Back to results
US 2009/0214474 A1Published application
Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
OwnerBarbara Brooke Jenningsinventor
Life of this patent
Estimating the term…
Abstract
The present invention relates to prevention of congenital deformations. The invention further relates to cancer inhibition and prevention. The invention further relates to methods and compositions to modulate, antagonize, or agonize disparate signaling pathways that may converge to regulate patterning events and gene expression during prenatal development, post-natal development, and during development in the adult organism.
Claims36
A compound selected from the group consisting of
- wherein (a) each of R101, R103, R105 R107, R109, and R111 is independently selected from H or a substituent R201;
- each of R102, R104, R106 R108, R110, and R112 is independently selected from OH, OR202, OP(═O)(OR211)(OR212), OP(═O)(OR213)—OP(═O)(OR211)(OR212), OP(═O)(OR113)—{OP(═O)(OR113)}a—OP(═O)(OR211)(OR212) (wherein a is 1-3) or a substituent R203;
- or —O—SO2—OR207, or —O—S(O)—OR207, or not more than 3 of R102, R104, R106 R108, R110, and R112 is independently H;
- or
- (b) both of the respective R groups on the same carbon are together ═O or ═N(R204), provided not more than 3 of the carbon atoms having an R group selected from R101 to R112 is C═O or C═N(R204);
- or
- (ii)
- where each of the groups R101-R112, in each unit are
- independently as set forth above except that one of such R groups in each of the terminal structures is a direct bond to the indicated oxygen instead of the foregoing, and one of such R groups in each intermediary structure is a direct bond to one of the two indicated oxygens instead of the above and a second of the R groups in each intermediary structure is a direct bond to the other indicated oxygen, p, r, and s are each 1, t and k are each independently an integer of from 0 to 2, and n is a an integer of from 0 to 8;
- pharmaceutically acceptable salts thereof, and mixtures thereof;
- or t=0 and one or more of the indicated —P(O)(OR212)— groups in structure B is replaced by a group selected from —C(O)—, —S(O)—, or —S(O)2—;
- or analogous structures in which a ring A and ring B, a ring B and a ring C or two rings B are further bound to each other to form super rings in which each super ring has as ring members at least two of rings selected from A, B, and C and at least two linking groups independently selected from −O—P(═O)(OR212)—O—, —OC(O)O—, —OS(O)—O—, or —OS(O)2—O— and R212 in each of the compounds of this subparagraph (ii) is as defined below or together with the oxygen to which it is attached and any remaining R101 through R112 forms an —O—;
- or
- or the corresponding compounds to structures (C), (D), and (E) wherein (a) the —P(OR212)(O)— group is replaced by —C(O)—, —S(O)—, or —S(O)2— or the (OR212) together with any remaining group R111 through R112 forms an —O— group resulting in additional fused rings;
- wherein each of R205 through R213 is itself independently selected from H, unsubstituted or substituted aliphatic groups, and unsubstituted or substituted aromatic groups,
- wherein the aliphatic groups are selected from straight chain and branched carbon chains which are saturated or unsaturated, of up to 30 carbon atoms, and cycloaliphatic rings having 3-10 ring members such rings being carbocyclic or heterocyclic where the heterocyclic rings have one to four heteroatoms selected from oxygen, sulfur, and nitrogen;
- the cycloaliphatic rings being saturated or partially unsaturated, and
- the aromatic groups having 6-8 ring members selected from carbon, oxygen, sulfur, and nitrogen;
- the aliphatic and aromatic groups further containing up to four fused rings of either cycloaliphatic rings, aromatic rings or both cycloaliphatic and aromatic rings, each of the aliphatic and aromatic rings being further unsubstituted or substituted by hydroxy, C1-30 alkoxy, C1-30 alkylthio, C1-20acyloxy, phosphate, halogen;
- trihalomethyl, cyano, and azido;
- each substituent being mono or multiply present as valence permits;
- each of the substituted aliphatic groups having one or more substituents independently selected from the group of hydroxy, C1-30 alkoxy, C1-30 alkylthio, C1-20acyloxy, phosphate, halogen;
- trihalomethyl, cyano, and azido;
- and further
- provided that in the foregoing substitution patterns, no substitution pattern results in a peroxy group;
- the R211 and/or the R212 of any —P(O)(OR211)(OR212) may be further joined to any free hydroxy group or to result in phosphate containing rings of 5-9 members per ring fused to the inositol or inositol derivative ring;
- and mixtures thereof;
- provided that if all six of R101, R103, R105 R107, R109, and R111 are H then at least one of R102, R104, R106 R108, R110, and R112 is other than OH, and provided that if each of R102, R104, R106 R108, R110 and R112 is OH, then at least one of R101, R103, R105 R107, R109, and R111 is other than H;
- or
- (iii) (a) in which any of the foregoing compounds having a free hydroxy group is esterified with an acidic group of folic acid or an acidic group of a polysaccharide-folic acid compound, or
- (b) in which any of the foregoing compounds having a free acidic group selected from the group consisting of —C(═O)(OH), —S(═O)(OH), and —S(═O)2(OH) is esterified with a free hydroxyl group of folic acid or of a polysaccharide-folic acid compound, or
- (c) in which any of the foregoing having a free amine or imine forms together with the acidic group of a folic acid or of a polysaccharide-folic acid compound a group
- (iv) pharmaceutically acceptable salts thereof, and
- (v) mixtures thereof.
