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  • Metadichol® Vitamin D Inverse Agonist

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    Dr P.R. Raghavan
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    Vitamin D, Inverse agonist, MRSA, Platelet counts, Lp(a) , Kidney diseases, MDS, Creatinine, Skin diseases, Psoriasis, Eczema, VDR, anti-malarial , Prostate cancer, Ferritin, Hemoglobin , white cell count improvement, Pluripotent stem cells, Liver diseases, PTH

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    Metadichol® Vitamin D inverse Agonist

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    Vitamin D, Inverse agonist, MRSA, Platelet counts, Lp(a) , Kidney diseases, MDS, Creatinine, Skin diseases, Psoriasis, Eczema, VDR, anti-malarial , Prostate cancer, Ferritin, Hemoglobin , white cell count improvement, Pluripotent stem cells, Liver diseases, PTH

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    112 visualizzazioni45 pagine

    Metadichol® Vitamin D Inverse Agonist

    Caricato da

    Dr P.R. Raghavan
    Vitamin D, Inverse agonist, MRSA, Platelet counts, Lp(a) , Kidney diseases, MDS, Creatinine, Skin diseases, Psoriasis, Eczema, VDR, anti-malarial , Prostate cancer, Ferritin, Hemoglobin , white cell count improvement, Pluripotent stem cells, Liver diseases, PTH

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    0800900629282 2) United States Patent (10) Patent Noz US 9,006,292 B2 Raghavan (4s) Date of Patent: Apr. 14, 2015 (91) METADICHOL® LIQUID AND GEL (22) us.c. NANOPARTICLE FORMULATIONS cee AGIK 31/45 (2013.01); AOIK 9/14 (GoiSi}, aot 4742 (3013.01), B82Y 30.00 Applicant: NawoRx, Ine, Chappaqua, NY (US) Garson, ¥108977773 Goix0} (58) Fleld of Ctassifeation Search Tnveator’ PalayakotalR, Raghavan, Choppaqus, Coe AbIK 31/085; BS2¥ 30/00 NYS) ust 314728, 977/773 ‘See aplication fie for complete search history. (73) Assignee: NunoRs, Ine. Chappaqua, NY (US) 66) References Cited (4) Notice: Suibjct to any disclaimer, the term of this patent is extended of adjusted under 35 US. PATENT DOCUMENTS USC. 1540) by 29 days, 470871 A 61987 Clark 20090198616 AL 102003 Howard aonsiyrass) AL ‘42005 “Treadwell 200710196507 Al $2007 Majeed eal ROOHOLOLZR AL 72009 Squires a100215752 AL $2010. Raghiwan 65) Prior Publication Data SOIMODASIDO AL 22013. Chustnt al (21) Appl. Nos 147208,243, (22) Filed: Mar. 14,2014 US 201410275285.A1 Sep. 18, 2014 Primary E Raymond Henley, I (74) Awtornes, Agent, or Firm — Mong, Lewis & Bockius LLP Related US. Application Data (60) Provisional application No. 61/794,490, fled on Mar. (57) ae 15,2013. Te present invention provides methods of regulating physi- ological and metabolic parameters and of treating diseases by (SH Inve ‘administering metadictol toa subject in need of such rogue AGIK 31/045 (2005.01) Jation andor weatment. Metadichol can be administered as a Ba2v 3000 (201101), Tiguid or gel formulation, AGIK 9/14 (2006.01), AGIK 47/32 (2006.01) 12 Claims, 18 Drawing Sheets U.S. Patent Apr. 14, 2015 Sheet 1 of 15, US 9,006,292 B2 + 2 E 2 2 3 2s é ; P 4 og 8 ° als 3/5 Ayayoe asesayion] aanejay 8 4 allele w ws | B/S a HAE 2 Pe oe 9 ° Zz ai5/2 3 5/3|8 s 55|2 5 vo e E S E © v 2 3% oc & 2ee2e220 - AYAre asesayI9N7 aAjeEjay US 9,006,292 B2 Sheet 2 of 15 Apr. 14, 2015 U.S. Patent 082 jiu oeipeony $2k $28 7@3yNdld 60s Is OH US 9,006,292 B2 Sheet 3 of 15 Apr. 14,2015 US. Patent 8 >1299M € ayndld auljaseq US 9,006,292 B2 Sheet 4 of 15 Apr. 14,2015 U.S. Patent bands U.S. Patent Apr. 14, 2015 Sheet 5 of 15 US 9,006,292 B2 FIGURE 5 U.S. Patent Apr. 14, 2015 Sheet 6 of 15, US 9,006,292 B2 week 12. FIGURE 6 week 8 US 9,006,292 B2 Sheet 7 of 15 Apr. 14,2015 US. Patent 799M £3aynodld auyjaseq U.S. Patent Apr. 14, 2015 Sheet 8 of 15, US 9,006,292 B2 FIGURE 8 US 9,006,292 B2 Sheet 9 of 15 Apr. 14,2015 US. Patent syaam ¢ @ 6 3uNDId U.S. Patent Apr. 14, 2015 Sheet 10 of 15 US 9,006,292 B2 Week 4 FIGURE 10 baseline US 9,006,292 B2 Sheet 11 of 15 Apr. 14,2015 US. Patent