DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2005/0238639 A1 Conrad 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 2005/0238639 A1 Conrad Et Al US 2005O238639A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0238639 A1 Conrad et al. (43) Pub. Date: Oct. 27, 2005 (54) USE OF RELAXIN TO INCREASE ARTERIAL Related U.S. Application Data COMPLIANCE (60) Provisional application No. 60/554,716, filed on Mar. (75) Inventors: Kirk P. Conrad, Cranberry TWP, PA 19, 2004. Provisional application No. 60/554,116, (US); Sanjeev G. Shroff, Pittsburgh, PA filed on Mar. 18, 2004. (US) Publication Classification Correspondence Address: (51) Int. Cl. ................................................ A61K 39/395 TOWNSEND AND TOWNSEND AND CREW, (52) U.S. Cl. .......................................................... 424/130.1 LLP (57) ABSTRACT TWO EMBARCADERO CENTER The present invention provides methods for increasing arte EIGHTH FLOOR rial compliance. The methods generally involve administer SAN FRANCISCO, CA 94111-3834 (US) ing to an individual in need thereof an effective amount of relaxin. The present invention further provides methods of increasing arterial compliance in individuals who have Type (73) Assignee: BAS Medical, Inc., San Mateo, CA 1 or Type 2 diabetes. The present invention further provides methods of increasing arterial compliance in perimeno (21) Appl. No.: 11/084,670 pausal, menopausal, and post-menopausal women. The present invention further provides methods of increasing arterial compliance in individuals who have or who are at (22) Filed: Mar. 18, 2005 risk of developing age-associated arterial Stiffness. 13S 135 B 135 C E. f* or ; o 100 5 100 1 O O SS S- -- Low Dose rhrLX (n=6) S. -H Low Dose rhRLX (n=6) -H Low Dose rhrux (n-6) -O- Vehicle (n=6) -O-Vehicle (n-6) f -O- vehicle (n=6 - -A- High Dose rhrLX (n=7) ? - A- High Dose rhrLX (n=7) ? -A- High Dose rhRLX (n=7) O O 3 6 8 10 O 3 6 8 10 O 3 s 8 O Days of rhrLX or Vehicle Administration Days of rhrLX or Wehicle Administration days of thrLX or vehicle Administration Patent Application Publication Oct. 27, 2005 Sheet 1 of 11 US 2005/0238639 A1 00, 0 (auese go 96) eunio/Aeous (euese Jo 96) ele Jee 0!,999.00),899.0 89€ 0 (euese Jo 96) ind no be peo Patent Application Publication Oct. 27, 2005 Sheet 2 of 11 US 2005/0238639 A1 Elg?, 0499£0 enssel elue JW ueeN 0nssel esnfeunio/A exoS u-1 0 (euese Jo 96) (euese jo') euesse Jenose A oue SAS eoueduod elev eqos) Patent Application Publication Oct. 27, 2005 Sheet 3 of 11 US 2005/0238639 A1 d N C S;O E o 3 5 s p to es C is was 9 e 3 52 e Vr we o o 2 CY E F S. m t g es d C o o O Y O se v. ver s s s (6Huu) enssed Ieuev (5Hulu) enssed eeuw Patent Application Publication Oct. 27, 2005 Sheet 5 of 11 US 2005/0238639 A1 O n ve 00}, (eueSego 96 enssed IeueuvueeW O vm ve (euese JO %) (euriases O%) ee JeeH indino oeputeo Patent Application Publication Oct. 27, 2005 Sheet 6 of 11 US 2005/0238639 A1 se s 9. o s so to 9 E ts 5 - 5 33 3 E to is d s O s s s s C g SN p es v- s w y (euese JO %) (dd/MS) bouleIIduo elueuw eqois Se s S. s s s s N t s w s v r (aulase JO %) (eele oW) enueduo leew ecos) se e s s v (auese O %) eouesse Jenosen ouesAs Patent Application Publication Oct. 27, 2005 Sheet 7 of 11 02), s 08 Patent Application Publication Oct. 27, 2005 Sheet 8 of 11 US 2005/0238639 A1 (euastegjo 9.) (ddiAS) esoue duo ejey eqo) kA (eueSego 9) ("ov) eoueiduoojeev eqois s s t vs. (eueSego) aouesseuenosewoguesAS Patent Application Publication Oct. 27, 2005 Sheet 9 of 11 US 2005/0238639 A1 Patent Application Publication Oct. 27, 2005 Sheet 10 of 11 US 2005/0238639 A1 s O (aueSego) did INS "eoueduoo Ieually eqolso d 5 e (euese Jo 94) se3W 'eoueduoso elievedo) 5 5 es s s es (s n