DOCSLIB.ORG

Novel Pharmacological Strategies for Analgesia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Novel Pharmacological Strategies for Analgesia Annals ofthe Rheumatic Diseases 1996;55:715-722 715 REVIEW: PAIN Series editor: Bruce L Kidd Ann Rheum Dis: first published as 10.1136/ard.55.10.715 on 1 October 1996. Downloaded from Novel pharmacological strategies for analgesia Martin Perkins, Andy Dray Acute transient pain, associated with negligible The two most studied of these are bradykinin tissue damage, serves as a physiological and kallidin, a nonapeptide and a decapeptide warning of potential tissue damage. Somewhat respectively. Both are cleaved from precursor more persistent pain, associated with molecules following the activation of a hyperalgesia and tenderness, is often associated biochemical cascade. In the plasma, bradykinin with inflammation. This is also a normal (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) is protective response to mild injury and resolves produced from high molecular weight rapidly once the injury has healed. However kininogen (HMWK) whereas in tissue kallidin there are various persistent pain conditions in (lysyl-bradykinin) is liberated from its which the stimulus and pain are unrelated. precursor, low molecular weight kininogen Thus the pain sensation outlasts its biological (LMWK)4 by the action ofproteolytic enzymes usefulness. In these conditions pain can no (fig 1). longer be regarded as a purely physiologically Both bradykinin and kallidin are rapidly protective symptom. This may arise as a result degraded by peptidases known as kininases of chronic pathological lesions or degenerative giving rise to inactive metabolites with the processes, but in many cases there may be no exception of des-Arg9bradykinin or des- discernible pathology. These types of chronic Arg'0kallidin which lack the carboxy- terminal pain state-which occur with migraine, arginine. These are the only metabolites of rheumatoid arthritis, osteoarthritis, low back bradykinin or kallidin with significant activity.4 pain, cancer pain, and neuropathic pain-are Bradykinin and kallidin mediate their effects poorly understood and for the most part diffi- through two main classes of receptor, B1 and cult to treat. Thus chronic pain sufferers of one B2.' The genes for both of these receptors have kind or another account for approximately 10- recently been cloned and have been shown to 20% ofthe adult population, while about 5-8% belong to the superfamily of receptors of G experience pain which is inadequately treated.' protein coupled, 7-transmembrane spanning http://ard.bmj.com/ Present treatment for most pain states has domains receptors.6 7 Less is known about the relied heavily on the use of non-steroidal anti- molecular characteristics ofthe B1 receptor but inflammatory drugs (NSAID) and opioid anal- it has little homogeneity with the B2 receptor8 gesics. Although variants of these classes of and in keeping with current pharmacological drug have been developed there has been little studies it seems likely that antagonists for this conceptual innovation in analgesia for many receptor will be different from those developed years. Furthermore both classes of drug at B2 sites. on October 1, 2021 by guest. Protected copyright. produce side effects, such as gastrointestinal Bradykinin and kallidin acts preferentially disturbances, gastric ulceration, renal damage, on the B2 receptor, and this accounts for the and hypersensitivity reactions with NSAID, majority of the acute pharmacological effects and nausea, constipation, confusion, respira- of bradykinin. The preferred agonists for the tory depression, and possibly dependence with B1 receptor, however, are the active metabolites, opioids. Despite considerable effort these des-Arg'bradykinin and desArg'0kallidin. problems have not yet been overcome. An Bradykinin exerts a variety of effects on important reason for this has been the many body tissues but it is its actions on noci- relatively slow advance, until recently, in ceptive neurones that are of most relevance to understanding the pathogenesis of chronic pain and analgesia. Bradykinin has two main pain. Some of these advances have been effects on these neurones-activation and reviewed and are leading a conceptual shift in sensitisation-and both