DOCSLIB.ORG

The Significance of NK1 Receptor Ligands and Their Application In

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Significance of NK1 Receptor Ligands and Their Application In pharmaceutics Review The Significance of NK1 Receptor Ligands and Their Application in Targeted Radionuclide Tumour Therapy Agnieszka Majkowska-Pilip * , Paweł Krzysztof Halik and Ewa Gniazdowska Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland * Correspondence: [email protected]; Tel.: +48-22-504-10-11 Received: 7 June 2019; Accepted: 16 August 2019; Published: 1 September 2019 Abstract: To date, our understanding of the Substance P (SP) and neurokinin 1 receptor (NK1R) system shows intricate relations between human physiology and disease occurrence or progression. Within the oncological field, overexpression of NK1R and this SP/NK1R system have been implicated in cancer cell progression and poor overall prognosis. This review focuses on providing an update on the current state of knowledge around the wide spectrum of NK1R ligands and applications of radioligands as radiopharmaceuticals. In this review, data concerning both the chemical and biological aspects of peptide and nonpeptide ligands as agonists or antagonists in classical and nuclear medicine, are presented and discussed. However, the research presented here is primarily focused on NK1R nonpeptide antagonistic ligands and the potential application of SP/NK1R system in targeted radionuclide tumour therapy. Keywords: neurokinin 1 receptor; Substance P; SP analogues; NK1R antagonists; targeted therapy; radioligands; tumour therapy; PET imaging 1. Introduction Neurokinin 1 receptor (NK1R), also known as tachykinin receptor 1 (TACR1), belongs to the tachykinin receptor subfamily of G protein-coupled receptors (GPCRs), also called seven-transmembrane domain receptors (Figure1)[ 1–3]. The human NK1 receptor structure [4] is available in Protein Data Bank (6E59). Tachykinins, widely distributed within the central (CNS) and peripheral (PNS) nervous system, are small bioactive neuropeptides which share a conserved C-terminal pentapeptide sequence, Phe-X-Gly-Leu-Met-NH2. Examples of these neurotransmitters belonging to the tachykinin group include Substance P (SP), the first neuropeptide discovered in mammals [5], neurokinin A (NKA) and neurokinin B (NKB). These compounds listed above are the preferential ligands for NK1, NK2 and NK3 receptors, respectively, although they can bind additional NK receptors with varying affinity [6]. Pharmaceutics 2019, 11, 443; doi:10.3390/pharmaceutics11090443 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2019, 11, 443 2 of 28 Pharmaceutics 2019, 11, x FOR PEER REVIEW 2 of 29 Figure 1. SchematicSchematic model model of of NK1 NK1 receptor of full length isoform (NK1R-Fl) [[3].3]. Within thethe neurokinin neurokinin receptor receptor family, family, there there are three are pharmacologicallythree pharmacologically distinct receptordistinct subtypes:receptor subtypes:NK1R (TACR1, NK1R SPR),(TACR1, NK2R SPR), (TACR2) NK2R (TACR2) and NK3R and (TACR3) NK3R (TACR3) [7–9]. NK1R [7–9]. is NK1R widely is expressedwidely expressed in both inthe both CNS the and CNS PNS, and whereas PNS, whereas NK2R isNK2R preferentially is preferentially expressed expressed in PNS in [9 ].PNS NK1R [9]. containsNK1R contains 407 amino 407 aminoacids, andacids, NK2R and NK2R and NK3R and NK3R (the longest (the longest one) consistone) consist of 398 of and398 and 465 amino465 amino acids, acids, respectively respectively [3]. [3].NK1R NK1R exists exists in two in isoforms,two isoforms, as a full-length as a full-length peptide peptide (NK1R-Fl, (NK1R-Fl, Figure 1Figure) and in 1) the and truncated in the truncated isoform (NK1R-Tr),isoform (NK1R-Tr), containing containing 311 amino 311 acids amino (96 amino acids acids(96 amino less at acids the C-terminus) less at the C-terminus) [3]. NK1R displays [3]. NK1R