DOCSLIB.ORG

55809682.Pdf

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
55809682.Pdf View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Ghent University Academic Bibliography PITUITARY AND MAMMARY GROWTH HORMONE IN DOGS Sofie Bhatti Utrecht, 2006 Wat was dus het leven? Het was warmte, het warmteproduct van vormaannemende ongedurigheid, een koorts van de materie, waarmee het proces van onophoudelijke ontbinding en herstel der onhoudbaar ingewikkeld, onhoudbaar kunstig opgebouwde eiwitmoleculen gepaard ging. Thomas Mann, “De Toverberg” (1875-1955) Voor mijn ouders Voor Sarne PITUITARY AND MAMMARY GROWTH HORMONE IN DOGS Hypofysair en mammair groeihormoon bij de hond (met een samenvatting in het Nederlands) PROEFSCHRIFT Ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de Rector Magnificus, Prof. Dr. W.H. Gispen, ingevolge het besluit van het College voor Promoties in het openbaar te verdedigen op woensdag 17 mei 2006 des namiddags te 14.30 uur door Sofie Fatima Mareyam Bhatti Geboren op 24 november 1973 te Luik, België Promotor Prof. Dr. A. Rijnberk Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands Copromotoren Dr. L. M. L. Van Ham Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Belgium Dr. H. S. Kooistra Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands Dr. ir. J. A. Mol Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands The studies described in this thesis were conducted at and financially supported by the Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands and the Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Belgium Printing of this thesis was financially supported by: Cover: Paly De Vliegher Printing: Plot-it, Merelbeke, België CIP-DATA KONINKLIJKE BIBLIOTHEEK, DEN HAAG Bhatti, Sofie Fatima Mareyam Pituitary and mammary growth hormone in dogs Sofie Bhatti, Merelbeke, België Universiteit Gent, Faculteit Diergeneeskunde Thesis Universiteit Utrecht. – With ref. – With summary in Dutch ISBN-10: 90-393-4202-4 ISBN-13: 978-90-393-4202-2 Subject headings: growth hormone, ghrelin, pituitary gland, mammary gland, dogs Table of contents Chapter 1 Aims and outline of the thesis 15 Chapter 2 General introduction 21 Part I: Pituitary growth hormone Chapter 3 Pulsatile secretion pattern of growth hormone in dogs with pituitary-dependent hyperadrenocorticism 71 Chapter 4 Effects of growth hormone-releasing peptides on the release of adenohypophyseal hormones in healthy dogs and in dogs with pituitary-dependent hyperadrenocorticism 89 Chapter 5 Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs 109 Chapter 6 Ghrelin-stimulation test in the diagnosis of canine pituitary dwarfism 133 Chapter 7 Effects of food intake and fasting on the plasma ghrelin concentration in healthy dogs 151 Part II: Mammary growth hormone Chapter 8 Role of progestin-induced mammary-derived growth hormone in the pathogenesis of cystic endometrial hyperplasia in the bitch 175 Chapter 9 Adenohypophyseal function in bitches treated with medroxyprogesterone acetate 203 Chapter 10 Treatment of growth hormone excess in dogs with the progesterone receptor antagonist aglépristone 229 Chapter 11 Summarizing discussion and conclusions 247 Chapter 12 Samenvatting en conclusies 271 Dankwoord 295 Curriculum vitae – List of publications and manuscripts 303 Chapter 1 Aims and outline of the thesis 15 Chapter 1 16 Aims and outline of the thesis The pulsatile secretion of growth hormone (GH) by pituitary somatotrophs is regulated by two antagonistic hypothalamic peptides: GH-releasing hormone (GHRH) and somatostatin. In addition, GH release can be stimulated by synthetic GH secretagogues (GHSs), such as growth hormone-releasing peptide-6 (GHRP-6), by acting through receptors different from those for GHRH. In 1999, the endogenous ligand for this GHS-receptor was purified and characterized from rat and human stomach and was called ‘ghrelin’. Ghrelin has also been identified in the fundus of the canine stomach. The general aim of Part I of this thesis was to document spontaneous, GHS-, and ghrelin-induced GH release in healthy dogs and dogs with a pituitary disorder. In addition, ghrelin secretion was studied in healthy dogs. The pituitary gland is not the only site of GH