DOCSLIB.ORG

Effects of Catecholamine Metabolites on Beta-Adrenoceptor-Mediated Relaxation of Smooth Muscle: Evaluation in Mouse and Guinea-Pig Trachea and Rat Aorta

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Effects of Catecholamine Metabolites on Beta-Adrenoceptor-Mediated Relaxation of Smooth Muscle: Evaluation in Mouse and Guinea-Pig Trachea and Rat Aorta Vol. 43, No. 3 Biol. Pharm. Bull. 43, 493–502 (2020) 493 Regular Article Effects of Catecholamine Metabolites on Beta-Adrenoceptor-Mediated Relaxation of Smooth Muscle: Evaluation in Mouse and Guinea-Pig Trachea and Rat Aorta Fumiko Yamaki, Anna Koike, Hikari Kono, Xiaoyue Zhang, Kento Yoshioka, Keisuke Obara,* and Yoshio Tanaka Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toho University; 2–2–1 Miyama, Funabashi, Chiba 274–8510, Japan. Received October 3, 2019; accepted December 17, 2019 The β-adrenoceptor (β-AR)-mediated pharmacological effects of catecholamine (CA) metabolites are not well known. We examined the effects of seven CA metabolites on smooth muscle relaxation in mouse and guinea pig (GP) tracheas and rat thoracic aorta. Among them, metadrenaline (MA) significantly re- laxed GP trachea (β2-AR dominant), even in the presence of clorgiline, a monoamine oxidase-A inhibitor. 4 In mouse trachea (β1-AR dominant), normetadrenaline (NMA) and MA (10 M each) apparently did not affect isoprenaline (ISO)-induced relaxation, but significantly inhibited it in the presence of clorgiline. ISO- induced relaxation was also unaffected by 3,4-dihydroxyphenylglycol (DHPG) (104 M), but significant sup- pression was observed with the addition of 3,5-dinitrocatechol, a catechol-O-methyltransferase inhibitor. In GP trachea, NMA, MA, 3,4-dihydroxymandelic acid (DOMA), and DHPG (104 M each) significantly aug- mented ISO-induced relaxation. However, in the presence of clorgiline plus 3,5-dinitrocatechol, both NMA and MA (104 M) significantly suppressed ISO-induced relaxation. DHPG (104 M) also significantly sup- pressed ISO-induced relaxation in the presence of 3,5-dinitrocatechol. In rat thoracic aorta, DHPG (104 M) significantly suppressed relaxation induced by CGP-12177 A (a β3-AR partial agonist) in the presence of 3,5-dinitrocatechol plus propranolol. Our findings indicate that 1) MA may possess β2-AR agonistic action; 2) NMA and MA augment β2-AR-mediated tracheal relaxation in the absence of CA metabolic inhibitors, though themselves possessing β1-, β2-AR antagonistic action (β2 > β1); 3) DHPG exhibits β1-, β2-, β3-AR an- tagonistic action, and this is particularly marked for β3-AR. Our observations may help explain some of the pathologies associated with pheochromocytoma, which is characterized by increased CA metabolite levels. Key words metadrenaline; normetadrenaline; 3,4-dihydroxyphenylglycol; β-adrenoceptor; tracheal relax- ation; aortic relaxation INTRODUCTION mediated pharmacological actions requires further study. In order to clarify whether various CA metabolites exert Catecholamine (CA) metabolites are generated through their pharmacological actions through β-ARs, we investi- oxidative deamination of noradrenaline (NA) and adrenaline gated their possible agonistic/antagonistic effects on β-AR (AD) by monoamine oxidase (MAO) and their O-methylation using smooth muscle preparations in which functional β1-AR 1,2) by catechol-O-methyltransferase (COMT) (Fig. 1). It is gen- or β2-AR was dominantly