted side effect, Such as an oral or a digestive 0637. In one embodiment, the compositions and methods mucositis. In one aspect, the combination of compounds (in of the invention are formulated for, packaged for use by, gredients). Such as drugs, of the invention activates a heat and/or are directed to a patient population where drug regi shock and/or other protective response in a cell and/or in an men compliance can be problematic, e.g., a stressed, chal individual (e.g., a patient). In one aspect, a therapy of the lenged or non-compliant patient population, e.g., a cancer invention can be administered in a manner that is timed opti patient population, a pediatric or geriatric population, or a mally and/or timed to achieve a prophylactic benefit in cell mentally compromised patient population, which in various and/or in an individual (e.g., a patient). embodiments includes patients having mild or severe mental 0642 An exemplary therapy of this invention is adminis retardation, slow cognition, dementia, senility, Alzheimer's tered at least two days prior to start of mucositis-causing drug disease, traumatic brain injury, chemical brain damage, men or cancer therapy (Such as chemotherapy and/or radiation tal diseases (e.g., dissociative disorder, obsessive-compulsive therapy that causes mucositis); in an alternative embodiment, disorder, delusional disorder, Schizophrenia, mania, panic a therapy of this invention may be discontinued at about 6 disorder, depression, dyslexia, any learning disability and the hours prior to a mucositis-causing chemotherapy or a mucosi like) post-traumatic stress disorder, traumatic war neurosis, tis-causing radiation therapy. post-traumatic stress syndrome (PTSS), physical disability Example: Exemplary Combinations of Ingredients in a (e.g., blindness) and the like. It is important to minimize the Therapy of this Invention are Exemplified by Ingredients that frequency and number of medications a patient must take. can Activate a Cell's Heat Shock Response. Patients who are required to take a medication only once or 0643 An exemplary therapy of this invention comprises is twice a day will have much higher compliance compared to a a combination of ingredients that can activate a heat shock those who require medication of multiple pills three or more response in a cell including: geranylgeranylacetone or ger times a day. Thus, in one embodiment, the invention provides nate, Zinc, tin, salicylates, dexamethasone, cocaine, nicotine, therapeutic combinations, formulations, packaging and the alpha-adrenergic agonist, ppar-gamma agonist, biomolecu like to increase patient compliance with their needed drug lar-geldanamycin, cyclopentanone, prostanoids enprostil, regimen (the frequency and number of medications an indi paracetamol, ketotiphen, levamisole, diazepam, bromocrip vidual must take); for example, in one aspect, a therapeutic tine, and dopamine. combination of the invention is formulated and/or packaged Example: Exemplary Combinations of Ingredients in a for accurate and timely patient compliance, e.g., including Therapy of this Invention are Exemplified by Ingredients that once a day dosaging, multiple dosaging, or chrono-dosing as can Reduce a Cell's Inflammatory/Progressive Tissue Dam described herein. age Response. US 2011/0158983 A1 Jun. 30, 2011 60

0644 An exemplary therapy of this invention comprises is 0650. In the ITT population the change in LBM at Week 12 a combination of ingredients that can reduce an inflamma in Group B was again of 3.63.56 kg and Group Chad again tory/progressive tissue damage response in a cell, including: of 3.4+6.25. In contrast Group A showed a loss of 4.4+4.03 kg an ACE inhibitor, an ARB, a phenylbutyrate or a PPAR (p=0.0313). gamma (insulin sensitizer), and/or probucol, calcitriol an 0651 Similar positive trends in both body weight and NSAID. functional measures (as assessed by grip strength) were also Example: Exemplary Therapy of this