DOCSLIB.ORG

Synthesis and Pharmacological Studies on Some 2–Hydroxy Haloalkylamines As H2 Antagonist

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Synthesis and Pharmacological Studies on Some 2–Hydroxy Haloalkylamines As H2 Antagonist Π Synthesis and pharmacological studies on some 2–hydroxy haloalkylamines as H2 antagonist A thesis submitted in fulfillment of the Requirement of the University of Khartoum. For: Master Degree of Pharmacy (M. Pharm.) To: DEPARTMENT OF PHARMACOLOGY FACULTY OF PHARMACY UNIVERSITY OF KHARTOUM By: Amna Elhassan Hamad (B. Pharm., U. of K.) Supervisor: Prof. Abdallah Awad Abdallah Co – Supervisor: Dr. Osama Yousif Mohamed December 2003 This work is dedicated to: My parents, brothers and sisters, for their support and supreme encouragement To my family: Engineer Mohammed I. Hamad, for his encouragement and motivation To my kids and daughters: Ahmed, Abubakr, Omer, Osama, Huda and Nuha. For their infinite patience & endurance during all time I spend away from them. ACKNOWLEDGEMENT Initially I solely thank Almighty Allah for accomplishing this work. I would like to express my thanks and gratitude to my supervisor Dr. Abdalla Awad Abdalla, former Professor of Medicinal Chemistry (CTS) for his courtesy and careful supervision and for his continuous guidance. My sincere thanks and gratitude to my Co–Supervisor, Associated Professor Osama Yousif Mohammed, Department of Pharmacology (U. of K.) for his valuable advises throughout all stages of the study. Special thanks and gratitude to Dr. Abdel Wahab Hassan Mohammed, Head Department of Pharmacology, Medicinal and Aromatic Plants Institute National Center for Research, for his valuable advises and helps. And my appreciation and thanks giving to all staff members of Medicinal and Aromatic Plants Institute, especially Reem Hassan Ahmed (B. V. & MSc. V, U. of K.). Thanks to all staff members of Pharmacology and Pharmaceutical Chemistry Departments, Faculty of Pharmacy, U. of K. for their co– operation. My greatest and deepest gratitude to Ali Hassan Hamad B. Sc., U. of K., for his intangible support and encouragement. LIST OF CONTENTS Subjects Page List of Contents: ………………………………………………….. I List of Tables: …………………………………………………….. IV List of Schemes: …………………………………………………… IV List of Figures: ………………………………………………….. V Abstract in Arabic: ………………………………………………. VI Abstract in English: ……………………………………………… VII MEDICINAL CHEMISTRY CHAPTER ONE: INTRODUCTION 1.1 Histamine and anti–histaminic drugs: …….…………………… 1 1.1.1 Histamine: ………………………..……………….….. 1 1.1.1.1 Histamine releasing substances: …………… 2 1.1.1.2 Anti–histamines: …………………………… 3 1.2 Pharmacology: ………………………………….……………. 3 1.3 Chemistry: …………………………..…………….…….….…. 5 1.3.1 Salt formation: ………………………………….…….. 5 1.3.2 Structure–activity relationships (SAR): ……....………. 5 1.4 Ethanolamine derivatives: ……………….……………………. 7 1.5 Ethylene diamine derivatives: ………………………………..... 9 1.6 Propylamine derivatives: …………………………………….... 12 1.7 Testing of antihistamines: ………………………………….….. 14 1.8 Gastric secretion: ………………………………………….…… 14 1.9 Cardiovascular effect of histamine: ……………………....…… 14 1.10 Histamine receptors: ……………………………………….…... 15 1.11 Histamine agonist: ……………………………………….……..16 1.12 Histamine antagonist: ………………………………………..... 16 1.13 Aim of the project: …………………………………………….. 18 CHAPTER TWO EXPERIMENTAL 2.1 Apparatus and materials: ………………………………………. 21 2.2 Methods: ……………………………………………………..…23 2.2.1 Preparation of the 2–(N,N dibenzylamino)–I–P– haloaryl–I– hydroxy–ethanes: ………………………………………23 2.2.1.1 Preparation of the bromoacetophenones from the acetophenones: ………………………………23 2.2.1.2 The preparation of the bromohydrins from the bromoacetophenone: …………..………..….. 26 2.2.1.3 Preparation of the 1–hydroxy–I–aryl–2–(N,N–diben– zyl amino) ethane: …………………………. 29 2.2.1.4 The preparation of 1–hydroxy–I–aryl–2–(N,N–diben– zylamino) ethanes hydrochloride salts: ….