a Fe - _. TT aYuNSI4 U.S. Patent Apr. 14, 2015 Sheet 12 of 15 US 9,006,292 B2 FIGURE 12 U.S. Patent Apr. 14, 2015 Sheet 13 of 15 US 9,006,292 B2 FIGURE 13 U.S. Patent Apr. 14, 2015 Sheet 14 of 15 US 9,006,292 B2 FIGURE 14 U.S. Patent Apr. 14, 2015 Sheet 15 of 15 US 9,006,292 B2 FIGURE 15 w a i 1 4 oO US 9,006,292 B2 1 METADICHOL® LIQUID AND GEL. NANOPARTICLE FORMULATIONS. PRIORITY CLAIM ‘This application claims prorty to US. Patent Application No. 61/794, 490, ied Mar 15,2013, the contents of whichare ‘ncomporated by relerence in their entirety forall purposes FIELD OF THE INVENTION “The present invention relates to @ novel formulation of Metadichol® a Nano particulate in liquid oral and in poly- meric Nano gel formulation, The Metadichol® formulation (previously described in US patent application (Ser. No. 121691,706)) behaves as an inverse agonist against the Vita- ‘iin D receptor (VDR). This aplication relates to methods of treating, and preventing diseases and extends the therapettic ‘effects beyond what is observed with 1,25 dihydroxy Vitamin 1, (Caletrol) the active form of Vitamin D in the human body. BACKGROUND OF THE INVENTION Vitamin D, acquired either from dietary sources or via Ultraviolet iradiation of -dehydrocholesterol in the epider- mis, is metabolized to its hormonal form. The Keratinocytes ‘of the skin are unique in being not only the primary souree of vitamin D for the body, but also possessing the enzymatic machinery to metabolize Vitamin D to active metabolites “Many functions of the skin are regulated hy vitamin D andlor its reveptor: these include inhibition of proliferation, stim- lation of differentiation including formation af the permeabil- lay barier, promotion of innate immunity, elation of the hair follicle eyele, and suppression of tumors. ‘When exposed 1 ultraviolet radiation, cells inthe epider. mis convert @ cholesterol related steroid to vitamin D oF ‘holecaleiferol. Vitamin D is essential for proper develo: ‘ment of the bones. The ultraviolet radiation necessary for vitamin D synthesis (specifically, UV-B) only reaches the Eanh's surface in much abundance for afew hours a day ‘when the sun is high. Much less of it reaches the Ban's surface at high latitudes than at low latitudes, and very litle reaches the Earths surface on cloudy days or during the winter Bven so, the average fiir-skinned person can make and store several days” worth of vitamin D with just one hour's exposure to the midday sun. Dark-skinned people Fiving at high latimides are much more likely to sue from vitamin D deficiency than are light-skinned people. The most important source of Vitamin D is throvgh the sction of sunoa cholesterol on the skin. Vitamin D modulates Teeell responses and has anti-inilammatory properties, and boos inate immune responses by induction ofthe humia ‘gene for eathelicdin, Cathelicdin’s and defensins are small, Peptides with amphipathic structures that allow them to dis- up the integity of the pathogen cell membrane, resulting in ts death, Most immune cells or those epithelial cells that are Jn contact wth the environment express these proteins, Det ‘ciency in these peptides results in increased susceptibility (0 infection, ‘Vitamin D enters the ceculation and is tamsported wo the liver where itis hydroxylated to form 25-hyroxywitamin Ds (caleidiol; the major circulating form of vitamin D), In the kidneys, the 25-hydroxyvitamin D-L-hydroxylase enzyme ‘catalyzes a second hydroxylation of 25-hydroxyvitamin resulting in the formation of 1.25-dibydroxyoitamin D, (cle ‘rick J Hay, ET.AL, Journal of investigative Dermatology (28 ‘Oct. 2013) estimated the GBD attributable to 15 categories of skin disease from 1990 to 2010 for 187 countries, At the _lobal level, skin conditions were the fourth leading eause of ronftal disease burden. Using more data than has hova used. 30 previously, the burden due to these diseases is enormous in both high- and low-income countries. These results argue strongly to