va s r v w (euese go ') eouesse JenoseAgueSAS Patent Application Publication Oct. 27, 2005 Sheet 11 of 11 US 2005/0238639 A1 S E s s se SC S as s S; 3 3 s as a is is s v (eueSeguous efueuo effeueoue) (dd.INS) bouleIduoso Ieua IV eqois) w v s w o s a. c s s 5 f 3. s vs s Vs S S. : l a 3 Oil s es es s w N c (eueSeguo effuelo efieueoued) ("ov) aoueduooeueuw eqois e un us s o v. N. ce as V c. E is E d a as " YeaE N. SCs 6 E 3 3 g is is - - es ver Se s s w N (aueSeguouy afuelo efieueola) eouesse JenosewolueSAS US 2005/0238639 A1 Oct. 27, 2005 USE OF RELAXIN TO INCREASE ARTERIAL preSSure waveform using the area method. In another COMPLIANCE embodiment, global arterial compliance may be calculated as the Stroke Volume-to-pulse pressure ratio, where the CROSS-REFERENCE TO RELATED Stroke Volume is defined as the ratio of cardiac output to APPLICATIONS heart rate. 0001. The present application claims priority to U.S. 0008. In related embodiments, the local arterial compli Patent Application No. 60/554,716, filed Mar. 19, 2004, the ance or the regional arterial compliance of a Subject may be teachings of which are hereby incorporated by reference in measured in addition to or as an alternative to the global their entirety. arterial compliance measurement and, if the local or regional arterial compliance is diminished relative to the local or STATEMENT REGARDING FEDERALLY regional arterial compliance expected for a similarly situated SPONSORED RESEARCH healthy individual, relaxin may be administered to increase 0002 The U.S. government may have certain rights in arterial compliance in that individual. this invention, pursuant to Grant No. RO 1 HL67937 0009. In further embodiments, the subject to whom awarded by the National Institutes of Health. relaxin is administered Suffers from one or more of the following disorders: atherosclerosis, Type 1 diabetes, Type 2 FIELD OF THE INVENTION diabetes, coronary artery disease, Scleroderma, Stroke, dias 0003. The present invention is in the field of arterial tolic dysfunction, familial hypercholesterolemia, isolated compliance, and in particular, the use of relaxin to increase Systolic hypertension, primary hypertension, Secondary arterial compliance. hypertension, left Ventricular hypertrophy, arterial StiffneSS asSociated with long-term tobacco Smoking, arterial Stiffness BACKGROUND OF THE INVENTION asSociated with obesity, arterial Stiffness associated with age, Systemic lupus erythematosus, preeclampsia, and hypercho 0004 Arterial compliance declines with age even in lesterolemia. In related embodiments, the invention provides healthy individuals with no overt cardiovascular disease. methods of increasing arterial compliance in perimeno With age, a decrease is seen in the ability of the large and pausal, menopausal, and post-menopausal women and in Small arteries to distend in response to an increase in individuals who are at risk of one of the aforementioned preSSure. The age-associated reduction in arterial compli disorders. ance is an independent risk factor for the development of cardiovascular disease, and is associated with a number of 0010. In an additional embodiment of the invention, other pathological conditions. For example, reduced arterial administration of relaxin increases arterial compliance by at compliance is also associated with both Type 1 diabetes least 10%, 15%, 20% or more, relative to the measured mellitus and Type 2 diabetes mellitus. It has been reported arterial compliance before administration. In Still further that diabetic arteries appear to age at an accelerated rate embodiments, the invention provide for the administration compared to arteries of non-diabetic individuals. See, e.g., of relaxin to individuals with diminished arterial compliance Arnett et al. (1994) Am J Epidemiol. 