two displaysnonstoichiometric two nonstoichiometric binding sites, bi thending more sites, abundant the more NK-1M abundant (“majority”—representing NK-1M (“majority”—representing 80–85% of the 80–85%total receptor of the population) total receptor and NK-1mpopulation) (“minority”—so-called and NK-1m (“minority”—so-called “septide sites” or “septide-sensitive”)“septide sites” or “septide-sensitive”)defined according to defined the different according binding to potenciesthe different of SPbinding and its potencies analogues of [ 10SP– and14]. its NK1R analogues contains [10– an 14].extracellular NK1R contains N-terminus, an extracellular three extracellular N-terminus, loops three (E1, E2extracellular and E3), seven loops transmembrane (E1, E2 and E3), domains, seven transmembranethree intracellular domains, loops (C1, three C2 andintracellular C3, as well loops as a (C1, possible C2 and C4 C3, loop) as andwell an as intracellulara possible C4 C-terminus. loop) and an intracellularThe wide overexpression C-terminus. of NK1R in various human organs has led to successful development of highlyThe wide selective overexpression agonists and of antagonists NK1R in various of this human receptor organs for the has treatment led to successful of various development diseases [8]. ofSome highly NK1R selective ligands, agonists for example and antagonists SP, its analogues of this and receptor derivatives, for the have treatment been investigated of various indiseases preclinical [8]. Someand clinical NK1R studies. ligands, Moreover, for example based SP, on highits analogues density of transmembraneand derivatives, NK1Rs have onbeen human investigated cancer cells, in preclinicalnew therapeutic and clinical approaches studies. involve Moreover, the use based of radiolabelledon high density NK1R of transmembrane ligands in targeted NK1Rs radionuclide on human cancertumour cells, therapy new [ 2therapeutic,15–17]. approaches involve the use of radiolabelled NK1R ligands in targeted radionuclideThe aim tumour of this reviewtherapy is[2,15–17]. to discuss data from recent literature concerning the chemical and biologicalThe aim aspects of this of naturalreview is and to syntheticdiscuss data NK1R from ligands recent in literature classical andconcerning nuclear the medicine, chemical with and a biologicalspecific focus aspects on targeted of natural radionuclide and synthetic therapy. NK1R ligands in classical and nuclear medicine, with a specific focus on targeted radionuclide therapy. 2. NK1R Ligands in Classical Medicine 2. NK1R Ligands in Classical Medicine 2.1. Significance of NK1R Agonists 2.1. SignificanceThe endogenous of NK1R peptide Agonists ligands of NK1R are tachykinins, a large family of neuropeptides produced by neuronal and glial cells [5,18]. These compounds play an important role in nociception, The endogenous peptide ligands of NK1R are tachykinins, a large family of neuropeptides synaptic transmission (as excitatory neurotransmitters) and neuroimmunomodulation. They have a produced by neuronal and glial cells [5,18]. These compounds play an important role in nociception, variety of effects on physiological and pathological conditions, as well as intrinsic neuroprotective and synaptic transmission (as excitatory neurotransmitters) and neuroimmunomodulation. They have a neurodegenerative properties [19]. The tachykinin family is characterized by a common C-terminal variety of effects on physiological and pathological conditions, as well as intrinsic neuroprotective 5-amino-acid sequence Phe-X-Gly-Leu-Met-NH , where X is either an aromatic (Phe or Tyr) or a and neurodegenerative properties [19]. The tach2 ykinin family is characterized by a common C- branched chain aliphatic (Val or Ile) amino acid residue [19–21]. terminal 5-amino-acid sequence Phe-X-Gly-Leu-Met-NH2, where X is either an aromatic (Phe or Tyr) The most widespread and tested agonistic peptide ligand