DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2017/0035784 A1 Lancaster Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2017/0035784 A1 Lancaster Et Al US 20170035784A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0035784 A1 Lancaster et al. (43) Pub. Date: Feb. 9, 2017 (54) COMPOSITIONS OF OBETICHOLIC ACID (22) Filed: Apr. 26, 2016 AND METHODS OF USE Related U.S. Application Data (71) Applicants: Intercept Pharmaceuticals, Inc., New York, NY (US); Sumitomo Dainippon (60) Provisional application No. 62/153,040, filed on Apr. Pharma Co., Ltd., Osaka (JP) 27, 2015, provisional application No. 62/317,933, filed on Apr. 4, 2016. (72) Inventors: Richard Gail Lancaster, San Diego, CA (US); Kay K. Olmstead, Publication Classification Escondido, CA (US); Masashi Kagihiro, Osaka (JP); Mitsuhiro (51) Int. Cl. Matono, Osaka (JP); Ikuko Taoka, A 6LX 3/575 (2006.01) Osaka (JP); Mark Pruzanski, New A6II 45/06 (2006.01) York, NY (US); David Shapiro, A69/20 (2006.01) Rancho Sante Fe, CA (US); Roya (52) U.S. Cl. Hooshmand-Rad, San Diego, CA (US); CPC ........... A61K3I/575 (2013.01); A61K 9/2059 Richard Pencek, San Diego, CA (US); (2013.01); A61 K9/2054 (2013.01); A61 K Cathi Sciacca, San Diego, CA (US); 45/06 (2013.01); A61K 9/2072 (2013.01) Lise Eliot, San Diego, CA (US); Jeffrey Edwards, San Diego, CA (US); (57) ABSTRACT Leigh A. MacConell, Encinitas, CA (US); Tonya K. Marmon, San Diego, The disclosure relates to obeticholic acid formulations with CA (US) improved stability, dissolution, and/or solubility, methods of preparing the same for use and methods of treating various (21) Appl. No.: 15/139,138 diseases and conditions. Patent Application Publication Feb. 9, 2017. Sheet 1 of 37 US 2017/0035784 A1 C O O O O ve C O S ve O v O v O O v cs N sv OO 5 O V O os 8 an cs 9 CD 5 <C od S. oS 25 c Ois qs O ne OO v - H v H qs O ve C c. c. c. c. c. N N Cn vs O (%) (SueO eunON Patent Application Publication Feb. 9, 2017. Sheet 2 of 37 US 2017/0035784 A1 C O O O O ve C O O O ve OO 92 O 92 O O v g - N S2 E 5 S, CN aOO 5 CN 2 ccS 32t as CD s S n S - 75 .9 s 9 s O O H MO H d ve C C C C e O s CN O (%) (Sued eunON Patent Application Publication Feb. 9, 2017. Sheet 3 of 37 US 2017/0035784 A1 pact of AP Agglomeration and Jet Willing on the Dissolution of OCA fablets, 10 ng (900 in dissolution volune) G. &O. :-38.-- 8.------------------------------------------------------------------------------------------------------------------------------------------------------------------------- * Unmilled Non-Agglomerated AP (OCA) & Unmilled. Agglomerated AP (OCA) ... Jeti-MiEled AP (OCA) Patent Application Publication Feb. 9, 2017. Sheet 4 of 37 US 2017/0035784 A1 FG. 4 Patent Application Publication Feb. 9, 2017. Sheet 5 of 37 US 2017/0035784 A1 Buffers Dissolutioi Vedium Free acid BCS imit (5 mg) BCS imit (10 mg) F.G. 5 Patent Application Publication Feb. 9, 2017. Sheet 6 of 37 US 2017/0035784 A1 -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Biorelevant buffers Proposed disso medium Free acid BCS imit (5 mg) BCS imit (10 mg) 0.O O - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - F.G. 6 Patent Application