of these actions have pain pathophysiology and management. In the been shown to be mediated primarily by the B, light of this we shall discuss some recent initia- receptor. Sandoz Institute for tives for the discovery and development of new Bradykinin depolarises sensory neurones by Medical Research, analgesic drugs based on knowledge of the activation of phospholipase C and stimulation Gower Place, London and neurochemical changes WC1E 6BN, United pathophysiological of protein kinase C, with an increase in Kingdom that occur in the nociceptive pathway after membrane sodium ion conductance.9 '0 This M Perkins injury. probably underlies the overt pain response to A Dray bradykinin. With respect to sensory neurone Correspondence to: Kinin receptor inhibition activity, bradykinin has been shown to increase Dr M N Perkins. Kinins are a family of small peptides which are nociceptor C fibre discharge in somatic and Accepted for publication produced locally in response to tissue injury or visceral sensory neurones both in vitrol' 1' and 19 February 1996 trauma and particularly during inflammation. in vivo." 716 Perkins, Dray Following administration to somatic and vis- Recently several studies have showed that ceral tissue sites bradykinin elicits powerful during inflammation there is an increasing nocifensor behaviours.13 '5 Bradykinin is also contribution ofB, receptors to the accompany- Ann Rheum Dis: first published as 10.1136/ard.55.10.715 on 1 October 1996. Downloaded from algogenic in man following topical application ing hyperalgesia. Thus B1 receptor antagonists or intracutaneous injection.16 17 Bradykinin also such as Leu8,des-Arg9bradykinin are consist- has a powerful sensitising action on nociceptors, ently antinociceptive.23 26 27 28 enhancing their responsiveness to mechanical The B, receptor appears to be expressed or and thermal stimulation.'8"20 This property of synthesised de novo in tissues following trauma bradykinin is possibly of more relevance in or when inflammatory mediators such as man, increasing both the perception and dura- cytokines are present.2329 Indeed a close tion of pain. interaction has been shown between kinins other Although bradykinin is one of the first inflammatory mediators, particularly cytokines. inflammatory mediators to be produced in In particular, interleukin-1[ upregulates B, and response to trauma or inflammation, prostaglan- B2 receptors as well as enhances responses to dins also play a major role in inflammation and bradykinin and desArg' bradykinin.23 27 3032 The enhance bradykinin induced responses. Not potential exists, therefore, for a powerful only is the neuronal activation by bradykinin reinforcement between kinins and other potentiated by prostaglandins but they may inflammatory mediators leading to a sustained also enhance bradykinin evoked release of the hyperalgesic state. neurogenic inflammatory mediators substance P and calcitonin gene related peptide Cyclo-oxygenase inhibition (CGRP).2 One of the major treatments for inflammatory There are therefore strong experimental pain has been the reduction of prostaglandin grounds for targeting the B2 receptor in the levels by inhibition of cyclo-oxygenase (COX) treatment of inflammatory pain and conse- activity with NSAID. However, the develop- quently selective B2 receptor antagonists based ment of tolerance and unacceptable side on the peptide structure of bradykinin have effects, such as gastric haemorrhage and neph- been developed (fig 2), the most potent being rotoxicity, have severely limited the usefulness HOE 140.22 The use of this and other of this approach with respect to chronic or per- peptidergic antagonists has shown that the sistent inflammatory pain. It had been thought acute activation and sensitisation of sensory that there was a single cyclo-oxygenase enzyme neurones by bradykinin are mediated by the B responsible for prostaglandin production; receptor.5 23 Furthermore, in several models of however, recently two isoforms of cyclo- nociception, selective B2 receptor antagonists24 25 oxygenase have been demonstrated-a consti- are antinociceptive. tutive and an inducible enzyme (fig 3).3 The BRADYKININ and INFLAMMATORY PAIN http://ard.bmj.com/ Activation of kallikrein enzymes Precursor molecules high and low molecular weight kininogen on October 1, 2021 