DOCSLIB.ORG

Alshaer Danah Mahdi 2020.Pdf (14.70Mb)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Alshaer Danah Mahdi 2020.Pdf (14.70Mb) Synthesis and physiochemical characterization of new siderophore- inspired peptide-chelators with 1- hydroxypridine-2-one (1,2-HOPO) Thesis Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy by Danah Mahdi AlShaer 2020 Supervisor: Prof. Beatriz Garcia de la Torre Co-supervisor: Prof. Fernando Albericio Synthesis and physiochemical characterization of new siderophore-inspired peptide• chelators with 1-hydrnxypridine-2-one (1,2-JB[OPO) 217078895 Danah Mahdi AllSlh.aer A thesis submitted to the School of Health Sciences, College of Health Sciences, University of KwaZulu-Natal, Westville, for the degree of Doctor of Philosophy by research in Pharmaceutical Chemistry. This is the thesis in which the chapters are written as a set of discrete research publications that have followed each journal's format with an overall introduction and final summary. These chapters have been published in internationally recognized, peer-reviewed journals. This is to certify that the contents of this thesis are the original research work of Mrs Danah Mahdi AllSllnaer, carried out under our supervision at the Peptide Sciences Laboratory, Westville campus, University of KwaZulu-Natal, Durban, South Africa. Supervisor: --"-:I-----::... Date: gth December 2020 Date: 8th December 2020 As the candidate's supervisors we agree to the submission of this thesis Table of Contents Abstract……………..…………………………………………………………………..……1 Declaration 1: Plagiarism.……………………………………………………….…………..2 Declaration 2: Publications ….………………………………………………….…...….…..3 Acknowledgment………………………………………..………………...…………….…..5 Aim and objectives……….….……………………………………………………………...6 Chapter 1: (Introduction) Hydroxamate Siderophores: Natural Occurrence, Chemical Synthesis, Iron Binding Affinity and Use as Trojan Horses Against ………..……….. 7 Reprint………………………………………………………………………………………8 Chapter 2: Solid-phase synthesis of peptides containing 1-Hydroxypyridine-2-one (1,2-HOPO) …………………………………………………….………………………. 39 Reprint………………………………………………………………………………………40 Chapter 3: Protocol for efficient solid-phase synthesis of peptides containing 1- hydroxypyridine-2-one (1,2-HOPO) ………………………….………………………. 44 Reprint………………………………………………………………………………………45 Chapter 4: Chapter 4. Synthesis of new peptide-based Ligands with 1,2-HOPO pendant chelators and the thermodynamic evaluation of their iron (III) complexes ………………………………………………………………………………………..……. 53 1. Introduction ….……...………….…….….……………………………………………. 53 2. Results and discussion….……………………………………….….…………………. 55 2.1 Synthesis of Ligands……..………………………………….….…………………. 55 2.2 Physiochemical characterization of ligands and their Fe(III) complexes………… 57 2.2.1 Ligand-Fe (III) complex stoichiometry determination ….…………..……… 57 2.2.2 Determination of pKa values………………...……… ….…………..……… 59 2.2.3 Iron (III) complexation…..………………………..………………………… 61 3. Conclusion….……...………….….…….….……………………………………………. 63 4. Experimental.……...………….….…….….……………………………………………. 63 5. References …………………………………………………….….………..……………. 66 Chapter 5: 2019 FDA TIDES (Peptides and Oligonucleotides) Harvest ……………. 68 Reprint………………………………………………………………………………………69 Chapter 6: 2018 FDA TIDES Harvest …………………………………..……………. 85 Reprint………………………………………………………………………………………86 Chapter 7: 2017 FDA peptide Harvest …………………………………..……………. 92 Reprint………………………………………………………………………………………93 Chapter 8: Conclusion and future perspectives………………………..……………. 103 Supplementary information Abstract Compounds containing hydroxamate moieties (N-hydroxyl amides) in their structure have found a vast range of therapeutic applications such as antibacterial, anti-tumour, anti-immune suppressor, and for iron overloading treatment. Hydroxamate chelators binds to Fe (III) tightly through its electron donating oxygens. The binding strength is maximized in compounds containing three hydroxamic moieties due to the so called “chelate effect”. As all microorganisms require iron for surviving, they develop endogenous siderophores to acquire iron from the surroundings. Siderophores contain hydroxamate, catecholates, α-hydroxy carboxylates groups, among others, in their structures. The acquisition of iron by