include skin disease prevention and treatment in ‘tue global healt strategies as a matter of urgency Circulating 1.25 dihydroxy D3, bound by DBP (D binding protein), can be delivered systemically 1 vitamin D target ‘ells that retzin the hormone through expression of the nuclear vitamin D receptor (VDR). Intestinal epithelial ells and osteoblasts represent primary sites of VDR (Vitamin D Revoptor) expression, where the receptor mediates the actions of 1.25 dihydroxy D3 to promote intestinal calcium and phosphate absorption, and to remodel skeletal mince, respectively (Haussler, etal. 2013, Caleif Tissue Int, 92:77. 98). When occupied by 1,25D, VDR interacts withthe rein- ‘oid X reveptor (RXR) to fore a blero dimer that binds 10 vitamin D respoasive elements inthe region of genes directly controlled by 1.28D. By recruiting complexes of either co- ‘etivators oF co-eepressors,.ligand-activated VDR-RXR ‘modulates the transcription of genes encoding proteins that promulgate the traditional functions of vitamin D, including Signaling intestinal calcium and phosphate absorption to ‘effect skelotal and calcium homeostasis. The disease targets, ‘eavisioned for vitamin D analogs, appropriately, include ‘osteoporosis by bone-mineral mobilization, secondary hyperparathyroidism to reduce PTH gene transcription and blocking chief cell hyperplasia, autoimmune diseases such as psoriasis and asthma, organ-transplant rejection, benign pros- tate hyperplasia, involuntary bladder conto, blood pressure ‘control by suppressing renin biosynthesis, type I diabetesand insulin seeretion by affecting pancreatic cell function ani inflammatory evens via eyeloonygenase-2 (COX-2) inhibi tion, and cancer va the established ant proliferative and pro differentiating eects ona variety of cll fines, such as breast, prostate and colon. (Pike, etal, 2012, Rev Endocr Metab Disord, 13:45-55), In this fashion, 1.28 dibydroxy D3 clic i two major Junctions of preventing rickets in children and osteomalacia 6 inaduls, as wellas strengthening bone via remodeling. Thus, although vitamia D has no diret role in bone calcification it isresponsibleforsupplying adequate amounts of caleiumand phosphors minerals xtra renal 1,25 dinydroxy Vitamin D, can also be pro- duced locally in a number of cell types that express VDR. ‘notably skin, cells ofthe immune system, colon, pancreas, and the vasculature, The significance of local effets of 125 dihydroxy D,-VDR i not defined fully, butt appears that vitamin D, likely cooperating with other regulators, exerts immuno regulation, antimicrobial defense, xenobiotic detoxification, anti-cancer aeons, control of insulin ssere- ‘ion and cardiovascular benefits, (Hussler, etal 2013, Calcif Tissue Int 92:77-98), 1, 25-lihydroxyeholecaliferol, ie, calito, the biologi cally active form of vitamin D'is a secosteroid that acts ‘through binding to the VDR inside ces. VDRS have been suggested to reside in the eytoplasm and inthe nucleus with- ‘out hormone in an unbound state. The VD binds several Torms of cholecalciferol; however its allinity for 1,25-ihy- droxycholocaleifeol is roughly 1,000 times that of 25-hy- treatment; drugs used in combination or coincidental withthe specific agent and ike factors well known inthe medical ars. ‘The Methods ‘The present invention provides methods of wsing these Nano particles of Metadichol® in liquid or gel form and prevent diseare and to regulate metabolism, In various ‘embodiments, the Nano paricleNano particles ofthe inven- tion in iguid form are of tse to regulating Lp(a), Apa (a) and Apo (b)proten levels, Uric aed, Parathyroid hormone levels, ‘decreasing bun ratios in kidney patiens, Regulating Phos- phorous ad Calcium levels, Poassinm levels in hypertension pationts, ert loves, TSH levels, nevtropenia, modulating aspartate aminotransferase (AST) or serum glutamic-oxalo= acetic transaminase (SGOT), alanine aminotransferase (ALT) or serum glutamate pyrivate transaminase [SGPT), levels, modulating. absolle