by guest. Protected copyright. PLASMA TISSUE desArg9Bk BRADYKININ Kallidin desArqlOKd ArgProGlyPheSerProPheArg LysArgProProGlyPheSerProPheArg |RECEPTORS| Linked with trauma/injury Majority of Bk's actions Immunocompetent cells - inflammatory SENSORY NERVESA EXCITATION NOCICEPTORS SENSITISATION Figure 1 Theformation of kininsfoUlowing trauma andlor an inflammatory insult. Both bradykinin and kallidin act on the B2 receptor. In addition, kallidin can be converted to bradykinin by the action ofaminopeptidases. The preferred agonistsfor the B1 receptor are desArg9bradykinin (desArg9Bk) and desArgJ°kallidin (desArglOKd) which areformed by the action ofkininase I-peptidase which removes the carboxy-terminal arginine residue ofbradykinin and kallidin, respectively. Bradykinin and kallidin act directly on nociceptive neurones to cause overt excitation, leading to pain, and sensitisation of the terminals resulting in a reduction in thresholdfor activation. In addition, both these kinins act on immunocompetent cells (for example, macrophages) to release other inflammatory
Load more

Recommended publications
  • View Full Page
    The Journal of Neuroscience, October 1, 1997, 17(19):7471–7479 Presynaptic Versus Postsynaptic Localization of m and d Opioid Receptors in Dorsal and Ventral Striatopallidal Pathways M. Foster Olive,1,2 Benito Anton,2 Paul Micevych,3 Christopher J. Evans,2 and Nigel T. Maidment2 1Interdepartmental Neuroscience Ph.D. Program and Departments of 2Psychiatry and Biobehavioral Sciences and 3Neurobiology, University of California at Los Angeles, Los Angeles, California 90024 Parallel studies have demonstrated that enkephalin release of cells that were adjacent to enkephalin and synaptophysin from nerve terminals in the pallidum (globus pallidus and ventral immunoreactivities. Injections of the anterograde tracer pallidum) can be modulated by locally applied opioid drugs. To Phaseolus vulgaris leucoagglutinin (PHA-L) or the retrograde investigate further the mechanisms underlying these opioid tracer Texas Red-conjugated dextran amine (TRD) into the effects, the present study examined the presynaptic and dorsal and ventral striatum resulted in labeling of striatopallidal postsynaptic localization of d (DOR1) and m (MOR1) opioid fibers and pallidostriatal cell bodies, respectively. DOR1 immu- receptors in the dorsal and ventral striatopallidal enkephalin- nostaining in the pallidum co-localized only with TRD and not ergic system using fluorescence immunohistochemistry com- PHA-L, whereas pallidal MOR1 immunostaining co-localized bined with anterograde and retrograde neuronal tracing tech- with PHA-L and not TRD. These results suggest that pallidal niques. DOR1 immunostaining patterns revealed primarily a enkephalin release may be modulated by m opioid receptors postsynaptic localization of the receptor in pallidal cell bodies located presynaptically on striatopallidal enkephalinergic neu- adjacent to enkephalin- or synaptophysin-positive fiber termi- rons and by d opioid receptors located postsynaptically on nals.
    [Show full text]
  • Pharmacological Potential of the Endogenous Dipeptide Kyotorphin and Selected Derivatives
    fphar-07-00530 January 10, 2017 Time: 16:35 # 1 REVIEW published: 12 January 2017 doi: 10.3389/fphar.2016.00530 Pharmacological Potential of the Endogenous Dipeptide Kyotorphin and Selected Derivatives Juliana Perazzo, Miguel A. R. B. Castanho and Sónia Sá Santos* Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal The endogenous peptide kyotorphin (KTP) has been extensively studied since it was discovered in 1979. The dipeptide is distributed unevenly over the brain but the majority is concentrated in the cerebral cortex. The putative KTP receptor has not been identified yet. As many other neuropeptides, KTP clearance is mediated by extracellular peptidases and peptide transporters. From the wide spectrum of biological activity of KTP, analgesia was by far the most studied. The mechanism of action is still unclear, but researchers agree that KTP induces Met-enkephalins release. More recently, KTP was proposed as biomarker of Alzheimer disease. Despite all that, KTP limited pharmacological value prompted researchers to develop derivatives more lipophilic and therefore more prone to cross the blood–brain barrier (BBB), and also more resistant to enzymatic degradation. Conjugation of KTP with functional molecules, such as ibuprofen, generated a new class of compounds with additional biological properties. Edited by: Chris Bailey, Moreover, the safety profile of these derivatives compared to opioids and their efficacy University of Bath, UK as neuroprotective agents greatly increases their pharmacological
