Methods, treatments, and compositions for modulating Hedgehog pathways
First Claim
1. A method for the prevention of or reducing the risk of birth defects comprising administering to a female of child bearing years a co-therapy comprising a first therapy of a component(a) which is a D-chiroinositol component selected from the group consisting of(i) D-chiroinositol,(ii) at least one phosphate of D-chiroinositol having said phosphate substituent selected from the group consisting of(iia) from 1 to 6 monophosphate groups per molecule,(iib) 1 to 6 pyrophosphate groups per molecule,(iic) 1 to 6 polyphosphate groups per molecule,(iid) cyclic derivatives of the forgoing wherein one or more phosphate groups together with the D-chiroinositol ring to which they are attached form at least one phospho containing ring,(iii) a derivative of (a)(i) or (a)(ii) which has, where valence permits,(A) at least one further substituent selected from the group consisting of(1) an aliphatic group which may be branched or unbranched or cyclic, saturated or unsaturated, unsubstituted or further substituted, and uninterrupted or interrupted by one or more heteroatoms, each of which may be unsubstituted or further substituted;
- (2) an aromatic group which may be unsubstituted or further substituted;
(3) a heteroaromatic group which may be unsubstituted or further substituted;
(4) —
CF3, —
CN, halo, optionally further substituted amino, azido, nitro, sulfhydryl, carboxy, esterified carboxy, amidated carboxy, carbamoyl, sulfato, sulfinyl, —
C(O)SH or a thioester thereof, —
C(S)OH or ester or amide thereof, —
C(S)SH, or thioester thereof, —
C(O)H, etherified hydroxy, or(5) a phosphorus containing group selected from phosphoryl, phosphonate and phosphinate each of which can be unsubstituted or further substituted or derivatized;
or(B)(1) a hydroxyl or hydrogen on a carbon of the inositol ring replaced by SH, amino, or halo;
(2) a hydrogen and a hydroxyl attached to the same carbon of the inositol ring replaced by ═
O, or ═
S;
(3) a hydroxy of the inositol ring replaced by hydrogen; and
(iv) mixtures thereof,(b) pharmaceutically acceptable salts thereof, and(c) mixtures thereof; and
a second therapy of a component comprising folic acid, one or more non-folic acid folate sources, pharmaceutically acceptable salts thereof and mixtures thereof.
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Accused Products
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 gene expression during prenatal development, post-natal development and during development in the adult organism.
109 Citations
51 Claims
-
1. A method for the prevention of or reducing the risk of birth defects comprising administering to a female of child bearing years a co-therapy comprising a first therapy of a component
(a) which is a D-chiroinositol component selected from the group consisting of (i) D-chiroinositol, (ii) at least one phosphate of D-chiroinositol having said phosphate substituent selected from the group consisting of (iia) from 1 to 6 monophosphate groups per molecule, (iib) 1 to 6 pyrophosphate groups per molecule, (iic) 1 to 6 polyphosphate groups per molecule, (iid) cyclic derivatives of the forgoing wherein one or more phosphate groups together with the D-chiroinositol ring to which they are attached form at least one phospho containing ring, (iii) a derivative of (a)(i) or (a)(ii) which has, where valence permits, (A) at least one further substituent selected from the group consisting of (1) an aliphatic group which may be branched or unbranched or cyclic, saturated or unsaturated, unsubstituted or further substituted, and uninterrupted or interrupted by one or more heteroatoms, each of which may be unsubstituted or further substituted; -
(2) an aromatic group which may be unsubstituted or further substituted; (3) a heteroaromatic group which may be unsubstituted or further substituted; (4) —
CF3, —
CN, halo, optionally further substituted amino, azido, nitro, sulfhydryl, carboxy, esterified carboxy, amidated carboxy, carbamoyl, sulfato, sulfinyl, —
C(O)SH or a thioester thereof, —
C(S)OH or ester or amide thereof, —
C(S)SH, or thioester thereof, —
C(O)H, etherified hydroxy, or(5) a phosphorus containing group selected from phosphoryl, phosphonate and phosphinate each of which can be unsubstituted or further substituted or derivatized;
or(B)(1) a hydroxyl or hydrogen on a carbon of the inositol ring replaced by SH, amino, or halo; (2) a hydrogen and a hydroxyl attached to the same carbon of the inositol ring replaced by ═
O, or ═
S;(3) a hydroxy of the inositol ring replaced by hydrogen; and (iv) mixtures thereof, (b) pharmaceutically acceptable salts thereof, and (c) mixtures thereof; and a second therapy of a component comprising folic acid, one or more non-folic acid folate sources, pharmaceutically acceptable salts thereof and mixtures thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 40)
-
- 12. A method of reducing or preventing breast tissue sensitivity to estrogenic insult (a) from dietary or environmental or medicinal sources in a patient in need thereof and/or (b) a patient of greater than average risk of such sensitivity comprising administering to said patient an estrogenic sensitivity reducing amount of a member selected from the group consisting of D-chiroinositol, a D-chiroinositol phosphate, a derivative of either, and mixtures thereof.