neutrophil and Lymphocyte ratios and modulating albumin in hyperlipidemia patients The Metadichol® gel formulations i topically used in tweating various skin diseases like aene, MRSA infection, Eczema, Psoriasis, and preventing and/or treating skin dis- ‘eases including, bit not limited to, psoriasis and atopic der- mattis 2s well as providing anti-aging benefits which results in reduced appearance of wrinkles and aged skin, improved skin color, treatment of photo damaged skin, improvement ia skin’s radiance and clanity and finish, and an overall healthy tnd youthful appearance of the skia, involving aberrant rngiogenesis and hyperplasia Tan exemplary embodiment, the formulations are admin- jaterod in a therapeutically effective amount to a subject to treat a particular disease or disorder and wherein the subjeot isnot otherwise in nesd of treatment with Metadichol. In various embodiments, the Metadichol® is administered 10 teat a single disease or regulate a single metabolic factor. Thus, ian exemplary embodiment, the invention provides 3 method to reat Lipoprotein (a) in a subject notin need of treatment for hyperlipidemia, hypercholesterolemia, hyper tension, ete. Inan exemplary embodiment, the invention pro- Vides a method of regulating parathyroid hormones levels in subject notin need of treatment for kidney disease, hyper- Tipidemia, hypercholesterolemia, etc. In various embodi- ions, the invention provides a method of treating Potassium levels ina subject not i noed of treatment for hypertension, 0 o 16 iabetes ee, In various embodiments, the invention provides ‘a method to decrease or prevent neutropenia in a subject who {is notin need of weatment for weatment for Kidney diseases, Inflammation ete, In an exemplary embodiment, the inven” ‘ion provides a method of inereasing Apo Protein a) levels in subject notin need of treatment for hyperlipidemia, hyper- cholesterolemia, et. In other embodiment, the invention provides a method of modulating AST and ALT levels in a ‘subject notin need of treatment for hyperlipidemia, hypere- bolesterlemia, ec Tn various embodiments, the Metadichol® ge is used in Hevea, Psoriasis, Lipoma tumors on emoving wrinkles and ‘warts and in MRSA and her skin inetions ‘Non-imiting examples of methods of the invention are set {orth below: Urie Acid The invention provides @ method of decreasing Uric acid levels in a subject and, therefore, reducing the deleterious consequences of this oxidation. The method includes admin- istering lo a subject therapeutically effective amount of ‘Metadichol¥ to decrease protein oxidation ina subject. Uric acids present in small amounts in everyone's bodies and is made ftom the breskdcwn of purines, which are released as part ofthe body's normal fanetioning and ean be absorbed by the bod'from certain types of food (Such as meat for seafood), In addition 2 number of epidemiological studies Ihave reported a relation between serum uric aid levels and a Wide vieity of eadiovaseular conditions, including hyper tension, (Acosta, etal. 2005, 1 Am Soe Nephrol 16,009- 1919; Henig M, etal. 2006, Cleveland Clinie Journal of Medicine, 73(12):1059-64), Uric acid may play a role in the metabolic syndrome Historically, the elevated level of uri acid abserved in the metabolic syndrome has been attributed tobyperiasulinensi, ince insulin reduces renal excretion of trie seid. Hiypenuri- ‘emia, however, often precedes the development of hyperin- Sulinemi, obesity, and diabetes. Hyperaricemia may also be present in the metabolic syndrome in people wo are not foverwcight or obese. (Tyagi, etal, Nutrition & Metabolism, 2004, 1:10), Hyperaricemia is strongly associated with peripheral, carotid, and coronary vascular disease, with the ‘development of stroke, with preeclampsia, and with vascular ‘dementia, The relationship of uric acid with cardiovascular events is parcularlystong, especially inpatients at high isk Tor heart disease and in women. In cononary artery disease, (azz, et a, 2006, The