….. 32 2.2.2 Experimental discussion: ……………..……………….. 34 2.2.2.1 Bromination: ……………………………...… 34 2.2.2.2 Reduction: ………………………………….. 37 2.2.2.3 Coupling of bromohydrin with dibenzylamine 38 CHAPTER THREE DISCUSSION 3.1 Receptors: ……………………………………………..………..40 3.2 Agonist: ……………………………………………..…………. 41 3.3 Antagonist: …………………………………………….………. 41 3.4 Ligands: …….……………………………….…………..……...41 PHARMACOLOGY CHAPTER FOUR: INTRODUCTION 4.1 Histamine: ………………………...…….…….…………..…… 53 4.1.1 Histamine synthesis: ……………………………….….. 53 4.1.2 Histamine storage and release: ………….…………….. 54 4.1.3 Histamine metabolism: ……………………………….. 55 4.1.4 Histamine receptors: …………………………………... 56 4.1.5 Chemical structure of histamine and its agonist: ……… 57 4.1.6 Chemical structure of histamine antagonist: ………….. 57 4.1.7 Structure activity relationship of histamine agonist and antagonist: …………………………………………….. 58 4.2 Peptic ulcer: ……………………………………………………. 60 4.2.1 Peptic ulcer prevalence: ……………………………….. 60 4.2.2 Types of peptic ulcer: ………..…………………….…. 61 4.2.3 Peptic ulcer etiology: ………………………………….. 62 4.2.4 Ulcer treatment: ……………………………………….. 64 4.2.4.1 Surgical treatment: ……………….…………. 65 4.2.4.2 Medical treatment (Medicines): …………….. 65 4.2.4.2.1 Antacids: ……………………..…………. 66 4.2.4.2.2 Sucralfate: ……………………………….. 67 4.2.4.2.3 Bismuth chelate: ……..……………….…. 67 4.2.4.2.4 Prostaglandin analog: Misoprostol: …….. 67 4.2.4.2.5 Histamine H2 receptors antagonists e.g. cimetidi– ne, ranitidine and famotidine: ………..….. 68 4.2.4.2.6 Proton pump inhibitors: ……………….... 69 4.2.4.2.7 Treatment of H pylori infection efficacy: .. 69 4.2.5 Efficacy: ………………………………………………. 70 4.2.6 Side effects: ………………………..…………………. 70 4.2.7 Drug–drug interaction: ………..……………………… 71 4.2.8 Rationale: ………………………………………………72 CHAPTER FIVE: EXPERIMENTAL 5.1 Chemicals and their sources: ………………………………….. 73 5.2 Equipments and instruments: ………………………………….. 73 5.3 Animals: ……………………………………………………….. 74 5.4 Methods: ………………………………………………………..74 5.4.1 Contracting rat uterus: ……………………………….. 74 5.4.2 Evaluation of antiulcerogenic activity using experimentally induced ulcer in rat stomach and duodenum: …………. 75 5.4.3 Guinea pig ileum preparation: ……..………..………… 76 5.4.4 Guinea pig atrium preparation: ……………..……..…... 77 5.4.5 The principle of pA2 system: ………………..…..…….. 78 5.4.6 Determination of pA2 value of cimetidine P–chlor, and P– bromoalkyl–amine acting on rat uterus: ………………. 79 5.4.7 Determination of pA2 value of mepyramine 2–chloralkylamine and 2–bromoalkylamine acting on guinea pig ileum: … 79 5.5 Materials (Preparation of test solution and blank): ……………. 80 CHAPTER SIX: RESULTS & DISCUSSION 6.1 The antiulcerogenic activity of 2–chloroalkylamine, 2–bromoa lkyl– amine and cimetidine on experimentally aspirin–induced ulcers in rat: …………………………………………………………... 81 6.2 Effect on guinea pig atria: ……………………………………... 82 6.3 Effect on the contracting rat uterus: ……………………..…….. 82 6.4 Effect on isolated guinea pig ileum: ………………………....... 83 6.5 Median inhibitory concentration (IC50) of cimetidine, 2–chloro and 2– bromo–alkylamine on aspirin induced ulcer in rat (n = 5): ..…. 83 6.6 pA2 values for cimetidine, 2–chloro and 2–bromoalkylamine versus histamine acting on rat uterus: …….…………………………... 83 6.7 pA2 values for mepyramine, 2–chloro, and 2–bromoalkylamine versus histamine acting on guinea pig ileum: …………………………. 84 6.8 Results Discussion: …..……………………………..…………. 97 CHAPTER SEVEN : SUMMARY AND CONCLUSION: ……… 101 CHAPTER EIGHT: SUGGESTION FOR FUTURE WORK: …. 102 REFERENCES: ………………………………………………………………. 103 LIST OF TABLES Tables Title Page Tab. 1 Starting materials and specifications: ………..………………… 22 Tab. 2 Chemical nomenclature of the compounds synthesized: ……… 22 Tab. 3 Bromoacetophenones: ……………………..…………………... 25 Tab. 4 Bromohydrins: ……………………………..………………….. 28 Tab. 5 Aminoalcohols liquids: ……………..