siderophores in microorganisms goes through specific cycles that includes sequestration of Fe(III), recognition and uptake of the ferri- siderophore through the cell membrane, and then release of the iron in the cytoplasm. Many natural hydroxamate siderophores contain a peptidyl backbone. In this work, peptides containing one or more units of 1,2-hydroxypyridine-N-oxide (1,2-HOPO) have been synthesized. The introduction of these units on the peptides has been done by means of 4- carboxy-1-hydroxypyridil-2-one (1,2-HOPO-4-COOH) using solid-phase peptides synthesis (SPPS) protocols. The obtention of the new “siderophores” containing three 1,2-HOPO units have been done by two different approaches, sequential and convergent. The compounds have been evaluated as potential iron chelators. Thus, the pKa values and the thermodynamic constants of all ligands have been spectrophotometrically determined. The Fe(III) affinities of the two hexadentate ligands (ligand B and ligand C) have been determined by competition experiments against EDTA. The results showed that the iron complex ligand B is stronger that the iron complex EDTA since the last is not be able to replace it. Hence, this new siderophore could be a promising candidate to be used in further therapeutic applications. 1 Declaration 1- Plagiarism I, Danah Mahdi AlShaer, declare that, 1. The research report in this thesis, except where othe1wise indicated, is my original work. 2. This thesis has not been submitted forany degree or examination at any other university. 3. This thesis does not contain other person's data, pictures, graphs, or other information, unless specificallyacknowledged as being sourced from other persons. 4. This thesis does not contain other person's writing, unless specificallyacknowledged as being sourced from other researchers. Where other written sources have been quoted, then: a. Their words have been re-written, but the general informationattributed to them has been referenced. b. Where their exact words have been used, then their writing has been placed in italics and inside quotation marks and referenced. 5. This thesis does not contain text, graphics or tables copied and pasted from the intern,t, unless specificallyacknowledged, and the source being detailed in the thesis and in the references sections. Signed -----------�----------------- 2 Declaration 2- Publication List of publications originated from this Thesis 1. Al Shaer, D.; Al Musaimi, O.; de la Torre, B, G.; Albericio, F. Hydroxamate siderophores: Natural occurrence, chemical synthesis, iron binding affinity and use as Trojan horses against pathogens. Eur. J.Med.Chem. 2020, 208. 10.1016/j.ejmech.2020.112791. (Al Shaer D., and Al Musaimi, O. contributed to searching for information and in writing the manuscript, the remaining authors are supervisors). 2. Al Shaer, D. ; Albericio, F.; de la Torre, B, G. Solid-phase synthesis of peptides containing 1-Hydroxypyridine-2-one (1,2-HOPO). Tetrahedron Lett. 2020, 61. 10.1016/j.tetlet.2020.152299. (Al Shaer, D. contributed in the synthesis, analysis, characterization of all compounds in this work, the remaining authors are supervisors). 3. Al Shaer, D.; de la Torre, B, G.; Albericio, F. Protocol for efficient solid-phase synthesis of peptides containing 1-hydroxypyridine-2-one (1,2-HOPO). MethodsX 2020, 7. 10.1016/j.mex.2020.101082. (Al Shaer, D. contributed in the synthesis, analysis, characterization of all compounds in this work, also in writing the manuscript, the remaining authors are supervisors). 4. Al Shaer, D. ; Albericio, F.; de la Torre, B, G. Synthesis of new peptide-based Ligands with 1,2-HOPO pendant chelators and the thermodynamic evaluation of their iron (III) complexes (submitted manuscript). (Al Shaer, D. contributed to the synthesis, analysis, characterization of all compounds in this work, the remaining authors are supervisors). 5. Al Shaer, D.; Al Musaimi, O.; Albericio, F.; de la Torre, B, G. 2019 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharmaceuticals (Basel). 2020, 13, doi:10.3390/ph13030040. (Al Shaer D., and Al Musaimi, O. contributed equally to searching for information and in writing the manuscript, the remaining authors are supervisors. 