31 more elements
A composition comprising one or more inositols of the formula
- and an additional active agent which is not an inositol
- wherein said additional active agent selected from the group consisting of
- (i) folic acid, a non-folic acid folate source, pharmaceutically acceptable salts thereof, and mixtures thereof;
- (ii) (A) estrogenic material,
- (B) progestogenic material,
- (C) antiandrogenic material,
- (D) a compound selected from 13-cis-Retinoic Acid, 2-CdA, 2-Chlorodeoxyadenosine, 5-Azacitidine, 5-Fluorouracil, 5-FU, 6-Mercaptopurine, 6-MP, 6-TG, 6-Thioguanine, Abraxane, Accutane®, Actinomycin-D, Adriamycin®, Adrucil®, Agrylin®, Ala-Cort®, Aldesleukin, Alemtuzumab, ALIMTA, Alitretinoin, Alkaban-AQ®, Alkeran®, All-transretinoic Acid, Alpha Interferon, Altretamine, Amethopterin, Amifostine, Aminoglutethimide, Anagrelide, Anandron®, Anastrozole, Arabinosylcytosine, Ara-C, Aranesp®, Aredia®, Arimidex®, Aromasin®, Arranon® Arsenic Trioxide, Asparaginase, ATRA Avastin®, Azacitidine, BCG, BCNU, Bevacizumab, Bexarotene, BEXXAR®, Bicalutamide, BiCNU, Blenoxane®, Bleomycin, Bortezomib, Busulfan, Busulfex®, C225, Calcium Leucovorin, Campath®, Camptosar®, Camptothecin-11, Capecitabine Carac™, Carboplatin, Carmustine, Carmustine, Wafer Casodex®, CC-5013, CCNU, CDDP, CeeNU, Cerubidine®, Cetuximab, Chlorambucil, Cisplatin, Citrovorum Factor, Cladribine, Cortisone, Cosmegen®, CPT-11, Cyclophosphamide, Cytadren®, Cytarabine, Cytarabine Liposomal Cytosar-U,® Cytoxan®, Dacarbazine, Dacogen, Dactinomycin, Darbepoetin Alfa, Dasatinib, Daunomycin, Daunorubicin, Daunorubicin Hydrochloride, Daunorubicin Liposomal, DaunoXome®, Decadron, Decitabine, Delta-Cortef®, Deltasone®, Denileukin, diftitox, DepoCyt™, Dexamethasone, Dexamethasone acetate, Dexamethasone Sodium Phosphate, Dexasone, Dexrazoxane, DHAD, DIC, Diodex, Docetaxel, Doxil®, Doxorubicin, Doxorubicin liposomal, Droxia™, DTIC, DTIC-Dome®, Duralone®, Efudex®, Eligard™, Ellence™, Eloxatin™, Elspar®, Emcyt®, Epirubicin, Epoetin alfa, Erbitux™, Erlotinib, Erwinia, L-asparaginase, Estramustine, Ethyol, Etopophos®, Etoposide, Etoposide Phosphate, Eulexin®, Evista®, Exemestane, Fareston®, Faslodex®, Femara®, Filgrastim, Floxuridine, Fludara®, Fludarabine, Fluoroplex®, Fluorouracil, Fluorouracil (cream), Fluoxymesterone, Flutamide, Folinic Acid, FUDR®, Fulvestrant, G-CSF, Gefitinib, Gemcitabine, Gemtuzumab, ozogamicin, Gemzar®, Gleevec™, Gliadel® Wafer, GM-CSF, Goserelin, Granulocyte—Colony Stimulating Factor, Granulocyte Macrophage Colony Stimulating Factor, Halotestin®, Herceptin®, Hexadro, Hexylen®, Hexamethylmelamine, HMM, Hycamtin®, Hydrea®, Hydrocort Acetate®, Hydrocortisone, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate, Hydrocortone Phosphate, Hydroxyurea, Ibritumomab, Ibritumomab Tiuxetan, Idamycin®, Idarubicin, Ifex®, IFN-alpha I fosfamide, IL-11, IL-2, Imatinib mesylate, Imidazole Carboxamide, Interferon alfa, Interferon Alfa-2b (PEG Conjugate), Interleukin-2, Interleukin-11, Intron A® (interferon alfa-2b), Iressa®, Irinotecan, Isotretinoin, Kidrolase®, Lanacort®, Lapatinib, L-asparaginase, LCR, Lenalidomide, Letrozole, Leucovorin, Leukeran, Leukine™, Leuprolide, Leurocristine, Leustatin™ Liposomal, Ara-C Liquid Pred®, Lomustine, L-PAM, L-Sarcolysin, Lupron®, Lupron Depot®, Matulane®, Maxidex, Mechlorethamine, Mechlorethamine Hydrochloride, Medralone®, Medrol®, Megace®, Megestrol, Megestrol Acetate, Melphalan, Mercaptopurine, Mesna, Mesnex™, Methotrexate, Methotrexate Sodium, Methylprednisolone, Meticorten®, Mitomycin, Mitomycin-C, Mitoxantrone, M-Prednisol®, MTC, MTX, Mustargen®, Mustine, Mutamycin®, Myleran®, Mylocel™, Mylotarg®, Navelbine®, Nelarabine, Neosar®, Neulasta™, Neumega®, Neupogen®, Nexavar®, Nilandron®, Nilutamide, Nipent®, Nitrogen