…………………………. 31 Tab. 6 Aminoalcohol Hcl salts: ……………..………………………… 33 Tab. 7 Effect of 2–chloro alkylamine on aspirin–induced ulcer in rat: .. 85 Tab. 8 Effect of 2–bromoalkylamine on asprinin–induced ulcer in rat: . 85 Tab. 9 Effect of cimetidine on asprinin–induced ulcer in rat: ………… 86 Tab. 10 The value of pA2 of cimetidine, P–chlor, and P–bromoalkylamine versus histamine acting on rat uterus: ……….………………… 86 Tab. 11 The value of pA2 of mepyramine, P–chloro and P–bromo alkylamine Versus histamine acting on guinea pig ileum: ………………… 87 Tab. 12 Median inhibitory concentration (IC50) of cimetidine, 2–chloroalky– lamine and 2–bromoalkylamine on aspirin–induced ulcer in the rat (n = 6): …………………………………………………………. 87 LIST OF SCHEMES Scheme No. Title of Scheme PAGE Scheme 1 General scheme for the preparation of intermediates and the amino–hydroxy ethanes: ……………………………. 20 LIST OF FIGURES Fig.No. Figures Title Page Fig. 1 Chemical structure of histamine agonist and antagonist: … 16 Fig. 2 Examples of the structures of the agonists of histamine Receptors: ………………………..……………..…………. 48 Fig. 3 The effect of an ideal competitive antagonist on the dose response curve for an agonist: …………….……………..…………. 49 Fig. 4 An outline of the mode of action of a competitive antagonist (6) with an antagonist: …………….………..………………… 50 Fig. 5 The effect of a non–competitive antagonist on the dose–response curve of agonist: ……………..………………..……………….. 51 Fig. 6 The effect of an ideal antagonist on the response of a receptor: …………………………………………………... 52 Fig. 7 (a) No desensitization (b) Desensitization: ……………….. 52 Fig. 8 2–chloroalkylamine versus histamine acting on rat uterus: … 88 Fig. 9 2–bromoalkylamine versus histamine acting on rat uterus: … 89 Fig. 10 2–chloroalkylamine versus histamine acting on guinea pig atrium: …………………………………………………………. 90 Fig. 11 2–bromoalkylamine versus histamine acting on guinea pig atrium: …………………………………………………………. 91 Fig. 12 2–chloroalkylamine versus histamine acting on guinea pig ileum: …………………………………………………………...92 Fig. 13 2–bromoalkylamine versus histamine acting on guinea
Load more

Recommended publications
  • Multidimensional Analysis of Extended Molecular Dynamics Simulations Shows the Complexity of Signal
    bioRxiv preprint doi: https://doi.org/10.1101/604793; this version posted April 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. TITLE Multidimensional analysis of extended molecular dynamics simulations shows the complexity of signal transduction by the histamine H3 membrane receptor Short title: Molecular dynamics of signal transduction AUTHORS Herrera-Zuniga LD1,4, Moreno-Vargas LM2,4, Correa-Basurto J1,3, Prada D2, Curmi P1, Arrang, JM4, Maroun, RC1,4* 1 SABNP, UMR-S U1204, INSERM/Université d’Evry-Val d’Essonne/Université Paris-Saclay, 91025 Evry, FRANCE 2 Computational Biology and Drug Design Research Unit. Federico Gomez Children's Hospital of Mexico City, MEXICO 3 Laboratory for the Design and Development of New Drugs and Biotechnological Innovation) SEPI-ESM, MEXICO 4 INSERM U894, Paris, FRANCE *Corresponding author 1 bioRxiv preprint doi: https://doi.org/10.1101/604793; this version posted April 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT In this work, we study the mechanisms of activation and inactivation of signal transduction by the histamine H3 receptor (H3R), a 7TM GPCR through extended molecular dynamics (MD) simulations of the receptor embedded in a hydrated double layer of dipalmitoyl phosphatidyl choline (DPPC), a zwitterionic poly-saturated ordered lipid. Three systems were prepared: the apo H3R, representing the constitutively active receptor; and the holo-systems: the H3R coupled to an antagonist/inverse agonist (ciproxifan) and representing the inactive state of the receptor; and the H3R coupled to the endogenous agonist histamine and representing the active state of the receptor.
