DOCSLIB.ORG

Effects of Anisodine Hydrobromide on the Cardiovascular and Respiratory Functions in Conscious Dogs

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Effects of Anisodine Hydrobromide on the Cardiovascular and Respiratory Functions in Conscious Dogs Drug Design, Development and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Effects of Anisodine Hydrobromide on the Cardiovascular and Respiratory Functions in Conscious Dogs This article was published in the following Dove Press journal: Drug Design, Development and Therapy Yunlu Liu 1,2 Purpose: Anisodine hydrobromide (Ani) is isolated from the medicinal plant Anisodus Lin Wang1 tanguticus (Maxim.) Pascher for clinical use. Although considerable research regarding Feng Wan3 Ani has been reported, the safety profiles of Ani are currently unknown. This study Na Yang1 investigated the cardiorespiratory effects of Ani in conscious dogs to provide clinicians a detailed safety profile of Ani on the cardiorespiratory system. 1 Institute of Laboratory Animal Sciences, Materials and Methods: Using the Latin square design, the study was divided into six Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, phases, where in each phase, six telemetered beagle dogs received one dose of normal saline Chengdu, People’s Republic of China; or sotalol hydrochloride or Ani (0.1, 0.4, 1.6, or 6.4 mg/kg). Electrocardiogram, blood 2Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan pressure (BP) and respiratory parameters were collected before and after administration for Provincial People’s Hospital, Chengdu, 24 hours. Statistical comparisons were performed at scheduled time-points. People’s Republic of China; 3College of Results: The heart rate was significantly increased, PR and QTCV intervals were significantly Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, shortened in Ani 0.4, 1.6, 6.4 mg/kg treatment group after drug administration. Compared with People’s Republic of China the saline group, a significant increase in heart rate and shortening of PR, QTCV intervals were observed in the Ani 1.6, 6.4 mg/kg treatment groups from 5 min to 4 h time-points. Diastolic and mean BP were significantly increased in Ani 1.6, 6.4 mg/kg from 1 h to 2 h time-points compared to those of the saline control. Accelerated breathing was observed in the first 20 min after Ani 0.4, 1.6, and 6.4 mg/kg treatment, although not statistically significant.Furthermore, no significant differences were observed in any of the corresponding indexes of Ani 0.1 mg/kg treatment group at different time-points compared to those of the saline group. Conclusion: Ani may have adverse effects on the cardio-respiratory systems of dogs at doses above 0.4 mg/kg, whereas Ani 0.1 mg/kg was devoid of potentially deleterious effects on cardiorespiratory function. Keywords: anisodine hydrobromide, electrocardiogram, blood pressure, cardio-respiratory function, telemetered dogs, safety Introduction Anisodine, a tropane alkaloid extracted from the root of Anisodus tanguticus 1 Correspondence: Na Yang (Maxim.) Pascher in the family Solanaceae, has shown significant therapeutic Institute of Laboratory Animal Sciences, effects on various conditions, such as ocular diseases,2–5 motion sickness and Sichuan Academy of Medical Sciences & 6 7 8 Sichuan Provincial People’s Hospital, Ying migraine, acute circulatory shock, and organophosphorus pesticide poisoning. Long Community, Zhong he Street Office, In view of the unstable chemical properties of anisodine, researchers have devel­ High Tech Zone, Chengdu 610212, People’s Republic of China oped anisodine hydrobromide (Ani). Tel +86 13880145342 Ani acts as non-specific muscarinic cholinoceptor antagonist competing with Fax +86 2867087558 Email [email protected] acetylcholine for binding to the muscarinic cholinergic receptor to block the nerve submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 4263–4276 4263 DovePress © 2020 Liu et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php http://doi.org/10.2147/DDDT.S268113 and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Liu et al Dovepress impulse and physiological functions associated with cho­ parameters were collected by a telemetry system using linergic neurotransmission.9 The autonomic receptors dis­ electrical impedance technology, a common detection tributed in the cardiac, vascular, and airway smooth method showing strong correlation with pneumotacho­ muscle are mainly muscarinic cholinoceptors.10–12 Thus, graph results in the clinic.26 the antimuscarinic activity of Ani could potentially lead to various physiological effects on the cardiorespiratory sys­ Materials and Methods tem. Early experimental and clinical studies have reported The study was reviewed and approved by the Welfare and that structurally-related tropane alkaloids (such as aniso­ Ethics of Experimental Animals Committee of Institute of damine, scopolamine, and atropine) have