Mustard, Novaldex®, Novantrone®, Octreotide, Octreotide acetate, Oncospar®, Oncovin®, Ontak®, Onxal™, Oprevelkin, Orapred®, Orasone®, Oxaliplatin, Paclitaxel, Paclitaxel Protein-bound, Pamidronate, Panitumumab, Panretin®, Paraplatin®, Pediapred®, PEG Interferon, Pegaspargase, Pegfilgrastim, PEG-INTRON™, PEG-L-asparaginase, PEMETREXED, Pentostatin, Phenylalanine Mustard, Platinol®, Platinol-AQ®, Prednisolone, Prednisone, Prelone®, Procarbazine, PROCRIT®, Proleukin®, Prolifeprospan 20 with Carmustine Implant, Purinethol®, Raloxifene, Revlimid®, Rheumatrex®, Rituxan®, Rituximab, Roferon-A® (Interferon Alfa-2a), Rubex®, Rubidomycin hydrochloride, Sandostatin®, Sandostatin LAR®, Sargramostim, Solu-Cortef®, Solu-Medrol®, Sorafenib, SPRYCEL™, STI-571, Streptozocin, SU11248, Sunitinib, Sutent®, Tamoxifen, Tarceva®, Targretin®, Taxol®, Taxotere®, Temodar®, Temozolomide, Teniposide, TESPA, Thalidomide, Thalomid®, TheraCys®, Thioguanine, Thioguanine Tabloid®, Thiophosphoamide, Thioplex®, Thiotepa, TICE®, Toposar®, Topotecan, Toremifene, Tositumomab, Trastuzumab, Tretinoin, Trexall™, Trisenox®, TSPA, TYKERB®, VCR, Vectibix™, Velban®, Velcade® VePesid®, Vesanoid® Viadur™, Vidaza®, Vinblastine, Vinblastine Sulfate, Vincasar Pfs®, Vincristine, Vinorelbine, Vinorelbine tartrate, VLB, VM-26, Vorinostat, VP-16, Vumon®, Xeloda®, Zanosar®, Zevalin™, Zinecard®, Zoladex®, Zoledronic acid, Zolinza, Zometa® abarelix, abraxane (paclitaxel), adriamycin (doxorubicin), algestone, amadinone, aminoglutethimide, anagestrone, anastrozole, androisoxazole, androstanolone, androstenediol, 4-androstene-3,16,17-trione, aredia (pamidronate disodium), arimidex (anastrozole), aromasin (exemestane), bazedoxifene, benorterone, bicalutamide, bolandiol, bolasterone, bolazine, boldenone, bolenol, bolmantalate, buserelin, calusterone, chemotherapy regimens, (cyclophosphamide (cytoxan), methotrexate (amethopetrin, Mexate, folex, and fluororucil (fluorourcil, 5-fu, adrucil) (this therapy is called CMF), cyclophospamide, doxorubicin (adriamycin) and fluorouracil (this therapy is called CAF), doxorubicin (adriamycin) and cyclophosphamide, doxorubicin (adriamycin) and cyclophosphamide with paclitaxel (taxol), doxorubicin (adriamycin) followed by CMF, cyclophosphamide, eprubicin9ellence), and fluororacil, chlorotrianisene, chorionic gonadotropin, cioteronel, cingestol, clogestone, clomegestone, clometherone, clomifene, clostebol, conjugated estrogens, cyproterone, cytoxan (cyclophasphamide), danazol, delmadinone, deslorelin, desogestrel, detirelix, dienestrol, diethylstilbestrol, dimethisterone, dihydrogestrone, drospirenone, drostanolone, dydrogesterone, ellence (epirubicin), epiestriol, epimestrol, epitiostanol, epristeride, equilin, esterified estrogens, estradiol, estrazinol, estriol, estrofurate, estrone, estropipate, ethinylestradiol, ethisterone, ethylestrenol, ethynerone, ethynodiol, etonogestrel, evista (raloxifene), exemestane, fareston (toremifene), femara (letrozole), fenestrel, finasteride, fluoxymesterone, fluorogestone, flutamide, formebolone, formestane, fosfestrol, fulvestrant, furazabol, ganirelin, gestaclone, gestadienol, gestodene, gestonorone, gestrinone, gonadorelin, goserelin, haloprogesterone, herceptin (trastuzumab), histrelin, 4-hydroxy-19-nortestosterone, hydroxyprogesterone, ibutamoren, idoxifene, letrozole, leuprolide, leuprorelin, levonorgestrel, lutrelin, lynestrenol, mebolazine, medrogestone, medroxyprogesterone, megace (megestrol), melengestrel, menotropins (especially