Publication Feb. 9, 2017. Sheet 7 of 37 US 2017/0035784 A1 |sodTs 90UDpunqW 9ADey e3UDPunqW eN.De Patent Application Publication Feb. 9, 2017. Sheet 8 of 37 US 2017/0035784 A1 000|| Z/UU 8/'5)|–| 08 09 07 0Z 00|| 08 09 07 OZ e3UDpundy eNDey 00600800/00900900,700200Z Patent Application Publication Feb. 9, 2017. Sheet 10 of 37 US 2017/0035784 A1 090||000|09600609800809/100/09900909G097007099,009, (z/u.)96JD?.0-01-SSDWºsasjun00 Patent Application Publication Feb. 9, 2017. Sheet 11 of 37 US 2017/0035784 A1 09 / 99 07 Sdo (Sueu Patent Application Publication Feb. 9, 2017. Sheet 12 of 37 US 2017/0035784 A1 0960' (Z)?ODI?qnSpº?deudy#6]IgNHWNOGLI=fidu!(SuDOSÇZ‘uluuLLZ'yl-G60'y])uDOSISEH n) OO N. co r n CN Patent Application Publication Feb. 9, 2017. Sheet 13 of 37 US 2017/0035784 A1 * 3: 8 : : {x : & & & & & as 3. it g 2 is at 3 38 : : is 38 x s & is 38 FIG. 10 Patent Application Publication Feb. 9, 2017. Sheet 16 of 37 US 2017/0035784 A1 3. FIG. 13 Patent Application Publication Feb. 9, 2017. Sheet 17 of 37 US 2017/0035784 A1 & 2 S E 3i 3 Baselirie LP is FIG. 14A Patent Application Publication Feb. 9, 2017. Sheet 18 of 37 US 2017/0035784 A1 Titti s 2 . s" so st Baselire 8, Pi: F.G. 14B Patent Application Publication Feb. 9, 2017. Sheet 19 of 37 US 2017/0035784 A1 i.s t - 3 3 8 Baseline 8, Pil F.G. 14C Patent Application Publication Feb. 9, 2017. Sheet 20 of 37 US 2017/0035784 A1 e SE All : 3: AP Nixia Rate s Time entis F.G. 15A Patent Application Publication Feb. 9, 2017. Sheet 21 of 37 US 2017/0035784 A1 eat SE fotai Esilii is: x *ise: it is: 8s 33 : 383, itratigrit 3E30: 3: ; 38, i8 regit}E 8:3 Title initis FIG. 15B Patent Application Publication Feb. 9, 2017. Sheet 22 of 37 US 2017/0035784 A1 s 8:338 8:38: 388:8g F.G. 16 Patent Application Publication Feb. 9, 2017. Sheet 23 of 37 US 2017/0035784 A1 S tear (SE {{ { } {g actiherapy {{A : rig -- is A. ** 8 x : :a::seisse 883 : F.G. 17A Patent Application Publication Feb. 9, 2017. Sheet 24 of 37 US 2017/0035784 A1 Mono : +UCA = 6 r = : r = 1 n = 9. Mean BLALP 401 (UIL) 445 (UL : 307 (UL) 304 (UFL) - - 250- : O Placebo -30- OCA 10 mg FIG. 17B Patent Application Publication Feb. 9, 2017. Sheet 25 of 37 US 2017/0035784 A1 §§***** 88%(5948 Patent Application Publication US 2017/0035784 A1 woo-oinel-----…-…-…-- w Siempsa peaf et JOIlluo e Siempse Sufia:A lot OC WOO-OOÁIÐ o s: SerpSociate CIOO uOeuueuOO eul Patent Application Publication Feb. 9, 2017. Sheet 27 of 37 US 2017/0035784 A1 VOOfiuGZVOO6uuO|VOOG eSOO-efuS eSOO-ed nW Patent Application Publication Feb. 9, 2017. Sheet 28 of 37 US 2017/0035784 A1 -------------------------------------------------------------- fas: 30: 38 s cs :::::::32: Y:3: 888 *-------3-------+-------#-------+---+---+-------&-------+-------&------+------+------+-------* $33A 8,883 w : ers -o- Ole Patent Application Publication Feb. 9, 2017. Sheet 29 of 37 US 2017/0035784 A1 8: 8. w 33:83 :X: 3883. yO ful O. Patent Application Publication Feb. 9, 2017. Sheet 30 of 37 US 2017/0035784 A1 g N (D as -.2 g d 2 O b s e ge Se se (u?u-Ju) (931&O'onw s 2 t 3. 