Invention Using seen in the treatment Groups (B and C) but not in the control VT-212TM Group (A). However, these improvements did not reach sta tistical significance. Also, the results from the exploratory 0645. In one embodiment, the invention provides a treat analyses including QoI (CMSAS) assessments, while being ment for mucositis, such as an oral or a digestive mucositis, inconclusive, primarily due to the variability of the data, are comprising or consisting of a combination of Vicus Thera Suggestive of positive efficacy trends. peutics (Morristown N.J.) product VT-212TM, which is GGA 0652 Taken together, it appears that the VT-122 regimen and etodolac. In one aspect, the drug combination comprises is effective in treating cachexia (as assessed by increase in or consists of VT-212TM and/or VT-211TM, which are used to LBM and Supported by changes in other parameters including target the initial stage of a maladaptive response to prevent, weight loss and functional measures) in patients with Stage delay, and/or reduce the severity of ulceration that is often IV NSCLC. seen about 7 to 10 days after mucotoxic therapies. 0653. In addition, it was reported by the investigators that 0646 VT-212, i.e. GGA and etodolac, was administered to disease progression was stopped in Some patients, in 2 40 patients who had colorectal cancer and were scheduled to patients there was reduction of liver metastases and in 1 receive a chemotherapy (5-FU or 5-fluorouracil). Investiga patient there was complete disappearance of brain tors observed a reduction in mucositis. metaStaSeS. Example: Exemplary Therapy of this Invention Using 0654) A number of aspects of the invention have been VT-122TM described. Nevertheless, it will be understood that various 0647. A randomized, open label, controlled, multi dose modifications may be made without departing from the spirit study was conducted using a propranolol-etodolac drug com and scope of the invention. Accordingly, other aspects are bination (specifically, VT-122TM an oral, multi-targeted, within the scope of the following claims. chrono-modulated, fixed dose combination of propranolol and etodolac) for stage IV non-small cell lung cancer 1. A therapeutic combination of drugs comprising or con (NSCLC) subjects with cachexia who had failed prior che sisting of motherapy, and were not receiving active therapy. Subjects meeting protocol defined eligibility criteria received a a combination of at least two contains; chrono-dosed administration of propranolol and etodolac in (a) wherein the at least two compounds comprise or consist divided daily doses for one week to assess their ability to of: (i) a geranylgeranyl acetone (GAA) or an analog of tolerate these two drugs administered simultaneously. Those geranylgeranyl acetone or equivalent thereof, and, (ii) an Subjects who tolerated this simultaneous administration of angiotensin-converting enzyme inhibitor (ACE inhibi propranolol and etodolac were randomized in parallel into tor); one of the following three groups: nutritional control (arm A) (b) the therapeutic combination of drugs of (a), wherein the or propranolol with low (arm B) or high (arm C) doses of GGA comprises a SELBEXTM: etodolac. (c) the therapeutic combination of drugs of (a), wherein the 0648. A statistically significant difference was observed in ACE inhibitor comprises a captopril; the “intention to treat” (“ITT'; including all subjects who (d) the therapeutic combination of drugs of (a), wherein the received at least one dose of VT-122TM) patient population, GGA comprises a SELEBEXTM and the ACE inhibitor (Last Observation Carried Forward) in the proportion of sub comprises a captopril; jects who responded with a clinically meaningful improve (e) the therapeutic combination of drugs of (c) or (d), ment of 25% in lean body mass at week 6, Week 9 and Week wherein the captopril comprises a CAPOTINTM: 12 (Group A, n=0/12: Group B, n=7/12, p=0.0191: Group C, (f) wherein