of NK1R is human endogenous or a branched chain aliphatic (Val or Ile) amino acid residue [19–21]. undecaneuropeptide Substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH , SP(1–11), SP, The most widespread and tested agonistic peptide ligand of NK1R is human2 endogenous [Arg1]SP, Figure2). At physiological pH, SP characteristically holds a positive charge on N-terminal undecaneuropeptide Substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2, SP(1–11), amino acid residues. The C-terminus contains hydrophobic residues providing the SP peptide with SP, [Arg1]SP, Figure 2). At physiological pH, SP characteristically holds a positive charge on N- terminal amino acid residues. The C-terminus contains hydrophobic residues providing the SP peptide with an amphiphilic character [22]. The interaction between SP and NK1R results in Pharmaceutics 2019, 11, 443 3 of 28 Pharmaceutics 2019, 11, x FOR PEER REVIEW 3 of 29 an amphiphilic character [22]. The interaction between SP and NK1R results in internalisation of the membrane-boundinternalisation of complex,the membrane-bound via a clathrin-dependent complex, via mechanism, a clathrin-dependent to the acidified mechanism, endosomes, to where the theacidified complex endosomes, disassociates where [8, 22the– 24complex]. disassociates [8,22–24]. H2N H2N O O O O H H N N N H2N N H N N O O H O O NH H N H2N O O O NH O H HN N NH N 2 O H2N S Figure 2. Structure of Substance P(1–11). The SP SP fragment fragment responsible responsible for NK1R for affinity NK1R is a ffia nityfive amino is a acid five sequence, amino Phe acid7–Phe sequence,8–Gly9– 7 8 9 10 11 PheLeu10–Phe–Met11–Gly, located–Leu at the–Met C-terminus, located of at the the peptide C-terminus [21,25,26]. of the Tachykinins peptide [21 are,25, 26degraded]. Tachykinins by neutral are degradedendopeptidases by
Load more

Recommended publications
  • Vasopressin Release from the Rat Hypothalamo-Neurohypophysial System: Effects of Tachykinin NK–1 and NK–2 Receptors Agonis
    Neuroendocrinology Letters No.4 August Vol.26, 2005 Copyright © 2005 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu Vasopressin release from the rat hypothalamo-neurohy- pophysial system: Effects of tachykinin NK–1 and NK–2 receptors agonists and antagonists ARTICLE ORIGINAL Marlena Juszczak Department of Pathophysiology, Medical University of Lodz, Lodz, Poland. Correspondence to: Marlena Juszczak, Ph.D., D.Sc. Department of Pathophysiology Medical University of Lodz Narutowicza 60 90-136 Lodz, POLAND TEL/FAX: +48 42 6306187 [email protected] Submitted: July 7, 2004 Accepted: October 15, 2004 Key words: tachykinin receptors; substance P; neurokinin A; vasopressin Neuroendocrinol Lett 2005; 26(4):367–372 PMID: 16136007 NEL260405A13 © Neuroendocrinology Letters www.nel.edu Abstract OBJECTIVES: Present experiments were undertaken to study the influence of pep- tide NK–1 and NK–2 receptor agonists and antagonists as well as substance P and neurokinin A (the natural ligands for these tachykinin receptors) on vasopres- sin (AVP) secretion from the rat hypothalamo-neurohypophysial (HN) system in vitro. RESULTS: The results showed that both substance P and highly selective tachykinin 9 11 NK–1 receptor agonist, i.e., [Sar ,Met(O2) ]-Substance P, enhanced significantly AVP secretion, while the NK–1 receptor antagonist (Tyr6,D–Phe7,D–His9)-Sub- stance P (6–11) – sendide – was found to antagonize the substance P–induced hormone release from isolated rat HN system (all peptides at the concentration of 10–7 M/L). The NK–2 receptor selective agonist (β–Ala8)–Neurokinin A (4–10) was essentially inactive in modifying AVP release from the rat HN system in vitro, while neurokinin A (the natural ligand for this tachykinin receptor) was found to stimulate the AVP release; this effect of neurokinin A has been diminished by the 5 6,8,9 10 NK–2 receptor antagonist (Tyr ,D–Trp ,Lys–NH2 )–Neurokinin A (4–10).