140:669-682; Rowe at a predetermined rate So as to maintain a Serum concen (1987) Am J Cardiol. 60:68G-71G; Cameron et al. (2003) tration of relaxin from 0.5 to 80 ng/ml. In one embodiment, Diabetes Car. 26(7):2133-8; Kass et al. (2001) Circulation the relaxin is recombinant human relaxin. In yet another 104: 1464-1470; Avolio et al. (1983) Circulation 68:50-58; embodiment, the relaxin is recombinant H2 relaxin. In U.S. Pat. No. 6,251,863; U.S. Pat. No. 6,211,147. related embodiments, the relaxin may be administered daily, in an injectable formulation, as a Sustained release formu 0005 There is a need in the art for methods of increasing lation, or as a contiuous infusion. arterial compliance, and for treating disorders associated with or resulting from reduced arterial compliance. The present invention addresses these needs. BRIEF DESCRIPTION OF THE DRAWINGS 0011 FIGS. 1A-C depict the percent change from base SUMMARY OF THE INVENTION line for cardiac output (FIG. 1A), heart rate (FIG. 1B), and 0006 The present invention provides methods of treating stroke volume (FIG. 1C) in female rats administered low individuals with diminished arterial compliance an effective dose recombinant human relaxin (rhRLX; 4 ug/h), high dose amount of a formulation comprising a relaxin receptor rhRLX (25 ug/h), or vehicle. agonist. In a preferred embodiment the relaxin receptor 0012 FIGS. 2A-D depict percent change from baseline agonist is a recombinant human relaxin, e.g., human H2 for Systemic vascular resistance (FIG. 2A), mean arterial relaxin. pressure (FIG. 2B), global arterial compliance (FIG. 2C), 0007. In one embodiment of the invention, the invention and ratio of Stroke Volume-to-pulse pressure in female rats provides a method of increasing arterial compliance in a administered low dose rhRLX, high dose rhRLX, or vehicle.
Load more

Recommended publications
  • Vaginal Delivery System
    (19) & (11) EP 2 062 568 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 27.05.2009 Bulletin 2009/22 A61K 9/00 (2006.01) (21) Application number: 07397042.8 (22) Date of filing: 22.11.2007 (84) Designated Contracting States: • Hanes, Vladimir AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Tarrytown, NY 10591 (US) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE • Keinänen, Antti SI SK TR 20540 Turku (FI) Designated Extension States: • Holmberg, Svante AL BA HR MK RS 20900 Turku (FI) • Nikander, Hannu (71) Applicant: Bayer Schering Pharma Oy 21330 Paattinen (FI) 20210 Turku (FI) (74) Representative: Matilainen, Mirja Helena et al (72) Inventors: Oy Jalo Ant-Wuorinen AB, • Talling, Christine Iso Roobertinkatu 4-6 A 20610 Turku (FI) 00120 Helsinki (FI) (54) Vaginal delivery system (57) The present invention is related to an intravag- brane (3) encasing the core, said core and membrane inal delivery system for the controlled release of a pro- essentially consisting of a same or different polymer com- gestogen and an estrogen, comprising additionally a position, wherein at cast one of the cores comprises a therapeutically active or a health-promoting substance progestogen or a mixture of a progestogen and an es- (1) capable of giving and/or enhancing the protection trogen, and another core may comprise an estrogen or against bacterial and fungal infections, and/or enhancing a progestogen, and wherein the membrane or the surface the protection against sexually transmitted diseases. The of the membrane or at least one of the cores comprises delivery system consists of one or more compartments said therapeutically active or a health-promoting sub- (2,4,5), one of each comprising a core (7) and a mem- stance.