expressed. The smooth muscle erally recognized that CA metabolites do not show pharmaco- preparations used were mouse and GP trachea in which 2) logical activity. However, normetadrenaline (NMA) and me- β1-AR-/β2-AR-mediated relaxations were exclusively and tadrenaline (MA), COMT metabolites of NA/AD, can act as easily detected.5,6) In addition, rat thoracic aorta (TA) that 7,8) agonists of adrenoceptors (ARs). For example, NMA and MA produces β3-AR-mediated relaxation was also used. CA have been shown to contract the nictitating membrane smooth metabolites examined in this study were NMA, MA, DOMA, muscle via α-AR in cats, and to possess positive chronotropic DHPG, VMA, MHPG, and MHPG sulfate (MHPG-S), which 3) action in guinea pig (GP) atrial muscle through β (β1)-AR. have been reported to increase in the blood and urine of Extending from this work, we recently found that NMA/MA patients with pheochromocytoma.1,9,10) The present pharmaco- contracted rat prostate and thoracic aorta through activation of logical approaches are clinically significant, since the informa- α1A-AR/α1D-AR (our unpublished observation). tion about CA metabolites’ β-AR-mediated effects on smooth In contrast, four CA metabolites, 3,4-dihydromandelic acid muscle relaxation may help further understanding of the pa- (DOMA), 3,4-dihydroxyphenylglycol (DHPG), vanillylman- thology of pheochromocytoma. delic acid (VMA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were reported not to show β (β1)-AR stimulatory MATERIALS AND METHODS or antagonistic actions in GP atrial muscle.3) In addition, we found that five CA metabolites (NMA, DOMA, DHPG, VMA, Drugs The following drugs were used: DL-normetanephrine and MHPG) did not show β3-AR agonistic activity, based on (DL-normetadrenaline, or NMA), hydrochloride, DL- observations of relaxant responses in rat urinary bladder prep- metanephrine (DL-metadrenaline, or MA), hydrochloride, DL- 4) arations. However, whether CA metabolites exhibit β-AR- 3,4-dihydroxymandelic acid (DOMA), DL-3,4-dihydroxyphenyl * To whom correspondence should be addressed. e-mail: [email protected] © 2020 The Pharmaceutical Society of Japan 494 Biol. Pharm. Bull. Vol. 43, No. 3 (2020) Fig. 1. Metabolic Pathways of Noradrenaline (NA) and Adrenaline (AD) by Monoamine Oxidase (MAO) and Catechol-O-Methyltransferase (COMT) NMA: normetadrenaline; MA: metadrenaline; DOMA: 3,4-dihydroxymandelic acid; DHPG; 3,4-dihydroxyphenylglycol; VMA: vanillylmandelic acid; MHPG: 3-methoxy-4-hydroxyphenylglycol; MHPG-S; MHPG sulfuric acid; DHMA: 3,4-dihydroxymandelaldehyde; MHMA: 3-methoxy-4-hydroxymandelaldehyde; AO: aldehyde oxidase; AR: aldehyde reductase. glycol (DHPG), DL-4-hydroxy-3-methoxymandelic acid (VMA), on May 17, 2017, 18-54-294, accredited on May 7, 2018, and 4-hydroxy-3-methoxyphenylglycol (MHPG) hemipiperazinium 19-55-294, accredited on April 10, 2019) and was conducted salt, 4-hydroxy-3-methoxyphenylglycol sulfate (MHPG-S) in accordance with the User’s Guidelines for the Laboratory potassium salt, (−)-adrenaline (AD) (+)-bitartrate salt, car- Animal Center of the Faculty of Pharmaceutical Sciences, bamyl choline chloride, (−)-isoproterenol (isoprenaline; ISO) Toho University. hydrochloride, N-methyl-N-propargyl-3-(2,4-dichlorophenoxy) Preparation of Trachea and TA Tissues The mice and propylamine (clorgiline) hydrochloride, 3,5-dinitrocatechol, GPs were anesthetized with isoflurane