    [Show full text]
  • 10Th International Congress on Amino Acids and Proteins (ICAAP)
    Amino Acids (2007) 33: I–LXX DOI 10.1007/s00726-007-0578-0 Printed in The Netherlands 10th International Congress on Amino Acids and Proteins (ICAAP) Kallithea, Greece August 20–25, 2007 Abstracts Presidents: M. Liakopoulou-Kyriakides, Aristotle University, Greece R. Harris, University of Chichester, U.K. K. C. Chou, Gordon Life Science Institute, U.S.A. Honorary President: G. Lubec, University of Vienna, Austria II Contents Amino Acids Metabolism – Diseases . III Amino Acids Racemization . V Bioinformatics and Biomedical. VIII Biotechnology – Enzyme Technology – Food Science . XII Drug Design. XIV Metabotropic Glutamate . XVII Neurobiology . XVIII Plant Amino Acids . XXXIV Polyamines – Transglutaminases. XXXVIII Proteins – Analysis . XLV Sports Exercise and Health . LII Synthesis Amino Acids – Medicinal Chemistry . LXII Transport . LXVIII 10th International Congress on Amino Acids and Proteins (ICAAP) Amino Acids Metabolism – Diseases Homocysteine and methylated arginines – novel Using male Wistar rats two separate studies were performed in which endogenous factors of the chronic musculoskeletal pain? the effect of glutamine on leucine oxidation, protein synthesis and pro- teolysis was estimated. At in vivo study, alanyl-glutamine or saline so- I. G. Bondarenko and J. Chydenius lution were infused to endotoxemic, whole body irradiated, or intact Nutritional=Clinical Biochemistry CHYDENIUS Clinic, Helsinki, (control) rats. At in vitro study, M. soleus and M. extensor digitorum Finland longus were incubated in medium containing 0, 500 or 2000 mmol Recurrent character of chronic musculoskeletal pain suggests that glutamine=L. The parameters of protein metabolism and leucine oxida- 14 there are endogenous chemical mediators sustaining local aseptic inflam- tion were measured using L-[1- C]leucine and=or according to the mation in the connective tissue involved.
    [Show full text]
  • Five Decades of Research on Opioid Peptides: Current Knowledge and Unanswered Questions
    Molecular Pharmacology Fast Forward. Published on June 2, 2020 as DOI: 10.1124/mol.120.119388 This article has not been copyedited and formatted. The final version may differ from this version. File name: Opioid peptides v45 Date: 5/28/20 Review for Mol Pharm Special Issue celebrating 50 years of INRC Five decades of research on opioid peptides: Current knowledge and unanswered questions Lloyd D. Fricker1, Elyssa B. Margolis2, Ivone Gomes3, Lakshmi A. Devi3 1Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; E-mail: [email protected] 2Department of Neurology, UCSF Weill Institute for Neurosciences, 675 Nelson Rising Lane, San Francisco, CA 94143, USA; E-mail: [email protected] 3Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, Annenberg Downloaded from Building, One Gustave L. Levy Place, New York, NY 10029, USA; E-mail: [email protected] Running Title: Opioid peptides molpharm.aspetjournals.org Contact info for corresponding author(s): Lloyd Fricker, Ph.D. Department of Molecular Pharmacology Albert Einstein College of Medicine 1300 Morris Park Ave Bronx, NY 10461 Office: 718-430-4225 FAX: 718-430-8922 at ASPET Journals on October 1, 2021 Email: [email protected] Footnotes: The writing of the manuscript was funded in part by NIH grants DA008863 and NS026880 (to LAD) and AA026609 (to EBM). List of nonstandard abbreviations: ACTH Adrenocorticotrophic hormone AgRP Agouti-related peptide (AgRP) α-MSH Alpha-melanocyte stimulating hormone CART Cocaine- and amphetamine-regulated transcript CLIP Corticotropin-like intermediate lobe peptide DAMGO D-Ala2, N-MePhe4, Gly-ol]-enkephalin DOR Delta opioid receptor DPDPE [D-Pen2,D- Pen5]-enkephalin KOR Kappa opioid receptor MOR Mu opioid receptor PDYN Prodynorphin PENK Proenkephalin PET Positron-emission tomography PNOC Pronociceptin POMC Proopiomelanocortin 1 Molecular Pharmacology Fast Forward.