-
15. A composition comprising (a) a first component selected from folic acid, a non-folic acid folate source, pharmaceutically acceptable salts thereof, and mixtures thereof;
- and (b) a second component selected from the group consisting of (1) D-chiroinositol, (2) one or more phosphorylated derivatives of D-chiroinositol, (3) further derivatives of either, (4) pharmaceutically acceptable salts of any of the foregoing, and (4) mixtures thereof.
- View Dependent Claims (16, 17)
-
18. A composition comprising a component comprising a first therapy of a component
(a) which is an inositol component selected from the group consisting of (i) scyllo-inositol, epi-inositol, cis-inositol, allo-inositol, neo-inositol, muco-inositol, dextro-inositol, levo-inositol, and D-chiro-inositol, (ii) at least one phosphate of said inositol having said phosphate substituent selected from the group consisting of (iia) from 1 to 6 monophosphate groups per molecule, (iib) 1-6 pyrophosphate groups per molecule, (iic) 1-6 polyphosphate groups per molecule, (iid) cyclic derivatives of the forgoing wherein one or more phosphate groups together with the inositol ring to which they are attached form at least one phospho containing ring, (iii) a derivative of (a)(i) or (a)(ii) which has, where valence permits, (A) at least one further substituent selected from the group consisting of (1) an aliphatic group which may be branched or unbranched or cyclic, saturated or unsaturated, unsubstituted or further substituted, and uninterrupted or interrupted by one or more heteroatoms, each of which may be unsubstituted or further substituted; -
(2) an aromatic group which may be unsubstituted or further substituted; (3) a heteroaromatic group which may be unsubstituted or further substituted; (4) —
CF3, —
CN, halo, optionally further substituted amino, azido, nitro, sulfhydryl, carboxy, esterified carboxy, amidated carboxy, carbamoyl, sulfato, sulfinyl, —
C(O)SH or a thioester thereof, —
C(S)OH or ester or amide thereof, —
C(S)SH, or thioester thereof, —
C(O)H, etherified hydroxy, or(5) a phosphorus containing group selected from phosphoryl, phosphonate and phosphinate each of which can be unsubstituted or further substituted or derivatized;
or(B)(1) a hydroxyl or hydrogen on a carbon of the inositol ring replaced by SH, sulfato, amino, or halo; (2) a hydrogen and a hydroxyl attached to the same carbon of the inositol ring replaced by ═
O, or ═
S;(3) a hydroxy of the inositol ring replaced by hydrogen; and (iv) mixtures thereof, (b) pharmaceutically acceptable salts thereof, and (c) mixtures thereof; and and a second component selected form the group consisting of (1) a folic acid or other folate source; (2) an estrogenic hormone; (3) an estrogenic mimetic non-hormone; (4) an androgen ablative compound; (5) antiprogestogens, androgens, antiandrogens, estrogens, selective estrogen receptor modulators, aromatase inhibitors, gonadotropins, ovulation stimulators, gonadotropin releasing hormone agonists, gonadotropin releasing hormone antagonists, LHRH agonists, progestins, and anti-progestins; (6) 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), cyclophosphamide, 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(7) 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 incompatibility.