    [Show full text]
  • Histamine Receptors
    Tocris Scientific Review Series Tocri-lu-2945 Histamine Receptors Iwan de Esch and Rob Leurs Introduction Leiden/Amsterdam Center for Drug Research (LACDR), Division Histamine is one of the aminergic neurotransmitters and plays of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit an important role in the regulation of several (patho)physiological Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The processes. In the mammalian brain histamine is synthesised in Netherlands restricted populations of neurons that are located in the tuberomammillary nucleus of the posterior hypothalamus.1 Dr. Iwan de Esch is an assistant professor and Prof. Rob Leurs is These neurons project diffusely to most cerebral areas and have full professor and head of the Division of Medicinal Chemistry of been implicated in several brain functions (e.g. sleep/ the Leiden/Amsterdam Center of Drug Research (LACDR), VU wakefulness, hormonal secretion, cardiovascular control, University Amsterdam, The Netherlands. Since the seventies, thermoregulation, food intake, and memory formation).2 In histamine receptor research has been one of the traditional peripheral tissues, histamine is stored in mast cells, eosinophils, themes of the division. Molecular understanding of ligand- basophils, enterochromaffin cells and probably also in some receptor interaction is obtained by combining pharmacology specific neurons. Mast cell histamine plays an important role in (signal transduction, proliferation), molecular biology, receptor the pathogenesis of various allergic conditions. After mast cell modelling and the synthesis and identification of new ligands. degranulation, release of histamine leads to various well-known symptoms of allergic conditions in the skin and the airway system. In 1937, Bovet and Staub discovered compounds that antagonise the effect of histamine on these allergic reactions.3 Ever since, there has been intense research devoted towards finding novel ligands with (anti-) histaminergic activity.
    [Show full text]
  • Histamine Inhibits the Production of Interleukin-12 Through Interaction with H2 Receptors
    Histamine inhibits the production of interleukin-12 through interaction with H2 receptors. T C van der Pouw Kraan, … , R Leurs, L A Aarden J Clin Invest. 1998;102(10):1866-1873. https://doi.org/10.1172/JCI3692. Research Article IL-12 is essential for T helper 1 (Th1) development and inhibits the induction of Th2 responses. Atopic diseases, which are characterized by Th2 responses, are associated with the overproduction of histamine. Here we present evidence that histamine, at physiological concentrations, strongly inhibits human IL-12 p40 and p70 mRNA and protein production by human monocytes. The use of specific histamine receptor antagonists reveals that this inhibition is mediated via the H2 receptor and induction of intracellular cAMP. The inhibition of IL-12 production is independent of IL-10 and IFN-gamma. The observation that histamine strongly reduces the production of the Th1-inducing cytokine IL-12 implies a positive feedback mechanism for the development of Th2 responses in atopic patients. Find the latest version: https://jci.me/3692/pdf Histamine Inhibits the Production of Interleukin-12 through Interaction with H2 Receptors Tineke C.T.M. van der Pouw Kraan,* Alies Snijders,‡ Leonie C.M. Boeije,* Els R. de Groot,* Astrid E. Alewijnse,§ Rob Leurs,§ and Lucien A. Aarden* *CLB, Sanquin Blood Supply Foundation, Department of Auto-Immune Diseases, Laboratory for Experimental and Clinical Immunology, Academic Medical Centre, University of Amsterdam, 1066CX Amsterdam, The Netherlands; ‡Laboratory of Cell Biology and Histology, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands; and §Department of Pharmacochemistry, Free University, Leiden/Amsterdam Centre for Drug Research, 1081 HV Amsterdam, The Netherlands Abstract a Th2 response (4–6), while various organ-specific autoim- mune diseases are characterized by Th1-like responses (7).