the at least two compounds comprise or consist n=5/12, p=0.0174; combined treatment group, n=12/24, p=0. of a VT-211TM; 0061). A favorable trend in response rates between Group B (g) the therapeutic combination of drugs of any of (a) to (f), and Group C vs. Group A was also seen at week 4: however, formulated and/or dosaged for the treatment of mucosi this difference did not achieve statistical significance. tis; or 0649. A statistically significant difference was observed in (h) the therapeutic combination of drugs of(g), wherein the the Efficacy Evaluable population (all subjects who were mucositis comprises an oral mucositis; a digestive randomized into the study, remained in the study and were at mucositis; an esophageal mucositis and/or an intestinal least 80% compliant with study medication for a minimum of mucositis; 4 weeks, and who do not have any major protocol deviations) (i) the therapeutic combination of drugs of any of (a) to (h), in the proportion of subjects who responded with a clinically formulated and/or dosaged for use with a Surgery, a meaningful improvement of 25% in lean body mass at Week chemotherapy and/or an anti-cancer therapy: 6, Week 9, and Week 12 (Group A, n=0/6: Group B, n=6/7, (j) the therapeutic combination of drugs of any of (a) to (f), p=0.0048; Group C, n=4/5, p=0.1161; combined, n=10/12, formulated and/or dosaged to treat, ameliorate, dimin p=0.0058). At 4 weeks there was a clinically significant dif ish, improve and/or inhibit unwanted side effects and/or ference between Group A and Group C, and strong trend but disease state symptoms associated with or caused by not statistical significance between Group A and Group C or cancer, anti-cancer therapy, radiation, radiation therapy the combined treatment groups. or chemoradiation; US 2011/0158983 A1 Jun. 30, 2011

(k) the therapeutic combination of drugs of any of (a) to (f). nabumetone, a naproxen, an oxaprozin, a piroXicam, a formulated and/or dosaged to treat, ameliorate, dimin Salsalate, a Sulindac, a tolmetin, a COX-2-selective ish, improve and/or inhibit unwanted side effects and/or inhibitor or a combination thereof; disease state symptoms associated with or caused by (d) the therapeutic combination of (c), wherein the COX anemia; cognitive impairment; cytoprotection defi 2-selective inhibitor comprises a celecoxib, a rofecoxib, ciency; depression or despair; difficulties with activities an etoricoxib, a Valdecoxib, a parecoxib, a meloxicam or of daily living, discomfort, emesis; excessive sympatho a lumiracoxib; neural drive; fatigue; a neutropenia or a febrile neutro (e) the therapeutic combination of (b), wherein the wherein penia; frustration; hair loss; heart failure; an infection, a the propranolol is INDERALTM, AVLOCARDYLTM, bacterial infection; an inflammation; intolerance to a DERALINTM, DOCITONTM, INDERALICITM, INNO medical therapy; lack of appetite; lack of energy; lack of PRAN XLTM, or SUMIALTM; motivation; myeloprotection deficiency; rash; pain; (f) the therapeutic combination of (c), wherein the wherein reduced physical activity; wasting; worrying; pruritis; the etodolac is LODINETM, LODINE SRTM or ECCOX Xerostomia; cardiotoxicity; ototoxicity; nephrotoxicity; OLACTM; or the celecoxib is CELEBREXTM or CEL and/or peripheral neuropathy; and/or stress or anxiety EBRATM; or the rofecoxib is VIOXXTM, CEOXXTM or related to any of the above: CEEOXXTM: or the etoricoxib is ARCOXIATM, (1) the therapeutic combination of drugs of any of (a) to (l), ALGIXTM or TAUXIBTM; or the valdecoxib is BEX wherein the GGA or the analog or GGA is formulated TRATM; the parecoxib is DYNASTATTM; or the for a dosage regimen of between about 0.10 mg to about naproxen is XENOBIDTM, ALEVETM, ANAPROXTM, 20.00gm per day, or between about 30 mg to 3 gm per MIRANAXTM, NAPROGESICTM, NAPROSYNTM, day; NAPRELANTM, PROXENTM or SYNFLEXTM: or the nabumetone is RELAFENTM, RELIFEXTM or GAMB (m) the therapeutic combination of drugs of any of (a) to (l), ARANTM: or the diclofenac is FLECTOR PATCHTM, wherein the ACE inhibitor is formulated for a dosage VOLTARENTM, VOLTAROLTM, DICLONTM, regimen of between about 0.10 mg to about 10.00gmper DICLOFLEX DIFENTM, DIFENETM, CATAFLAMTM, day, or between about 10 mg to 450 mg per day; PENNSAIDTM, PANAMORTM, RHUMALGANTM, (n) the therapeutic combination of drugs of any of (a) to MODIFENACTM, ABITRENTM, OLFENTM, VOVE (m), wherein the compounds are manufactured in the RANTM, ARTHROTECTM, DEDOLORTM, DEFLA form of a package, a kit, a container, ablister package, a MATTM, VETAGESICTM or ZOLTEROLTM; clamshell, a tray and/or a shrink wrap; or (g) the therapeutic combination of (a), wherein the cancer (o) the therapeutic combination of drugs of any of (a) to (n), drug or therapeutic agent for the treatment of a cancer wherein each compound of the therapeutic combination comprises or consists of is independently formulated as a tablet, a pill, a lozenge, (i) a monoclonal antibody, a peptide, a synthetic a capsule, a caplet, a patch, a spray, an inhalant, a gel, a polypeptide or peptidomimetic, a nucleic acid, a Syn geltab, a nanosuspension, a nanoparticle, a microgel thetic nucleic acid, a lipid, a carbohydrate and/or a and/or a pellet, and the tablet, pill, lozenge, capsule, gel, Small molecule: geltab, nanosuspension, nanoparticle, microgel and/or a (ii) a Sorafenib or equivalent, or a NEXAVARTM; a Suni pellet. tinib or equivalent, or SUTENTTM; an erlotinib or 2. A therapeutic combination comprising or consisting of equivalent, or TARCEV ATM; an imatinib or equiva (a) at least one member of a first group, at least one member lent, or GLEEVECTM: a lapatinib or equivalent, or of a second group, and at least one member of a third TYKERBTM: a bevacizumab or equivalent, or AVAS grOup, TINTM: a trastuzumab or equivalent, or HERCEP wherein members of the first group are selected from the TINTM: a cetuximab or equivalent, or ERBITUXTM: a group consisting of beta adrenergic receptor antagonists bevacizumab or equivalent, or AVASTINTM or BIBW (beta blockers), 2992; a gefitinib or equivalent, or IRESSATM; a ranibizumab or equivalent, or LUCENTISTM; a wherein members of the second group are selected from pegaptainib or equivalent, or MACUGENTM: a dasat the group consisting of non-steroidal anti-inflammatory inib or equivalent, or BMS-354825TM; a Sunitinib or drugs (NSAID), equivalent, or SUTENTTM; a pazopanib or equivalent; wherein members of the second group are selected from a nilotinib or equivalent, or TASIGNATM; a panitu the group consisting of a cancer drug or a therapeutic mumab or equivalent, or VECTIB IXTM: a bandetinib agent for the treatment of a cancer, or equivalent; a brivanib or equivalent, or E7080TM; a (b) the therapeutic combination of (a), wherein the beta thalidomide or equivalent, or THALOMIDTM; lenali adrenergic receptor antagonist (beta blocker) comprises domide or equivalent, or REVLIMIDTM; A bort or consists of an atenolol, a nadolol, a metoprolol, a ezomib or equivalent, or VELCADETM; disulfiram or propranolol, a carteolol, a carvedolol, a labetalol, an equivalent, or ANTABUSETM or ANTABUSTM; or an oXprenolol, a penbutolol, a pindolol, a Sotalol, a timolol epigallocatechin gallate (EGCG) or equivalent; a or a combination thereof; demecolcine, an etoglucid or elsamitrucin, a (c) the therapeutic combination of (a) or (b), wherein the lonidamine, a lucanthone, a mitotane or a mitogua non-steroidal anti-inflammatory drug or drugs (NSAID) Zone or equivalent; or any combination thereof; comprise or consist of an aspirin, a diclofenac, a (iii) a protein kinase inhibitor or a histone deacetylase diflunisal, an etodolac, a fenoprofen, a flurbiprofen, an inhibitor; wherein optionally the protein kinase ibuprofen, an indomethacin, a ketoprofen; a ketorolac, a inhibitor comprises or consists of a tyrosine kinase meclofenamate, a mefenamic acid, a meloxicam, a inhibitor or a serine/threonine kinase inhibitor; or the US 2011/0158983 A1 Jun. 30, 2011 62