    [Show full text]
  • ATP, 489 Absolute Configuration Benzomotphans, 204 Levotphanol
    Index AIDA, 495 Affinity labeling, analogs of (Cont.) cAMP, 409, 489 motphine,448 ATP, 409, 489 naltrexone, 449 [3H] ATP, 489 norlevotphanol,449 Absolute configuration normetazocine, 181 benzomotphans, 204 norpethidine, 232 levotphanol, 115 oripavine, 453 methadone and analogs, 316 oxymotphone, 449 motphine, 86 K-Agonists, 179,405,434 phenoperidine, 234 Aid in Interactive Drug Analysis, 495 piperazine derivatives, 399 [L-Ala2] dermotphin, 363 prodines and analogs, 272 [D-Ala, D-Leu] enkephalin (DADL), 68, 344 sinomenine, 28, 115 [D-Ala2 , Bugs] enkephalinamide, 347, 447 viminol, 400 [D-Ala2, Met'] enkephalinamide, 337, 346, Ac 61-91,360 371,489 Acetylcholine, 5, 407 [D-Ala2]leu-enkephalin, 344, 346, 348 Acetylcholine analogs, 186, 191 [D-Ala2] met-enkephalin, 348 l-Acetylcodeine, 32 [D-Ala2] enkephalins, 347 Acetylmethadols (a and (3) Alfentanil, 296 maintenance of addicts by a-isomer, 304, 309 (±)-I1(3-Alkylbenzomotphans, 167, 170 metabolism, 309 11(3-Alkylbenzomotphans, 204 N-allyl and N-CPM analogs, 310, 431 7-Alkylisomotphinans, 146 stereochemistry, 323 N-Alkylnorketobemidones, 431 synthesis, 309 N-Alkylnorpethidines, 233 X-ray crystallography, 327 N-Allylnormetazocine, 420 6-Acetylmotphine, receptor binding, 27 N-Allylnormotphine, 405 Acetylnormethadol, 323 N-Allylnorpethidine, 233 8(3-Acyldihydrocodeinones, 52 3-Allylprodines (a and (3), 256 14-Acyl-4,5-epoxymotphinans, 58 'H-NMR and stereochemistry, 256 7-Acylhydromotphones, 128 X-ray crystallography, 256 Addiction, 4 N-Allylnormetazocine, 420 Adenylate cyclase, 6, 409, 413, 424,
    [Show full text]
  • Brain Opioid-Mediated Analgesia by Systemic Administration of Dipeptide Kyotorphin Analog
    WCP2018 PO3-2-22 Poster session Brain opioid-mediated analgesia by systemic administration of dipeptide kyotorphin analog Hiroyuki Neyama1, Yusuke Hamada2, Minoru Narita2, Hiroshi Ueda1 1Department of Pharmacology and Therapeutic Innovation, Nagasaki University, Institute of Biomedical Sciences, Japan, 2Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan Kyotorphin (L-Tyrosine-L-Arginine) is an opioid-like analgesic dipeptide, which was isolated from bovine brain. Regarding the mechanisms underlying centrally administered kyotorphin-induced analgesia, we have proposed that the met-enkephalin release is one of mechanisms (Nature 1979). The previous studies revealed that kyotorphin binds to putative specific Gi-coupled receptor, and Leucine-Arginine (LR) is a specific antagonist (JBC, 1979). We also found N- methyl derivatives of kyotorphin (NMYR) and LR (NMLR) are potent and stable agonist and antagonist, respectively (Peptides, 2000). The subcutaneous (s.c.) or per os (p.o.) administration of NMYR causes potent analgesic effects in thermal and mechanical nociception tests in mice. The analgesia was completely blocked by the intracerebroventricular (i. c.v.) injection of NMLR, but slight blocked by the intrathecal (i.t.) injection. Furthermore, the loss of NMYR analgesia was observed in mu opioid receptor (MOPr) KO mice or by the i.c.v. injection of naloxone. These results are consistent to the findings that NMYR analgesia was lost in fibromyalgia-like pain models, which lose central morphine analgesia, but remains in partial sciatic nerve ligation model, which remains central, but not peripheral morphine analgesia. In the in vitro assay, kyotorphin has no positive allosteric agonist activity in CHO cells expressing MOPr or delta opioid receptor.