Journal of Clinical Fypertension 8(7)S10). ‘Serum uri acid isa strong predictor of stroke inpatients ‘with aon-insulin dependent diabetes mellitus ND cerebrovas- cular disease, (Puig, etal, 2007, Nutrition, Metaboliom & Cardiovascular Diseases, 17, 403414). Gout isatypeofartiritiseausedby ure acid buik-up inthe joints (dhe places where two or more bones come together). ‘When uric ace levels inthe body are high (known as hype ruricemia), uric avid erystalscan form i the Mid around the joins there is too much uric acid around the joints, iflam- ‘mation (a condition in which apart of your body can become red, swollen and painful) ean eur, which may lead to. go attack (Tavsche A K, et al, 2006, Der Internist, 47(5)509- 20) Leseh-Nyhan Syndrome TTesch-Nyhan syndrome, an extremely rare inherited i ‘order, isalso ass iated with very high serum uric acid levels Spasticty, involuntary movement and eognitve retardation as well 38 manifestations of gout are sen in cases of this syndrome. (Nyhan W.L2008, Journal ofthe History ofthe Neurosciences, 14(1) 1-10). US 9,006,292 B2 17 Uric Acid Stone Formation ‘Saturation levels of uri acid in blood may result in one orm ot kidney Sones when the urate crystallizes in the kid- ney. Urieacid stones, which form in theabsence of secondary ‘elses such as chronie diarehea, vigorous exorcise, dehyde tion, and animal protein loading, are felt to be secondary to ‘obesity and insulin resistance seen in metabolic syndrome. Increased dictary acd leads to increased endogenous acid producti in the liver and muscles, which i turn leads to an Increased acid load to the kidneys. This lod is handled more poorly because of renal ft infiltration and insulin resistance, Which are Felt o impair ammonia excretion (a buffer). The urine is therefore quite avidie, and uric acid becomes insoluble, crystallizes and stones form, In addition, natirally present prontoter and inhibitor factors may be affected, This ‘explains the high prevalence of urie stones and unusually acidic urine soon in patients with type 2 diabetes. Ure acid ‘enstals can also promote the formation of calcium oxalate stones, acting as “seed erystals” (heterogeneous nucleation). (PakC-Y, etal. 2008; The Jounal of Urology, 180(3)'813-9) ‘iyperaricemia has been shown to be associated with his ‘ological liver damage in patients with non-aleoholie fatty liver disease (NAFLD). Is elinical relevance arises from the fact that a considerable proportion of subjects (20-30%) develop a condition namely non-alcoholic steatoeppattis > (NASH) that is a potentially progressive hepatic disorder leading to end-stage liver disease and hepatocellular carei- roma, Inaddition NAFLDis considered the hepatic maaifes- tation of insulin resistance (IR), and is therefore strongly associated with metabo syndrome, obesity type TI diabe> tes, dyslipidemia and hypertension, also representing, ‘ogether with the above cited conditions an independent ear diovascular risk fctor. In these patients. (Non-aloahoic fatty liver disease (NAFLD) is @ leading cause of chronic liver disease worldwide. (S. Petia, etal, linen Pharmacol Ther, 2011, 34:757-766), Uric Acid and Parkinson's Disease (PD) PD is the second most common age related neurodegen- ‘erative condition in the US, affecting approximately one per- ‘ent ofthe population over the ageof 65 in North Americaand Europe. The symptoms of PD are characterized by lose of ‘dopaminergic neurons in the substantia nigra. While the ‘ease of this loss is thought to be multifactorial, there is ‘evidence (0 support oxidative ress as a factor in neurode= teneration, Researchers have proposed that elevated levels of lricaeid yield a protective effect gains the development and progression of PD on the ass ofthese principles. There is also evidence to support the association between high det urate and a decreas incidence of PD. It should bested that there are numerous risks associated with hyperuricemia lets, such as gout, stroke and hypertension. At this