    [Show full text]
  • Substrate Inhibition of 17 Beta-Hydroxysteroid Dehydrogenase Type 1 in Living Cells and Regulation Among the Steroid-Converting Enzymes in Breast Cancers
    Substrate inhibition of 17 beta-hydroxysteroid dehydrogenase type 1 in living cells and regulation among the steroid-converting enzymes in breast cancers Thèse Hui Han Doctorat en médecine moléculaire Philosophiæ doctor (Ph. D.) Québec, Canada © Hui Han, 2018 Substrate inhibition of 17 beta-hydroxysteroid dehydrogenase type 1 in living cells and regulation among the steroid-converting enzymes in breast cancers Thèse Hui Han Sous la direction de : Sheng-xiang Lin, directeur de recherche RÉSUMÉ Cette étude a permis de démontrer les fonctions et les mécanismes de la 17bêta- hydroxystéroïde déshydrogénase de type 1 (17β-HSD1) et de la stéroïde sulfatase (STS) au niveau du cancer du sein, y compris la cinétique moléculaire et cellulaire, la liaison du ligand étudiée par la titration de fluorescence, la régulation des stéroïdes et la régulation mutuelle entre les enzymes stéroïdiennes et les cellules cancéreuses du sein. 1), L’inhibition de la 17β-HSD1 par son substrat a été démontrée par la cinétique enzymatique au niveau cellulaire pour la première fois, soutenant ainsi la fonction biologique de l’inhibition produite par le substrat. 2), En tant qu’inhibiteur, la dihydrotestostérone (DHT) n’a pas affecté la concentration du substrat estrone (E1) à laquelle l’activité enzymatique a commencé à diminuer, mais certaines augmentations de vitesse ont été observées, suggérant une diminution significative de l’inhibition par le substrat. 3), Les résultats de la modulation de l’ARNm ont démontré que la transcription du gène codant la 17β-HSD7 diminuait en réponse à l’inhibition de la 17β-HSD1 ou au knockdown dans les cellules du cancer du sein par la modification estradiol (E2).
    [Show full text]
  • Estriol Therapy for Autoimmune and Neurodegenerative Diseases and Disorders
    (19) TZZ¥Z__T (11) EP 3 045 177 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 20.07.2016 Bulletin 2016/29 A61K 31/565 (2006.01) A61K 31/566 (2006.01) A61K 31/568 (2006.01) A61K 45/06 (2006.01) (2006.01) (2006.01) (21) Application number: 16000349.7 A61K 31/785 A61P 25/00 (22) Date of filing: 26.09.2006 (84) Designated Contracting States: (72) Inventor: Voskuhl, Rhonda R. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Los Angeles, CA 90024 (US) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR (74) Representative: Müller-Boré & Partner Patentanwälte PartG mbB (30) Priority: 26.09.2005 US 720972 P Friedenheimer Brücke 21 26.07.2006 US 833527 P 80639 München (DE) (62) Document number(s) of the earlier application(s) in Remarks: accordance with Art. 76 EPC: This application was filed on 11-02-2016 as a 13005320.0 / 2 698 167 divisional application to the application mentioned 06815626.4 / 1 929 291 under INID code 62. (71) Applicant: The Regents of the University of California Oakland, CA 94607 (US) (54) ESTRIOL THERAPY FOR AUTOIMMUNE AND NEURODEGENERATIVE DISEASES AND DISORDERS (57) The present invention relates to a dosage from comprising estriol and glatiramer acetate polymer-1 for use in the treatment of multiple sclerosis (MS), as well as to a kit comprising estriol and glatiramer acetate polymer-1. EP 3 045 177 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 045 177 A1 Description [0001] This invention was made with Government support under Grant No.