histone deacetylase inhibitor comprises or consists of (x) (1) a matrix metalloproteinase (MMP) inhibitor; (2) a vorinostat (rINN) or ZOLINZATM, or suberoylanil an mTOR (mammalian target of rapamycin) inhibitor, ide hydroxamic acid (SAHA); or (3) an mTOR inhibitor comprising or consisting of (iv) an angiogenesis inhibitor; wherein optionally the angiogenesis inhibitor comprises or consists of a vas a temsirolimus or equivalent, or TORISELTM: cular endothelial growth factor (VEGF)-mediated (xi) a composition comprising a macrollide ring or a angiogenesis inhibitor; macrollide antibiotic; wherein optionally the mac (v) an inducer of apoptosis or a mitotic and anti-micro rolide or composition comprising a macrollide ring tubule inhibitor (inhibition of microtubule function); comprises or consists of a clarithromycin or equiva wherein optionally the inducer of apoptosis or mitotic lent, or BIAXINTM, KLARICIDTM, KLABAXTM, inhibitor or anti-microtubule inhibitor comprises or CLARIPENTM, CLARIDARTM, FROMILIDTM or consists of a raltitrexed or equivalent, or TOMU CLACIDTM; an azithromycin or equivalent, or DEXTM: a doxorubicin or equivalent, or ADRIAM ZITHROMAXTM, ZITROMAXTM O YCINTM: a fluorouracil or 5-fluorouracil or equiva SUMAMEDTM; a dirithromycin or equivalent; an lent; a paclitaxel or equivalent, or TAXOLTM or erythromycin or equivalent; a roXithromycin or ABRAXANETM; a docetaxelorequivalent, or TAXO equivalent, or ROXOTM, SURLIDTM, RULIDETM, TERETM; a larotaxel, tesetaxel or ortataxel or equiva lent; an epothilone or an epothilone A, B, C, D, E or F BIAXSIGTM, ROXARTM, ROXIMYCINTM or or equivalent; an ixabepilone (also known as aza COROXINTM: a tellithromycin or equivalent or epothilone B) or equivalent, or B MS-247550TM; a KETEKTM; a josamycin or equivalent; a kitasamycin Vincristine (also known as leurocristine) or equiva or equivalent; amidecamycin or equivalent, oleando lent, or ONCOVINTM: a vinblastin, vinblastine, vin mycin or equivalent; aroXithromycin or equivalent, or desine, vinflunine, vinorelbine or NAVELBINETM or ROXOTM, SURLIDTM, RULIDETM, BIAXSIGTM, equivalent; or, any combination thereof. ROXARTM, ROXIMYCINTM or COROXINTM, a (vi) an alkylating agent; wherein optionally the alkylat troleandomycin or equivalent; or a tylosin or equiva ing agent comprises or consists of a cisplatin or lent; or, any combination thereof; equivalent; a cisplatinum or equivalent; a cis-diam (xii) an immunosuppressant composition and/or drug or minedichloridoplatinum(II) (CDDP) or equivalent; a pharmaceutical; wherein optionally the immunosup carboplatin or equivalent; a oxaloplatin or equivalent; pressant composition or drug or pharmaceutical com a cyclophosphamide (cytophosphane) or equivalent, prises or consists of a sirolimus or equivalent (also or ENDOXANTM, CYTOXANTM, NEOSARTM or known as rapamycin), or RAPAMUNETM; a tacroli REVIMMUNETM; a mechlorethamine or equivalent; mus or equivalent, or FK-506TM or FUJIMYCINTM: a a chlormethine or equivalent; a mustine or equivalent; ciclosporin (or cyclosporine or cyclosporin) or a nitrogen mustard or equivalent; a chlorambucil or equivalent; or a cortisone or equivalent; equivalent, or LEUKERANTM: or, a combination thereof (xiii) a proton pump inhibitor (a PPI) or a PPI compris (vii) a topoisomerase inhibitor; wherein optionally the ing or consisting of an H-receptor antagonist topoisomerase inhibitor comprises or consists of an (HRA); wherein optionally the H-receptor antago etoposide or equivalent, or EPOSINTM, ETOPO nist (HRA) comprises or consists of a cimetidine or PHOSTM, VEPESIDTM or VP-16TM; an amsacrine or equivalent, or TAGAMETTM, TAGAMET HBTM or equivalent; a topotecan or equivalent, or HYCAM TAGAMET HB200TM; a ranitidine or equivalent, or TINTM: a teniposide or equivalent, or VUMONTM or TRITECTM or ZANTACTM; a famotidine or equiva VM-26TM; an epipodophyllotoxin or equivalent; a lent, or PEPCIDINETM or PEPCIDTM; anizatidine or