3. E w l C HH Y (5N HH. HIH s (u/5u-Ju) (93.200nw Patent Application Publication Feb. 9, 2017. Sheet 31 of 37 US 2017/0035784 A1 Off Treatment 0.2 O 24 48 72 96 Weeks -H OCA -e- Placebo FIG. 24A Patent Application Publication Feb. 9, 2017. Sheet 32 of 37 US 2017/0035784 A1 Off Treatment O 24 48 72 96 Weeks -- OCA -e- Placebo FIG. 24B Patent Application Publication Feb. 9, 2017. Sheet 33 of 37 US 2017/0035784 A1 s Off Treatment O 0.4 - SS up 0.2 9,E?) is LL 0.063. C Z O -0.2 v -0.4 u O 24 48 72 96 Weeks -- OCA -e Placebo FIG. 24C Patent Application Publication Feb. 9, 2017. Sheet 34 of 37 US 2017/0035784 A1 isia: {}{A :8: - s a s : s ; :8: wisc 3&c. s is C3 V ???oddÁëO9 {{i;82; wago. 383. Olde pode Patent Application Publication Feb. 9, 2017. Sheet 35 of 37 US 2017/0035784 A1 ra | | s: Patent Application Publication Feb. 9, 2017. Sheet 36 of 37 US 2017/0035784 A1 38: 8 &A 8883 s ::::::::::38 23: aSOO-efuS asochrad, Patent Application Publication Feb. 9, 2017. Sheet 37 of 37 US 2017/0035784 A1 4. :-***·*** 3******************************************************************************••••••••••••••• *::::::::} : 3323:33. WOO ful ga. US 2017/0035784 A1 Feb. 9, 2017 COMPOSITIONS OF OBETICHOLIC ACID wherein obeticholic acid or a pharmaceutically acceptable AND METHODS OF USE salt, ester, or amino acid conjugate thereof is in the form of particles, and wherein at least 50% of the particles have a BACKGROUND diameter of less than 200 um. Such compositions include all those described herein. 0001. The farnesoid X receptor (FXR), also known as the 0005. Another aspect of the disclosure relates to treating bile acid receptor (BAR) or NR1H4, is a member of the a disease or condition described herein in a patient in need nuclear receptor Superfamily of ligand-activated transcrip thereof by administering a composition that includes obet tion factors. FXR forms with retinoid X receptor (RXR) a icholic acid, or a pharmaceutically acceptable salt, ester, or heterodimer receptor crucial for bile acid homeostasis. FXR amino acid conjugate thereof, where the obeticholic acid or is expressed in various tissues including the liver, kidney, a pharmaceutically acceptable salt, ester, or amino acid intestine, colon, ovary, and adrenal gland, and is activated by conjugate thereof is in the form of particles. a variety of naturally occurring bile acids, including the 0006 Another aspect of the disclosure relates to treating primary bile acid chenodeoxycholic acid (CDCA) and its a disease or condition described herein in a patient in need taurine and glycine conjugates. Upon activation, the FXR thereof by administering a composition that includes obet RXRheterodimer binds the promoter region of target genes icholic acid, or a pharmaceutically acceptable salt, ester, or and regulates their expression. amino acid conjugate thereof, where the obeticholic acid or 0002 6-Ethyl-chenodeoxycholic acid (6-ECDCA, or a pharmaceutically acceptable salt, ester, or amino acid obeticholic acid, or OCA), a bile acid derivative, shows a conjugate thereof is in the form of particles, and wherein at potent FXR activating activity, and accordingly offers great least 50% of the particles have a diameter of 200 um or less.