humegon, pergonal, repronex, mesabolone, mestranol, mesterolone, metandienone, metenolone, methandriol, methenolone, methestrol, methyltestosterone, methynodiol, metribolone, mibolerone, mifepristone, nafarelin, nafoxidine, nandrolone, nilutamide, nitromifene, norboletone, norbolethone, norclostebol, norelgestromin, norethandrolone, norethindrone, norethisterone, norethynodrel, norgestimate, norgestomet, norgestrel, norgestrienone, nylestriol, oxabolone, oxandrolone, oxendolone, oxogestone, oxymesterone, oxymetholone, polyestradiol (especially polyestradiol phosphate), pralmorelin, prasterone, progesterone, quinbolone, quinestrol, quinestradol, quingestanol, quingestrone, raloxifene, rismorelin, somalapor, somatrem, somatropin, somenopor, somidobove, stanozolol, stenbolone, sumorelin, tamoxifen, taxol (palitaxel), taxotere (docetaxel), testosterone, tibolone, tigestrol, tiomesterone, topterone, toremifene, trenbolone, trimegestone, trioxifene, triptorelin, urofollitropin, vorozole, xeloda (capecitabine), zanoterone, and zeranol, zoladex (goserelin), zometa (zoledronic), and
- (E) mixtures thereof;
- and
- (iii) mixtures thereof
- provided that the compounds included in a single formulation are compatible with each other or are separated from each other so as to avoid said potential incompatability.
8 more elements
A cotherapy comprising an inositol component selected from a sulfato phosphorylate of an inositol isomer, the inositol isomer selected from the group consisting of scyllo-inositol, epi-inositol, cis-inositol, allo-inositol, neo-inositol, muco-inositol, dextro-inositol, levo-inositol, and D-chiro-inositol;
- said inositol component having at least one phosphoryl group selected from monophosphoryl groups, pyrophosphoryl, groups, and polyphosphory groups and a second component selected from a growth factor.
A method of adhering an active agent in an implantable formulation to a delivery site for the active agent comprising the use of a dendrimitic molecule or a fibroblast to which the active agent is encased, coated on, or bound to, whether by an ionic, covalent, or hydrogen bonding, including binding said active agent to one or more dendritic protrusions thereof.
A method of delivery of an active agent comprising the administration of a nanorobotic delivery system having been designed to be implanted in or around the site of specific delivery, which delivers the active agent or active agent precursor on a single prolonged or multiple release schedule which can be pre-programmed for delivery over short or extended periods, which may migrate to or be adhered in place at the delivery site, which adhesion, is via an adhesion mediated by an entity selected form the group consisting of fibroblasts, monoclonal antibodies, charged particle portions, antisence DNA, and antisence RNA.
A method of treatment of a mammal inclusive of humans and mammalian pets, mammalian farm animals, mammalian zoo animals, mammalian research animals, and other mammalian commercial animals comprising administering thereto for a therapy for which
- (a) as a first therapy an inositol stereoisomeric compound selected from
- (i) a D-chiro inositol, an inositol derivative, or an inositol metabolite or a member selected from the group of D-chiro-inositol phosphates, D-chiro-inositol esters, D-chiro-inositol ethers, D-chiro-inositol acetals, D-chiro-inositol ketals, polysaccharides containing D-chiro-inositols, and D-chiro-inositol phospholipids;
- (ii) pharmaceutically acceptable salts thereof, and
- (iiv) mixtures thereof
- alone or in combination with
- (b) a second therapy of other active agents, said second therapy and said treatment being independently selected from
- (1) reduction of or prevention of tumor load, distant metastasis, or as a synergistic inhibitor with one or more compounds, such as anti-cancer therapeutic agents;
- etc.