    [Show full text]
  • INTERRELATIONSHIPS of the ESTROGEN-PRODUCING ENZYMES NETWORK in BREAST CANCER DISSERTATION Presented in Partial Fulfillment Of
    INTERRELATIONSHIPS OF THE ESTROGEN-PRODUCING ENZYMES NETWORK IN BREAST CANCER DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Wendy L. Rich, M.S. ∗∗∗∗∗ The Ohio State University 2009 Dissertation Committee: Approved by Pui-Kai Li, Ph.D., Adviser Robert W. Brueggemeier, Ph.D. Karl A. Werbovetz, Ph.D. Adviser Graduate Program in Pharmacy Charles L. Shapiro M.D. ABSTRACT In the United States, breast cancer is the most common non-skin malignancy and the second leading cause of cancer-related death in women. However, earlier detection and new, more effective treatments may be responsible for the decrease in overall death rates. Approximately 60% of breast tumors are estrogen receptor (ER) positive and thus their cellular growth is hormone-dependent. Elevated levels of estrogens, even in post- menopausal women, have been implicated in the development and progression of hormone-dependent breast cancer. Hormone therapies seek to inhibit local estrogen action and biosynthesis, which can be produced by pathways utilizing the enzymes aromatase or steroid sulfatase (STS). Cyclooxygenase-2 (COX-2), typically involved in inflammation processes, is a major regulator of aromatase expression in breast cancer cells. STS, COX-2, and aromatase are critical for estrogen biosynthesis and have been shown to be over-expressed in breast cancer. While there continues to be extensive study and successful design of potent aromatase inhibitors, much remains unclear about the regulation of STS and the clinical applications for its selective inhibition. Further studies exploring the relationships of STS with COX-2 and aromatase enzymes will aid in the understanding of its role in cancer cell growth and in the development of future hormone- dependent breast cancer therapies.
    [Show full text]
  • WO 2015/054658 Al 16 April 2015 (16.04.2015) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/054658 Al 16 April 2015 (16.04.2015) P O P C T (51) International Patent Classification: (74) Agents: PATHAK, Rahul et al; Squire Patton Boggs C07D 401/12 (2006.01) A61K 39/395 (2006.01) (US) LLP, 275 Battery Street, Suite 2600, San Francisco, C07D 409/12 (2006.01) A61K 47/48 (2006.01) California 941 11 (US). C07D 257/08 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US20 14/060 169 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) International Filing Date: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 10 October 2014 (10.10.2014) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (26) Publication Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (30) Priority Data: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 61/890,1 18 11 October 2013 ( 11. 10.2013) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]
  • United States Patent 19 11 Patent Number: 5,446,070 Mantelle (45) Date of Patent: "Aug
    USOO544607OA United States Patent 19 11 Patent Number: 5,446,070 Mantelle (45) Date of Patent: "Aug. 29, 1995 54 COMPOST ONS AND METHODS FOR 4,659,714 4/1987 Watt-Smith ......................... 514/260 TOPCAL ADMNSTRATION OF 4,675,009 6/1987 Hymes .......... ... 604/304 PHARMACEUTICALLY ACTIVE AGENTS 4,695,465 9/1987 Kigasawa .............................. 424/19 4,748,022 5/1988 Busciglio. ... 424/195 75 Inventor: Juan A. Mantelle, Miami, Fla. 4,765,983 8/1988 Takayanagi. ... 424/434 4,789,667 12/1988 Makino ............ ... 514/16 73) Assignee: Nover Pharmaceuticals, Inc., Miami, 4,867,970 9/1989 Newsham et al. ... 424/435 Fla. 4,888,354 12/1989 Chang .............. ... 514/424 4,894,232 1/1990 Reul ............. ... 424/439 * Notice: The portion of the term of this patent 4,900,552 2/1990 Sanvordeker .... ... 424/422 subsequent to Aug. 10, 2010 has been 4,900,554 2/1990 Yanagibashi. ... 424/448 disclaimed. 4,937,078 6/1990 Mezei........... ... 424/450 Appl. No.: 112,330 4,940,587 7/1990 Jenkins ..... ... 424/480 21 4,981,875 l/1991 Leusner ... ... 514/774 22 Filed: Aug. 27, 1993 5,023,082 6/1991 Friedman . ... 424/426 5,234,957 8/1993 Mantelle ........................... 514/772.6 Related U.S. Application Data FOREIGN PATENT DOCUMENTS 63 Continuation-in-part of PCT/US92/01730, Feb. 27, 0002425 6/1979 European Pat. Off. 1992, which is a continuation-in-part of Ser. No. 0139127 5/1985 European Pat. Off. 813,196, Dec. 23, 1991, Pat. No. 5,234,957, which is a 0159168 10/1985 European Pat.