Load more

Recommended publications
  • 16A-Fluoro-5-Androsten-17-0Ne
    MILITARY MEDICINE, 167, Suppl. 1:060,2002 Inhibition of Adjuvant-Induced Arthritis by 16a-Fluoro-5-Androsten-17-0ne Guarantor: Arthur G. Schwartz, PhD Contributors: Arthur G. Schwartz, PhD; Laura L. Pashko, PhD The adrenal steroid dehydroepiandrosterone (DHEA) produces tant receptor and that inhibition ofthis enzyme by DHEA me­ cancer-preventive, antiatherosclerotic, antidiabetic, Immuno­ diates some of the biological effects of the steroid. DHEA is a modulating, and anti-inflammatory effects in laboratory ani­ potent uncompetitive inhibitor of G6PDH, the rate-controlling mals. The clinical use of DHEAis limited by its androgenicity. Downloaded from https://academic.oup.com/milmed/article/167/suppl_1/60/4820113 by guest on 01 October 2021 enzyme in thepentose phosphate pathway, 10 and it appearsthat Wehave developed a synthetic congener ofDHEAcalled fluaster­ the antiproliferative and antitumor-promoting effects of the one that, in animal tests, lacks the androgenicity, estrogenicity, and peroxisome-proliferating effects of DHEA but retains the DHEA class of steroids is mediated through inhibition of cancer-preventive, antidiabetic, and anti-inflammatory efficacy. G6PDH.1,11,12 Two important metabolic consequences ofG6PDH This report discusses how fluasterone ameliorates the develop­ inhibition are a lowering ofNADPH-reducing equivalents avail­ ment of joint inflammation in an adjuvant-arthritis model in able forbiosynthetic processes, including ribo- and deoxyribo­ Lewis rats. nucleotide synthesis, and a reduction in ribose-5-phosphate,
    [Show full text]
  • Cyclodextrins As Drug Carrier Molecule: a Review
    Sci Pharm www.scipharm.at Review Open Access Cyclodextrins as Drug Carrier Molecule: A Review ARUN RASHEED *, ASHOK KUMAR C. K., SRAVANTHI V. V. N. S. S. Department of Pharmaceutical Chemistry, Sree Vidyanikethan College of Pharmacy, Sri Sainath Nagar, Tirupati, Andhra Pradesh, India-517502 * Corresponding author. E-mail: [email protected] (R. Arun) Sci Pharm. 2008; 76: 567–598 doi:10.3797/scipharm.0808-05 Published: November 1st 2008 Received: August 5th 2008 Accepted: October 31st 2008 This article is available from: http://dx.doi.org/10.3797/scipharm.0808-05 © Arun et al; licensee Österreichische Apotheker-Verlagsgesellschaft m. b. H., Vienna, Austria. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract The cyclodextrins have a wide range of applications in different areas of drug delivery and pharmaceutical industry due to their complexation ability and other versatile characteristics. The most common pharmaceutical application of cyclodextrin is to enhance the solubility, stability, safety and bioavailability of drug molecules. The purpose of this review is to discuss and summarize some of the findings and applications of cyclodextrin (CD) and their derivatives in different areas of drug delivery. This article highlights the molecular structure, properties like complexation, solubility etc. of cyclodextrins and focuses on its use for parenteral, oral, ophthalmic and nasal drug delivery. Other routes including dermal, rectal, sublingual and pulmonary delivery are also briefly addressed. The objective of this contribution is to focus on the potential use of chemically modified cyclodextrins as high-performance drug carriers in drug delivery systems with emphasis on the more recent developments.
    [Show full text]
  • An Orally Bioavailable Synthetic Analog of an Active Dehydroepiandrosterone Metabolite Reduces Established Disease in Rodent Models of Rheumatoid Arthritis
    0022-3565/09/3293-1100–1109$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 329, No. 3 Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics 145086/3474987 JPET 329:1100–1109, 2009 Printed in U.S.A. An Orally Bioavailable Synthetic Analog of an Active Dehydroepiandrosterone Metabolite Reduces Established Disease in Rodent Models of Rheumatoid Arthritis Halina Offner, Gary S. Firestein, David L. Boyle, Raymond Pieters, James M. Frincke, Armando Garsd, Steven K. White, Christopher L. Reading, and Dominick L. Auci Department of Neurology, Oregon Health and Science University, Portland, Oregon (H.O.); Institute for Risk Assessment Sciences-Immunotoxicology, Utrecht University, Utrecht, The Netherlands (R.P.); Division of Rheumatology, Allergy and Immunology, University of California at San Diego School of Medicine, La Jolla, California (D.L.B., G.S.F.); and Hollis-Eden Pharmaceuticals Inc., San Diego, California (J.M.F., A.G., S.K.W., C.L.R., D.L.A.) Downloaded from Received August 20, 2008; accepted March 17, 2009 ABSTRACT Dehydroepiandrosterone (DHEA) treatment provides diverse anti- even when treatments were delayed until 7 days after the onset jpet.aspetjournals.org inflammatory benefits in rodent models of diseases, including of arthritis. Furthermore, dose-dependent benefit was observed rheumatoid arthritis (RA), but only limited benefits to patients. In in the DBA mouse model of collagen antibody-induced arthritis, rodents, DHEA is metabolized to (among others) androstene- as well as reductions in IL-6 and matrix metalloproteinase-3 3␤,7␤,17␤-triol (AET), which retains potent anti-inflammatory mRNA levels in joints at the peak of disease and at the end of activity.