- (2) prevention or diminishing the aberrant cell from obtaining drug resistance;
- (3) estrogenic or antiandrogenic therapeutic substances (generally as a means of inhibiting the response of breast tissue to estrogen excess insult (absolute estrogenegic substance excess or relative estrogen excess as compared to androgenic substances);
- (4) folic acid or other folate sources (primarily with respect to reducing the incidence of fetal malformations)
- (5) prevention of or correction of improper signaling the phosphatidylinositol/PI3K signaling pathways
- (6) the prevention and/or minimization of fetal malformations, some of which are due to sonic hedgehog (Shh) and/or other hedgehog variants such as Indian (Ihh) and Desert (Dhh), etc. signaling defects;
- (7) prevention and/or minimization of signaling defects in the sonic hedgehog (Shh) and/or other hedgehog variants such as Indian (Ihh) and Desert (Dhh), etc. pathways;
- (8) the prevention and/or inhibition of breast cancer and metastases thereof some of which are due to one or more of sequela of estrogen exposure or estrogen surplus exposure (whether during hormonal therapy (males or females) or birth control use) or super-active estrogen receptors, or due to excess number of estrogen receptors (receptor expansion), or excessively sensitive estrogen receptors in mammary epithelial breast tissue (whether due to derangements in signaling pathways or other bases such as estrogen receptor overexpression in certain predisposed phenotypes, whether due to developmental, or to environmental, or endogenous exposures);
- (9) increasing the therapeutic efficacy of anti-cancer agents, especially those related to the prevention or treatment of breast and prostate cancers, and the prevention or reduction of aberrant cells becoming resistant to one or more anti-cancer agents;
- (10) manipulating cell growth and differentiation in culture;
- (11) manipulating cell growth and differentiation in culture for implantation of such cells;
- (12) for regenerating neural tissue, hepatic tissue, pancreatic tissue, intestinal tissue, spleenic tissue, cardiac tissue, among others;
- (13) regulating or inhibiting growth of cells;
- (14) treatment of excessive or inappropriate hair growth conditions, psoriasis, actinic keratosis, acne, miscellaneous dermatitis conditions, etc;
- (15) inducing an anti-angiogenic state;
- (16) treating and preventing tumor growth via inducing an anti-angiogenic state in said local and distant metastatic tumors;
- (17) correcting the inherent mechanism of tumor stem cell autoregulation;
- (18) decreasing the risk of deep vein thrombosis (DVT's) and Pulmonary emboli (PE's) while using chemotherapeutic agents, antiestrogens such as tamoxifen etc., hormonal therapies such as androgen ablative therapies, or estrogenic hormone therapy, whether for birth control or hormone replacement, or sexual reassignment;
- (19) reducing the numbers and size of tumors locally or distant especially in breast cancers, but also cancers originating from blood, colon, lung, liver, pancreas, cervix, prostate, skin, and soft tissue;
- (20) preventing breast cancer or precursors thereof in utero;
- (21) correcting the inherent mechanism of stem cell autoregulation;
- (22) increasing the efficacy of standard chemotherapeutic agents;
- (23) reducing the potential hazardous risk of tamoxifen-associated cardiovascular disease;
- (24) reducing the numbers and size of tumors locally or distant especially in breast cancers, but also cancers originating from blood, colon, lung, liver, cervix, prostate, skin, and soft tissue;
- (25) treatment of women pre-pregnancy to prevent or reduce the chance of fetal malformations especially by administering D-chiro-inositol or a derivative thereof;
- (26) co-therapy treatment for women pre-pregnancy to prevent or reduce the chance of fetal malformations with both a folate source and an inositol or derivative thereof, especially by administering D-chiro-inositol or a derivative thereof;
- (27) treatment of women during the first trimester of pregnancy to prevent or reduce the chance of fetal malformations by co-administering an inositol or a derivative thereof (especially a D-chiroinositol or a derivative thereof) and a folate source;
- (28) treatment of women who are taking birth control pills but who might nonetheless become pregnant by including an inositol or a derivative thereof (especially a D-chiroinositol or a derivative thereof) and optionally a folate source into the pills that do not contain an estrogenic substance, not the pills that do contain an estrogenic substance or all of the pills;
- (29) treatment of women who are taking birth control pills and who may have excess estrogen insult with hyperactive/sensitive estrogen receptor (ER) positive breast tissue by including an inositol or a derivative thereof (especially a D-chiroinositol or derivative thereof) and optionally a folate source into the pills containing the estrogenic active agent of the birth control pills or into each of the pills in the birth control pill packet;
- (30) treatment of women who are on estrogenic hormone therapy and who may have estrogen-receptor (ER) and/or, ErbB receptor overexpression phenotype mediated by the (PI3K-Akt) pathway by administering as co-therapy with said estrogenic hormone therapy an inositol or a derivative thereof (especially D-chiro inositol or a derivative thereof) thereby blocking the downstream signaling elements resulting in cell cycle arrest in the G1 phase, thereby downregulating these important receptors;