6. Al Shaer, D.; Al Musaimi, O.; Albericio, F.; de la Torre, B, G. 2018 FDA Harvest. Pharmaceuticals (Basel). 2019, 12, doi: 10.3390/ph12020052. 3 (Al Shaer D., and Al Musaimi, O. contributed equally to searching for information and in writing the manuscript, the remaining authors are supervisors. 7. Al Musaimi, O.; Al Shaer, D.; de la Torre, B.G.; Albericio, F. 2017 FDA peptide harvest. Pharmaceuticals (Basel) 2018, 11. 10.3390/ph11020042. (Al Shaer D., and Al Musaimi, O. contributed equally to searching for information and in writing the manuscript, the remaining authors are supervisors). 4 Acknowledgements My heartful thanks and praises to almighty God “Allah” for giving me the health, patience and strength to move on in life, and for all his blessings. Then, special thanks to my supervisors Prof. Beatriz de la Torre and Prof. Fernando Albericio for their continuous support, guidance, inspiration, and motivation all throughout my PhD study, my gratitude cannot be expressed by words, THANK YOU BOTH. Next, many thanks and appreciation go to my colleague and husband Dr. Othman Al Musaimi, and all my group mates Dr. Anamika, Dr. Ashish, Dr. Edikarlos, Dr. Al Hassan, Dr. Srinivas, Nandhini, Amit, Amanda,
Load more

Recommended publications
  • Targeting Somatostatin Receptors: Preclinical Evaluation of Novel 18F-Fluoroethyltriazole-Tyr3-Octreotate Analogs for PET
    Journal of Nuclear Medicine, published on August 18, 2011 as doi:10.2967/jnumed.111.088906 Targeting Somatostatin Receptors: Preclinical Evaluation of Novel 18F-Fluoroethyltriazole-Tyr3-Octreotate Analogs for PET Julius Leyton1, Lisa Iddon2, Meg Perumal1, Bard Indrevoll3, Matthias Glaser2, Edward Robins2, Andrew J.T. George4, Alan Cuthbertson3, Sajinder K. Luthra2, and Eric O. Aboagye1 1Comprehensive Cancer Imaging Center at Imperial College, Faculty of Medicine, Imperial College London, London, United Kingdom; 2MDx Discovery (part of GE Healthcare) at Hammersmith Imanet Ltd., Hammersmith Hospital, London, United Kingdom; 3GE Healthcare AS, Oslo, Norway; and 4Section of Immunobiology, Faculty of Medicine, Imperial College London, London, United Kingdom Key Words: somatostatin receptor; octreotide; 18F-fluoroethyl- The incidence and prevalence of gastroenteropancreatic triazole-Tyr3-octreotate; positron emission tomography; and neuroendocrine tumors has been increasing over the past 3 neuroendocrine decades. Because of high densities of somatostatin receptors J Nucl Med 2011; 52:1–8 (sstr)—mainly sstr-2—on the cell surface of these tumors, 111In- DOI: 10.2967/jnumed.111.088906 diethylenetriaminepentaacetic acid-octreotide scintigraphy has become an important part of clinical management. 18F-radio- labeled analogs with suitable pharmacokinetics would permit PET with more rapid clinical protocols. Methods: We compared the affinity in vitro and tissue pharmacokinetics by PET of 5 structurally related 19F/18F-fluoroethyltriazole-Tyr3-octreotate The incidence and prevalence of gastroenteropancreatic (FET-TOCA) analogs: FET-G-polyethylene glycol (PEG)-TOCA, neuroendocrine tumors (GEP-NETs) has increased signifi- FETE-PEG-TOCA, FET-G-TOCA, FETE-TOCA, and FET-bAG- cantly over the past 3 decades (1). The most common site TOCA to the recently described 18F-aluminum fluoride NOTA- of primary GEP-NETs is the gastrointestinal tract (60%).
    [Show full text]
  • Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future
    International Journal of Molecular Sciences Review Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future Anna Kathrin Stueven 1, Antonin Kayser 1, Christoph Wetz 2, Holger Amthauer 2, Alexander Wree 1, Frank Tacke 1, Bertram Wiedenmann 1, Christoph Roderburg 1,* and Henning Jann 1 1 Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany; [email protected] (A.K.S.); [email protected] (A.K.); [email protected] (A.W.); [email protected] (F.T.); [email protected] (B.W.); [email protected] (H.J.) 2 Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Nuclear Medicine, Universitätsmedizin Berlin, 10117 Berlin, Germany; [email protected] (C.W.); [email protected] (H.A.) * Correspondence: [email protected]; Tel.: +49-30-450-553022 Received: 3 May 2019; Accepted: 19 June 2019; Published: 22 June 2019 Abstract: In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2).