    [Show full text]
  • Inhibition of Carcinogen-Activating Enzymes by 16␣-Fluoro-5-Androsten-17-One
    [CANCER RESEARCH 62, 3685–3690, July 1, 2002] Inhibition of Carcinogen-activating Enzymes by 16␣-Fluoro-5-androsten-17-one Henry P. Ciolino,1 Christopher J. MacDonald, and Grace Chao Yeh Cellular Defense and Carcinogenesis Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, Maryland 21702- 1201 ABSTRACT decrease in the incidence of a number of different types of cancer in humans (5, 6). In animal models, DHEA has been shown to inhibit In the present study, we examined the effect of a synthetic analogue of both spontaneous and chemically induced carcinogenesis in rodents the chemopreventive hormone dehydroepiandrosterone, 16␣-fluoro-5- (7–9). Specifically, DHEA inhibits both skin and mammary tumori- androsten-17-one, also known as fluasterone, on the activity and expres- sion of carcinogen-activating enzymes in MCF-7 cells. The increase in genesis caused by the PAH DMBA (10–13). DHEA has been shown cytochrome P450 (CYP) 1A1 and 1B1 activity, as measured by to inhibit DMBA activation in vitro (14) and DMBA-DNA binding in ethoxyresorufin-O-deethylase activity, in cells treated with the carcino- vivo (15–18). The dramatic decline of DHEA levels in humans with gens dimethylbenzanthracene (DMBA) or 2,3,5,7-tetrachlorodibenzo-p- advancing age is, therefore, of substantial concern. However, DHEA dioxin (TCDD), was inhibited by cotreatment with fluasterone. However, supplementation is problematic, because it can be converted to both treatment of the cells with fluasterone after induction with DMBA or testosterone and estrone (19), and it exhibits considerable liver tox- TCDD failed to decrease enzyme activity, indicating that inhibition was icity (20) and hepatocarcinogenicity (21).
    [Show full text]
  • Metabolism, Alcohol and Toxicity About These Slides
    Best of ILC 2019 Metabolism, alcohol and toxicity About these slides • These slides provide highlights of new data presented at the International Liver Congress 2019 • Please feel free to use, adapt, and share these slides for your own personal use; however, please acknowledge EASL as the source • Definitions of all abbreviations shown in these slides, and a full copy of the original abstract text, are provided within the slide notes • Submitted abstracts are included in the slide notes, but data may not be identical to the final presented data shown on the slides These slides are intended for use as an educational resource and should not be used to make patient management decisions. All information included should be verified before treating patients or using any therapies described in these materials Contents 1. NAFLD: Clinical aspects except therapy LB-01 Double-blind, placebo-controlled, randomized trial of emricasan in subjects with NASH cirrhosis and severe portal hypertension GS-08 The prevalence of non-alcoholic fatty liver disease in young adults: An impending public health crisis? PS-061 NAFLD/NASH patients with AdvLD have high comorbidity burden, HCRU and costs: results from Italian administrative databases PS-203 Dietary risk factors for non-alcoholic fatty liver disease by cirrhosis status: The US multiethnic cohort LBP-01 In NAFLD, alcohol drinking habits and genetics predict progression to advanced liver disease: Follow-up of population surveys Click here to skip to this section 2. NAFLD: Therapy GS-01 Efficacy, safety,
    [Show full text]
  • Dehydroepiandrosterone Biosynthesis, Role, and Mechanism of Action in the Developing Neural Tube
    CORE Metadata, citation and similar papers at core.ac.uk ORIGINAL RESEARCH ARTICLE Provided by PubMed Central published: 07 February 2012 doi: 10.3389/fendo.2012.00016 Dehydroepiandrosterone biosynthesis, role, and mechanism of action in the developing neural tube Mark Galdo, Jennifer Gregonis, Christelle S. Fiore and Nathalie A. Compagnone* Laboratory for Spinal Cord Development and Regeneration, Department of Neurological Surgery, University of California, San Francisco, CA, USA Edited by: Dehydroepiandrosterone (DHEA) is synthesized from cholesterol by activity of P450scc Kazuyoshi Tsutsui, Waseda University, and P450c17, enzymes that we previously characterized in the developing nervous sys- Japan tem. We describe the localization of P450c17 in the differentiated field of the ventral spinal Reviewed