    [Show full text]
  • Amylase Release from Rat Parotid Gland Slices C.L
    Br. J. P!harmnic. (1981) 73, 517-523 THE EFFECTS OF SUBSTANCE P AND RELATED PEPTIDES ON a- AMYLASE RELEASE FROM RAT PAROTID GLAND SLICES C.L. BROWN & M.R. HANLEY MRC Neurochemical Pharmacology Unit, Medical Research Council Centre, Medical School, Hills Road, Cambridge CB2 2QH 1 The effects of substance P and related peptides on amylase release from rat parotid gland slices have been investigated. 2 Supramaximal concentrations (1 F.M) of substance P caused enhancement of amylase release over the basal level within 1 min; this lasted for at least 40 min at 30°C. 3 Substance P-stimulated amylase release was partially dependent on extracellular calcium and could be inhibited by 50% upon removal of extracellular calcium. 4 Substance P stimulated amylase release in a dose-dependent manner with an ED50 of 18 nm. 5 All C-terminal fragments of substance P were less potent than substance P in stimulating amylase release. The C-terminal hexapeptide of substance P was the minimum structure for potent activity in this system, having 1/3 to 1/8 the potency of substance P. There was a dramatic drop in potency for the C-terminal pentapeptide of substance P or substance P free acid. Physalaemin was more potent than substance P (ED50 = 7 nM), eledoisin was about equipotent with substance P (ED5o = 17 nM), and kassinin less potent than substance P (ED50 = 150 nM). 6 The structure-activity profile observed is very similar to that for stimulation of salivation in vivo, indicating that the same receptors are involved in mediating these responses.
    [Show full text]
  • CP.PMN.158 Netupitant and Palonosetron (Akynzeo)
    Clinical Policy: Netupitant and Palonosetron (Akynzeo), Fosnetupitant and Palonosetron (Akynzeo IV) Reference Number: CP.PMN.158 Effective Date: 09.01.06 Last Review Date: 02.21 Coding Implications Line of Business: HIM, Medicaid Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Description Netupitant/palonosetron (Akynzeo®) and fosnetupitant/palonosetron are fixed combination products of netupitant, a substance P/neurokinin 1 (NK1) receptor antagonist, and palonosetron hydrochloride, a serotonin (5-HT3) receptor antagonist. FDA Approved Indication(s) Akynzeo capsules are indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Akynzeo for injection is indicated in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. It is the policy of health plans affiliated with Centene Corporation® that Akynzeo is medically necessary when the following criteria are met: I. Initial Approval Criteria A. Prevention of Nausea and Vomiting Associated with Cancer Chemotherapy (must meet all): 1. Prescribed for the prevention of chemotherapy-induced nausea/vomiting; 2. Age ≥ 18 years; 3. If request is for Akynzeo capsules, member is scheduled to receive moderately to highly emetogenic cancer chemotherapy (see Appendix D); 4. If request is for Akynzeo for injection, member is scheduled to receive highly emetogenic cancer chemotherapy (see Appendix D); 5.
    [Show full text]
  • Fosaprepitant Dimeglumine (Emend® for Injection) Prior Authorization Drug Coverage Policy
    1 Fosaprepitant dimeglumine (Emend® for injection) Prior Authorization Drug Coverage Policy Effective Date: 9/1/2020 Revision Date: n/a Review Date: 3/13/20 Lines of Business: Commercial Policy type: Prior Authorization This Drug Coverage Policy provides parameters for the coverage of fosaprepitant dimeglumine. Consideration of medically necessary indications are based upon U.S. Food and Drug Administration (FDA) indications, recommended uses within the Centers of Medicare & Medicaid Services (CMS) five recognized compendia, including the National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium (Category 1 or 2A recommendations), and peer-reviewed scientific literature eligible for coverage according to the CMS, Medicare Benefit Policy Manual, Chapter 15, section 50.4.5 titled, “Off-Label Use of Anti-Cancer Drugs and Biologics.” This policy evaluates whether the drug therapy is proven to be effective based on published evidence-based medicine. Drug Description 1 Fosaprepitant is a prodrug of aprepitant and accordingly, its antiemetic effects are attributable to aprepitant. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV). Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin- induced emesis.