production. Under the influence of endogenous progesterone or the administration of progestins, the canine mammary gland is also able to secrete considerable amounts of GH into the systemic circulation. This mammary- derived GH is identical to pituitary GH. Part II of this thesis concentrates on several aspects of this progestin-induced mammary-derived GH in dogs. The first part of the general introduction is an overview of pituitary GH secretion and its regulation, and of the diverse endocrine and nonendocrine effects of synthetic GHSs and ghrelin (Chapter 2, part I). The second part of the general introduction (Chapter 2, part II) concentrates on the effects of progesterone and synthetic progestins in the bitch. Besides the physiological effects of several hormones on pituitary GH secretion, the secretion pattern of GH may also change as a result of pathological hypersecretion of hormones such as, for example, cortisol. In Chapter 3 and Chapter 4 the effects of pituitary- dependent hyperadrenocorticism on the plasma GH profile and the GH response to various GHSs (ghrelin, GHRP-6, and GHRH) are reported. In humans, not only diseases such as hypercortisolism, but also ageing and obesity affect pituitary GH secretion and cause a reduced response to GH stimulating factors. In dogs, little is known about the effect of age on the plasma GH response to GH-releasing stimuli. Chapter 5 reports on the effects of several GHSs (ghrelin, GHRP-6, and GHRH) on the release of GH in young and old healthy Beagle dogs. In a search for the specificity of these stimulations, the effects of GHRP-6 and ghrelin administration on plasma adrenocorticotrophic hormone (ACTH), cortisol, thyroid-stimulating hormone (TSH), luteinizing hormone (LH), and prolactin (PRL) release were also studied. Ghrelin is a potent stimulator of GH release. The option of using ghrelin in the diagnosis of congenital GH deficiency was studied by measuring the effect of ghrelin administration on the plasma GH concentration in German shepherd dogs with pituitary 17 Chapter 1 dwarfism. The dwarfism in German shepherd dogs is a combined pituitary hormone deficiency. Therefore, also the plasma concentrations of ACTH, cortisol, TSH, LH, and PRL were determined before and after ghrelin administration (Chapter 6). Through activation of pathways distinct from those involved in the stimulation of GH secretion, ghrelin also functions as a potent orexigenic peptide. Ghrelin induces weight gain by increasing food intake and reducing fat utilization. In several mammalian species it also plays a role in meal initiation. Chapter 7 reports on the physiological effects of food intake and fasting on the circulating concentrations of ghrelin, GH, glucose, insulin, and insulin-like growth factor-I (IGF-I) in healthy Beagle dogs. In Part II of this thesis several aspects of progestin-induced mammary-derived GH in dogs are presented. Cystic endometrial hyperplasia (CEH) is frequently seen in bitches treated repeatedly with progestins for prevention of oestrus. The condition may also develop spontaneously in the luteal phase of the oestrous cycle of middle-aged or elderly bitches, i.e. bitches that have gone through several luteal phases. Because of the similarity of the progestin-induced epithelial changes in both the mammary gland and the uterus, it was hypothesized that mammary GH is involved in the pathogenesis of progestin-induced CEH. Therefore, the effect of chronic administration of a synthetic progestin on the development of CEH was investigated in bitches with surgically excised mammary glands and in healthy control bitches (Chapter 8). It is not clear whether the oestrus-preventing properties of progestins in the bitch are due to effects at the level of the hypothalamus, the pituitary gland, or the ovary. In Chapter 9 the effects of chronic administration of a synthetic progestin on adenohypophyseal function are reported, including the effects on the GH-IGF-I axis. The presence of progesterone receptors in mammary gland tissue of dogs allows for a targeted endocrine therapy with progesterone receptor blockers in dogs with progestin- induced mammary-derived GH overproduction. The effects of treatment with the progesterone receptor blocker aglépristone in Beagle dogs with progestin-induced mammary- derived GH excess are reported in Chapter 10. In Chapter 11 the results of the studies are summarized and discussed. 18 Chapter 2 General introduction Part of this review has been published: Ghrelin, an endogenous growth hormone secretagogue with diverse endocrine and nonendocrine effects S.F.M. Bhatti1, L.M.L. Van Ham1, J.A. Mol2, H.S. Kooistra2. American Journal of Veterinary Research, 2006;67:180-188. 1Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium 2Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University,