pint, the data ‘we have suggests an association, but nota causa relationship between low senum urate and the incidence of PD, This asso- ‘iaton is intriguing as there is the potential that in the future physicians could modify a patients risk for PD by suggesting ‘ietary changes or using pharmacological supplement. Over- all, recent research supports an inverse relationship between, serum urate levels and the ineidence of PD in men, (Mandel, etal, 2009, Practical Neurology, p21). Fert Ferritin sa ubiquitous and speialized protein involved in the intracellular stage of ron; itisalso presen in serum and ‘other biological us, although its seeretion processes are stil unclear. Ferritin is nature's unique and conserved approach 10 controlled, safe use of iron and oxygen, with protein synthesis in animals adjusted by dual, genetic DNA ‘and mRNA sequences that selectively respond to ira oF 0 o 18 ‘oxidant signals and link feria to proteins of ira, oxygen and antioxidant metabolism. (Cairo, eta. 2008, Journal of Autoimmunity 30, 84-89), Feritin i key protein of iron metabolism that is cepable ‘ofsequestering large amounts of ion, and thusserves the dual function of ion detoxification and iron storage. The impor tance ofthese functions is underlined by its ubiquitous dis tcibution in many living species. The structural properties of the feritins are largely conserved from bacteria to man, although thee role in the regulation of iran talicking varies substantially Feritin synthesis is regulated by cytokines (TNFa. and IL-Laat various levels (canscriptional, post-ranserptional, ‘and trnslational) during development, cellular differentia ‘ion, proliferation, and inflammation. The celular response by cytokines to infection stimulates the expression of fri tenes. (Hintze K J, eta, 2006, Cell Mot Life Sci: 63:591- 600), Ferritin has been reported o exhibit different immunotogi- cal activities including binding to T lymphocytes, suppees- sion ofthe delayed type of hypersensitivity, suppression of antibody production by B lymphocytes, and decreased ‘hagoeytosisaf granulocytes (Marikina, K, eta, 999, Blood, 488:737-43). Ferritin and iron homeostasis have been implicated inthe pathogenesis of many diseases, including diseases involved ‘ron aequisition, transport and storage (primary hemochro- ‘matosis) as well asin atherosclerosis, Parkinson's disease, Alzheimer disease, and restles log syndrome. (Zandman, et Al, 2007, Autoimmunity Reviews, 6457-463), ‘Mtations inthe feritin gene ease the hereditary hyper: ferrtinemia-cataract syndrome and_neuroferitinopathy. Hyperfenitinemia is associated with inflammation, infec- ‘ions, and maljgnancies. Thyroid hormone, insulin and insw- lin growth factor have also been implicated in regulation of fervtin at the mRNA level (Beaumont C, et a, 1995, Nat Gone, 11:444-6; Nishiya K, ota, 1997, Clin Exp Rhewna- tol, 1539-44), ‘Some evidence points tothe importance of hyperferrtine- mia in RA, MS, and thyroiditis, Ferritin and iron homeostasis have boon implicated in the pathogenesis of many’ diseases, ‘including diseases involved in ron acquisition, transport and storage (primary hemochromatosis) as well as in aluerosle- nosis (Yau S. A, etal, 2005, Clin Chim Acta, 357:1-16). Genetic mutations ofthe ferritin IRE region a well as coding regions of fertin cause some hereditary human diseases Feritin IRE mutations eause the hereditary hyperferitne- Imia-eataract syndrome (Beaumont C, etal, 1997; Nar Genet, 11-44-4465) whieh isan autosomal dominant disease char- acterized by elevated ferritin levels and early-onset bilateral ‘Neurofeitinopathy, dominantly inherited movement isorder characterized by decreased levels of feritin and abnormal deposition of ferritin and iron inthe bain is eaused by a mutation inthe C-terminus ofthe ferritin L gene (Curtis AR J, etal, 2001, Nar Genet, 28:350-8). Ithas been shown, ‘that Serum ferritin concentration was foundto be related With

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