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(12) United States Patent (10) Patent No.: US 7,795,310 B2 Lee Et Al

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US00779531 OB2 (12) United States Patent (10) Patent No.: US 7,795,310 B2 Lee et al. (45) Date of Patent: Sep. 14, 2010 (54) METHODS AND REAGENTS FOR THE WO WO 2005/025673 3, 2005 TREATMENT OF METABOLIC DISORDERS OTHER PUBLICATIONS (75) Inventors: Margaret S. Lee, Middleton, MA (US); Tenenbaum et al., “Peroxisome Proliferator-Activated Receptor Grant R. Zimmermann, Somerville, Ligand Bezafibrate for Prevention of Type 2 Diabetes Mellitus in MA (US); Alyce L. Finelli, Patients With Coronary Artery Disease'. Circulation, 2004, pp. 2197 Framingham, MA (US); Daniel Grau, 22O2.* Shen et al., “Effect of gemfibrozil treatment in sulfonylurea-treated Cambridge, MA (US); Curtis Keith, patients with noninsulin-dependent diabetes mellitus'. The Journal Boston, MA (US); M. James Nichols, of Clinical Endocrinology & Metabolism, vol. 73, pp. 503-510, Boston, MA (US) 1991 (see enclosed abstract).* International Search Report from PCT/US2005/023030, mailed Dec. (73) Assignee: CombinatoRx, Inc., Cambridge, MA 1, 2005. (US) Lin et al., “Effect of Experimental Diabetes on Elimination Kinetics of Diflunisal in Rats.” Drug Metab. Dispos. 17:147-152 (1989). (*) Notice: Subject to any disclaimer, the term of this Abstract only. patent is extended or adjusted under 35 Neogi et al., “Synthesis and Structure-Activity Relationship Studies U.S.C. 154(b) by 0 days. of Cinnamic Acid-Based Novel Thiazolidinedione Antihyperglycemic Agents.” Bioorg. Med. Chem. 11:4059-4067 (21) Appl. No.: 11/171,566 (2003). Vessby et al., “Effects of Bezafibrate on the Serum Lipoprotein Lipid and Apollipoprotein Composition, Lipoprotein Triglyceride Removal (22) Filed: Jun. 30, 2005 Capacity and the Fatty Acid Composition of the Plasma Lipid Esters.” Atherosclerosis 37:257-269 (1980). Abstract only. (65) Prior Publication Data Windholz et al., eds., “Abstract No. 4866. The Merck Index. 10" ed., US 2006/OO69 161A1 Mar. 30, 2006 p. 723-724. Merck and Company, Inc.: Rahway, NJ (1983). Sone et al., “Ibuprofen-Related Hypoglycemia in a Patient Receiving Related U.S. Application Data Sufonylurea” Annals of Internal Medicine 134:344, 2001. Yuan et al., “Reversal of Obesity- and Diet-Induced Insulin Resis (60) Provisional application No. 60/584,380, filed on Jun. tance with Salicylates or Targeted Disruption of Ikk?’ Science 30, 2004, provisional application No. 60/649,329, 293: 1673-1677, 2001. filed on Feb. 2, 2005. Search Report from European Application No. 05768.186 mailed on Jun. 2, 2008. Chen et al., “The Pharmacological Interactions of (51) Int. Cl. Antihyperglycemic Agents (1)”,Journal of Chinese Physician 29:47, A6 IK3I/I9 (2006.01) 2001. (52) U.S. Cl. ........................ 514/568; 514/571; 514/866 Communication from the State Intellectual Property Office of the (58) Field of Classification Search ................. 514/568, People's Republic of China for Application No. 2005800289684 514/571,866 with English translation (issued Jul. 17, 2009), (pp. 1-16). See application file for complete search history. Yang et al., “The Comparison of Treatment of Type 2 Diabetes Mellitus Complicated with Hyperlipemia with Bezafibrate and (56) References Cited Pravastatin Sodium', Shanghai Medical Journal 21:478-480, 1998. U.S. PATENT DOCUMENTS * cited by examiner 6, 194.454 B1 2/2001 Dow .......................... 514,522 Primary Examiner Kevin Weddington 6,500,823 B1* 12/2002 Literati Nagy et al. ... 514/231.5 (74) Attorney, Agent, or Firm—Clark & Elbing LLP 6,576,256 B2 6/2003 Liang et al. 6.593,347 B2 * 7/2003 Bandarage et al. .......... 514,327 (57) ABSTRACT 2002/0016293 A1 2/2002 Ratain et al. ................... 514/9 The invention features compositions, methods, and kits for FOREIGN PATENT DOCUMENTS the treatment of metabolic disorders such as diabetes and WO WOO3,059294 T 2003 obesity. WO WOO3,082283 10, 2003 WO WO 2004/052362 6, 2004 6 Claims, 3 Drawing Sheets U.S. Patent Sep. 14, 2010 Sheet 1 of 3 US 7,795,310 B2 FIG. 1 U.S. Patent Sep. 14, 2010 Sheet 2 of 3 US 7,795,310 B2 FIG 2 300 250 2 O O 150 100 50 ChoW HF Pio 6 DF Bez Bez/DF U.S. Patent Sep. 14, 2010 Sheet 3 of 3 US 7,795,310 B2 FIG. 3 60 4. O 2 O Chow HF Pio 6 DF Bez BezIDF US 7,795,310 B2 1. 2 METHODS AND REAGENTS FOR THE Given that the strategies currently available for the man TREATMENT OF METABOLIC DSORDERS agement of diabetes are suboptimal, there is a compelling need for treatments that are more effective and are not asso CROSS-REFERENCE TO RELATED ciated with such debilitating side-effects. APPLICATIONS SUMMARY OF THE INVENTION This application claims benefit from U.S. Ser. No. 60/584, 380, filed Jun. 30, 2004, and U.S. Ser. No. 60/649,329, filed The present invention features compositions, methods, and Feb. 2, 2005, each of which is hereby incorporated by refer kits for treating, preventing, and reducing metabolic disor CCC. 10 ders. This invention is particularly useful for treating patients having or at risk of having any condition that is characterized BACKGROUND OF THE INVENTION by a state of hyperglycemia, which may be caused, for example, by an alteration in the insulin signaling pathway The invention relates to the treatment, prevention, and (e.g., a reduction in insulin production, resistance to insulin, reduction of metabolic disorders, such as diabetes and obe 15 or both). Exemplary disorders amenable to treatment accord sity. ing to this invention are obesity, diabetes (e.g., type 1 diabe As the levels of blood glucose rise postprandially, insulin is tes, type 2 diabetes, maturity-onset diabetes of the young secreted and stimulates cells of the peripheral tissues (skeletal (MODY), and gestational diabetes), satiety, endocrine defi muscles and fat) to actively take up glucose from the blood as ciencies of aging, and any of their associated complications a source of energy. Loss of glucose homeostasis as a result of (e.g., Syndrome X, diabetic retinopathy, diabetic nephropa faulty insulin secretion or action typically results in metabolic thy, diabetic neuropathy, peripheral vascular disease, hyper disorders such as diabetes, which may be co-triggered or lipidemia, hypertension, atherosclerosis, and coronary heart further exacerbated by obesity. Because these conditions are disease). often fatal, strategies to restore adequate glucose clearance In a first aspect, the invention features a composition that from the bloodstream are required. 