    [Show full text]
  • Peptides and Proteins Chapter
    Chapter 36: Peptides and proteins Karl Lintner Enterprise Technology/Sederma SAS, Le Perray en Yvelines, France BASIC CONCEPTS • Amino acids are the building blocks of peptides that link together to from proteins. • Peptides are biologically active communication tools that direct skin functioning. • Engineered peptides are a new category of active skin ingredients usually applied in a moisturizing vehicle. • Gene chip array analysis can be used to evaluate the effect of engineered peptides in fibroblast cultures. Of the essentially unlimited theoretical number of amino 1 Introduction acids that can be imagined on paper, only 20 (e.g. alanine, proline, tyrosine, histidine, phenylalanine, lysine, glutamine) Peptides, proteins, and amino acids are often mislabeled and are incorporated into peptides and proteins via the genetic the terms applied as if they were interchangeable, yet they code. Individually, these amino acids in isolation have no are different in their characteristics, uses, biological activi- specific intrinsic biological activity. Within cells, they exist ties, and cosmetic potential. After defining peptides and pro- in a pool from which they can be called upon to make pep- teins, the first part of the chapter discusses the specificities tides and proteins or, sometimes, biogenic amines, such as of these molecules and their physiologic, biological function, serotonin or dopamine. In the upper layers of the skin, they particularly in the skin; what can they do, what are the are part of the natural moisturizing factor (NMF) where they obstacles to their use in cosmetic products and how these participate in the skin water holding capacity contributing obstacles can be overcome. In the second part, concrete to both osmolytic and hygroscopic properties.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2008/0124279 A1 Andremont Et Al
    US 2008O124279A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0124279 A1 Andremont et al. (43) Pub. Date: May 29, 2008 (54) COLONIC DELIVERY USING ZN/PECTIN (52) U.S. Cl. .......................................... 424/9.1; 424/493 BEADS WITH AEUDRAGT COATING (76) Inventors: Antoine Andremont, Malakoff (FR); Helene Huguet, Paris (FR) (57) ABSTRACT Correspondence Address: Drug delivery systems that can deliver therapeutic and/or INTELLECTUAL PROPERTY f TECHNOLOGY diagnostic agents to the colon are disclosed. The systems LAW include pectin beads crosslinked with Zinc or any divalent PO BOX 14329 cation of interest, which beads are then coated with RESEARCH TRIANGLE PARK, NC 27709 Eudragit R-type polymers. The drug delivery systems are orally administrable, but can deliver the active agents to the (21) Appl. No.: 11/985.465 colon. In some embodiments, they can administer the agents to various positions in the gastro-intestinal tract, including the (22) Filed: Nov. 15, 2007 colon. The agent can be a small molecule, peptide, protein, nucleic acid, or complex structures of natural, recombinant or Related U.S. Application Data synthetic origin. In still other embodiments, the agent is a diagnostic agent. The agents can be used to diagnose, treat or (60) Provisional application No. 60/859,600, filed on Nov. investigate humans and animals for a variety of conditions, 17, 2006. including infectious diseases, inflammatory diseases, cancers O O and the like. Colon-specific delivery is obtained by formulat Publication Classification ing a prophylactic, therapeutic, and/or diagnostic agent with (51) Int. Cl. specific polymers that degrade in the colon, Such as pectin.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2012/0076842 A1 Fournial Et Al