-
-
19. A method of co-therapy comprising administering to a mammal a first component
(a) which is a inositol component selected from the group consisting of (i) scyllo-inositol, epi-inositol, cis-inositol, allo-inositol, neo-inositol, muco-inositol, dextro-inositol, levo-inositol, and D-chiro-inositol, (ii) at least one phosphate of inositol having said phosphate substituent selected from the group consisting of (iia) from 1 to 6 monophosphate groups per molecule, (iib) 1-6 pyrophosphate groups per molecule, (iic) 1-6 polyphosphate groups per molecule, (iid) cyclic derivatives of the forgoing wherein one or more phosphate groups together with the inositol ring to which they are attached form at least one phospho containing ring, (iii) a derivative of (a)(i) or (a)(ii) which has, where valence permits, (A) at least one further substituent selected from the group consisting of (1) an aliphatic group which may be branched or unbranched or cyclic, saturated or unsaturated, unsubstituted or further substituted, and uninterrupted or interrupted by one or more heteroatoms, each of which may be unsubstituted or further substituted; -
(2) an aromatic group which may be unsubstituted or further substituted; (3) a heteroaromatic group which may be unsubstituted or further substituted; (4) —
CF3, —
CN, halo, optionally further substituted amino, azido, nitro, sulfhydryl, carboxy, esterified carboxy, amidated carboxy, carbamoyl, sulfato, sulfinyl, —
C(O)SH or a thioester thereof, —
C(S)OH or ester or amide thereof, —
C(S)SH, or thioester thereof, —
C(O)H, etherified hydroxy, or(5) a phosphorus containing group selected from phosphoryl, phosphonate and phosphinate each of which can be unsubstituted or further substituted or derivatized;
or(B)(1) a hydroxyl or hydrogen on a carbon of the inositol ring replaced by SH, -sulfato, amino, or halo; (2) a hydrogen and a hydroxyl attached to the same carbon of the inositol ring replaced by ═
O, or ═
S;(3) a hydroxy of the inositol ring replaced by hydrogen; and (iv) mixtures thereof, (b) pharmaceutically acceptable salts thereof, and (c) mixtures thereof, and a second component selected form the group consisting of (1) a folic acid or other folate source; (2) an estrogenic hormone; (3) an estrogenic mimetic non-hormone; (4) an androgen ablative compound; (5) antiprogestogens, androgens, antiandrogens, estrogens, selective estrogen receptor modulators, aromatase inhibitors, gonadotropins, ovulation stimulators, gonadotropin releasing hormone agonists, gonadotropin releasing hormone antagonists, LHRH agonists, progestins, and anti-progestins; (6) 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), cyclophosphamide, 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(7) 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 incompatibility. - View Dependent Claims (20, 26, 27, 28, 29, 30, 31, 32, 33, 44, 45)
-
-
21. A method of reducing or preventing breast tissue sensitivity to estrogenic insult from estrogenic, progestogenic, or antiandrogenic therapy in patient receiving such therapy comprising administering to said patient co-therapy therewith using an estrogenic sensitivity reducing amount of at least one compound selected from the group consisting of D-chiroinositol, a D-chiroinositol phosphorylated derivative, a further derivative of either, pharmaceutically acceptable salts of the foregoing, and mixtures thereof.
-
22. A co-therapy method comprising administering
(a) D-chiroinositol or a P, PP, or Poly P derivative thereof, or further derivatives of the foregoing (b) optionally folic acid or another folate source, and (c) one or more agents selected from the groups of classes of active agents consisting of antiprogestogens, androgens, antiandrogens, estrogens, selective estrogen receptor modulators, aromatase inhibitors, gonadotropins, ovulation stimulators, gonadotropin releasing hormone agonists, gonadotropin releasing hormone antagonists, LHRH agonists, progestins, and anti-progestins.