    [Show full text]
  • Tanibirumab (CUI C3490677) Add to Cart
    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
    [Show full text]
  • Downloaded from Bioscientifica.Com at 09/23/2021 09:50:19AM Via Free Access
    5 181 S W J Lamberts and Octreotide 181:5 R173–R183 Review L J Hofland ANNIVERSARY REVIEW Octreotide, 40 years later Correspondence should be addressed Steven W J Lamberts and Leo J Hofland to S W J Lamberts Division of Endocrinology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands Email [email protected] Abstract Octreotide remains 40 years after its development a drug, which is commonly used in the treatment of acromegaly and GEP-NETs. Very little innovation that competes with this drug occurred over this period. This review discusses several aspects of 40 years of clinical use of octreotide, including the application of radiolabeled forms of the peptide. European Journal of Endocrinology (2019) 181, R173–R183 Introduction A peptide inhibiting the release of growth hormone initial enthusiasm for its clinical use. From 1978 on, a (GH) was accidentally detected in the hypothalamus of number of drug companies started programs to synthesize rats during studies of the distribution of GH-releasing long-acting somatostatin analogs. factor (1). This peptide, called somatostatin, is a peptide Octreotide (SMS 201-995) was one of the first hormone that plays an inhibitory role in the regulation biologically stable somatostatin analogs to be synthesized of multiple physiological functions, including pituitary, (8): it has a much longer half-life in the human circulation European Journal of Endocrinology pancreatic and gastrointestinal hormone secretion (2, 3). than somatostatin and binds with a high affinity to Somatostatin exerts its biological effects by interaction SST2 (9). The structure of natural somatostatin and with specific somatostatin receptors (SSTs) expressed on octreotide is shown in Fig.
    [Show full text]
  • Multi-Discipline Review(S)
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210828Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA/BLA Multi-Disciplinary Review and Evaluation (NDA 210828) 505(b)(2) (Ga-68-DOTATOC) NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NME & 505 (b)(2) Application Number(s) NDA 210828 Priority or Standard Standard Submit Date(s) May 23, 2018 Received Date(s) May 23, 2018 PDUFA Goal Date August 23, 2019 Division/Office Office of Drug Evaluation IV/Division of Medical Imaging Products (DMIP/ODEIV) Review Completion Date TBD Established/Proper Name Ga-68-DOTATOC injection (Proposed) Trade Name Not applicable Pharmacologic Class Radioactive diagnostic agent Code name IC2000 Applicant University of Iowa Health Care/P.E.T. Imaging Center Dosage Form Injection: Clear, colorless solution containing 18.5 to 148 MBq/mL (0.5 to 4 mCi/mL) of Ga-68-DOTATOC injection at end of synthesis (EOS) (approximately 14 mL volume) in a 30 mL multiple-dose vial. Applicant proposed Dosing For adults: 148 MBq (4 mCi); for pediatric patients: 1.59 Regimen MBq/kg (0.043 mCi/kg) with a range of 11.1 MBq (0.3 mCi) to 111 MBq (3 mCi) Applicant Proposed For localization of somatostatin receptor positive (b) (4) Indication(s)/Population(s) neuroendocrine tumors (NETs) in (b) (4) adult and pediatric patients. Applicant Proposed Indicated for use with positron emission tomography (PET) for SNOMED CT Indication localization of somatostatin receptor positive neuroendocrine (b) (4) Disease Term for Each tumors (NETs) in adult and pediatric (b) (4) Proposed Indication patients.