    [Show full text]
  • MASCC/ESMO ANTIEMETIC GUIDELINE 2016 with Updates in 2019
    1 ANTIEMETIC GUIDELINES: MASCC/ESMO MASCC/ESMO ANTIEMETIC GUIDELINE 2016 With Updates in 2019 Organizing and Overall Meeting Chairs: Matti Aapro, MD Richard J. Gralla, MD Jørn Herrstedt, MD, DMSci Alex Molassiotis, RN, PhD Fausto Roila, MD © Multinational Association of Supportive Care in CancerTM All rights reserved worldwide. 2 ANTIEMETIC GUIDELINES: MASCC/ESMO These slides are provided to all by the Multinational Association of Supportive Care in Cancer and can be used freely, provided no changes are made and the MASCC and ESMO logos, as well as date of the information are retained. For questions please contact: Matti Aapro at [email protected] Chair, MASCC Antiemetic Study Group or Alex Molassiotis at [email protected] Past Chair, MASCC Antiemetic Study Group 3 ANTIEMETIC GUIDELINES: MASCC/ESMO Consensus A few comments on this guideline set: • This set of guideline slides represents the latest edition of the guideline process. • This set of slides has been endorsed by the MASCC Antiemetic Guideline Committee and ESMO Guideline Committee. • The guidelines are based on the votes of the panel at the Copenhagen Consensus Conference on Antiemetic Therapy, June 2015. • Latest version: March 2016, with updates in 2019. 4 ANTIEMETIC GUIDELINES: MASCC/ESMO Changes: The Steering Committee has clarified some points: 2016: • A footnote clarified that aprepitant 165 mg is approved by regulatory authorities in some parts of the world ( although no randomised clinical trial has investigated this dose ). Thus use of aprepitant 80 mg in the delayed phase is only for those cases where aprepitant 125 mg is used on day 1. • A probable modification in pediatric guidelines based on the recent Cochrane meta-analysis is indicated.
    [Show full text]
  • V·M·I University Microfilms International a Bell & Howell Information Company 300 North Zeeb Road, Ann Arbor
    Characterization of the cloned neurokinin A receptor transfected in murine fibroblasts Item Type text; Dissertation-Reproduction (electronic) Authors Henderson, Alden Keith. Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 27/09/2021 18:29:56 Link to Item http://hdl.handle.net/10150/185828 1/. INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed through, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note. will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy.
    [Show full text]
  • Europium-Labeled Ligands for Receptor Binding Studies
    Europium-labeled Ligands for Receptor Binding Studies Katja Sippola, Maija-Liisa Mäkinen, Sanna Rönnmark, Joni Helenius, Riitta Heilimö, Anu Koivikko, Pertti Hurskainen and Christel Gripenberg-Lerche PerkinElmer Life and Analytical Sciences, Wallac Oy 1 Introduction 2 Methods Time-resolved fluorescence enhancement technique DELFIA® enables development of highly sensitive assays for screening. We have developed a family of Europium-labeled peptides and proteins designed for ligand receptor binding assays that can be easily automated The DELFIA® ligand receptor binding assay is based on dissociation-enhanced time-resolved fluorescence. DELFIA® Eu-labeled ligand and and optimized either for 96 or 384 well format. These Eu-labeled ligands provide an excellent non-radioactive alternative that is both receptor membrane preparate are incubated on an filter plate (PALL AcroWell or AcroPrep) after which unbound labeled ligand is removed by stabile and sensitive. filtration. Eu is dissociated from the bound ligand by using DELFIA® Enhancement Solution. Dissociated Eu creates highly fluorescent complexes, ® The new tachycinin members of the DELFIA ligand family are Substance P and Neurokinin A. These peptide ligands have many which are measured in a multilabel counter with TRF option, e.g. EnVision™. physiological roles, e.g. they stimulate smooth muscle contraction and glandular secretion and are involved in immune responses and neurotransmission. 3 DELFIA® Neurokinin A assays on 96 well filtration plates 4 DELFIA® Substance P assays on 96 well
    [Show full text]
  • Antiemetics/Antivertigo Agents
    Antiemetic Agents Therapeutic Class Review (TCR) May 1, 2019 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage or retrieval system without the express written consent of Magellan Rx Management. All requests for permission should be mailed to: Magellan Rx Management Attention: Legal Department 6950 Columbia Gateway Drive Columbia, Maryland 21046 The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient, medical professional or layperson seeking information about a specific course of treatment for a specific medical condition. All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician and/or other medical professional in regard to the best course of treatment for their specific medical condition. This publication, inclusive of all forms contained herein, is intended to be educational in nature and is intended to be used for informational purposes only. Send comments and suggestions to [email protected]. May 2019 Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2019 Magellan Rx Management. All Rights Reserved. 3 FDA-APPROVED INDICATIONS Drug Manufacturer Indication(s) NK1 receptor antagonists aprepitant capsules generic, Merck In combination with other antiemetic agents for: (Emend®)1 .