    US 2012.0076842A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0076842 A1 Fournial et al. (43) Pub. Date: Mar. 29, 2012 (54) COSMETIC USE OF TYR-ARGDIPEPTIDE Publication Classification TO COMBAT CUTANEOUS SAGGING (51) Int. Cl. Inventors: A61K 8/64 (2006.01) (75) Arnaud Fournial, Paris (FR): A61O 19/02 (2006.01) Philippe Mondon, Paris (FR) A6IR 8/02 (2006.01) Assignee: A61O 19/00 (2006.01) (73) SEDERMA, Le Perray enYvelines A6IR 8/II (2006.01) (FR) A61O 19/08 (2006.01) (21) Appl. No.: 13/322,090 A61O 1704 (2006.01) (52) U.S. Cl. ............ 424/401: 514/18.8; 424/62: 424/59; (22) PCT Fled: May 25, 2010 424/94.1: 514/440 (57) ABSTRACT (86) PCT NO.: PCT/B10/52309 The present invention concerns a new cosmetic use of Tyr S371 (c)(1), Arg dipeptide to stimulate molecules of the extracellular (2), (4) Date: Nov. 22, 2011 matrix in order to prevent and treat cutaneaous sagging, in particular due to natural gravity. (30) Foreign Application Priority Data The invention is useful in the preparation of tightening, May 26, 2009 (FR) ....................................... O9.53444 finning, contouring, and lifting cosmetic products. Patent Application Publication Mar. 29, 2012 Sheet 1 of 2 US 2012/0076842 A1 Rrofile duri; she sistics: if the constrain Psile Esri: the applicatist cd the crisiaint &^ is t: ---- sks :----.: -- 88: --- - with Sk -8.5 s Š. -1. 3 s: : s: -. 2.s..................gr:grgrsor3S s 2. ridth: rsy wath in Fig. 1 Fig.2 rofessie applicass site Eistrait: is . S.
    [Show full text]
  • Liquid Chromatography-Mass Spectrometry Strategies for in Vivo Neurochemical Monitoring with Microdialysis
    Liquid Chromatography-Mass Spectrometry Strategies for in vivo Neurochemical Monitoring with Microdialysis by Jenny-Marie T. Wong A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Chemistry) in the University of Michigan 2016 Doctoral Committee: Professor Robert T. Kennedy, Chair Professor Kristina I. Håkansson Professor Mark E. Meyerhoff Professor Martin G. Myers Jr. © Jenny-Marie T. Wong All Rights Reserved 2016 DEDICATION To my friends and family who have always supported me. ii ACKNOWLEDGEMENTS I thank Professor Robert T. Kennedy for accepting me into his group, and challenging me to think deeper and to achieve more. His support and encouragement during my time at the University of Michigan means so much. I also extend my gratitude to my dissertation committee members, Professor Kristina Håkansson, Professor Mark Meyerhoff, and Professor Martin G. Myers Jr., whose insight, thoughtful questions, and advice has helped shape my research, given me a broader perspective, and deepened my understanding. I extend special thanks to my previous mentors Professor Joseph A. Gardella, Dr. AnneMarie Block, Dr. Susan Leong, and Mrs. Anne Ruppert, who continue to mentor me, and encouraged me to pursue chemistry with research opportunities early in my academic career. Your support and encouragement has made this journey possible. I also thank my colleagues Dr. Omar Mabrouk, Dr. Neil Hershey, Dr. Peng Song, Dr. Thomas Slaney, Dr. Jing Nie, Dr. Shuwen Sun, Dr. Ying Zhou, Dr. Kennon Deal, Dr. Shi Jin, Dr. Erik Guetschow, Doc Colladeen Dugan, Dr. Jim Grinias, Dr. Katy Nesbitt, Paige Malec, Non Ngernsutivorakul, Alec Valenta, Daniel Steyer, Claire Ouimet, Dr.