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2016/0220580 A1 Rubin Et Al
    US 2016O220580A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0220580 A1 Rubin et al. (43) Pub. Date: Aug. 4, 2016 (54) SMALL MOLECULESCREENING FOR (60) Provisional application No. 61/497,708, filed on Jun. MOUSE SATELLITE CELL PROLIFERATION 16, 2011. (71) Applicant: PRESIDENT AND FELLOWS OF Publication Classification HARVARD COLLEGE, Cambridge, (51) Int. Cl. MA (US) A 6LX3/553 (2006.01) (72) Inventors: Lee L. Rubin, Wellesley, MA (US); A613 L/496 (2006.01) Amanda Gee, Alexandria, VA (US); A613 L/4439 (2006.01) Amy J. Wagers, Cambridge, MA (US) A613 L/404 (2006.01) (52) U.S. Cl. CPC ............. A6 IK3I/553 (2013.01); A61 K3I/404 (21) Appl. No.: 15/012,656 (2013.01); A61 K3I/496 (2013.01); A61 K 31/4439 (2013.01) (22) Filed: Feb. 1, 2016 (57) ABSTRACT The invention provides methods for inducing, enhancing or Related U.S. Application Data increasing satellite cell proliferation, and an assay for screen (63) Continuation-in-part of application No. 14/126,716, ing for a candidate compound for inducing, enhancing or filed on Jun. 13, 2014, now Pat. No. 9.248,185, filed as increasing satellite cell proliferation. Also provided are meth application No. PCT/US2012/042964 on Jun. 18, ods for repairing or regenerating a damaged muscle tissue of 2012. a Subject. Patent Application Publication Aug. 4, 2016 Sheet 1 of 44 US 2016/0220580 A1 FIG. A Patent Application Publication Aug. 4, 2016 Sheet 2 of 44 US 2016/0220580 A1 FIG. C. FIG. 2A Patent Application Publication Aug.
    [Show full text]
  • Evaluation of Anxiolytic Effects of Aripiprazole and Hydroxyzine As a Combination in Mice
    Original Article Evaluation of anxiolytic effects of aripiprazole and hydroxyzine as a combination in mice Abstract Context: Anxiety disorders are chronic, common, and often comorbid. There is an unmet need in its treatment. Aripiprazole and hydroxyzine are well‑known therapeutic options used as monotherapy in clinics. They have different mechanisms and site of actions. Aim: The objective of the present study was to evaluate the anxiolytic effect of aripiprazole and hydroxyzine in combination. Materials and Methods: Swiss albino mice (male) received treatment of 5% of Tween 80 in 0.9% saline (10 ml/kg; control group), “aripiprazole alone” (1 mg/kg), “hydroxyzine alone” (3 mg/kg), and aripiprazole (0.5 mg/kg) + hydroxyzine (1.5 mg/kg) through the intraperitoneal route. Statistical Analysis Used: statistical analysis. One‑way ANOVA followed by Tukey’s honest significant difference was employed for Results: The in vivo outcomes (elevated plus maze, light/dark transition, and marble burying tests) of was found to be better than control and aripiprazole‑treated groups. The combination‑treated group showed hydroxyzine monotherapy‑treated group showed a significant anxiolytic activity. The combination‑treated group group but not better than the hydroxyzine group. The in vitro results were in compliance with the in vivo results. a significant increase in the level of serotonin in different brain regions as compared to aripiprazole‑treated monotherapy. However, hydroxyzine showed better anxiolytic activity when compared to control, aripiprazole The combinational approach was found to be beneficial in anxiolytic treatment as compared to aripiprazole monotherapy, and combination groups. Conclusions: The anxiolytic effect of combination‑treated group was found to be better than aripiprazole monotherapy and lesser than hydroxyzine monotherapy.
    [Show full text]
  • Antipsychotics for Amphetamine Psychosis. A
    Antipsychotics for Amphetamine Psychosis. A Systematic Review Dimy Fluyau, Emory University Paroma Mitra, New York University Kervens Lorthe, Miami Regional University Journal Title: Frontiers in Psychiatry Volume: Volume 10 Publisher: Frontiers Media | 2019-10-15, Pages 740-740 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.3389/fpsyt.2019.00740 Permanent URL: https://pid.emory.edu/ark:/25593/v48xp Final published version: http://dx.doi.org/10.3389/fpsyt.2019.00740 Copyright information: © Copyright © 2019 Fluyau, Mitra and Lorthe. This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). Accessed October 1, 2021 4:49 PM EDT SYSTEMATIC REVIEW published: 15 October 2019 doi: 10.3389/fpsyt.2019.00740 Antipsychotics for Amphetamine Psychosis. A Systematic Review Dimy Fluyau 1*, Paroma Mitra 2 and Kervens Lorthe 3 1 School of Medicine, Emory University, Atlanta, GA, United States, 2 Langone Health, Department of Psychiatry, NYU, New York, NY, United States, 3 Department of Health, Miami Regional University, Miami Springs, FL, United States Background: Among individuals experiencing amphetamine psychosis, it may be difficult to rule out schizophrenia. The use of antipsychotics for the treatment of amphetamine psychosis is sparse due to possible side effects. Some arguments disfavor their use, stating that the psychotic episode is self-limited. Without treatment, some individuals may not fully recover from the psychosis and may develop full-blown psychosis, emotional, and cognitive disturbance. This review aims to investigate the clinical benefits and risks of antipsychotics for the treatment of amphetamine psychosis.