    [Show full text]
  • Resolution of Refractory Pruritus with Aprepitant in a Patient With
    Case Report Resolution of refractory pruritus with aprepitant in a patient with microcystic adnexal carcinoma Johanna S Song, MD,ab Hannah Song, BA,a Nicole G Chau, MD,ac Jeffrey F Krane, MD, PhD,ad Nicole R LeBoeuf, MD, MPHabe aHarvard Medical School; bDepartment of Dermatology, Brigham and Women’s Hospital; cCenter for Head and Neck Oncology, Dana-Farber Cancer Institute; dHead and Neck Pathology Service, Brigham and Women’s Hospital; and eCenter for Cutaneous Oncology, Dana-Farber Cancer Institute, all in Boston, Massachusetts ubstance P is an important neurotransmit- biopsied, and the patient was diagnosed with MAC ter implicated in itch pathways.1 After bind- with gross nodal involvement. Laboratory findings ing to its receptor, neurokinin-1 (NK-1), including serum chemistries, blood urea nitrogen, substance P induces release of factors including complete blood cell count, thyroid, and liver func- S 2 histamine, which may cause pruritus. Recent lit- tion were normal. Positron emission tomography- erature has reported successful use of aprepitant, an computed tomography (PET-CT) imaging was NK-1 antagonist that has been approved by the US negative for distant metastases. Food and Drug Administration for the treatment Treatment was initiated with oral aprepitant – of chemotherapy-induced nausea and vomiting, for 125 mg on day 1, 80 mg on day 2, and 80 mg on treatment of pruritus. We report here the case of a day 3 –with concomitant weekly carboplatin (AUC patient with microcystic adnexal carcinoma (MAC) 1.5) and paclitaxel (30 mg/m2) as well as radiation. who presented with refractory pruritus and who had Within hours after the first dose of aprepitant, the rapid and complete resolution of itch after adminis- patient reported a notable cessation in his pruri- tration of aprepitant.
    [Show full text]
  • Basal Ganglia & Cerebellum
    1/2/2019 This power point is made available as an educational resource or study aid for your use only. This presentation may not be duplicated for others and should not be redistributed or posted anywhere on the internet or on any personal websites. Your use of this resource is with the acknowledgment and acceptance of those restrictions. Basal Ganglia & Cerebellum – a quick overview MHD-Neuroanatomy – Neuroscience Block Gregory Gruener, MD, MBA, MHPE Vice Dean for Education, SSOM Professor, Department of Neurology LUHS a member of Trinity Health Outcomes you want to accomplish Basal ganglia review Define and identify the major divisions of the basal ganglia List the major basal ganglia functional loops and roles List the components of the basal ganglia functional “circuitry” and associated neurotransmitters Describe the direct and indirect motor pathways and relevance/role of the substantia nigra compacta 1 1/2/2019 Basal Ganglia Terminology Striatum Caudate nucleus Nucleus accumbens Putamen Globus pallidus (pallidum) internal segment (GPi) external segment (GPe) Subthalamic nucleus Substantia nigra compact part (SNc) reticular part (SNr) Basal ganglia “circuitry” • BG have no major outputs to LMNs – Influence LMNs via the cerebral cortex • Input to striatum from cortex is excitatory – Glutamate is the neurotransmitter • Principal output from BG is via GPi + SNr – Output to thalamus, GABA is the neurotransmitter • Thalamocortical projections are excitatory – Concerned with motor “intention” • Balance of excitatory & inhibitory inputs to striatum, determine whether thalamus is suppressed BG circuits are parallel loops • Motor loop – Concerned with learned movements • Cognitive loop – Concerned with motor “intention” • Limbic loop – Emotional aspects of movements • Oculomotor loop – Concerned with voluntary saccades (fast eye-movements) 2 1/2/2019 Basal ganglia “circuitry” Cortex Striatum Thalamus GPi + SNr Nolte.