    [Show full text]
  • Powerpoint Sunusu
    PRODRUGS OF ALCOHOLS AND PHENOLS • Acylation or alkylation of alcohols or phenols could lead to a less polar prodrug while phosphorylation can lead to a more water soluble prodrug. A. Aliphatic and Aromatic Esters • Drugs containing hydroxyl groups, including alcohols and phenols can have a variety of physical/chemical properties that have advantages and disadvantages. • Esterification of the hydroxyl group has been one of the preferred prodrug strategies to mask polar groups within a drug molecule and thereby promote membrane permeability. • Acyl groups that have been incorporated to form promoieties for the hydroxyl group range from lower alkyl groups to long-chain fatty acids. • Valacyclovir is a water soluble L-valine ester prodrug of the HIV reverse transcriptase inhibitor acyclovir. • Valacyclovir was developed to increase the oral absorption and plasma levels of acyclovir. Increased plasma concentrations of acyclovir are important to maintain antiviral activity, especially in immunocompromissed patients and in the treatment of less sensitive viruses such as cytomegalovirus (CMV) and varicella zoster virus (VZV). • Valacyclovir is rapidly absorbed and converted to acyclovir by enzymatic hydrolysis in the intestine and liver. • It is hydrolysed by a valacyclovir hydrolase to produce acyclovir and L-valine. • A series of alkyl, cycloalkyl, and aryl ester prodrugs of the nonselective -adrenergic antagonist timolol have been prepared by esterifying the hydroxyl group of timolol. • All the prodrugs studied were more lipophilic than timolol and the most promising examples penetrated the cornea substantially better than timolol. • The rate of ester hydrolysis of alkyl, cycloalkyl, and aryl ester- prodrug was about equal in plasma and phosphate buffer, making it difficult to design a prodrug which is stable in vitro but will convert quickly to an active drug in vivo.
    [Show full text]
  • Metabolic Activation of Proestrogenic Diphenyl and Related Compounds by Rat Liver Microsomes
    298 Journal of Health Science, 49(4) 298–310 (2003) Metabolic Activation of Proestrogenic Diphenyl and Related Compounds by Rat Liver Microsomes Shigeyuki Kitamura,*, a Seigo Sanoh,a Ryuki Kohta,a Tomoharu Suzuki,a Kazumi Sugihara,a Nariaki Fujimoto,b and Shigeru Ohtaa aGraduate School of Biomedical Sciences and bResearch Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1–2–3, Minami-ku, Hiroshima 734–8551, Japan (Received April 14, 2003; Accepted April 24, 2003) In this study, liver microsome-mediated activation of diphenyl (DP), diphenylmethane (DPM) and 2,2- diphenylpropane (DPP) to estrogens was demonstrated. These three compounds were negative in estrogen reporter assay using estrogen-responsive human breast cancer cell line MCF-7. However, they exhibited estrogenic activity after incubation with liver microsomes of 3-methylcholanthrene-treated rats in the cases of DP and DPM, or of phenobarbital-treated rats in the cases of DP and DPP, in the presence of NADPH. When these compounds were incubated with liver microsomes in the presence of NADPH, monohydroxyl and dihydroxyl derivatives were formed. These hydroxylated metabolites, 4-hydroxydiphenyl, 3-hydroxydiphenyl, 2-hydroxydiphenyl, 4-hydroxydiphenyl- methane, 2-(4-hydroxyphenyl)-2-phenylpropane (4-OH-DPP), 4,4′-dihydroxydiphenyl, 4,4′-dihydroxydiphenyl- methane and 2,2-bis(4-hydroxyphenyl)propane (bisphenol A), all exhibited estrogenic activity in MCF-7 cells. Binding assay of these hydroxylated compounds with rat uterus estrogen receptor was also positive. These results suggest that the estrogenic activities of DP, DPM and DPP were due to the formation of hydroxylated metabolites by the liver cytochrome P450 system. Key words —–— diphenyl, estrogenic activity, metabolic activation, human breast cancer cell line MCF-7, endo- crine disruption, cytochrome P450 INTRODUCTION exert biological effects.