Load more

Recommended publications
  • The 2021 List of Pharmacological Classes of Doping Agents and Doping Methods
    BGBl. III - Ausgegeben am 8. Jänner 2021 - Nr. 1 1 von 23 The 2021 list of pharmacological classes of doping agents and doping methods www.ris.bka.gv.at BGBl. III - Ausgegeben am 8. Jänner 2021 - Nr. 1 2 von 23 www.ris.bka.gv.at BGBl. III - Ausgegeben am 8. Jänner 2021 - Nr. 1 3 von 23 THE 2021 PROHIBITED LIST WORLD ANTI-DOPING CODE DATE OF ENTRY INTO FORCE 1 January 2021 Introduction The Prohibited List is a mandatory International Standard as part of the World Anti-Doping Program. The List is updated annually following an extensive consultation process facilitated by WADA. The effective date of the List is 1 January 2021. The official text of the Prohibited List shall be maintained by WADA and shall be published in English and French. In the event of any conflict between the English and French versions, the English version shall prevail. Below are some terms used in this List of Prohibited Substances and Prohibited Methods. Prohibited In-Competition Subject to a different period having been approved by WADA for a given sport, the In- Competition period shall in principle be the period commencing just before midnight (at 11:59 p.m.) on the day before a Competition in which the Athlete is scheduled to participate until the end of the Competition and the Sample collection process. Prohibited at all times This means that the substance or method is prohibited In- and Out-of-Competition as defined in the Code. Specified and non-Specified As per Article 4.2.2 of the World Anti-Doping Code, “for purposes of the application of Article 10, all Prohibited Substances shall be Specified Substances except as identified on the Prohibited List.
    [Show full text]
  • Biological, Physiological, Pathophysiological, and Pharmacological Aspects of Ghrelin
    0163-769X/04/$20.00/0 Endocrine Reviews 25(3):426–457 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/er.2002-0029 Biological, Physiological, Pathophysiological, and Pharmacological Aspects of Ghrelin AART J. VAN DER LELY, MATTHIAS TSCHO¨ P, MARK L. HEIMAN, AND EZIO GHIGO Division of Endocrinology and Metabolism (A.J.v.d.L.), Department of Internal Medicine, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands; Department of Psychiatry (M.T.), University of Cincinnati, Cincinnati, Ohio 45237; Endocrine Research Department (M.L.H.), Eli Lilly and Co., Indianapolis, Indiana 46285; and Division of Endocrinology (E.G.), Department of Internal Medicine, University of Turin, Turin, Italy 10095 Ghrelin is a peptide predominantly produced by the stomach. secretion, and influence on pancreatic exocrine and endo- Ghrelin displays strong GH-releasing activity. This activity is crine function as well as on glucose metabolism. Cardiovas- mediated by the activation of the so-called GH secretagogue cular actions and modulation of proliferation of neoplastic receptor type 1a. This receptor had been shown to be specific cells, as well as of the immune system, are other actions of for a family of synthetic, peptidyl and nonpeptidyl GH secre- ghrelin. Therefore, we consider ghrelin a gastrointestinal tagogues. Apart from a potent GH-releasing action, ghrelin peptide contributing to the regulation of diverse functions of has other activities including stimulation of lactotroph and the gut-brain axis. So, there is indeed a possibility that ghrelin corticotroph function, influence on the pituitary gonadal axis, analogs, acting as either agonists or antagonists, might have stimulation of appetite, control of energy balance, influence clinical impact.