by inhalation and eu- (−)-phenylephrine hydrochloride, salbutamol hemisulfate salt, thanized by exsanguination from the carotid arteries. There- (±)-CGP-12177 A hydrochloride, (±)-propranolol hydrochloride, after, the tracheal tissues were quickly removed and immersed indomethacin (all from Sigma-Aldrich, St. Louis, MO, U.S.A.), in Locke-Ringer solution of the following composition (mM): (−)-(R)-noradrenaline (NA) hydrogen tartrate monohydrate, NaCl, 154; KCl 5.6; CaCl2, 2.2; MgCl2, 2.1; NaHCO3, 5.9; D- silodosin (FUJIFILM Wako Pure Chemical Corporation, Osaka, (+)-glucose, 2.8. The tracheal tissues were cleaned of unnec- Japan), (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl) oxy]-3- essary adipose and connective tissues under a dissecting mi- [(1-methylethyl) amino]-2-butanol hydrochloride (ICI-118551) croscope. Subsequently, tracheal cartilage containing smooth (Tocris Bioscience, Ellisville, MO, U.S.A.), acetylcholine muscles was cut into pieces about 2 mm long. In this series of chloride (Daiichi Sankyo Co., Ltd., Tokyo, Japan), and (±)- experiments, the intimal surface of tracheal tissue was gently phentolamine mesylate (Novartis Pharma K.K., Tokyo, Japan). rubbed with moistened filter paper to remove tracheal epithe- All other chemicals used were commercially available and of lium as much as possible. reagent grade. The rats were anesthetized with isoflurane by inhalation Indomethacin was dissolved in 100% ethanol as a stock and euthanized by exsanguination from the carotid arteries. solution at 10−2 M, and 3,5-dinitrocatechol was dissolved in Thereafter, the TA was quickly removed and immersed in dimethyl sulfoxide (DMSO) as a stock solution at 5 × 10−3 M. normal Tyrode’s solution of the following composition (mM): All other drugs were prepared as aqueous stock solutions. All NaCl, 158.3; KCl, 4.0; CaCl2, 2.0; MgCl2, 1.05; NaH2PO4, stock solutions were diluted with distilled water to obtain de- 0.42; NaHCO3, 10.0; D-(+)-glucose, 5.6. After removing the sired concentrations. surrounding adipose and connective tissue under a dissecting Animals Male Wistar rats (8–11 weeks old; weight microscope, the isolated TA was then cut into spiral segments 150–280 g; Sankyo Labo Service Co., Tokyo, Japan), male (approximately 2 mm in width and 20 mm in length), and the ddY mice (8–12 weeks old; weight 35–46 g; Sankyo Labo endothelium was removed by gentle rubbing of the intimal Service Co.), and male Hartley GP (5–8 weeks old; weight surface with filter paper. 290–465 g; Kyudo Co., Ltd., Saga, Japan) were housed under Recordings of Isometric Tension Changes of Smooth controlled conditions at a temperature of 21–22°C, relative Muscle Tissues Tracheal tissues were suspended with stain- air humidity of 50 ± 5%, and a fixed 12 h light-dark cycle less steel hooks (outer diameter 200 µm) in a 5-mL organ (08 : 00–20:00), with food and water available ad libitum. This bath (UC-5; UFER Medical Instrument, Kyoto, Japan) filled study was approved by the Toho University Animal Care with Locke-Ringer solution. Rat TAs were suspended with and User Committee (approval numbers
Load more

Recommended publications
  • Rutamarin: Efficient Liquid–Liquid Chromatographic Isolation from Ruta Graveolens L