25 includes (a) bezafibrate or an analog thereof, and (b) Although diabetes may arise secondary to any condition diflunisal or an analog thereof, wherein the bezafibrate and that causes extensive damage to the pancreas (e.g., pancreati diflunisal are present in amounts that, when administered to a tis, tumors, administration of certain drugs such as corticos patient, are sufficient to treat, prevent, or reduce a metabolic teroids or pentamidine, iron overload (e.g., hemochromato disorder (e.g., diabetes or obesity). Exemplary combinations sis), acquired or genetic endocrinopathies, and Surgical 30 are bezafibrate and diflunisal; bezafibrate and bismuth Sub excision), the most common forms of diabetes typically arise salicylate; bezafibrate and nimosulide; bezafibrate and from primary disorders of the insulin signaling system. There oxaprozin, bezafibrate and diclofenac; bezafibrate and Sun are two major types of diabetes, namely type 1 diabetes (also dilac.; bezafibrate and ibuprofen; clofibrate and diflunisal; known as insulin dependent diabetes (IDDM)) and type 2 clofibrate and bismuth subsalicylate; clofibrate and nimo diabetes (also known as insulin independent or non-insulin 35 sulide; clofibrate and oxaprozin; clofibrate and diclofenac: dependent diabetes (NIDDM)), which share common long clofibrate and Sundilac; clofibrate and ibuprofen; clofibrinc term complications in spite of their different pathogenic acid and diflunisal; clofibric acid and bismuth subsalicylate: mechanisms. clofibric acid and nimosulide; clofibric acid and oxaprozin, Type 1 diabetes, which accounts for approximately 10% of clofibric acid and diclofenac; clofibric acid and sundilac, all cases of primary diabetes, is an organ-specific autoim 40 clofibric acid and ibuprofen; clinofibrate and diflunisal; cli mune disease characterized by the extensive destruction of nofibrate and bismuth subsalicylate; clinofibrate and nimo the insulin-producing beta cells of the pancreas. The conse sulide; clinofibrate and oxaprozin; clinofibrate and quent reduction in insulin production inevitably leads to the diclofenac; clinofibrate and Sundilac; clinofibrate and ibupro deregulation of glucose metabolism. While the administra fen, gemfibrozil and diflunisal; gemfibrozil and bismuth sub tion of insulin provides significant benefits to patients suffer 45 salicylate; gemfibrozil and nimosulide; gemfibrozil and ing from this condition, the short serum half-life of insulin is oxaprozin, gemfibrozil and diclofenac; gemfibrozil and Sun a major impediment to the maintenance of normoglycemia. dilac, and gemfibrozil and ibuprofen. An alternative treatment is islet transplantation, but this strat In a second aspect, the invention features a composition egy has been associated with limited Success. that includes (a) bezafibrate or an analog thereof; and (b) Type 2 diabetes, which affects a larger proportion of the 50 cinnamic acid or an analog thereof, wherein the beZafibrate population, is characterized by a deregulation in the secretion and diflunisal are present in amounts that, when administered of insulin and/or a decreased response of peripheral tissues to to a patient, are sufficient to treat, prevent,
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    PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/146284 Please be advised that this information was generated on 2021-10-07 and may be subject to change. 4 --. 'HARMACOLLOÒICAUNTERVENTIO N IN ?RESEW\KA]ÍÓ[JT PHARMACOLOGICAL INTERVENTION IN PRETERM LABOUR Dose studies on ritodrine administration C.A.G. HOLLEBOOM Druk: Haveka bv, Alblasserdam I.S.B.N. 90-9009763-5 Thesis Catholic University Nijmegen.- With réf.- With summary in dutch Subject heading: preterm labour/ tocolysis/ ritodrine Financial support for the publication of this thesis by Solvay Pharma bv, Research Fonds Bronovo, Novo Nordisk Farma bv, Schering Nederland bv, Organon Nederland bv, Glaxo Wellcome bv, Ferring bv, Pfizer bv, Wyeth Laboratoria bv and Zeneca bv, is gratefully acknowledged. Cover illustration: Roses; flowers of love, life and birth.* Cover design: Annemieke van Rosmalen * J. Hall. Dictionary of subjects and symbols in art. New York, 1979. PHARMACOLOGICAL INTERVENTION IN PRETERM LABOUR Dose studies on ritodrine administration een wetenschappelijke proeve op het gebied van de Medische Wetenschappen Proefschrift ter verkrijging van de graad van doctor aan de Katholieke Universiteit Nijmegen, volgens besluit van het College van Decanen in het openbaar te verdedigen op dinsdag 26 november 1996 des namiddags om '3.30 uur precies door Caspar Adriaan Godfried Holleboom geboren op 30 april 1955 te Lubuk Pakan, Indonesië Promotores: Prof. Dr. J.M.W.M. Merkus Prof. Dr. M.J.N.C. Keirse, Flinders University, Adelaide, Australia Manuscriptcommissie: Prof.
  • Effects of Clofibrate Derivatives on Hyperlipidemia Induced by a Cholesterol-Free, High-Fructose Diet in Rats