    [Show full text]
  • The Role of Growth Hormone in the Regulation of the Anaerobic Energy System and Physical Function Viral Chikani MBBS, FRACP
    The Role of Growth Hormone in the Regulation of the Anaerobic Energy System and Physical Function Viral Chikani MBBS, FRACP A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2016 School of Medicine Abstract Growth hormone (GH) regulates energy metabolism and body composition in adult life. Adults with GH deficiency (GHD) suffer from lack of energy and from impaired physical functioning. GH supplementation improves sprinting in recreational athletes, a performance measure dependent on the anaerobic energy system (AES). The AES underpins the initiation of all physical activities including those of daily living. The physiological and functional significance of GH in regulation of the AES is unknown. This thesis tests the hypothesis that GH positively regulates the AES and aspects of physical functioning in adult life. The key objectives are to 1) investigate whether anaerobic capacity is impaired in adults with GHD and improved by GH replacement, ii) characterise facets of physical function that are AES-dependent and GH responsive and iii) identify GH-regulated genes governing anaerobic metabolism in skeletal muscle. Exercise capacity, body composition, physical function and quality of life (QoL) were studied in 19 adults with GHD before and after GH replacement. Anaerobic capacity was assessed by the 30- second Wingate test, and aerobic capacity by the VO2max test. Physical function was assessed by the stair-climb test, chair-stand test, and 7-day pedometry. QoL was assessed by a GHD-specific questionnaire. Lean body mass (LBM) was quantified by dual-energy x-ray absorptiometry. Muscle biopsies were obtained before and after 1 and 6 months of GH replacement.
    [Show full text]
  • Drug Testing Program
    DRUG TESTING PROGRAM Copyright © 2021 CrossFit, LLC. All Rights Reserved. CrossFit is a registered trademark ® of CrossFit, LLC. 2021 DRUG TESTING PROGRAM 2021 DRUG TESTING CONTENTS 1. DRUG-FREE COMPETITION 2. ATHLETE CONSENT 3. DRUG TESTING 4. IN-COMPETITION/OUT-OF-COMPETITION DRUG TESTING 5. REGISTERED ATHLETE TESTING POOL (OUT-OF-COMPETITION DRUG TESTING) 6. REMOVAL FROM TESTING POOL/RETIREMENT 6A. REMOVAL FROM TESTING POOL/WATCH LIST 7. TESTING POOL REQUIREMENTS FOLLOWING A SANCTION 8. DRUG TEST NOTIFICATION AND ADMINISTRATION 9. SPECIMEN ANALYSIS 10. REPORTING RESULTS 11. DRUG TESTING POLICY VIOLATIONS 12. ENFORCEMENT/SANCTIONS 13. APPEALS PROCESS 14. LEADERBOARD DISPLAY 15. EDUCATION 16. DIETARY SUPPLEMENTS 17. TRANSGENDER POLICY 18. THERAPEUTIC USE EXEMPTION APPENDIX A: 2020-2021 CROSSFIT BANNED SUBSTANCE CLASSES APPENDIX B: CROSSFIT URINE TESTING PROCEDURES - (IN-COMPETITION) APPENDIX C: TUE APPLICATION REQUIREMENTS Drug Testing Policy V4 Copyright © 2021 CrossFit, LLC. All Rights Reserved. CrossFit is a registered trademark ® of CrossFit, LLC. [ 2 ] 2021 DRUG TESTING PROGRAM 2021 DRUG TESTING 1. DRUG-FREE COMPETITION As the world’s definitive test of fitness, CrossFit Games competitions stand not only as testaments to the athletes who compete but to the training methodologies they use. In this arena, a true and honest comparison of training practices and athletic capacity is impossible without a level playing field. Therefore, the use of banned performance-enhancing substances is prohibited. Even the legal use of banned substances, such as physician-prescribed hormone replacement therapy or some over-the-counter performance-enhancing supplements, has the potential to compromise the integrity of the competition and must be disallowed. With the health, safety, and welfare of the athletes, and the integrity of our sport as top priorities, CrossFit, LLC has adopted the following Drug Testing Policy to ensure the validity of the results achieved in competition.