    molecules Article Rutamarin: Efficient Liquid–Liquid Chromatographic Isolation from Ruta graveolens L. and Evaluation of Its In Vitro and In Silico MAO-B Inhibitory Activity Ewelina Kozioł 1, Simon Vlad Luca 2,3, Hale Gamze A˘galar 4 , Begüm Nurpelin Sa˘glık 4 , Fatih Demirci 4,5, Laurence Marcourt 6 , Jean-Luc Wolfender 6 , Krzysztof Jó´zwiak 7 and Krystyna Skalicka-Wo´zniak 1,* 1 Independent Laboratory of Natural Products Chemistry, Department of Pharmacognosy, Medical University of Lublin, 20-093 Lublin, Poland; [email protected] 2 Department of Pharmacognosy, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania; [email protected] 3 Biothermodynamics, TUM School of Life and Food Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany 4 Department of Pharmacognosy, Faculty of Pharmacy, Anadolu University, Eskisehir 26470, Turkey; [email protected] (H.G.A.); [email protected] (B.N.S.); [email protected] (F.D.) 5 Faculty of Pharmacy, Eastern Mediterranean University, Famagusta 99628, Cyprus 6 Institute of Pharmaceutical Sciences of Western Switzerland, IPSWS, University of Geneva, CMU, 1211 Geneva 4, Switzerland; [email protected] (L.M.); [email protected] (J.-L.W.) 7 Department of Biopharmacy, Medical University of Lublin, 20-093 Lublin, Poland; [email protected] * Correspondence: [email protected] Academic Editors: Tomasz Tuzimski and James Barker Received: 29 April 2020; Accepted: 5 June 2020; Published: 9 June 2020 Abstract: Naturally occurring coumarins are a group of compounds with many documented central nervous system (CNS) activities. However, dihydrofuranocoumarins have been infrequently investigated for their bioactivities at CNS level.
    [Show full text]
  • The Antidepressant-Like Effect of Flavonoids from Trigonella Foenum-Graecum Seeds in Chronic Restraint Stress Mice Via Modulation of Monoamine Regulatory Pathways
    molecules Article The Antidepressant-like Effect of Flavonoids from Trigonella Foenum-Graecum Seeds in Chronic Restraint Stress Mice via Modulation of Monoamine Regulatory Pathways Jiancheng Wang, Cuilin Cheng *, Chao Xin and Zhenyu Wang * Harbin Institute of Technology, 92 West Dazhi Street, Nangang District, Harbin 150001, China; [email protected] (J.W.); [email protected] (C.X.) * Correspondence: [email protected] (C.C.); [email protected] (Z.W.); Tel.: +86-1884-578-1315 (C.C.); +86-1303-996-0001 (Z.W.) Academic Editor: Thomas Efferth Received: 27 February 2019; Accepted: 19 March 2019; Published: 20 March 2019 Abstract: Fenugreek (Trigonella Foenum-Graecum) seeds flavonoids (FSF) have diverse biological activities, while the antidepressant-like effect of FSF has been seldom explored. The aim of this study was to evaluate the antidepressant-like effect of FSF and to identify the potential molecular mechanisms. LC-MS/MS was used for the determination of FSF. Chronic restraint stress (CRS) was used to establish the animal model of depression. Observation of exploratory behavior in the forced swimming test (FST), tail suspension test (TST) and sucrose preference test (SPT) indicated the stress level. The serum corticosterone (CORT) level was measured. The monoamine neurotransmitters (5-HT, NE and DA) and their metabolites, as well as monoamine oxidase A (MAO-A) enzyme activity in the prefrontal cortex, hippocampus and striatum, were evaluated. The protein expression levels of KLF11, SIRT1, MAO-A were also determined by western blot analysis. The results showed that FSF treatment significantly reversed the CRS-induced behavioral abnormalities, including reduced sucrose preference and increased immobility time.