- (31) treatment of women who are on estrogenic hormone therapy and who may have estrogen-receptor and/or, ErbB receptor overexpression phenotype mediated by the (PI3K-Akt) pathway by administering as a single composition said estrogenic hormone therapy drug and an inositol or a derivative thereof (especially D-chiro inositol or a derivative thereof);
- (32) treatment of women who are on anti-androgenic hormone therapy and who may have estrogen-receptor and/or, ErbB receptor overexpression phenotype mediated by the (PI3K-Akt) pathway-receptor overexpression phenotype by administering as co-therapy with said anti-androgenic hormone therapy an inositol or a derivative thereof (especially D-chiro inositol or a derivative thereof);
- (33) treatment of women who are on anti-androgenic hormone therapy and who may have estrogen-receptor and/or, ErbB receptor overexpression phenotype mediated by the (PI3K-Akt) pathway by administering as a single composition said anti-androgenic hormone therapy dug and an inositol or a derivative thereof (especially D-chiro inositol or a derivative thereof);
- (34) treatment of men who are on estrogenic hormone therapy and who may have estrogen-receptor and/or, ErbB receptor overexpression phenotype mediated by the (PI3K-Akt) pathway by administering as co-therapy with said estrogenic hormone therapy an inositol or a derivative thereof (especially D-chiro inositol or a derivative thereof);
- (35) treatment of men who are on estrogenic hormone therapy and who may have estrogen-receptor and/or, ErbB receptor overexpression phenotype mediated by the (PI3K-Akt) pathway by administering as a single composition said estrogenic hormone therapy dug and an inositol or a derivative thereof (especially D-chiro inositol or a derivative thereof);
- (36) treatment of men who are on anti-androgenic hormone therapy and who may have estrogen-receptor and/or, ErbB receptor overexpression phenotype mediated by the (PI3K-akt) pathway by administering as co-therapy with said anti-androgenic hormone therapy an inositol or a derivative thereof (especially D-chiro inositol or a derivative thereof);
- (37) treatment of men who are on anti-androgenic hormone therapy and who may have estrogen-receptor and/or, ErbB receptor overexpression phenotype mediated by the (PI3K-Akt) pathway by administering as a single composition said anti-androgenic hormone therapy drug and D-chiro-inositol (or a phosphate or other derivative thereof);
- (38) reduce or prevent fetal malformation occurrence where the fetal malformation is a neural tube defect, a cranio-facial defect, an anorectal malformation spectrum, caudal regression syndrome, neuralectoderm derived pediatric tumors, etc.;
- (39) modulating the phosphatidylinositol/PI3K signaling pathway with compounds and/or therapy of the present invention;
- (40) modualting the sonic hedgehog, the receptors patched and smoothened, and GL1,2,3 transcription family pathway;
- (41) prevention or amelioration or treatment of a phosphatidylinositol/PI3K signaling pathway signaling defect;
- (42) prevention or amelioration or treatment of a defect in the signaling pathway associated with sonic hedgehog, the receptors patched and/or smoothened, and/or GL1,2,3 transcription family signaling pathway;
- (43) treatment for increasing the chemotherapeutic efficacy by synergistic action of an inositol or a derivative thereof (especially D-chiro inositol or a derivative thereof) with standard chemotherapeutic agents in cancer treatments, especially breast, prostate, blood, colon, lung, liver, pancreatic, cervix, skin, and soft tissue cancers;
- (44) correction of tumor stem cell autoregulation;
- (45) manipulating cell growth for the regeneration of neural, hepatic, pancreatic, intestinal, spleenic, and/or cardiac tissue;
- (46) inhibition of cell growth in the treatment of psoriasis, actinic keratosis, acne, dermatitis, conditions of inappropriate or excess hair growth, and/or cosmetic purposes;
- (47) obtaining at least one of Shh loss-of-function or patched or smoothened gain-of-function by administration of an inositol or a derivative thereof (especially D-chiro inositol or a derivative thereof);
- (48) prevention or treatment of VATER/VACTERL association (vertebral [defects], [imperforate] anus, tracheoesophageal [fistula], radial and renal [dysplasia])rachischisis (aka spinal dysraphism) such as spina bifida (including, but not limited to spina bifida aperta (aka spinabifida cystica);
- spinabifida occulta;
- and occult spinal disorder, among others) and (b) craniorachischisis (aka cranial dysraphism) such as cranium bifida (aka encephalocele or craniocele) each of spina bifida and cranium bifida being of any of the following types meningocele, myelomeningocele, lipomeningocele, and lipomyelomeningocele among others;
- (c) anencephaly;
- and (d) chiari malformation;
- (2) caudal regression syndrome, caudal dysplasia sequence, congenitalsacral agenesis;
- sironmelia (mermaid syndrome), sacral regression and the like;
- (3) cranio-facial defects such as, without limitation, facial cleft (aka prosopoanoschisis, including without limitation cleft palate, cleft lip, velopharyngeal malformation (including without limitation bifid uvula), etc.);
- (4) anorectal malformations including, but not limited to (a) imperforate anus, (b) rectoperineal fistula, (c) recto-bladder neck fistula;