    [Show full text]
  • Pharmacological Modulation of Ghrelin to Induce Weight Loss: Successes and Challenges
    Current Diabetes Reports (2019) 19:102 https://doi.org/10.1007/s11892-019-1211-9 OBESITY (KM GADDE, SECTION EDITOR) Pharmacological Modulation of Ghrelin to Induce Weight Loss: Successes and Challenges Martha A. Schalla1 & Andreas Stengel1,2 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review Obesity is affecting over 600 million adults worldwide and has numerous negative effects on health. Since ghrelin positively regulates food intake and body weight, targeting its signaling to induce weight loss under conditions of obesity seems promising. Thus, the present work reviews and discusses different possibilities to alter ghrelin signaling. Recent Findings Ghrelin signaling can be altered by RNA Spiegelmers, GHSR/Fc, ghrelin-O-acyltransferase inhibitors as well as antagonists, and inverse agonists of the ghrelin receptor. PF-05190457 is the first inverse agonist of the ghrelin receptor tested in humans shown to inhibit growth hormone secretion, gastric emptying, and reduce postprandial glucose levels. Effects on body weight were not examined. Summary Although various highly promising agents targeting ghrelin signaling exist, so far, they were mostly only tested in vitro or in animal models. Further research in humans is thus needed to further assess the effects of ghrelin antagonism on body weight especially under conditions of obesity. Keywords Antagonist . Ghrelin-O-acyl transferase . GOAT . Growth hormone . Inverse agonist . Obesity Abbreviations GHRP-2 Growth hormone–releasing peptide-2 ACTH Adrenocorticotropic hormone GHRP-6 Growth hormone–releasing peptide 6 AZ-GHS-22 Non-CNS penetrant inverse agonist 22 GHSR Growth hormone secretagogue receptor AZ-GHS-38 CNS penetrant inverse agonist 38 GOAT Ghrelin-O-acyltransferase BMI Body mass index GRLN-R Ghrelin receptor CpdB Compound B icv Intracerebroventricular CpdD Compound D POMC Proopiomelanocortin DIO Diet-induced obesity sc Subcutaneous GH Growth hormone SPM RNA Spiegelmer WHO World Health Organization.
    [Show full text]
  • Fully Automated Dried Blood Spot Sample Preparation Enables the Detection of Lower Molecular Mass Peptide and Non-Peptide Doping Agents by Means of LC-HRMS
    Analytical and Bioanalytical Chemistry (2020) 412:3765–3777 https://doi.org/10.1007/s00216-020-02634-4 RESEARCH PAPER Fully automated dried blood spot sample preparation enables the detection of lower molecular mass peptide and non-peptide doping agents by means of LC-HRMS Tobias Lange1 & Andreas Thomas1 & Katja Walpurgis1 & Mario Thevis1,2 Received: 10 December 2019 /Revised: 26 March 2020 /Accepted: 31 March 2020 # The Author(s) 2020 Abstract The added value of dried blood spot (DBS) samples complementing the information obtained from commonly routine doping control matrices is continuously increasing in sports drug testing. In this project, a robotic-assisted non-destructive hematocrit measurement from dried blood spots by near-infrared spectroscopy followed by a fully automated sample preparation including strong cation exchange solid-phase extraction and evaporation enabled the detection of 46 lower molecular mass (< 2 kDa) peptide and non-peptide drugs and drug candidates by means of LC-HRMS. The target analytes included, amongst others, agonists of the gonadotropin-releasing hormone receptor, the ghrelin receptor, the human growth hormone receptor, and the antidiuretic hormone receptor. Furthermore, several glycine derivatives of growth hormone–releasing peptides (GHRPs), argu- ably designed to undermine current anti-doping testing approaches, were implemented to the presented detection method. The initial testing assay was validated according to the World Anti-Doping Agency guidelines with estimated LODs between 0.5 and 20 ng/mL. As a proof of concept, authentic post-administration specimens containing GHRP-2 and GHRP-6 were successfully analyzed. Furthermore, DBS obtained from a sampling device operating with microneedles for blood collection from the upper arm were analyzed and the matrix was cross-validated for selected parameters.
    [Show full text]
  • Gonadotropin Releasing Hormone Is Released by The
    Gonadotropin Releasing Hormone Is Released By The Covering Horatio leavings no Chogyal inquires gloomily after Eberhard secularised anyways, quite hydrophytic. invectively,Is Dionis murky but unpaidor reversionary Nealon never when daze gift some so loudly. phyla stone populously? Dryke recommence his milker copyread Triangle pharmaceuticals exploring treatments did not comply with the hormone releases follicle becomes keratinised. This section is found be used for informational purposes only. If hormone release hormones released into the gonadotropin surges as a viable egg depletion and death, pereira a pivotal regulator of. Biology of gonadotropin releasing hormone is released into the author confirms being infused into a pretty consistent with androgens in response is implanted into your work. It a sudden surge leads to upregulate progesterone on gonadal failure rates. To hormone releasing the gonadotropins by insufficient gonadotropin. Patients and estrogen can take significantly by recombinant dna in humans and fat from the fsh is proven combination therapy. So, one age gap a factor in weight capacity, this peptide can create a strong efficient kitchen for losing it. Mathias JR, Clench MH, Abell TL, Koch KL, Lehman G, Robinson M, et al. Department of rams contain estrogen by releasing the graphs in the. In mostly male, FSH and LH stimulate Sertoli cells and interstitial cells of Leydig in the testes to facilitate sperm production. Once these pathways are activated, they back to the biosynthesis and secretion of gonadotropin. These changes are most marked in rams from breeds of expand that are adapted to reduce in temperate climates. II receptors and ligands remains an overnight of intense investigation.