    [Show full text]
  • The Selective Estrogen Enzyme Modulators in Breast Cancer: a Review
    Biochimica et Biophysica Acta 1654 (2004) 123–143 www.bba-direct.com Review The selective estrogen enzyme modulators in breast cancer: a review Jorge R. Pasqualini* Hormones and Cancer Research Unit, Institut de Pue´riculture, 26 Boulevard Brune, 75014 Paris, France Received 21 January 2004; accepted 12 March 2004 Available online 15 April 2004 Abstract It is well established that increased exposure to estradiol (E2) is an important risk factor for the genesis and evolution of breast tumors, most of which (approximately 95–97%) in their early stage are estrogen-sensitive. However, two thirds of breast cancers occur during the postmenopausal period when the ovaries have ceased to be functional. Despite the low levels of circulating estrogens, the tissular concentrations of these hormones are significantly higher than those found in the plasma or in the area of the breast considered as normal tissue, suggesting a specific tumoral biosynthesis and accumulation of these hormones. Several factors could be implicated in this process, including higher uptake of steroids from plasma and local formation of the potent E2 by the breast cancer tissue itself. This information extends the concept of ‘intracrinology’ where a hormone can have its biological response in the same organ where it is produced. There is substantial information that mammary cancer tissue contains all the enzymes responsible for the local biosynthesis of E2 from circulating precursors. Two principal pathways are implicated in the last steps of E2 formation in breast cancer tissues: the ‘aromatase pathway’ which transforms androgens into estrogens, and the ‘sulfatase pathway’ which converts estrone sulfate (E1S) into E1 by the estrone-sulfatase.
    [Show full text]
  • Supplemental Figure
    ● Agonist ● Antagonist ● Interference AR AUC 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 17beta−Trenbolone 5alpha−Dihydrotestosterone 17−Methyltestosterone Testosterone propionate Norethindrone Norgestrel GSK232420A 4−Androstene−3,17−dione Progesterone 17beta−Estradiol Mifepristone 17alpha−Ethinylestradiol Hydroxyflutamide 17alpha−Hydroxyprogesterone Corticosterone Nilutamide Basic Blue 7 Triphenyltin hydroxide Bicalutamide Tributyltin benzoate 17alpha−Estradiol Gentian Violet Equilin Zinc pyrithione Triticonazole Fenitrothion Mestranol Tributyltin methacrylate 2,2−Bis(4−hydroxyphenyl)−1,1,1 Dibutyltin dichloride Flutamide Methyltrioctylammonium chlorid Rhodamine 6G Tributyltetradecylphosphonium Emamectin benzoate Phenylmercuric acetate Cyproterone acetate Chlorothalonil 9−Phenanthrol 2,2',4,4'−Tetrahydroxybenzophe Melengestrol acetate Dehydroepiandrosterone 1−Chloro−2,4−dinitrobenzene SSR240612 Methylbenzethonium chloride Vinclozolin Tetraconazole Ziram Didecyldimethylammonium chlori Econazole nitrate Myristyltrimethylammonium chlo Clorophene Abamectin Octyl gallate 2−Chloro−4−phenylphenol Bisphenol A Propanil Dexamethasone sodium phosphate meso−Hexestrol Dichlorophen Hydroxyprogesterone caproate SSR241586 Bisphenol AF Prednisone Dichlone Reserpine Chlorobenzilate Diethylstilbestrol 3−Hydroxyfluorene Procymidone 4−Cumylphenol 4−Hydroxytamoxifen Napropamide PharmaGSID_48519 Clomiphene citrate (1:1) Chlorhexidine diacetate Tebuconazole Imazalil Dinocap PharmaGSID_48513 Linuron Prochloraz Zoxamide TDCPP Captan 3,3'−Dimethoxybenzidine dihydr 4−Phenylphenol