camptothecin or equivalent; an irinotecan or equiva equivalent, or TAZACTM or AXIDTM; wherein option lent, or CAMPTOSARTM; or, a combination thereof; ally the proton pump inhibitor (a PPI) comprises or (viii) a glycopeptide antibiotic; wherein optionally the consists of a benzimidazole compound or structure, or glycopeptide antibiotic comprises or consists of a an imidazopyridine compound or structure; wherein bleomycin or equivalent or a bleomycin A or B or optionally the imidazopyridine compound or struc equivalent; a mitomycin or a mitomycin C or equiva ture comprises or consists of a Zolpidem or equiva lent, a plicamycin (also known as mithramycin) or lent, or AMB IENTM, AMBIEN CRTM, IVEDALTM, equivalent, or MITHRACINTM: or, a combination NYTAMELTM, STILNOCTTM, STILNOXTM, ZOL thereof (ix) a steroid receptor inhibitor or steroid inhibitor (an DEMTM, ZOLNODTM or ZOLPIHEXALTM; an alpi anti-steroid); wherein optionally the steroid receptor dem (also called ananxyl) or equivalent; a Saripidem inhibitor comprises or consists of an estrogen receptor or equivalent; necopidem or equivalent; modulator (a SERM); and optionally the estrogen (h) the therapeutic combination of (a), wherein the thera receptor modulator comprises or consists of a tamox peutic combination is formulated and/or dosaged for use ifen or equivalent, or NOLVADEXTM, ISTUBALTM with a Surgery, a chemotherapy and/or an anti-cancer or VALODEXTM: and optionally the steroid inhibitor therapy; or an anti-steroid comprises or consists of a finas (i) the therapeutic combination of (a) to (h), formulated teride or equivalent, or PROSCARTM, PROPECIATM, and/or dosaged to treat, ameliorate, diminish, improve FINCARTM, FINPECIATM, FINAXTM, FINASTTM, and/or inhibit unwanted side effects and/or disease state FINARATM, FINALOTM, PROSTERIDETM, symptoms associated with or caused by anorexia; anor GEFINATM, APPECIATM, FINASTERID IV AXTM, exia-cachexia; anxiety; atrophy or muscle atrophy; FINASTERID or ALTERNOVATM; cachexia and/or cancer cachexia; US 2011/0158983 A1 Jun. 30, 2011

() the therapeutic combination of any of (a) to (h), formu 5. A method for allowing, enabling or facilitating the tol lated and/or dosaged to treat, ameliorate, diminish, erance and/or use of higher amounts and/or doses and/or improve and/or inhibit unwanted side effects and/or dis longer durations of a medical therapy, comprising: ease state symptoms associated with or caused by ane (a) administering to an individual in need thereof a thera mia; cognitive impairment; cytoprotection deficiency; peutically effective amount ofatherapeutic combination depression or despair; difficulties with activities of daily of claim 1 or claim 2: living; discomfort, emesis; excessive sympathoneural (b) the method of (a), wherein the medical therapy com drive; fatigue; a neutropenia or a febrile neutropenia; prises an anti-cancer therapy: frustration; hair loss; heart failure; an infection, a bacte (c) the method of (b), wherein the anti-cancer therapy rial infection; an inflammation; intolerance to a medical comprises a chemotherapy or a radiation therapy; or therapy; lack of appetite; lack of energy; lack of moti (d) the method of any of (a) to (c), wherein the therapeutic Vation; myeloprotection deficiency; rash; pain; reduced combination is administered in conjunction with (dur physical activity; wasting; worrying; pruritis, Xerosto ing), before and/or after an anti-cancer therapy. mia; cardiotoxicity; ototoxicity; nephrotoxicity; and/or 6. A method for reducing occurrences of drug resistance in peripheral neuropathy; and/or stress or anxiety related to a medical therapy, comprising: any of the above: (a) administering to an individual in need thereof a thera (k) the therapeutic combination of any of (a) to (), wherein peutically effective amount ofatherapeutic combination the therapeutic combination comprises or consists of a of claim 1 or claim 2: cancer drug or therapeutic agent for the treatment