- (d) persistent urogenital sinus, (e) persistent cloaca, etc.;
- (5) bucket-handle malformation;
- among others. Biemond syndrome, Ectrodactyly-ectoderma dysplasia, cleft lip/palate, Ellis Van Creveld syndrome, Muir-Torre syndrome, Chaiari malformation, Cowden syndrome, Carney complex, Birt-Hogg-Dube syndrome, Gorlin syndrome (ptc loss-of-function), Gorlin-Goltz syndrome, basal cell nevus syndrome, bifid-rib basal-cell nevus syndrome, basal cell cancer syndrome (shh gain of function), and multiple basal cell nevi, squamous cell carcinoma (increased ptc activity) Meckel Gruger syndrome, McKusick-Kaufmansyndrome, Mirror hand deformity (ulnar dimelia) Mohr syndrome, Oral-facial-digital syndrome, Pallister Hall syndrome, cephalopolysyndactyl), Post axial polydactyl), GreigRubinstein-Taybi syndrome, retinoblastoma, Cardiofaciocutaneous syndrome, Noonan syndrome, short rib polydactyl), extra deformed fingers and toes, Lowe syndrome including ocular and renal defects, Renal Colombo syndrome, retinoblastoma, retinitis pigmentosa, holoprosencephaly, macular degeneration (whether it be due to a Shh defects, age, or secondary conditions like diabetes mellitus), mental retardation;
- (49) modulation of ptc, hedgeho, and/or smoothened signaling pathways in the modulation of endodermal stem cells, in vitro or in vivo;
- (50) modulation of ptc, hedgeho, and/or smoothened signaling pathways in the modulation of endodermal stem cells, in vitro or in vivo for the creation or maintenance of artificial or partially artificial organs, especially for transplantation, or in the inducement of regeneration of organs, said organs being especially liver, lung, spleen, pancreas, pancreatic beta cells, smooth muscle, intestinal tissue, etc.;
- (51) modulation of tissue development as an adjunct to development of prosthetic devices;
- (52) regeneration of lung tissue in the treatment of emphysema;
- (53) prevention or treatment of timorous conditions selected from tumors related to Gorlin's syndrome (e.g., basal cell carcinoma, medulloblastoma, meningioma, etc.), tumors evidenced in pct knock-out mice (e.g., hemangioma, rhabdomyosarcoma, etc.), tumors resulting from gli-1 amplification (e.g., glioblastoma, sarcoma, etc.), tumors connected with TRC8, a ptc homolog (e.g., renal carcinoma, thyroid carcinoma, etc.), Ext-1-related tumors (e.g., bone cancer, etc.), Shh-induced tumors (e.g., lung cancer, chondrosarcomas, etc.), and other tumors (e.g., breast cancer, urogenital cancer (e.g., kidney, bladder, ureter, prostate, etc.), adrenal cancer, gastrointestinal cancer (e.g., stomach, intestine, etc.), etc.)
- (54) in vitro generation of skeletal tissue, such as from skeletogenic stem cells, as well as the in vivo treatment of skeletal tissue deficiencies including bone or connective tissue, no matter how the deficiency originated, e.g. whether as a result of surgical intervention, removal of tumor, ulceration, implant, fracture, or other traumatic or degenerative conditions;
- (55) regulation of the rate of chondrogenesis and/or osteogenesis;
- (56) restoring cartilage function to a connective tissue;
- (57) repair of defects or lesions in cartilage tissue which is the result of degenerative wear such as that which results in arthritis, as well as other mechanical derangements which may be caused by trauma to the tissue, such as a displacement of torn meniscus tissue, meniscectomy, a Taxation of a joint by a torn ligament, malignment of joints, bone fracture, or by hereditary disease;
- (58) remodeling cartilage matrix, such as in plastic or reconstructive surgery, as well as periodontal surgery. The present method may also be applied to improving a previous reparative procedure, for example, following surgical repair of a meniscus, ligament, or cartilage, as well as prevention of the onset or exacerbation of degenerative disease if applied early enough after trauma;
- (59) treating afflicted connective tissue to regulate a cartilage repair response in the connective tissue by managing the rate of differentiation and/or proliferation of chondrocytes embedded in the tissue;
- (60) treating afflicted connective tissue to regulate a repair response in the connective tissue where the connective tissue is articular cartilage, interarticular cartilage (menisci), costal cartilage (connecting the true ribs and the sternum), ligaments, and tendons, diarthroidal joint, such as a knee, an ankle, an elbow, a hip, a wrist, a knuckle of either a finger or toe, or a tempomandibular joint;
- (61) enhance attachment of prosthetic devices;
- (62) control of endochondral ossification in the formation of a “model” for ossification in the generation of bone
- (63) regulation of speramatogenesis and/or ovarian function;
- (64) promotion of wound healing, reducing or avoiding scarring of wounds once healed;
- (65) treatment of corneopathies marked by corneal epithelial cell proliferation, as for example in ocular epithelial disorders such as epithelial downgrowth or squamous cell carcinomas of the ocular surface, degenerative diseases of the retina;
- (66) dermatological diseases, such as lesions resulting from autoimmune disorders such as psoriasis, atopic dermatitis, such as skin trauma resulting from allergies associated with an immune response caused by allergens such as pollens, foods, dander, insect venoms and plant toxins, etc.;