    [Show full text]
  • The Serotonin Syndrome
    The new england journal of medicine review article current concepts The Serotonin Syndrome Edward W. Boyer, M.D., Ph.D., and Michael Shannon, M.D., M.P.H. From the Division of Medical Toxicology, he serotonin syndrome is a potentially life-threatening ad- Department of Emergency Medicine, verse drug reaction that results from therapeutic drug use, intentional self-poi- University of Massachusetts, Worcester t (E.W.B.); and the Program in Medical Tox- soning, or inadvertent interactions between drugs. Three features of the sero- icology, Division of Emergency Medicine, tonin syndrome are critical to an understanding of the disorder. First, the serotonin Children’s Hospital, Boston (E.W.B., M.S.). syndrome is not an idiopathic drug reaction; it is a predictable consequence of excess Address reprint requests to Dr. Boyer at IC Smith Bldg., Children’s Hospital, 300 serotonergic agonism of central nervous system (CNS) receptors and peripheral sero- 1,2 Longwood Ave., Boston, MA 02115, or at tonergic receptors. Second, excess serotonin produces a spectrum of clinical find- [email protected]. edu. ings.3 Third, clinical manifestations of the serotonin syndrome range from barely per- This article (10.1056/NEJMra041867) was ceptible to lethal. The death of an 18-year-old patient named Libby Zion in New York updated on October 21, 2009 at NEJM.org. City more than 20 years ago, which resulted from coadminstration of meperidine and phenelzine, remains the most widely recognized and dramatic example of this prevent- N Engl J Med 2005;352:1112-20. 4 Copyright © 2005 Massachusetts Medical Society. able condition.
    [Show full text]
  • Pharmaceutical Appendix to the Harmonized Tariff Schedule
    Harmonized Tariff Schedule of the United States Basic Revision 3 (2021) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States Basic Revision 3 (2021) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • Noradrenergic Function and Clinical Outcome in Antidepressant Pharmacotherapy Helen L
    Noradrenergic Function and Clinical Outcome in Antidepressant Pharmacotherapy Helen L. Miller, M.D., R. David Ekstrom, M.A., M.P.H., George A. Mason, Ph.D., R. Bruce Lydiard, M.D., Ph.D., and Robert N. Golden, M.D. Controversy remains regarding the role of noradrenergic and at the conclusion of the treatment trial. Changes in systems in determining clinical response to antidepressant urinary excretion of 6-sulfatoxymelatonin distinguished pharmacotherapy. Pineal gland production of melatonin can antidepressant responders from nonresponders, with a serve as a physiologic index of noradrenergic function. The significant increase observed in the former group and a aim of this study was to examine the effects of significant decrease in the latter. The degree of clinical antidepressant treatment on 24-hour urinary excretion of response was correlated with the change in the principle metabolite of melatonin, 6-sulfatoxymelatonin 6-sulfatoxymelatonin excretion. These results suggest that in treatment responders and nonresponders. Twenty-four enhanced noradrenergic function may play an important outpatients meeting DSM-III-R criteria for Major role in determining clinical response to Depression received treatment with either fluvoxamine or antidepressant pharmacotherapy. imipramine for 6 weeks while participating in a placebo- [Neuropsychopharmacology 24:617–623, 2001] controlled double-blind clinical trial. Twenty-four hour © 2001 American College of Neuropsychopharmacology. excretion of 6-sulfatoxymelatonin was measured at baseline Published by Elsevier Science Inc. KEY WORDS: Antidepressants; Melatonin; Norepinephrine; a substantial minority do not, and insights regarding Pineal gland; Depression the necessary psychobiologic components of treatment response could help predict, and perhaps prevent, The introduction of effective antidepressant pharmaco- some cases of treatment failure.
    [Show full text]
  • Wo 2008/127291 A2
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 23 October 2008 (23.10.2008) WO 2008/127291 A2 (51) International Patent Classification: Jeffrey, J. [US/US]; 106 Glenview Drive, Los Alamos, GOlN 33/53 (2006.01) GOlN 33/68 (2006.01) NM 87544 (US). HARRIS, Michael, N. [US/US]; 295 GOlN 21/76 (2006.01) GOlN 23/223 (2006.01) Kilby Avenue, Los Alamos, NM 87544 (US). BURRELL, Anthony, K. [NZ/US]; 2431 Canyon Glen, Los Alamos, (21) International Application Number: NM 87544 (US). PCT/US2007/021888 (74) Agents: COTTRELL, Bruce, H. et al.; Los Alamos (22) International Filing Date: 10 October 2007 (10.10.2007) National Laboratory, LGTP, MS A187, Los Alamos, NM 87545 (US). (25) Filing Language: English (81) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, (30) Priority Data: CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, 60/850,594 10 October 2006 (10.10.2006) US ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, (71) Applicants (for all designated States except US): LOS LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, ALAMOS NATIONAL SECURITY,LLC [US/US]; Los MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, Alamos National Laboratory, Lc/ip, Ms A187, Los Alamos, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, NM 87545 (US).