    [Show full text]
  • New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies
    molecules Article New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies Catarina Canário 1 , Mariana Matias 1, Vanessa Brito 1, Adriana O. Santos 1, Amílcar Falcão 2,3 , Samuel Silvestre 1,4,* and Gilberto Alves 1 1 CICS-UBI–Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal; [email protected] (C.C.); [email protected] (M.M.); [email protected] (V.B.); [email protected] (A.O.S.); [email protected] (G.A.) 2 Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; [email protected] 3 CIBIT-Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, 3000-548 Coimbra, Portugal 4 CNC–Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal * Correspondence: [email protected] Abstract: The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines. An estrogenicity assay, a cell cycle distribution analysis and a fluorescence microscopy study with Hoechst 3358 staining were performed with the most promising compound. In addition, molecular docking studies against estrogen receptor α, steroid sulfatase, 17β-hydroxysteroid dehy- drogenase type 1 and β-tubulin were also accomplished. The 2-nitroestrone oxime showed higher Citation: Canário, C.; Matias, M.; Brito, V.; Santos, A.O.; Falcão, A.; cytotoxicity than the parent compound on MCF-7 cancer cells.
    [Show full text]
  • Coumarins and Coumarin-Related Compounds in Pharmacotherapy of Cancer
    cancers Review Coumarins and Coumarin-Related Compounds in Pharmacotherapy of Cancer Esra Küpeli Akkol 1,* , Yasin Genç 2, Bü¸sraKarpuz 1, Eduardo Sobarzo-Sánchez 3,4 and Raffaele Capasso 5,* 1 Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Etiler 06330, Ankara, Turkey; [email protected] 2 Department of Pharmacognosy, Faculty of Pharmacy, Hacettepe University, Sıhhiye 06100, Ankara, Turkey; [email protected] 3 Instituto de Investigación e Innovación en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, 8330507 Santiago, Chile; [email protected] 4 Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain 5 Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici (Naples), Italy * Correspondence: [email protected] (E.K.A.); [email protected] (R.C.); Tel.: +90-312-2023185 (E.K.A); +39-081-678664 (R.C.) Received: 3 July 2020; Accepted: 17 July 2020; Published: 19 July 2020 Abstract: Cancer is one of the most common causes of disease-related deaths worldwide. Despite the discovery of many chemotherapeutic drugs that inhibit uncontrolled cell division processes for the treatment of various cancers, serious side effects of these drugs are a crucial disadvantage. In addition, multi-drug resistance is another important problem in anticancer treatment. Due to problems such as cytotoxicity and drug resistance, many investigations are being conducted to discover and develop effective anticancer drugs. In recent years, researchers have focused on the anticancer activity coumarins, due to their high biological activity and low toxicity. Coumarins are commonly used in the treatment of prostate cancer, renal cell carcinoma and leukemia, and they also have the ability to counteract the side effects caused by radiotherapy.
    [Show full text]