-
34. A method of modulating cell proliferation in an animal comprising administering to said animal
(a) an inositol component selected from the group consisting of (i) scyllo-inositol, epi-inositol, cis-inositol, allo-inositol, neo-inositol, muco-inositol, dextro-inositol, levo-inositol, and D-chiro-inositol, (ii) at least one phosphate of said inositol having said phosphate substituent selected from the group consisting of (iia) from 1 to 6 monophosphate groups per molecule, (iib) 1-6 pyrophosphate groups per molecule, (iic) 1-6 polyphosphate groups per molecule, (iid) cyclic derivatives of the forgoing wherein one or more phosphate groups together with the inositol ring to which they are attached form at least one phospho containing ring, (iii) a derivative of (a)(i) or (a)(ii) which has, where valence permits, (A) at least one further substituent selected from the group consisting of (1) an aliphatic group which may be branched or unbranched or cyclic, saturated or unsaturated, unsubstituted or further substituted, and uninterrupted or interrupted by one or more heteroatoms, each of which may be unsubstituted or further substituted; -
(2) an aromatic group which may be unsubstituted or further substituted; (3) a heteroaromatic group which may be unsubstituted or further substituted; (4) —
CF3, —
CN, halo, optionally further substituted amino, azido, nitro, sulfhydryl, carboxy, esterified carboxy, amidated carboxy, carbamoyl, sulfato, sulfinyl, —
C(O)SH or a thioester thereof, —
C(S)OH or ester or amide thereof, —
C(S)SH, or thioester thereof, —
C(O)H, etherified hydroxy, or(5) a phosphorus containing group selected from phosphoryl, phosphonate and phosphinate each of which can be unsubstituted or further substituted or derivatized;
or(B)(1) a hydroxyl or hydrogen on a carbon of the inositol ring replaced by SH, sulfato, amino, or halo; (2) a hydrogen and a hydroxyl attached to the same carbon of the inositol ring replaced by ═
O, or ═
S;(3) a hydroxy of the inositol ring replaced by hydrogen; and (b) pharmaceutically acceptable salts thereof, and (c) mixtures thereof; releasably bound to or embedded in or carried on or non-releasably bound to a first polymer carrier or first polymer matrix for administration as an oral, topical, parenteral, or implantable formulation; and optionally a second component active agent optionally (a) releasably bound to or (b) embedded in or (c) carried on or (d) non-releasably bound to a second polymer carrier or second polymer matrix for administration as an oral, topical, parenteral, or implantable formulation, said first and second polymer carrier and first and second polymer matrix being the same or different polymer, said second component active agent selected form the group consisting of (1) a folic acid or other folate source; (2) an estrogenic hormone; (3) an estrogenic mimetic non-hormone; (4) an androgen ablative compound; (5) antiprogestogens, androgens, antiandrogens, estrogens, selective estrogen receptor modulators, aromatase inhibitors, gonadotropins, ovulation stimulators, gonadotropin releasing hormone agonists, gonadotropin releasing hormone antagonists, LHRH agonists, progestins, and anti-progestins; (6) 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), cyclophosphamide, 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(7) 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 incompatibility. - View Dependent Claims (35, 36, 37, 38, 39, 41, 42)
-
-
43. A method for the modulation of a cell in culture or in vivo comprising contacting the cell with an effective amount of at least one compound selected from
(a) a inositol component selected from the group consisting of (i) scyllo-inositol, epi-inositol, cis-inositol, allo-inositol, neo-inositol, muco-inositol, dextro-inositol, levo-inositol, and D-chiro-inositol, (ii) at least one phosphate of inositol having said phosphate substituent selected from the group consisting of (iia) from 1 to 6 monophosphate groups per molecule, (iib) 1-6 pyrophosphate groups per molecule, (iic) 1-6 polyphosphate groups per molecule, (iid) cyclic derivatives of the forgoing wherein one or more phosphate groups together with the inositol ring to which they are attached form at least one phospho containing ring, (iii) a derivative of (a)(i) or (a)(ii) which has, where valence permits, (A) at least one further substituent selected from the group consisting of (1) an aliphatic group which may be branched or unbranched or cyclic, saturated or unsaturated, unsubstituted or further substituted, and uninterrupted or interrupted by one or more heteroatoms, each of which may be unsubstituted or further substituted; -
(2) an aromatic group which may be unsubstituted or further substituted; (3) a heteroaromatic group which may be unsubstituted or further substituted; (4) —
CF3, —
CN, halo, optionally further substituted amino, azido, nitro, sulfhydryl, carboxy, esterified carboxy, amidated carboxy, carbamoyl, sulfato, sulfinyl, —
C(O)SH or a thioester thereof, —
C(S)OH or ester or amide thereof, —
C(S)SH, or thioester thereof, —
C(O)H, etherified hydroxy, or(5) a phosphorus containing group selected from phosphoryl, phosphonate and phosphinate each of which can be unsubstituted or further substituted or derivatized;
or(B)(1) a hydroxyl or hydrogen on a carbon of the inositol ring replaced by SH, sulfato, amino, or halo; (2) a hydrogen and a hydroxyl attached to the same carbon of the inositol ring replaced by ═
O, or ═
S;(3) a hydroxy of the inositol ring replaced by hydrogen; and (iv) mixtures thereof, (b) pharmaceutically acceptable salts thereof, and (c) mixtures thereof; and optionally a second component active agent selected form the group consisting of (1) a folic acid or other folate source; (2) an estrogenic hormone; (3) an estrogenic mimetic non-hormone; (4) an androgen ablative compound; (5) antiprogestogens, androgens, antiandrogens, estrogens, selective estrogen receptor modulators, aromatase inhibitors, gonadotropins, ovulation stimulators, gonadotropin releasing hormone agonists, gonadotropin releasing hormone antagonists, LHRH agonists, progestins, and anti-progestins; (6) 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), cyclophosphamide, 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(7) 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 incompatibility.