    [Show full text]
  • Design, Synthesis and Evaluation of Peptide-Based Affinity
    Design, Synthesis and Evaluation of Peptide-Based Affinity Labels for Mu Opioid Receptors By C2009 Bhaswati Sinha Submitted to the Department of Medicinal Chemistry and the Faculty of the Graduate School of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Dissertation Committee: ____________________________________ Chairperson: Dr. Jane V. Aldrich ____________________________________ Dr. Michael F. Rafferty ____________________________________ Dr. Teruna J. Siahaan ____________________________________ Dr. Emily E. Scott ____________________________________ Dr. David S. Moore Dissertation Defended __________________ The Dissertation Committee for Bhaswati Sinha certifies that this is the approved version of the following dissertation: Design, Synthesis and Evaluation of Peptide-Based Affinity Labels for Mu Opioid Receptors ____________________________________ Chairperson: Dr. Jane V. Aldrich ____________________________________ Dr. Michael F. Rafferty ____________________________________ Dr. Teruna J. Siahaan ____________________________________ Dr. Emily E. Scott ____________________________________ Dr. David S. Moore Date Approved _________________ ii Dedicated to: My parents Kumkum DattaChowdhury Prithwish Chandra DattaChowdhury My brother Atish DattaChowdhury My husband Sandipan Sinha iii Acknowledgements I would like to take this opportunity to thank all those who have helped me earn the doctorate degree from the University of Kansas. First and foremost, I would like to thank my advisor Prof. Jane V. Aldrich for her excellent mentorship, support and guidance through out my graduate career at the University of Kansas. I was fortunate to have some great colleagues to work with and I would like to thank all of them for their co-operation, encouragement and helpful inputs. They are Anand Joshi, Wendy Hartsock, Kendra Dresner, Katherine Smith, Angela Peck, Dr. Wei-Jie Fang, Dr. Xin Wang, Dr.
    [Show full text]
  • Quality Control Record Opioid Peptide Library
    Quality Control Record Opioid Peptide Library Catalog No. L‐002 Well # Position* Catalog # Product Name M.W. PLATE I 1I‐A‐2 021‐01 Dynorphin, big (Human, Rat, Mouse, Porcine) 3982.26 2I‐A‐3 021‐03 Dynorphin A (Human, Rat, Mouse, Porcine) 2147.51 3I‐A‐4 021‐08 Dynorphin A (1‐6) / Endorphin (1‐6), alpha‐Neo / Leu‐Enkephalin‐Arg (Human, Rat, Mouse, Porcine) 711.38 4I‐A‐5 021‐21 Dynorphin A (1‐13) (Human, Rat, Mouse, Porcine) 1602.99 5I‐A‐6 021‐24 Dynorphin A (2‐13) amide (Human, Rat, Mouse, Porcine) 1439.82 6I‐A‐7 021‐30 Dynorphin A (2‐17) (Human, Rat, Mouse, Porcine) 1983.14 7I‐A‐8 021‐37 Dynorphin B / Rimorphin (Human, Rat, Mouse, Porcine) 1570.86 8I‐A‐9 021‐40 Endorphin, alpha‐Neo (Porcine) 1228.46 9I‐A‐10 021‐44 Endorphin, beta‐neo 1099.59 10 I‐A‐11 021‐55 Orphanin FQ / Nociceptin (Human, Rat, Mouse, Ox) 1809.06 11 I‐B‐2 021‐58 pro‐Orphanin FQ (85‐119) / pro‐Nociceptin (85‐119) / Nocistatin‐35 (Rat) 3907.25 12 I‐B‐3 021‐59 pro‐Orphanin FQ (141‐157) / pro‐Nociceptin (141‐157) 2081.4 13 I‐B‐4 021‐70 [Phe‐psi‐Gly]‐Orphanin FQ (1‐13) amide / [Phe‐psi‐Gly]‐Nociceptin (1‐13) amide (Human, Rat, Mouse, Ox) 1376.6 14 I‐B‐5 021‐71 Orphanin FQ (1‐13) amide / Nociceptin (1‐13) amide (Human, Rat, Mouse, Ox) 1381.6 15 I‐B‐6 021‐75 prepro‐Orphanin FQ (111‐127) / Nocistatin / PNP‐3 (Bovine) 1927.1 16 I‐B‐7 021‐78 prepro‐Orphanin FQ (98‐127) / Nocistatin‐30 (Human) 3561.98 17 I‐B‐8 021‐80 PNP‐3‐8P (Bovine) 1015.13 18 I‐B‐9 021‐81 PNP‐2/3 / Nocistatin‐41 (Mouse) 4375.71 19 I‐B‐10 021‐85 prepro‐Orphanin FQ (154‐181), free acid (Rat) / prepro‐Orphanin FQ
    [Show full text]