by: Synthia H. Mellon, University of cord in different motor neuron subtypes. We show that, during organogenesis, P450c17 California San Francisco, USA activity is regulated along the antero/posterior axis of the spinal cord concomitantly with Ishwar Parhar, Monash University, the gradient of neurogenesis. To examine whether DHEA may modulate this process, Malaysia we measured proliferation and differentiation of ventral neural precursors in primary and *Correspondence: explant cultures. Our results showed that DHEA-induced the expression of class II pro- Nathalie A. Compagnone, Innovative Concepts in Drug Development, tein Nkx6.1, motor neuron precursor Olig-2, and definitive motor neuron marker Isl-1/2. Innovation Park Michel Caucik, BP2 DHEA also promoted proliferation of ventrally committed precursors in isolated spinal cord 100 rte des houilleres, 13590 precursor cultures and in whole spinal cord explants. Both the proliferative and inductive Meyreuil, France. effects of DHEA were dependent on sonic hedgehog signaling.
    [Show full text]
  • Neurosteroids As Regulators of Neuroinflammation
    Frontiers in Neuroendocrinology 55 (2019) 100788 Contents lists available at ScienceDirect Frontiers in Neuroendocrinology journal homepage: www.elsevier.com/locate/yfrne Neurosteroids as regulators of neuroinflammation T Canelif Yilmaza,1, Kanelina Karalib,c,1, Georgia Fodelianakia, Achille Gravanisb,c, ⁎ Triantafyllos Chavakisa,d, Ioannis Charalampopoulosb,c, Vasileia Ismini Alexakia, a Institute of Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany b Department of Pharmacology, Medical School, University of Crete, Heraklion, Greece c Institute of Molecular Biology & Biotechnology, Foundation of Research & Technology-Hellas, Heraklion, Greece d Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK ARTICLE INFO ABSTRACT Keywords: Neuroinflammation is a physiological protective response in the context of infection and injury. However, Neurosteroids neuroinflammation, especially if chronic, may also drive neurodegeneration. Neurodegenerative diseases, such Estrogens as multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD) and traumatic brain injury (TBI), β 17 -estradiol display inflammatory activation of microglia and astrocytes. Intriguingly, the central nervous system (CNS) is a Progestogens highly steroidogenic environment synthesizing steroids de novo, as well as metabolizing steroids deriving from Progesterone the circulation. Neurosteroid synthesis can be substantially affected by neuroinflammation,
    [Show full text]
  • Full Text In
    Return to October 2000 Table of Contents ORIGINAL ARTICLE Safety and pharmacokinetic study with escalating doses of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy male volunteers Michael Davidson, MD Drs. Davidson and Maki are with the Chicago Center for Ashok Marwah, PhD Clinical Research, Chicago, Ill.; Drs. A. Marwah, P. Marwah and Lardy are with the Institute for Enzyme Ronald J. Sawchuk, PhD Research and Department of Biochemistry, University of Kevin Maki, PhD Wisconsin, Madison, Wisc.; Dr. Sawchuk is with the Department of Pharmaceutics, College of Pharmacy, Padma Marwah, PhD University of Minnesota, Minneapolis, Minn.; and Dr. Charles Weeks, PhD Weeks is with Humanetics Corp., Chanhassen, Minn. Henry Lardy, PhD Medical subject headings: dehydroepiandrosterone sulfate; pharmacokinetics; prasterone; randomized controlled trials; steroids (Original manuscript submitted Apr. 17, 2000; received in revised form July 10, 2000 accepted July 10, 2000) Clin Invest Med 2000;23(5):300-10. © 2000 Canadian Medical Association Abstract the normal range. No changes in vital signs, blood chem- istry or urinalysis occurred during treatment with 3ß- Objectives: To evaluate the safety and pharmacokinetics acetyl-7-oxo-DHEA compared to placebo. The adminis- of 3-acetyl-7-oxo-DHEA (3ß-acetoxyandrost-5-ene- tered steroid was not detected in the blood but was rapid- 7,17-dione) given orally. ly converted to 7-oxo-DHEA-S, the concentrations of Design: A randomized, double blind, placebo-controlled, which were proportional to dose. This steroid sulfate did escalating dose study. not accumulate; plasma concentrations 12 hours after the Setting: The Chicago Center for Clinical Research. 3ß-acetyl-7-oxo-DHEA dose at 7 and 28 days on the 200 Participants: Twenty-two healthy men.