    [Show full text]
  • United States Patent (10) Patent No.: US 8,859,550 B2 Chen Et Al
    US00885955OB2 (12) United States Patent (10) Patent No.: US 8,859,550 B2 Chen et al. (45) Date of Patent: *Oct. 14, 2014 (54) HETEROCYCLIC INHIBITORS OF FOREIGN PATENT DOCUMENTS HISTAMINE RECEPTORS FOR THE TREATMENT OF DISEASE Wo 2004:36 A 358 (75) Inventors: Pingyun Chen, Chapel Hill, NC (US); W. SS: A. 33. Stephen A. R. Carino, Del Mar, CA WO 2009098320 A2 8, 2009 (US); Ricky Wayne Couch, Durham, WO 2010030785 A2 3, 2010 NC (US); Daniel S. Kinder, Del Mar, W. 38H 73 A. 338 sS); Beth A. Norton, Del Mar, CA WO 20110894.00 A1 7, 2011 (73) Assignee: Kalypsys, Inc., Del Mar, CA (US) OTHER PUBLICATIONS c Khankari et al. Thermochimica Acta 1995, 248, 61-79. (*) Notice: Subject to any disclaimer, the term of this Conalty, M.L. et akl., “Anticancer agents—XII. Pyridazine and patent is extended or adjusted under 35 Benzodiazine derivatives.” Proceedings of the Royal Irish Academy, U.S.C. 154(b) by O days. Section B: Biological, Geological and Chemical Science (1976), 76(10), 151-63. This patent is Subject to a terminal dis- Kim, HS et al., “Synthesis of tetrazolo 1.5-aquinoxalines with anti Ca10. microbial activity,” Journal of the Korean Chemical Society (2001), 45(4), 325-333. (21) Appl. No.: 13/606.947 Smits R. A. et al., “Major advances in the developments of histamine H4 receptor ligands.” Drug Discovery Today, vol. 14, No. 15/16, Aug. (22) Filed: Sep. 7, 2012 2009. Beres M. et al., “Ring Opening of 1.2.3Triazolo 1.5- (65) Prior Publication Data alpha pyrazinium Salts: Synthesis and Some Transformations of a US 2013/0245001A1 Sep.
    [Show full text]
  • Die Rolle Der Duralen Mastzellen Im Maus Migräne-Modell = the Role Of
    Die Rolle der duralen Mastzellen im Maus Migräne-Modell Dissertation zur Erlangung des Grades eines Doktors der Naturwissenschaften der Fakultät für Biologie und Biotechnologie der Ruhr-Universität Bochum Internationale Graduiertenschule Biowissenschaften Ruhr-Universität Bochum (Lehrstuhl für Tierphysiologie) Vorgelegt von Elisabeth Dlugosch Aus Recklinghausen Bochum Oktober, 2017 Referent: Prof. Dr. Hermann Lübbert Korreferent: Prof. Dr. Stefan Herlitze The role of dural mast cells in a murine migraine model Dissertation to obtain the degree Doctor Rerum Naturalium (Dr. rer. nat.) at the Faculty of Biology und Biotechnology Ruhr University Bochum International Graduate School of Biosciences Ruhr University Bochum (Department of Animal Physiology) Submitted by Elisabeth Dlugosch From Recklinghausen Bochum October 2017 First Supervisor: Prof. Dr. Hermann Lübbert Second Supervisor: Prof. Dr. Stefan Herlitze Danksagung Danksagung Ich danke Herrn Prof. Dr. Hermann Lübbert für die Überlassung des Themas, die Bereitstellung des Arbeitsplatzes am Lehrstuhl für Tierphysiologie, sowie den fachlichen Rat. Mein Dank gilt auch Herrn Prof. Dr. Stefan Herlitze für die Übernahme des Korreferats. Des Weiteren möchte ich mich bei Herrn Dr. Frank Paris, Herrn Dr. Michael Andriske und Herrn Dr. Xinran Zhu für die wertvollen Tipps und fachliche Kritik bedanken. Außerdem möchte ich mich noch bei Tanja Behning für den technischen Support bedanken, Manfred Ebbinghaus für seine Hilfe bei den Hypoxie-Kammern, Maria Josten für die Hilfe bei der Zellkultur und Katja Schmidtke für die Hilfe bei den PCRs. Ein weiterer Dank geht an Frau Dr. Miriam Kremser und Herrn Dr. Daniel Segelcke für die hilfreichen Anregungen bei meiner Dissertation. Ein großer Dank gilt auch allen Mitarbeitern und Studenten des Lehrstuhls für Tierphysiologie für die tolle Arbeitsatmosphäre und all die lustigen Gespräche, die wir über die Zeit geführt haben.