    [Show full text]
  • Deciphering Emesis
    International Journal of Pharmaceutical Chemistry and Analysis 2021;8(1):19–24 Content available at: https://www.ipinnovative.com/open-access-journals International Journal of Pharmaceutical Chemistry and Analysis Journal homepage: https://www.ijpca.org/ Review Article Deciphering emesis 1, 2 Sunil Chaudhry *, Avisek Dutta 1Bioclinitech Technologies Pvt Ltd, Mumbai & GPATTutor.com,, India 2Cognizant Aolutions, Kolkata, West Bengal, India ARTICLEINFO ABSTRACT Article history: The incidence of nausea or vomiting changes much with etiopathogenesis. Multiple neurohumoural Received 04-03-2021 pathways lead to nausea and vomiting. The various classes of antiemetics target different pro-emetic Accepted 09-03-2021 pathways to alleviate nausea and vomiting. Some drugs target more than one pathway. It is demonstrated Available online 04-05-2021 that combination therapy is more effective than single anti-emetic agent. © This is an open access article distributed under the terms of the Creative Commons Attribution Keywords: License (https://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and Vomiting reproduction in any medium, provided the original author and source are credited. Chemoreceptor trigger zone Aprepitant Cannabinoid receptor agonist 5 HT receptor antagonist Neurokinin receptor antagonists 1. Introduction 5. Refractory: Nausea and/or vomiting that occurs in subsequent chemotherapy cycles despite maximum Vomiting or emesis, is defined as the involuntary, forceful antiemetic protocol expulsion of the contents of stomach through the mouth and 6. Anticipatory: Nausea and/or vomiting that is sometimes from nose. triggered by sensory stimuli associated with chemotherapy administration. 1 2. Types of Vomiting Features of Cancer Chemotherapy induced nausea and 2.1. Vomiting centre vomiting: The chemoreceptor trigger zone in the Area postrema plays 1.
    [Show full text]
  • Substance P and Antagonists of the Neurokinin-1 Receptor In
    Martinez AN and Philipp MT, J Neurol Neuromed (2016) 1(2): 29-36 Neuromedicine www.jneurology.com www.jneurology.com Journal of Neurology & Neuromedicine Mini Review Article Open Access Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System Alejandra N. Martinez1 and Mario T. Philipp1,2* 1Division of Bacteriology & Parasitology, Tulane National Primate Research Center, Covington, LA, USA 2Department of Microbiology and Immunology, Tulane University Medical School, New Orleans, LA, USA Article Info ABSTRACT Article Notes This review addresses the role that substance P (SP) and its preferred receptor Received: May 03, 2016 neurokinin-1 (NK1R) play in neuroinflammation associated with select bacterial, Accepted: May 18, 2016 viral, parasitic, and neurodegenerative diseases of the central nervous system. *Correspondence: The SP/NK1R complex is a key player in the interaction between the immune Division of Bacteriology and Parasitology and nervous systems. A common effect of this interaction is inflammation. For Tulane National Primate Research Center this reason and because of the predominance in the human brain of the NK1R, Covington, LA, USA its antagonists are attractive potential therapeutic agents. Preventing the Email: [email protected] deleterious effects of SP through the use of NK1R antagonists has been shown © 2016 Philipp MT. This article is distributed under the terms of to be a promising therapeutic strategy, as these antagonists are selective, the Creative Commons Attribution 4.0 International License potent, and safe. Here we evaluate their utility in the treatment of different neuroinfectious and neuroinflammatory diseases, as a novel approach to Keywords clinical management of CNS inflammation.
    [Show full text]