-
-
46. 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 phophsoryl group selected from monophosphoryl groups, pyrophosphoryl, groups, and polyphosphoryl groups and a second component selected from a growth factor.
-
47. 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
(a) an inositol stereoisomeric compound selected from (i) scyllo-inositol, epi-inositol, cis-inositol, allo-inositol, neo-inositol, muco-inositol, dextro-inositol, levo-inositol, and D-chiro-inositol, (ii) at least one phosphate of said inositol having said phosphate substituent selected from the group consisting of (iia) from 1 to 6 monophosphate groups per molecule, (iib) 1-6 pyrophosphate groups per molecule, (iic) 1-6 polyphosphate groups per molecule, (iid) cyclic derivatives of the forgoing wherein one or more phosphate groups together with the inositol ring to which they are attached form at least one phospho containing ring, (iii) a derivative of (a)(i) or (a)(ii) which has, where valence permits, (A) at least one further substituent selected from the group consisting of (1) an aliphatic group which may be branched or unbranched or cyclic, saturated or unsaturated, unsubstituted or further substituted, and uninterrupted or interrupted by one or more heteroatoms, each of which may be unsubstituted or further substituted; -
(2) an aromatic group which may be unsubstituted or further substituted; (3) a heteroaromatic group which may be unsubstituted or further substituted; (4) —
CF3, —
CN, halo, optionally further substituted amino, azido, nitro, sulfhydryl, carboxy, esterified carboxy, amidated carboxy, carbamoyl, sulfato, sulfinyl, —
C(O)SH or a thioester thereof, —
C(S)OH or ester or amide thereof, —
C(S)SH, or thioester thereof, —
C(O)H, etherified hydroxy, or(5) a phosphorus containing group selected from phosphoryl, phosphonate and phosphinate each of which can be unsubstituted or further substituted or derivatized;
or(B) (1) a hydroxyl or hydrogen on a carbon of the inositol ring replaced by SH, sulfato, amino, or halo; (2) a hydrogen and a hydroxyl attached to the same carbon of the inositol ring replaced by ═
O, or ═
S;(3) a hydroxy of the inositol ring replaced by hydrogen; and pharmaceutically acceptable salts thereof, and mixtures thereof, alone or in combination with other active agents, said therapy being for (b) (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 estrogenic 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) modulating 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, Cowden syndrome, Carney complex, Birt-Hogg-Dubé
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, hedgehog, and/or smoothened signaling pathways in the modulation of endodermal stem cells, in vitro or in vivo; (50) modulation of ptc, hedgehog, 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 spermatogenesis 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, hirsutism (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 alkaloids and chemotherapeutics agents) or other types of cancers;
etc.; and
/or(74) correction of aberrant Folbpl activity. - View Dependent Claims (48, 49)
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50. 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.
-
51. 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, such as, without limitation, a cancerous lesion excision site or into an inoperable tumor, and 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 extending for as much as multiple years, which may migrate or be adhered in place to the delivery site, which adhesion, is, without limitation, via fibroblasts, monoclonal antibodies, charged particle portions, antisense DNA, antisense RNA etc.
Specification