    [Show full text]
  • Overview of Results of Peptide Receptor Radionuclide Therapy with 3 Radiolabeled Somatostatin Analogs
    Overview of Results of Peptide Receptor Radionuclide Therapy with 3 Radiolabeled Somatostatin Analogs Dik J. Kwekkeboom, MD1; Jan Mueller-Brand, MD2; Giovanni Paganelli, MD3; Lowell B. Anthony, MD4; Stanislas Pauwels, MD5; Larry K. Kvols, MD6; Thomas M. O’Dorisio, MD7; Roelf Valkema, MD1; Lisa Bodei, MD3; Marco Chinol, PhD3; Helmut R. Maecke, PhD2; and Eric P. Krenning, MD1 1Department of Nuclear Medicine, Erasmus Medical Center, University Hospital Rotterdam, Rotterdam, The Netherlands; 2Department of Nuclear Medicine, University Hospital Basel, Basel, Switzerland; 3Department of Nuclear Medicine, European Institute of Oncology, Milan, Italy; 4Division of Hematology and Oncology, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana; 5Department of Nuclear Medicine, Universitaire Catholique Louvain, Brussels, Belgium; 6Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida; and 7Division of Endocrinology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa Key Words: somatostatin; somatostatin receptor; radionuclide A new treatment modality for inoperable or metastasized gas- therapy; gastroenteropancreatic tumors troenteropancreatic tumors is the use of radiolabeled soma- J Nucl Med 2005; 46:62S–66S tostatin analogs. Initial studies with high doses of [111In-diethyl- enetriaminepentaacetic acid (DTPA)0]octreotide in patients with metastasized neuroendocrine tumors were encouraging, al- though partial remissions were uncommon. Another radiola- beled somatostatin analog that is used for peptide receptor Neuroendocrine gastroenteropancreatic (GEP) tumors, radionuclide therapy (PRRT) is [90Y-1,4,7,10-tetraazacyclodode- which comprise pancreatic islet cell tumors, nonfunctioning -cane-N,NЈ,NЉ,Nٞ-tetraacetic acid (DOTA)0,Tyr3]octreotide. Vari- neuroendocrine pancreatic tumors, and carcinoids, are usu ous phase 1 and phase 2 PRRT trials have been performed with ally slow growing.
    [Show full text]
  • Use of DOTATATE PET/CT Scan in the Diagnosis and Staging Of
    WJOESWJOES DOTATATE10.5005/jp-journals-10002-1231 PET/CT in Thymic Carcinoid CASE REPORT Use of DOTATATE PET/CT Scan in the Diagnosis and Staging of Thymic Atypical Carcinoid Tumor in a Patient with Secondary ACTH-dependent Cushing Syndrome: Look Twice and Cut Once 1John Agzarian, 2Hisham Quandeel, 3Irina Bancos, 4Geoffrey B Johnson, 5Stephen C Scharf, 6Geoffrey B Thompson 7Joanne Yi, 8Xiaotun Zhang, 9K Robert Shen ABSTRACT Keywords: DOTATATE, Mediastinal, Positron emission tomog- raphy, Thymic carcinoid. Neuroendocrine thymic tumors represent the least common type of primary thymic tumor with a prevalence of 2 to 5%. We How to cite this article: Agzarian J, Quandeel H, Bancos I, present a case of locally advanced thymic atypical carcinoid Johnson GB, Scharf SC, Thompson GB, Yi J, Zhang X, Shen KR. tumor diagnosed incidentally while investigating progressive Use of DOTATATE PET/CT Scan in the Diagnosis and Staging of Thymic Atypical Carcinoid Tumor in a Patient with Second- Cushing syndrome. Computed tomography (CT) scan demon- ary ACTH-dependent Cushing Syndrome: Look Twice and Cut strated a large 2.9 cm exophytic thyroid nodule and a 2.0 cm Once. World J Endoc Surg 2018;10(2):127-133. anterior mediastinal mass. Biopsy of the thyroid nodule demon- strated benign thyroid tissue, and octreotide scan revealed avid Source of support: Nil uptake in the right thyroid lobe with minimal uptake in the thymic Conflict of interest: None tumor. 68Gallium-1,4,7,10-tetraazacyclododecane-N,N′,N″N′″- tetraacetic acid-D-Phe1,Tyr 3-octreotate (Ga-68 DOTATATE) positron emission tomography (PET)/CT scan showed intense INTRODUCTION uptake in the thyroid gland followed by a moderate amount of activity in the anterior mediastinal mass.