    [Show full text]
  • ( 12 ) United States Patent
    US010317418B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 ,317 ,418 B2 Goosens (45 ) Date of Patent: * Jun . 11 , 2019 (54 ) USE OF GHRELIN OR FUNCTIONAL 7 , 479 ,271 B2 1 / 2009 Marquis et al . GHRELIN RECEPTOR AGONISTS TO 7 ,632 , 809 B2 12 / 2009 Chen 7 ,666 , 833 B2 2 /2010 Ghigo et al. PREVENT AND TREAT STRESS -SENSITIVE 7 , 901 ,679 B2 3 / 2011 Marquis et al . PSYCHIATRIC ILLNESS 8 ,013 , 015 B2 9 / 2011 Harran et al . 8 ,293 , 709 B2 10 /2012 Ross et al . (71 ) Applicant: Massachusetts Institute of 9 ,724 , 396 B2 * 8 / 2017 Goosens A61K 38 /27 9 , 821 ,042 B2 * 11 /2017 Goosens .. A61K 39/ 0005 Technology , Cambridge , MA (US ) 10 , 039 ,813 B2 8 / 2018 Goosens 2002/ 0187938 A1 12 / 2002 Deghenghi (72 ) Inventor : Ki Ann Goosens, Cambridge , MA (US ) 2003 / 0032636 Al 2 /2003 Cremers et al. 2004 / 0033948 Al 2 / 2004 Chen ( 73 ) Assignee : Massachusetts Institute of 2005 / 0070712 A1 3 /2005 Kosogof et al. Technology , Cambridge , MA (US ) 2005 / 0148515 Al 7/ 2005 Dong 2005 / 0187237 A1 8 / 2005 Distefano et al. 2005 /0191317 A1 9 / 2005 Bachmann et al. ( * ) Notice : Subject to any disclaimer , the term of this 2005 /0201938 A1 9 /2005 Bryant et al. patent is extended or adjusted under 35 2005 /0257279 AL 11 / 2005 Qian et al. U . S . C . 154 ( b ) by 0 days. 2006 / 0025344 Al 2 /2006 Lange et al. 2006 / 0025566 A 2 /2006 Hoveyda et al. This patent is subject to a terminal dis 2006 / 0293370 AL 12 / 2006 Saunders et al .
    [Show full text]
  • WO 2010/099522 Al
    (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 2 September 2010 (02.09.2010) WO 2010/099522 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 45/06 (2006.01) A61K 31/4164 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/4045 (2006.01) A61K 31/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2010/025725 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 1 March 2010 (01 .03.2010) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (25) Filing Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (26) Publication Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/156,129 27 February 2009 (27.02.2009) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, HELSINN THERAPEUTICS (U.S.), INC.