    [Show full text]
  • ( 12 ) United States Patent
    US010292951B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 ,292 , 951 B2 Glick et al. (45 ) Date of Patent: May 21, 2019 ( 54 ) METHODS AND COMPOSITIONS FOR (58 ) Field of Classification Search TREATING CONDITIONS ASSOCIATED CPC . .. .. .. .. A61K 31 / 167 WITH AN ABNORMAL INFLAMMATORY See application file for complete search history . RESPONSES (56 ) References Cited (71 ) Applicant: First Wave Bio , Inc ., Ann Arbor, MI U . S . PATENT DOCUMENTS (US ) 3 , 079 ,297 A 2 / 1963 Schraufstatter et al. (72 ) Inventors : Gary D . Glick , Ann Arbor, MI (US ) ; 5 ,663 , 155 A * 9 / 1997 McCaffrey .. A61K 31/ 70 Luigi Franchi, Ann Arbor, MI (US ) ; 514 / 45 Giancarlo Santus, Milan ( IT ) ( Continued ) ( 73 ) Assignee : First Wave Bio , Inc ., Ann Arbor , MI FOREIGN PATENT DOCUMENTS (US ) CN 105063018 A * 11 / 2015 ( * ) Notice : Subject to any disclaimer, the term of this EP 0938338 9 /2009 patent is extended or adjusted under 35 (Continued ) U . S . C . 154 (b ) by 0 days . OTHER PUBLICATIONS (21 ) Appl . No. : 15 /255 , 102 CureZone .org ( http : / /www . curezone .org / forums/ fm .asp ? i = ( 22 ) Filed : Sep . 1 , 2016 2146880 # i, accessed May 15 , 2017, dated Feb . 2 , 2014 ). * (Continued ) (65 ) Prior Publication Data Primary Examiner — Benjamin J Packard US 2017 /0056347 A1 Mar. 2 , 2017 ( 74 ) Attorney , Agent, or Firm — Fish & Richardson P . C . (57 ) ABSTRACT This disclosure features chemical entities ( e . g ., a compound Related U . S . Application Data exhibiting activity as a mitochondrial uncoupling agent or a (60 ) Provisional application No . 62/ 213 ,016 , filed on Sep . pharmaceutically acceptable salt and / or hydrate and /or coc 1 , 2015 , provisional application No .
    [Show full text]
  • Hormone Epimers Regulate Er Stress and Core Regulatory Genes: Network Analysis with Applications to Glioma and Chronic Pressure Ulcers
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2013 HORMONE EPIMERS REGULATE ER STRESS AND CORE REGULATORY GENES: NETWORK ANALYSIS WITH APPLICATIONS TO GLIOMA AND CHRONIC PRESSURE ULCERS Thomas L. Shaak Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Life Sciences Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/531 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. ©THOMAS L. SHAAK 2013 All Rights Reserved HORMONE EPIMERS REGULATE ER STRESS AND CORE REGULATORY GENES: NETWORK ANALYSIS WITH APPLICATIONS TO GLIOMA AND CHRONIC PRESSURE ULCERS A Dissertation submitted in partial fulfillment of the requirements for the degree Doctor of Philosophy at Virginia Commonwealth University by THOMAS L. SHAAK, LtCol, USAF, BSC B.S. Microbiology, Pennsylvania State University, 1990 M.S. Health Systems Administration, University of Medicine and Dentistry of New Jersey, 2003 M.S. Integrated Life Science, Medical University of South Carolina, 2005 Director: Dr. Robert F. Diegelmann, PhD., Professor of Biochemistry Virginia Commonwealth University Richmond, Virginia August 2013 ACKNOWLEDGEMENT The author would like to thank several people and without them I do not think I would be here now. First, Dr. Douglas Wear, Dr. Mina Izadjoo, PhD., Dr. Sue Cross, PhD, Dr. Mohammed Alavi, PhD, Dr. Hyung Kim, DVM, PhD. all of whom inspired me when I thought I was beyond inspiration.