- (67) regulating hair growth in the treatment of trichosis characterized by abnormally rapid or dense growth of hair, e.g. hypertrichosis;
- regulating unwanted but normal hair growth;
- (68) treatment of folliculitis, such as folliculitis decalvans, folliculitis ulerythematosa reticulate, keloid folliculitis, pseudofolliculitis;
- (69) treatment of hyperplastic epidermal conditions, such as keratosis, as well as for the treatment of neoplastic epidermal conditions such as those characterized by a high proliferation rate for various skin cancers, as for example basal cell carcinoma or squamous cell carcinoma, dermatological diseases involving morbid proliferation and/or keratinization of the epidermis, as for example, caused by psoriasis or atopic dermatosis, basal cell nevus syndrome (BCNS), and other human carcinomas, adenocarcinomas, sarcomas and the like;
- (70) treatment of actinic keratoses, acne,
- (71) controlling the formation of megakaryocyte-derived cells and/or controlling the functional performance of megakaryocyte-derived cells;
- (72) treatment or prevention of a variety hyperplastic or neoplastic conditions affecting platelets;
- (73) reduction or elimination of side effects of other therapeutic agents, such side effects being without limitation, hirsuitism (excess hair growth due to hormones), shortened life spans, cardiovascular diseases (with the use chemotherapeutic agents like tamoxifen and herceptin) and vascular occlusion (stroke risk with hormonal/birthcontrol use), organ toxicity, hyperglycemia and diabetes exacerbation (with hormonal/birthcontrol use), steroidal glaucoma, hypertension (from birth control use or hormone use), and increased susceptibility to infections (from steroid akaloids and chemotherapeutics agents) or other types of cancers;
- etc.;
- and/or
- (74) correction of aberrant Folbp1 activity
- (75) use as a synergistic inhibitor of autoimmune diseases mediated by defective or overactive signaling pathways;
- (76) treatment of autoimmune diseases mediated by defective or overactive signaling pathways;
- (77) treatment of Achlorhydra Autoimmune Active Chronic Hepatitis, Addison's Disease, Alopecia Areata, Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig's Disease), Ankylosing Spondylitis Anti-GBM Nephritis or anti-TBM Nephritis, Antiphospholipid Syndrome Aplastic Anemia, Rhematoid Arthritis, Asthma, Atopic Allergy, Atopic Dermatitis, Autoimmune Inner Ear Disease (AIED), Autoimmune Lymphoproliferative Syndrome (ALPS), Balo Disease, Behcet's Disease, Berger's Disease (IgA Nephropathy), Bullous Pemphigoid, cardiomyopathy, Celiac Disease, Chronic Fatigue Immune Dysfunction Syndrome (CFIDS), Churg Strauss Syndrome, Cicatricial Pemphigoid Cogan's Syndrome, Cold Agglutunin Disease, Colitis, Cranial Arteritis, CREST Syndrome, Crohn's Disease, Cushing's Syndrome, Dego's Disease, Dermatitis, Dermatomyositis, Devic Disease, Type 1 Diabetes, Type 2 Diabetes, Dressler's Syndrome, Discoid Lupus, Eczema, Essential Mixed cryoglobulinemia, Eosinophilic Fasciitis, Epidermolysis Bullosa Acquisita, Evan's Syndrome, Fibromyalgia, Fibromyositis, Fibrosing Alveolitis, Gastritis, Giant Cell Artertis, Glomerulonephritis, Goodpasture's Disease, Grave's Disease, Guillian-Barre Syndrome, Hashimoto's Thyroiditis, Hemolytic Anemia, Henoch-Schonlein Purpura, Hepatitis, Hughes Syndrome, Idiopathic Adrenal Atrophy, Idiopathic Pulmonary Fibrosis, Idiopathic Thrombocytopenia Purpura, Inflammatory Demylinating Polyneuropathy, Irritable Bowel Syndrome, Kawasaki's Disease, Lichen Planus, Lou Gehrig's Disease, Lupoid Hepatitis, Lupus, Lyme Disease, Meniere's Disease, Mixed Connective Tissue Disease, Multiple Myeloma, Multiple Sclerosis, Myasthenia Gravis, Myositis, Ocular Cicatricial Pemphigoid, Osteoporosis, Pars Planitis, Pemphigus Vulgaris, Polyglandular Autoimmune Syndromes, Polymyalgia, Rheumatica (PMR) Polymyositis, Primary Biliary Cirrhois, Primary Sclerosing Cholangitis, Psoriasis, Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Scleritis, Scleroderma, Sjogren's Syndrome, Sticky Blood Syndrome, Still's Disease, Stiff Man Syndrome, Sydenham Chorea, Systemic Lupus Erythmatosis (SLE), Takayasu's Arteritis, Temporal Arteritis, Ulcerative Colitis, Vasculitis, Vitiligo, Wegener's granulomatosis, and Wilson's syndrome;
- and/or
- (78) inhibition of Akt;
- inhibition of PDK1;
- modulation of GSK3;
- modulation of PH domains;
- selective inhibition of one or more of Akt1, Akt2 and Akt3;
- selective inhibition of Akt isoforms containing at least one of an Akt PH domain and an Akt hinge portion;
- selective inhibition of PDK1;
- protective against TNF mediated cell apoptosis;
- sensitize cells to interferon alpha;
- modulations of the PI3K signaling activity;
- inhibitors of the activity of PI3-kinase/PDK1/AKT-dependent signaling pathway;
- treatment of irregularities in the activity of Akt and/or GSK3;
- inhibition of PKB;
- inhibition of pro-inflammatory cytokines;
- treatment of hepatitis;
- treatment of hepatitis in combination with an interferon;
- treatment of anemia;
- treatment of anemia secondary to enlarged spleen;
- treatment of anemia associated with chronic active hepatitis;
- inhibition of overexpression of SOC3 and or SHP2;
- upregulation of p27kip1;
- overcoming herceptin resistance;
- upregulating p21cip;
- inhibition or downregulating Ap-1;
- and/or inhibition or downregulating ppRb.
121 more elements
Dependencies are inferred from the claim text.