    [Show full text]
  • 3 Serotonin Syndrome
    PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the University of Virginia Children’s Hospital Volume 1 2 Number 3 March 2006 Serotoni n Syndrome: Pediatric and Neonatal Considerations Marcia L. Buck, Pharm.D., FCCP oxicity resulting from excessive serotonin is typically rapid . In a recent r eview of 41 cases T activity, referred to as serotonin syndrome, documented since 1995, 61.5% of patients was first described by Oates and Sjoerdsma in present ed within 6 hours of drug initiation, 1960. Since that time, over 100 cases have been dosage change, or overdose. 1 reported .1 Over the past decade, the diagnosis of serotonin syndrome has become more Mild cases may present with mydriasis, frequent, as the use of drugs which raise serum diaphoresis, tachycardia, shivering, clonus, serotonin concentrations has increased .1,2 The hyperreflexia, and tremor . A fever may or may syndrome may result from normal therapeutic use not be present. Clonus, hyperreflexia , and of d rugs which increase serotonin concentrations, tremor are typically more prominent in the lower but is more commonly associated with drug extremities. Moderate cases may present with overdose or interactions between two drug the symptoms previously described, as well as therapies. This issue of Pediatric hypertension, hyperthermia (a core temperature Pharmacotherapy will provide a brief review of up to 40 º C) , horizontal ocular clonus, nausea, serotonin syndrome, as well as some example s vomiting, hyperactive bowel sounds , and from the pediatric literature. diarrhea . Patients often have changes in mental status, including agitation, hypervigilance, and Mechanism pressured speech. 1-3 Serotonin (5 -hydroxytryptamine or 5 -HT) is produced in presynaptic neurons from L - Severe cases may present with profound tryptophan.
    [Show full text]
  • NCT02523690 IRB00072940 Evaluating Muscle
    NCT02523690 IRB00072940 Evaluating Muscle Weakness Improvement With Lorcaserin in ICU (EMILI) Protocol Version: February 10, 2017 (Date in header of protocol, 8/1/2016 was inadvertently not updated) Date: 1 August 2016 Principal Investigator: Dale Needham, MD PhD Application Number: IRB00072940 JHM IRB - eForm A – Protocol Use the section headings to write the JHM IRB eForm A, inserting the appropriate material in each. If a section is not applicable, leave heading in and insert N/A. When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at the top of JHM IRB eForm A. *************************************************************************************************** 1) Abstract (Provide no more than a one page research abstract briefly stating the problem, the research hypothesis, and the importance of the research.) It was recently discovery that patients recovering from sepsis/critical illness have great difficulty recruiting motor units to generate muscle force. Prior to this discovery, the primary etiology of muscle weakness in these patients was thought to be muscle disease (myopathy) and degeneration of peripheral nerve (neuropathy). However, since motor units are composed of a group of muscle fibers contacted by a single motor neuron arising from the spinal cord, these new findings suggested a problem within the spinal cord as the primary cause of weakness in affected patients. Consistent with these clinical findings in critically ill patients, there is a profound deficit in the excitability of motor neurons in the spinal cord of septic rats. Studies characterizing the impaired excitability in rat motor neurons point to a specific deficit in a slowly inactivating type of sodium current (i.e., the persistent sodium current).