of a (b) the method of (a), wherein the medical therapy com cancer, propranolol and etodolac, prises an anti-cancer therapy: (1) the therapeutic combination of any of (a) to (k), wherein (c) the method of (b), wherein the anti-cancer therapy the compounds are manufactured in the form of a pack comprises a chemotherapy or a radiation therapy; or age, a kit, a container, a blister package, a clamshell, a (d) the method of any of (a) to (c), wherein the therapeutic tray and/or a shrink wrap; or combination is administered in conjunction with (dur (m) the therapeutic combination of any of (a) to (l), wherein ing), before and/or after an anti-cancer therapy. each compound of the therapeutic combination is inde 7. A method for enabling dosage intensification or increas pendently formulated as a tablet, a pill, a lozenge, a ing frequency in a medical therapy, comprising: capsule, a caplet, a patch, a spray, an inhalant, a gel, a (a) administering to an individual in need thereof a thera geltab, a nanosuspension, a nanoparticle, a microgel peutically effective amount ofatherapeutic combination and/or a pellet, and the tablet, pill, lozenge, capsule, gel, of claim 1 or claim 2: geltab, nanosuspension, nanoparticle, microgel and/or a (b) the method of (a), wherein the medical therapy com pellet. prises an anti-cancer therapy: 3. A method for treating, ameliorating and/or diminishing (c) the method of (b), wherein the anti-cancer therapy a mucositis, or improving and/or inhibiting unwanted side comprises a chemotherapy or a radiation therapy; or effects and/or disease state symptoms associated with or (d) the method of any of (a) to (c), wherein the therapeutic caused by a mucositis, comprising: combination is administered in conjunction with (dur ing), before and/or after an anti-cancer therapy. (a) administering to an individual in need thereofathera 8. A method for enhancing patient response rates or peutically effective amount ofatherapeutic combination increasing patient Survival in a Surgery or a medical therapy, of claim 1: comprising: (b) the method of (a), wherein the mucositis comprises an (a) administering to an individual in need thereof a thera oral mucositis; a digestive mucositis; an esophageal peutically effective amount ofatherapeutic combination mucositis and/or an intestinal mucositis; of claim 1 or claim 2: (c) the method of (a) or (b), wherein the therapeutic com (b) the method of (a), wherein the surgery or medical bination is administered in conjunction with (during), therapy comprises an anti-cancer therapy: before and/or after an anti-cancer therapy; or (c) the method of (b), wherein the anti-cancer therapy (d) the method of (c), wherein the anti-cancer therapy comprises a chemotherapy or a radiation therapy; or comprises a radiation therapy or a chemotherapy. (d) the method of any of (a) to (c), wherein the therapeutic 4. A method for treating, ameliorating and/or diminishing combination is administered in conjunction with (dur an anorexia; anorexia-cachexia; anxiety; atrophy or muscle ing), before and/or after the Surgery or an anti-cancer atrophy, cachexia and/or cancer cachexia, or improving and/ therapy. or inhibiting unwanted side effects and/or disease state symp 9. A method for inducing a tissue protective state in an toms associated with or caused by an anorexia; anorexia individual, comprising: cachexia; anxiety; atrophy or muscle atrophy: cachexia and/ (a) administering to an individual in need thereof a thera or cancer cachexia, comprising: peutically effective amount ofatherapeutic combination (a) administering to an individual in need thereofathera of claim 1 or claim 2: peutically effective amount ofatherapeutic combination (b) the method of (a), wherein the tissue protective state is of claim 2: induced before, during and/or after a medical therapy or (b) the method of (a), wherein the therapeutic combination a Surgical trauma: is administered in conjunction with (during), before and/ (c) the method of (b), wherein the medical therapy or or after an anti-cancer therapy; or Surgical trauma comprises an anti-cancer therapy; (c) the method of (b), wherein the anti-cancer therapy (d) the method of (c), wherein the anti-cancer therapy comprises a radiation therapy or a chemotherapy. comprises a chemotherapy or a radiation therapy; or US 2011/0158983 A1 Jun. 30, 2011 64