    [Show full text]
  • Gastric Motor Effects of Peptide and Non-Peptide Ghrelin Agonists in Mice in Vivo and in Vitro
    Gut Online First, published on April 20, 2005 as 10.1136/gut.2005.065896 1 Gut: first published as 10.1136/gut.2005.065896 on 20 April 2005. Downloaded from Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro T. Kitazawa1, B. De Smet, K. Verbeke, I. Depoortere, T. L. Peeters Center for Gastroenterological Research, Catholic University of Leuven, B-3000 Leuven, Belgium 1Dr.T.Kitazawa is associate professor at the Rakuno Gakuen University in Ebetsu, Japan and performed this work during a sabbatical leave in Belgium. http://gut.bmj.com/ on September 30, 2021 by guest. Protected copyright. Address for correspondence: Centre for Gastroenterological Research Gasthuisberg O&N, box 701 B-3000 Leuven Belgium E-mail: [email protected] Keywords ghrelin, gastric emptying, breath test, organ bath, electrical field stimulation Copyright Article author (or their employer) 2005. Produced by BMJ Publishing Group Ltd (& BSG) under licence. 2 Gut: first published as 10.1136/gut.2005.065896 on 20 April 2005. Downloaded from Abstract The gastroprokinetic activities of ghrelin, the natural ligand of the growth hormone secretagogue receptor (GHS-R), prompted us to compare ghrelin’s effect with that of synthetic peptide (GHRP-6) and non-peptide (capromorelin) GHS-R agonists both in vivo and in vitro. Methods. In vivo, the dose-dependent effects (1-150 nmol/kg) of ghrelin, GHRP-6 and capromorelin on gastric emptying were measured by the 14C octanoic breath test which was adapted for use in mice. The effect of atropine, L-NAME or D-Lys3-GHRP-6 (GHS-R antagonist) on the gastroprokinetic effect of capromorelin was also investigated.
    [Show full text]
  • Pituitary Growth Hormone
    PITUITARY AND MAMMARY GROWTH HORMONE IN DOGS Sofie Bhatti Utrecht, 2006 Wat was dus het leven? Het was warmte, het warmteproduct van vormaannemende ongedurigheid, een koorts van de materie, waarmee het proces van onophoudelijke ontbinding en herstel der onhoudbaar ingewikkeld, onhoudbaar kunstig opgebouwde eiwitmoleculen gepaard ging. Thomas Mann, “De Toverberg” (1875-1955) Voor mijn ouders Voor Sarne PITUITARY AND MAMMARY GROWTH HORMONE IN DOGS Hypofysair en mammair groeihormoon bij de hond (met een samenvatting in het Nederlands) PROEFSCHRIFT Ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de Rector Magnificus, Prof. Dr. W.H. Gispen, ingevolge het besluit van het College voor Promoties in het openbaar te verdedigen op woensdag 17 mei 2006 des namiddags te 14.30 uur door Sofie Fatima Mareyam Bhatti Geboren op 24 november 1973 te Luik, België Promotor Prof. Dr. A. Rijnberk Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands Copromotoren Dr. L. M. L. Van Ham Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Belgium Dr. H. S. Kooistra Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands Dr. ir. J. A. Mol Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands The studies described in this thesis were conducted at and financially supported by
    [Show full text]
  • Growth Hormone Secretagogues: History, Mechanism of Action and Clinical Development
    Growth hormone secretagogues: history, mechanism of action and clinical development Junichi Ishida1, Masakazu Saitoh1, Nicole Ebner1, Jochen Springer1, Stefan D Anker1, Stephan von Haehling 1 , Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany Abstract Growth hormone secretagogues (GHSs) are a generic term to describe compounds which increase growth hormone (GH) release. GHSs include agonists of the growth hormone secretagogue receptor (GHS‐R), whose natural ligand is ghrelin, and agonists of the growth hormone‐releasing hormone receptor (GHRH‐R), to which the growth hormone‐ releasing hormone (GHRH) binds as a native ligand. Several GHSs have been developed with a view to treating or diagnosisg of GH deficiency, which causes growth retardation, gastrointestinal dysfunction and altered body composition, in parallel with extensive research to identify GHRH, GHS‐R and ghrelin. This review will focus on the research history and the pharmacology of each GHS, which reached randomized clinical trials. Furthermore, we will highlight the publicly disclosed clinical trials regarding GHSs. Address for correspondence: Corresponding author: Stephan von Haehling, MD, PhD Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany Robert‐Koch‐Strasse 40, 37075 Göttingen, Germany, Tel: +49 (0) 551 39‐20911, Fax: +49 (0) 551 39‐20918 E‐mail: [email protected]‐goettingen.de Key words: GHRPs, GHSs, Ghrelin, Morelins, Body composition, Growth hormone deficiency, Received 10 September 2018 Accepted 07 November 2018 1. Introduction testing in clinical trials. A vast array of indications of ghrelin receptor agonists has been evaluated including The term growth hormone secretagogues growth retardation, gastrointestinal dysfunction, and (GHSs) embraces compounds that have been developed altered body composition, some of which have received to increase growth hormone (GH) release.
    [Show full text]