    Effects of Clofibrate Derivatives on Hyperlipidemia Induced by a Cholesterol-Free, High-Fructose Diet in Rats

    Showa Univ. J. Med. Sci. 7(2), 173•`182, December 1995 Original Effects of Clofibrate Derivatives on Hyperlipidemia Induced by a Cholesterol-Free, High-Fructose Diet in Rats Hideyukl KURISHIMA,Sadao NAKAYAMA,Minoru FURUYA and Katsuji OGUCHI Abstract: The effects of the clofibrate derivatives fenofibrate (FF), bezafibrate (BF), and clinofibrate (CF), on hyperlipidemia induced by a cholesterol-free, high-fructose diet (HFD) in rats were investigated. Feeding of HFD for 2 weeks increased the high-density lipoprotein subfraction (HDL1) and decreased the low-density lipoprotein (LDL) fraction. The levels of total cholesterol (TC), free cholesterol, triglyceride (TG), and phospholipid in serum were increased by HFD feeding. Administration of CF inhibited the increase in HDL1 content. All three agents inhibited the decrease in LDL level. Both BF and CF decreased VLDL level. Administration of FF, BF, or CF inhibited the increases of serum lipids, especially that of TC and TG. The inhibitory effects of CF on HFD- induced increases in HDL1, TC, and TG were greater than those of FF and BF. These results demonstrate that FF, BF, and CF improve the intrinsic hyper- lipidemia induced by HFD feeding in rats. Key words: fenofibrate, bezafibrate, clinofibrate, fructose-induced hyperlipide- mia, lipoprotein. Introduction Clofibrate is one of the most effective antihypertriglycedemic agents currently available. However, because of its adverse effects, such as hepatomegaly1, several derivatives, such as clinofibrate (CF) and bezafibrate (BF) have been developed which are more effective and have fewer adverse effects. For example, it has been shown that the hypolipidemic effect of CF is greater than that of clofibrate while its tendency to produce hepatomegaly is less1.
  • Toiminta Unita on Ulla La Mungukurti |