    [Show full text]
  • Wo 2007/044693 A2
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 19 April 2007 (19.04.2007) WO 2007/044693 A2 (51) International Patent Classification: Tuscaloosa, AL 35401 (US). SWATLOSKI, Richard, P. A61K 31/555 (2006.01) A61K 31/28 (2006.01) [US/US]; 1801 Waterford Lane, Tuscaloosa, AL 35405 (21) International Application Number: (US). HOUGH, Whitney, L. [US/US]; 226 Wolf Creek PCT/US2006/039454 Drive, Albertville, AL 35951 (US). DAVIS, James, Hillard [US/US]; 324 Vanderbilt Drive, Mobile, AL (22) 10 October 2006 (10.10.2006) International Filing Date: 36608 (US). SMIGLAK, Marcin [PL/US]; 3302 Sixth (25) Filing Language: English Avenue East, Apt. C, Tuscaloosa, AL 35405 (US). PER- (26) Publication Language: English NAK, Juliusz [PL/PL]; UL. Nalkowskiej, 8A, PL-60-573 Poznan (PL). SPEAR, Scott, K. [US/US]; 302 County (30) Priority Data: Road 49, Bankston, AL 35542 (US). 60/724,604 7 October 2005 (07.10.2005) US 60/724,605 7 October 2005 (07.10.2005) US (74) Agents: KATZ, Mitchell, A. et al.; Needle & Rosenberg, 60/764,850 2 February 2006 (02.02.2006) US PC, Suite 1000, 999 Peachtree Street, Atlanta, GA 30309- (71) Applicant (for all designated States except US): THE 3915 (US). UNIVERSITY OF ALABAMA [US/US]; 222 Rose (81) Designated States (unless otherwise indicated, for every Administration Building, Post Office Box 870106, kind of national protection available): AE, AG, AL, AM, Tuscaloosa, AL 35487-0106 (US). AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, (72) Inventors; and CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, (75) Inventors/Applicants (for US only): ROGERS, Robin, GB, GD, GE, GH, GM, HN, HR, HU, ID, IL, IN, IS, JP, D.
    [Show full text]
  • Identification of [ C]Fluasterone Metabolites in Urine and Feces
    DMD Fast Forward. Published on February 5, 2009 as DOI: 10.1124/dmd.108.023614 DMD FastThis Forward.article has not Published been copyedited on and February formatted. The5, 2009final version as doi:10.1124/dmd.108.023614 may differ from this version. DMD #23614 Title page Identification of [14C]Fluasterone Metabolites in Urine and Feces Collected from Dogs following Subcutaneous and Oral Administration of [14C]Fluasterone Jason P. Burgess, Jonathan S. Green, Judith M. Hill, Qiao Zhan, Matthew Lindeblad, Alexander Lyubimov, Izet M. Kapetanovic, Arthur Schwartz, and Brian F. Thomas Downloaded from Analytical Chemistry and Pharmaceutics Group RTI International (J.P.B, J.S.G., J.M.H., Q.Z., B.F.T.) Research Triangle Park, North Carolina; Chemopreventive Agent Development Research Group, Division of Cancer Prevention, dmd.aspetjournals.org National Cancer Institute, National Institutes of Health (I.M.K.) Bethesda, Maryland; Toxicology Research Laboratory, University of Illinois at Chicago (M.L., A.L.) Chicago, Illinois; and Temple University School of Medicine (A.S.), Philadelphia, Pennsylvania. at ASPET Journals on October 2, 2021 1 Copyright 2009 by the American Society for Pharmacology and Experimental Therapeutics. DMD Fast Forward. Published on February 5, 2009 as DOI: 10.1124/dmd.108.023614 This article has not been copyedited and formatted. The final version may differ from this version. DMD #23614 Running title page 14 Excretion of [ C]Fluasterone Metabolites Brian F. Thomas, Ph.D. RTI International 3040 Cornwallis Road P.O. Box
    [Show full text]