    [Show full text]
  • Serotonin Syndrome Cristian Falup-Pecurariu Department of Neurology Faculty of Medicine, Transilvania University Brasov, Romania Introduction
    Serotonin Syndrome Cristian Falup-Pecurariu Department of Neurology Faculty of Medicine, Transilvania University Brasov, Romania Introduction • the Serotonin Syndrome - medication induced condition • serotoninergic hyperactivity • administration of drugs that increase serotonergic transmission • in patients treated for depression (the most common group), bipolar affective disorder, obsessive-compulsive disorder, eating disorders with depression, Parkinson’s disease, migraines, HIV/AIDS, drugs abuse. • Potentially lethal • Incidence: - rising -↑ use of serotonergic drugs - many cases go unrecognized Ables AZ, Nagubilli R. Am Fam Physician. 2010 May 1;81(9):1139-42. Gordon, M. F., & Leder, A. N. Movement Disorder Emergencies, 2012; 217–239. Signs and symptoms of serotonin toxicity Neuromuscular: Autonomic: • Tremor • Mydriasis • Hyperreflexia • Diaphoresis • Clonus • Tachycardia • Tachypnea Mental status: • Agitation • Excitement • Restlessness • Confusion • Delirium Foong AL, Grindrod KA, Patel T, Kellar J. Can Fam Physician. 2018;64(10):720-727 Boyer EW, Shannon M. N Engl J Med. 2005 Mar 17;352(11):1112-20 Boyer EW, Shannon M. N Engl J Med. 2005 Mar 17;352(11):1112-20 Sternbach Criteria Hunter Criteria Inclusion Criteria Presence of serotonergic medication Presence of serotonergic medication Exclusion Criteria Presence of other possible disease etiologies (e.g., infection, substance None abuse and withdrawal) and/or recent addition (or increase in dose) of neuroleptic medication. At least three of the following signs/symptoms: Any of the following combinations of primary (1) or secondary (2) Mental status changes (confusion, hypomania) signs/symptoms: Agitation 1: Spontaneous clonus alone Myoclonus 1: Inducible clonus AND Signs 2: Agitation or diaphoresis And Hyperreflexia 1: Ocular clonus AND Symptoms 2: Agitation or diaphoresis Diaphoresis 1: Tremor AND Shivering 2: Hyperreflexia Tremor 1: Hypertonicity AND fever (temperature >38) AND Diarrhea Incoordination 2: Ocular clonus or inducible clonus Fever Francescangeli J et al.
    [Show full text]
  • Drug Screening in Scn1a Zebrafish Mutant Identifies Clemizole As A
    ARTICLE Received 30 Apr 2013 | Accepted 6 Aug 2013 | Published 3 Sep 2013 DOI: 10.1038/ncomms3410 Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment Scott C. Baraban1,2, Matthew T. Dinday1 & Gabriela A. Hortopan1 Dravet syndrome is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development and persistent drug-resistant seizures. One of its primary monogenic causes are mutations in Nav1.1 (SCN1A), a voltage-gated sodium channel. Here we characterize zebrafish Nav1.1 (scn1Lab) mutants originally identified in a chemical mutagenesis screen. Mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviours. Although scn1Lab expression is reduced, microarray analysis is remarkable for the small fraction of differentially expressed genes (B3%) and lack of compensatory expression changes in other scn subunits. Ketogenic diet, diazepam, valproate, potassium bromide and stiripentol attenuate mutant seizure activity; seven other antiepileptic drugs have no effect. A phenotype-based screen of 320 compounds identifies a US Food and Drug Administration-approved compound (clemizole) that inhibits convulsive behaviours and electrographic seizures. This approach represents a new direction in modelling pediatric epilepsy and could be used to identify novel therapeutics for any monogenic epilepsy disorder. 1 Epilepsy Research Laboratory, Department of Neurological Surgery, University of California, San Francisco, Box 0520, 513 Parnassus Avenue San Francisco, California 94143, USA. 2 Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California 94143, USA. Correspondence and requests for materials should be addressed to S.C.B. (email: [email protected]). NATURE COMMUNICATIONS | 4:2410 | DOI: 10.1038/ncomms3410 | www.nature.com/naturecommunications 1 & 2013 Macmillan Publishers Limited.