    Toiminta Unita on Ulla La Mungukurti |

    TOIMINTAUNITA USON 20180071390A1ULLA LA MUNGUKURTI | ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018/ 0071390 A1 PATEL et al. (43 ) Pub . Date : Mar . 15 , 2018 ( 54 ) COMPOSITIONS OF PHARMACEUTICAL A61K 9 / 06 (2006 .01 ) ACTIVES CONTAINING DIETHYLENE A61K 9 /00 (2006 .01 ) GLYCOL MONOETHYL ETHER OR OTHER A61K 31 /573 ( 2006 .01 ) ALKYL DERIVATIVES A61K 31/ 565 ( 2006 .01 ) A61K 31/ 4439 ( 2006 . 01 ) ( 71 ) Applicant : THEMIS MEDICARE LIMITED , A61K 31 / 167 ( 2006 . 01 ) Mumbai (IN ) A61K 31 / 57 (2006 . 01) (52 ) U . S . CI. (72 ) Inventors : Dinesh Shantilal PATEL , Mumbai CPC .. .. .. A61K 47 / 10 ( 2013 . 01 ) ; A61K 9 /4858 ( IN ) ; Sachin Dinesh PATEL , Mumbai ( 2013 .01 ) ; A61K 9 /08 ( 2013 .01 ) ; A61K 9 / 06 ( IN ) ; Shashikant Prabhudas ( 2013 .01 ) ; A61K 9 / 0014 ( 2013 .01 ) ; A61K KURANI, Mumbai ( IN ) ; Madhavlal 31/ 573 ( 2013 .01 ) ; A61K 31 /57 ( 2013 .01 ) ; Govindlal PATEL , Mumbai ( IN ) A61K 31/ 565 ( 2013 .01 ) ; A61K 31 /4439 (73 ) Assignee : THEMIS MEDICARE LIMITED , ( 2013 .01 ) ; A61K 31/ 167 ( 2013 .01 ) ; A61K Mumbai (IN ) 9 /0048 ( 2013 .01 ) ; A61K 9 /0019 (2013 .01 ) ( 57 ) ABSTRACT (21 ) Appl. No .: 15 / 801, 390 The present invention relates to pharmaceutical composi tions of various pharmaceutical actives, especially lyophilic ( 22 ) Filed : Nov . 2 , 2017 and hydrophilic actives containing Diethylene glycol mono ethyl ether or other alkyl derivatives thereof as a primary Related U . S . Application Data vehicle and /or to pharmaceutical compositions utilizing (62 ) Division of application No. 14 /242 , 973 , filed on Apr. Diethylene glycol monoethyl ether or other alkyl derivatives 2 , 2014 , now Pat. No. 9 , 827 ,315 .
  • Actions of Non-Steroidal Anti-Inflammatory Drugs in Sheep

    Actions of Non-Steroidal Anti-Inflammatory Drugs in Sheep

    ACTIONS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN SHEEP by Elizabeth McCaulI Welsh B.V.M.S. , M.R.C.V.S. A thesis submitted for the degree of Doctor of Philosophy in the Faculty of Veterinary Medicine of the University of Glasgow Department of Veterinary Pharmacology August, 1993. ProQuest Number: 11007781 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 11007781 Published by ProQuest LLC(2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 GLASGOW UNIVERSITY LIBRARY i To my parents and Chris. CONTENTS Acknowledgements iv Declaration v Summary vi List of figures ix List of tables xii Abbreviations xvii Chapter 1- General Introduction 1 Chapter 2- General Materials and Methods 24 Chapter 3- The antinociceptive effects of non-steroidal anti-inflammatory drugs in sheep: 1 Clinical pain 36 3 .1 -Introduction 37 3.2- Materials and methods 47 3.3- Results 53 3.4- Discussion 98 Chapter 4- The antinociceptive effects of non-steroidal anti-inflammatory drugs in sheep: 2 Experimental pain 112 4.1-Introduction 113 4.2- Materials and methods 120 4.3- Results 123 4.4- Discussion 141 Chapter 5- The Pharmacokinetics of flunixin meglumine and carprofen (racemate) 150 iii 5.1- Introduction 151 5.2- Materials and methods 154 5.3- Results 159 5.4- Discussion 173 Chapter 6- Methods of lameness measurement 179 6.1- Introduction 180 6.2- Materials and methods 187 6.3- Results 192 6.4- Discussion 209 Chapter 7- General Discussion 218 References 226 ACKNOWLEDGEMENTS This work was generously funded by the Agricultural and Food Research Council.