    [Show full text]
  • Programme and Abstracts Book
    0 33. Annual Meeting European Histamine Research Society 28. April – 2. May 2004 Düsseldorf / Köln, Germany 1 Dear Histaminologists 28. April 2004 Welcome to the 33rd Annual Meeting of the European Histamine Research Society at the Kardinal Schulte Haus near Cologne. Many of you have seen Cologne at the occasion of the 1993 meeting. The host institution is now located 30 km to the north: Department of Neurophysiology, Heinrich-Heine-University, Düsseldorf. Heinrich Heine, the patron of our University and one of our major poets, was born in Düsseldorf in 1797, he died in Paris in 1856. He wrote romantic poems often with a unique and unusual ironic or disillusioning twist at the end. He was the founder of the modern feuilleton and wrote a bit caustic about his birthplace. Nevertheless, Düsseldorf is worth a visit, there is interesting recent architecture (e.g. O’Gehry) a fine art collection (20th century) and a jewel in the south: Benrath castle and park (1777). We meet at the south end of “Bergisches Land” that we will explore during our excursion. The chemical industry founded by Bayer and Leverkus is around us: Leverkusen and Wuppertal. Düsseldorf is a village (1/2 Mio inhabitants) located at the mouth of the river Düssel into the Rhine. A formerly romantic part of the Düssel-valley has been praised by the 17th century pastor Neander and is consequently called the Neanderthal, the valley where the first bones of the Neandertal-man were found in 1856. Schloss Burg is a mediaeval castle, its 12th century appearance has been restored and a museum recalls the long bygone times.
    [Show full text]
  • CEL MAI KO NA NA NA NA NA (12 ) United States Patent ( 10 ) Patent No
    US010064856B2CEL MAI KO NA NA NA NA NA (12 ) United States Patent ( 10 ) Patent No. : US 10 , 064 ,856 B2 Bosse et al. ( 45 ) Date of Patent: * Sep . 4 , 2018 ( 54 ) PHARMACEUTICAL COMPOSITIONS (52 ) U .S . CI. ??? . .. A61K 31/ 485 ( 2013 .01 ) ; A61K 9 / 209 @(71 ) Applicant : LOCL PHARMA , INC . , Las Vegas , ( 2013 . 01 ) ; A61K 9 / 2013 ( 2013 . 01 ) ; A61K NV ( US ) 9 /2027 ( 2013 .01 ) ; A61K 9 / 2054 ( 2013 .01 ) ; A61K 9 / 4808 ( 2013 .01 ) ; A61K 31 / 165 @(72 ) Inventors : Paul Bosse, Jupiter , FL (US ) ; John ( 2013 .01 ) ; A61K 31/ 167 ( 2013 .01 ) ; A61K Ameling , Jupiter, FL (US ) ; Bernard 31/ 24 ( 2013 .01 ) ; A6IK 31/ 403 ( 2013 .01 ) ; Schachtel, Jupiter, FL (US ) ; Ray A61K 31/ 404 (2013 .01 ) ; A61K 31 /4196 Takigiku , Loveland , OH (US ) ( 2013 . 01 ) ; A61K 31/ 422 ( 2013 . 01 ) ; A61K 31 / 437 ( 2013 .01 ) ; A61K 31/ 454 ( 2013 .01 ) ; @( 73 ) Assignee : LOCAL PHARMA , INC ., Las Vegas , A61K 31 /515 ( 2013 . 01 ) ; A61K 31/ 522 ( 2013 . 01 ) ; A61K 31 /5415 ( 2013 .01 ) ; A61K NV (US ) 45 / 06 ( 2013 .01 ) ; A61K 9 / 0024 ( 2013 .01 ) ; @( * ) Notice : Subject to any disclaimer , the term of this A61K 9 / 0056 ( 2013 . 01 ) ; A61K 9 / 1694 patent is extended or adjusted under 35 ( 2013 . 01 ) ; A61K 9 /2086 ( 2013 . 01 ) ; A61K U . S . C . 154 (b ) by 0 days . 47 / 36 ( 2013 .01 ) (58 ) Field of Classification Search This patent is subject to a terminal dis None claimer . See application file for complete search history . ( 21 ) Appl. No .: 15 / 683, 635 ( 56 ) References Cited ( 22 ) Filed : Aug . 22, 2017 U . S . PATENT DOCUMENTS 3 ,048 , 526 A 8 / 1962 Boswell (65 ) Prior Publication Data 3 , 108 , 046 A 10 / 1963 Harbit 3 , 536 ,809 A 10 / 1970 Norman US 2017 /0348303 A1 Dec .