    [Show full text]
  • X-Ray Microscope Röntgenstrahlmikroskop Microscope À Rayons X
    (19) TZZ ___T (11) EP 2 511 844 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: G06F 21/00 (2013.01) G21K 7/00 (2006.01) 12.08.2015 Bulletin 2015/33 (21) Application number: 12164870.3 (22) Date of filing: 10.10.2007 (54) X-ray microscope Röntgenstrahlmikroskop Microscope à rayons X (84) Designated Contracting States: • Stewart, Jeffrey, J. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Los Alamos, NM 87544 (US) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE • Harris, Michael, N. SI SK TR Los Alamos, NM 87544 (US) • Burrell, Anthony, K. (30) Priority: 10.10.2006 US 850594 P Los Alamos, NM 87544 (US) (43) Date of publication of application: (74) Representative: Lorente Berges, Ana 17.10.2012 Bulletin 2012/42 A2 Estudio Legal C/ Hermosilla Nº 59, bajo izq (62) Document number(s) of the earlier application(s) in 28001 Madrid (ES) accordance with Art. 76 EPC: 07874491.9 / 2 084 519 (56) References cited: WO-A1-97/25614 US-A1- 2003 023 562 (73) Proprietor: XRpro Sciences, Inc. US-A1- 2004 128 518 US-A1- 2004 235 059 Los Alamos, NM 87544 (US) US-A1- 2005 015 596 (72) Inventors: • POTTS PHILIP J ET AL: "Atomic spectrometry • Birnbaum, Eva, R. update__X-ray fluorescence spectrometry", Los Alamos, NM 87544 (US) JOURNAL OF ANALYTICAL ATOMIC • Koppisch, Andrew, T. SPECTROMETRY, ROYAL SOCIETY OF Los Alamos, NM 87544 (US) CHEMISTRY, vol. 21, no.
    [Show full text]
  • (Mdma; “Ecstasy”) on Rat Brain Mitochondria
    Ema Luís Pereira Gomes Alves NEUROTOXICITY OF METHYLENEDIOXYMETHAMPHETAMINE (MDMA; ECSTASY) ON RAT BRAIN MITOCHONDRIA Porto, 2007 Ema Luis Pereira Gomes Alves Neurotoxicity of methylenedioxymethamphetamine (MDMA;”ecstasy”) on rat brain mitochondria Porto 2007 Neurotoxicity of methylenedioxymethamphetamine (MDMA;”ecstasy”) on rat brain mitochondria Ema Luis Pereira Gomes Alves Dissertação apresentada à Faculdade de Farmácia da Universidade do Porto para obtenção do grau de doutor em toxicologia. Dissertation presented to the Faculty of Pharmacy of the University of Porto to to obtain a PhD degree in toxicology. Supervisor Professor Doutor Félix Dias Carvalho Professor Associado com Agregação da Faculdade de Farmácia da Universidade do Porto, Porto, Portugal. Co-Supervisor Doutora Maria Teresa Burnay Summavielle Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto Portugal Departamento de Ciências Biomédicas, Escola Superior de Tecnologias da Saúde (ESTSP), Instituto Politécnico do Porto (IPP), Porto, Portugal Co-Supervisor Professor Doutor José Barata Cutódio Departamento de Bioquímica, Faculade de Farmácia, Universidade de Coimbra, Coimbra, Portugal III “Para ser grande, sê inteiro: nada teu exagera ou exclui. Sê todo em cada coisa. Põe quanto és no mínimo que fazes. Assim em cada lago a lua toda brilha, porque alta vive.” Ricardo Reis Ao(s) Professore(s) Doutore(s) Félix Dias Carvalho e Maria Teresa Burnay Summavielle. Aos meus pais e irmãos. À memória da minha avó. VII O Decreto de Lei 288/70, art. 8, § 2,refere:
    [Show full text]