    [Show full text]
  • Selected Cases 2018
    25-28 October 2018 Regnum Carya Hotel, Antalya - Turkey SELECTED CASES www.endobridge.org 2018 STEERING COMMITTEE Susan Mandel President, ES Dolores Shoback Chair, Scientific & Educational Programs Committee, ES Aart J Van Der Lely President, ESE Jens Bollerslev Immediate Past Chair, Education Committee, ESE Camilla Schalin-Jäntti Chair, Education Committee, ESE Sevim Gullu President, SEMT Sadi Gundogdu Past President, SEMT Bulent O. Yildiz Founder & President, EndoBridge® Dilek Yazici Scientific Secreteriat, EndoBridge® Ozlem Celik Scientific Secreteriat, EndoBridge® 2 25 - 28 October, 2018 Antalya - Turkey 2018 SCIENTIFIC PROGRAM Friday, 26 October 2018 08.40 - 09.00 Welcome and Introduction to EndoBridge 2018 MAIN HALL Chairs: Sadi Gündoğdu, Aj van der Lely 09.00 - 09.30 Difficult cases with anterior pituitary tumors: Beyond the guidelines - Jens Otto Jorgensen 09.30 - 10.00 Radiological examination of the sellar region - Jean-François Bonneville 10.00 - 10.30 Evaluation and management of hypophysitis - Niki Karavitaki 10.30 - 11.00 Fluid and electrolyte balance following pituitary surgery - Alper Gürlek 11.00 - 11.20 Coffee Break 11.20 - 12.50 Interactive Case Discussion Sessions HALL A Pituitary - Niki Karavitaki, Züleyha Karaca HALL B Adrenal - Richard Auchus, Serkan Yener HALL C Neuroendocrine tumors- Camilla Schalin-Jäntti, Djuro Macut HALL D Male Reproductive Endocrinology - Dimitrios Goulis, Özlem Üstay Tarçın 12.50 - 14.00 Lunch 14.00 - 15.30 Interactive Case Discussion Sessions HALL A Pituitary - Jens Otto Jorgensen, Jean-François
    [Show full text]
  • Design and Synthesis of FVIII- and Upar-Selective Ligands and Cross- Linked Polymers As Media for NMR-Spectroscopy
    Technische Universität München Department Chemie Lehrstuhl II für Organische Chemie Design and Synthesis of FVIII- and uPAR-Selective Ligands and Cross- Linked Polymers as Media for NMR-Spectroscopy Sebastian Knör Vollständiger Abdruck der von der Fakultät für Chemie der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. K. Köhler Prüfer der Dissertation: 1. Univ.-Prof. Dr. H. Kessler 2. Univ.-Prof. Dr. A. Türler 3. Priv.-Doz. Dr. Viktor Magdolen Die Dissertation wurde am 23.05.2007 bei der Technischen Universität München eingereicht und durch die Fakultät für Chemie am 05.07.2007 angenommen. Die vorliegende Arbeit wurde am Lehrstuhl II für Organische Chemie der Technischen Universität München in der Zeit von Oktober 2002 bis Mai 2007 unter der Leitung von Prof. Dr. Horst Kessler angefertigt. Meiner Frau gewidmet Σ’αγαπώ πολύ Publier dans un petit journal ne veut pas dire petit résultat. Ce qui compte c'est que les gens l'essayent pour dire que ça marche!! In einem kleinen Journal zu publizieren heißt nicht, kleine Ergebnisse zu haben. Was zählt ist, dass die Leute es ausprobieren um zu sagen: Es geht! (Abdellah Benhida, Univ. Leuven) DANKSAGUNG Meinem Doktorvater, Herrn Professor Dr. Horst Kessler, danke ich besonders für die vielen interessanten Themen, die ich bearbeiten durfte. Insbesondere bedanke ich mich für die uneingeschränkte Unterstützung in jeder Hinsicht, für den großen wissenschaftlichen Freiraum, der mir gewährt wurde, sowie für die zahlreichen fruchtbaren und hilfreichen Diskussionen. Für die ausgezeichnete Zusammenarbeit auf dem Gebiet der Faktor VIII Liganden möchte ich mich ganz herzlich bei • Dr.