    [Show full text]
  • Wright1252943387.Pdf (1.09
    THE PRESYNAPTIC REGULATION OF ISOLATED NEONATAL RAT CAROTID BODY TYPE I CELLS BY HISTAMINE. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By DREW C. BURLON B.S., University of Dayton, 2006 2009 Wright State University WRIGHT STATE UNIVERSITY SCHOOL OF GRADUATE STUDIES August 11th, 2009 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY Drew Burlon ENTITLED The Presynaptic Regulation of Neonatal Rat Carotid Body Type I Cells by Histamine BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science. ___________________________ Christopher N. Wyatt, Ph.D. Thesis Director ___________________________ Timothy C. Cope, Ph.D. Department Chair Signatures of Committee on Final Examination ______________________________ Christopher N. Wyatt, Ph.D. ______________________________ Robert W. Putnam, Ph.D. ______________________________ Kathrin L. Engisch , Ph.D. ______________________________ Joseph F. Thomas, Ph.D. Dean, School of Graduate Studies ABSTRACT Burlon, Drew C. M.S., Department of Neuroscience, Cell Biology and Physiology, Wright State University, 2009. The Presynaptic Regulation of Isolated Neonatal Rat Carotid Body Type I Cells by Histamine. It has been previously shown that Carotid Body Type I cells have the ability to synthesize, package and release histamine in response to hypoxia, thereby contributing to the modulation of respiration within the rat. Here, isolated neonatal rat carotid body type I cells were used to identify the presynaptic effects of histamine and the specific receptor subtypes that modulate them. Although all four histamine receptor subtypes are expressed on the type I cells, and preliminary data showed promising results, further data proved that the activation of these receptors with histamine or selective agonists caused 2+ no rise in intracellular calcium ([Ca ]i) and histamine did not augment calcium entry.
    [Show full text]
  • Tommuniciun Clou Un Tai Tai Man United
    TOMMUNICIUNUS009808444B2 CLOU UN TAI TAI MAN UNITED (12 ) United States Patent (10 ) Patent No. : US 9 ,808 , 444 B2 Arnou (45 ) Date of Patent : Nov. 7 , 2017 ( 54 ) METHODS FOR RESTORATION OF on Aug. 20 , 2013 , provisional application No . HISTAMINE BALANCE 62 / 002 ,613 , filed on May 23, 2014 . @(71 ) Applicant : BioHealthonomics Inc. , Santa Monica , ( ) Int. Cl. CA (US ) A61K 31/ 417 ( 2006 . 01 ) A61K 45 / 06 ( 2006 .01 ) @(72 ) Inventor : Cristian Arnou , Santa Monica , CA (52 ) U .S . CI. (US ) CPC .. .. A61K 31/ 417 ( 2013. 01 ); A61K 45/ 06 ( 2013 .01 ) @(73 ) Assignee : BioHealthonomics Inc. , Santa Monica , (58 ) Field of Classification Search CA (US ) USPC .. .. .. 514 / 400 See application file for complete search history . @( * ) Notice : Subject to any disclaimer , the term of this patent is extended or adjusted under 35 (56 ) U . S . C . 154 (b ) by 0 days . References Cited U . S . PATENT DOCUMENTS (21 ) Appl. No. : 15 /341 ,839 9 ,511 ,054 B2 * 12 /2016 Arnou .. .. A61K 31/ 417 ( 22 ) Filed : Nov . 2 , 2016 * cited by examiner (65 ) Prior Publication Data Primary Examiner — Rei - Tsang Shiao US 2017 /0266163 A1 Sep . 21 , 2017 (74 ) Attorney , Agent, or Firm — Knobbe Martens Olson & Bear LLP Related U . S . Application Data (63 ) Continuation of application No. 14 /684 , 174 , filed on (57 ) ABSTRACT Apr. 10 , 2015 , now Pat. No. 9 ,511 , 054 , which is a Several embodiments provided herein relate to histamine continuation of application No. 14 / 315 , 206 , filed on dosing regimens are and uses of such regimens in the Jun . 25 , 2014 , now Pat. No . 9 ,023 ,881 , which is a restoration of histamine balance in subjects suffering from , continuation - in -part of application No .
    [Show full text]