(e) the method of any of (a) to (d), wherein the therapeutic 12. A package, a kit, a container, ablister package, a clam combination is administered in conjunction with (dur shell, a tray and/or a shrink wrap comprising: ing), before and/or after an anti-cancer therapy or a (a) a therapeutic combination of claim 1 or claim 2, Surgery. (b)atherapeutically effective amount ofatherapeutic com 10. A method for inducing a tissue regeneration in an bination of claim 1 or claim 2; or individual, comprising: (c) the package, a kit, a container, a blister package, a (a) administering to an individual in need thereofathera clamshell, a tray and/or a shrink wrap or (a) or (b). peutically effective amount ofatherapeutic combination wherein each compound of the therapeutic combination of claim 1 or claim 2 is independently formulated as a of claim 1 or claim 2: tablet, a pill, a lozenge, a capsule, a caplet, a patch, a (b) the method of (a), wherein the tissue regeneration is spray, an inhalant, a gel, a gel tab, a nanosuspension, a induced before, during and/or after a medical therapy or nanoparticle, a microgel and/or a pellet, and the tablet, a Surgical trauma: pill, lozenge, capsule, gel, geltab, nanosuspension, (c) the method of (b), wherein the medical therapy or nanoparticle, microgel and/or a pellet. Surgical trauma comprises an anti-cancer therapy; 13. At least one of a therapeutic combination of claim 1, or (d) the method of (c), wherein the anti-cancer therapy a package, a kit, a container, ablisterpackage, a clamshell, for comprises a chemotherapy or a radiation therapy; or use in the treatment, amelioration and/or diminishing of a (e) the method of any of (a) to (d), wherein the therapeutic mucositis, or improving and/or inhibiting unwanted side combination is administered in conjunction with (dur effects and/or disease state symptoms associated with or ing), before and/or after a medical therapy, a Surgical caused by a mucositis. trauma or an anti-cancer therapy. 14. At least one of a therapeutic combination of claim 2, or 11. A method for inducing a tissue repair in an individual, a package, a kit, a container, ablisterpackage, a clamshell, for comprising: use in the treatment, amelioration and/or diminishing of an (a) administering to an individual in need thereofathera anorexia; anorexia-cachexia; anxiety; atrophy or muscle atro peutically effective amount ofatherapeutic combination phy, cachexia and/or cancer cachexia; or unwanted side of claim 1 or claim 2: effects and/or disease state symptoms associated with or (b) the method of (a), wherein the tissue repair is induced caused by anorexia; anorexia-cachexia; anxiety; atrophy or before, during and/or after a medical therapy or a Surgi muscle atrophy, cachexia and/or cancer cachexia. cal trauma; 15. At least one of a therapeutic combination of claim 1 or (c) the method of (b), wherein the medical therapy or claim 2, or a package, a kit, a container, a blister package, a Surgical trauma comprises an anti-cancer therapy; clamshell, for use in allowing, enabling or facilitating the (d) the method of (c), wherein the anti-cancer therapy tolerance and/or use of higher amounts and/or doses and/or comprises a chemotherapy or a radiation therapy; or longer durations of a medical therapy, or an anti-cancer (e) the method of any of (a) to (d), wherein the therapeutic therapy, or a chemotherapy or a radiation therapy. combination is administered in conjunction with (dur 16-115. (canceled) ing), before and/or after a medical therapy, a Surgical trauma or an anti-cancer therapy.