    [Show full text]
  • Assessment Report
    13 October 2016 EMA/734748/2016 Committee for Medicinal Products for Human Use (CHMP) Assessment report SomaKit TOC International non-proprietary name: edotreotide Procedure No. EMEA/H/C/004140/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520 Send a question via our website www.ema.europa.eu/contact An agency of the European Union Table of contents 1. Background information on the procedure .............................................. 6 1.1. Submission of the dossier ..................................................................................... 6 1.2. Steps taken for the assessment of the product ........................................................ 7 2. Scientific discussion ................................................................................ 8 2.1. Problem statement ............................................................................................... 8 2.1.1. Disease or condition .......................................................................................... 8 2.1.2. Epidemiology .................................................................................................... 8 2.1.3. Biologic features ............................................................................................... 9 2.1.4. Clinical presentation .......................................................................................
    [Show full text]
  • Comparison of the Therapeutic Response to Treatment with a 177-Lutetium Labeled Somatostatin Receptor
    Journal of Nuclear Medicine, published on October 29, 2015 as doi:10.2967/jnumed.115.167007 Comparison of the therapeutic response to treatment with a 177-lutetium labeled somatostatin receptor agonist and antagonist in preclinical models Simone U. Dalm1, Julie Nonnekens1,2, Gabriela N. Doeswijk1, Erik de Blois1, Dik C. van Gent2, Mark W. Konijnenberg1 and Marion de Jong1 1Department of Nuclear Medicine & Radiology, Erasmus MC, Rotterdam, The Netherlands 2Department of Genetics, Erasmus MC, Rotterdam, The Netherlands Corresponding author: Simone U. Dalm (PhD student) Room: Na620 P.O box 2040 3000 CA Rotterdam, the Netherlands +31-107041033 [email protected] Word count: 4999 Running title: Therapy with SSTR agonist vs. antagonist ABSTRACT Peptide receptor scintigraphy (PRS) and peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin receptor (SSTR) agonists are successfully used in the clinic for imaging and treatment of neuroendocrine tumors. Contrary to the paradigm that internalization and the resulting accumulation of radiotracers in cells is necessary for efficient tumor targeting, recent studies have demonstrated superiority of radiolabeled SSTR antagonists for imaging purposes, despite little to no internalization in cells. However, studies comparing the therapeutic anti-tumor effects of radiolabeled SSTR agonists versus antagonists are lacking. The aim of this study was to directly compare the therapeutic effect of 177Lu-DOTA-octreotate, an SSTR agonist, and 177Lu-DOTA-JR11, an SSTR antagonist. Methods: We analyzed radiotracer uptake (both membrane-bound and internalized fractions) and the produced DNA double strand breaks, by determining the number of p53 binding protein 1 (53BP1) foci, after incubating SSTR2 positive cells with 177Lu-DTPA, 177Lu-DOTA-octreotate or 177Lu-DOTA-JR11.
    [Show full text]
  • [177Lu-DOTA0,Tyr3]Octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors
    Author Manuscript Published OnlineFirst on April 20, 2017; DOI: 10.1158/1078-0432.CCR-16-2743 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Title: Long-term efficacy, survival and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors Authors: Tessa Brabander1, Wouter A van der Zwan1, Jaap JM Teunissen1, Boen LR Kam1, Richard A Feelders2, Wouter W de Herder2, Casper HJ van Eijck3, Gaston JH Franssen3, Eric P Krenning1, Dik J Kwekkeboom1† 1Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands 2Department of Internal Medicine, Erasmus Medical Center, ENETS Center of Excellence, Rotterdam, The Netherlands 3Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands Corresponding author: Tessa Brabander, [email protected] Department of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. ‘s-Gravendijkwal 230 3015 CE Rotterdam Tel: +31107040321 Fax: +31107033737 Running head: Efficacy, survival and toxicity after 177Lu-DOTATATE. Keywords: Neuroendocrine tumors; Peptide receptor radionuclide therapy (PRRT), 177Lu-DOTATATE, toxicity. Conflict of Interest: DJ Kwekkeboom and EP Krenning are stockholders of Advanced Accelerators Applications, Geneva, France. 1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 20, 2017; DOI: 10.1158/1078-0432.CCR-16-2743 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. TRANSLATIONAL RELEVANCE Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate is a therapeutic option for metastasized or inoperable gastroenteropancreatic and bronchial neuroendocrine tumors that present the somatostatin receptors on their surface.
    [Show full text]