potential unde­ Laboratory Animal Science, Sichuan Academy of Medical sirable effects on the cardiovascular and respiratory Sciences & Sichuan Provincial People’s Hospital for com­ systems.13–18 Thus, it is necessary to investigate the effects pliance with Guide for the Care and Use of Laboratory of Ani on cardiorespiratory function systematically. Animals (No. Lunshen2018-016). It was conducted in Additionally, although some drugs, such as antibiotics, a research facility accredited by Sichuan Provincial tricyclic antidepressants, and antifungal agents do not act Laboratory Animal Management Committee. The flow­ on the cardiovascular system directly based on their chart of the study is detailed in Figure 1. mechanism of action, nonetheless they have been reported to lead to life-threatening adverse effects, and some patients have suffered serious heart damage after taking Animals and Surgical Preparation for these drugs in clinical practice.19–21 However, to the best Telemetry of our knowledge, no previous studies have extensively Six beagle dogs (three females and three males, 9–10 months assessed the cardiovascular and respiratory effects of Ani. old, 9–12 kg) were obtained from Marshal Biotechnology To this end, this study was designed to define the effects of (Beijing, China). All dogs were housed singly in stainless- Ani on the cardio-respiratory system by following the steel canine cages (1000×1000×2080 mm) for 80 days International Council for Harmonization (ICH) guidelines throughout the study, they were given 25 days to acclimate (S7A, S7B) and the China Food and Drug Administration to the housing environment and team members before the (CFDA) guidelines, to provide a comprehensive profile of implanted surgery started. All animals were fed the cardiorespiratory safety of Ani to the clinician. a maintenance diet. Filtered mains water was offered ad- Electrocardiogram (ECG), blood pressure, and respira­ libitum. Environmental controls were set to maintain the 12- tory indices were collected to describe the effects of Ani hour light-dark cycle (lights on 6:00 AM, off 6:00 PM), on the cardiorespiratory system. We especially focused on 20–25°C temperature and 40–70% humidity range. the prolongation of the QT interval of the ECG, which The animals were anesthetized with propofol (8–12 mg/ represents the cardiac repolarization disturbance that can kg intravascular), and maintained general effect by isoflurane cause torsade de pointes and sudden cardiac death.22 (1.5–5 volume % in oxygen) inhalation. With the sterile Furthermore, indicators of the PR interval and QRS dura­ surgical technique, telemetry transmitter (model number tion of the ECG were also used to evaluate atrioventricular TL11M3-D70-PCTR, Data Sciences International [DSI], and intraventricular conductivities. In order to validate and St. Paul, MN, USA) was implanted in the dogs. The respira­ define the sensitivity of the experimental system, sotalol tory electrodes were implanted subcutaneously on both sides hydrochloride (Sol), an antiarrhythmic agent, which is of the left and right seventh ribs. The ECG electrodes were known to prolong the PR interval and QT interval and implanted subcutaneously on the left side of the chest at the widen the QRS duration,23 was used as the positive control intersection of the last rib and the anterior axillary line and on drug. In addition, an implantable telemetry system the right side at the middle lower edge of the clavicle. The strongly recommended by ICH and CFDA in safety phar­ pressure catheter for blood pressure measurement was macology studies and has been used in the pharmaceutical implanted in the femoral artery, and the main implant body industry for safety evaluation,24 was applied in the present was fixedin the extra-abdominal oblique muscle. After post­ study. Beagle dogs were selected because of the stability operative care and recovery period were completed, animals of their genetic characteristics and completeness of genetic were assessed with indices for general physical conditions, background information, and feasibility of surgical opera­ including body weight, hematology, blood biochemistry, tion in telemetry experiments.25 In addition, respiratory
Load more

Recommended publications
  • NINDS Custom Collection II
    ACACETIN ACEBUTOLOL HYDROCHLORIDE ACECLIDINE HYDROCHLORIDE ACEMETACIN ACETAMINOPHEN ACETAMINOSALOL ACETANILIDE ACETARSOL ACETAZOLAMIDE ACETOHYDROXAMIC ACID ACETRIAZOIC ACID ACETYL TYROSINE ETHYL ESTER ACETYLCARNITINE ACETYLCHOLINE ACETYLCYSTEINE ACETYLGLUCOSAMINE ACETYLGLUTAMIC ACID ACETYL-L-LEUCINE ACETYLPHENYLALANINE ACETYLSEROTONIN ACETYLTRYPTOPHAN ACEXAMIC ACID ACIVICIN ACLACINOMYCIN A1 ACONITINE ACRIFLAVINIUM HYDROCHLORIDE ACRISORCIN ACTINONIN ACYCLOVIR ADENOSINE PHOSPHATE ADENOSINE ADRENALINE BITARTRATE AESCULIN AJMALINE AKLAVINE HYDROCHLORIDE ALANYL-dl-LEUCINE ALANYL-dl-PHENYLALANINE ALAPROCLATE ALBENDAZOLE ALBUTEROL ALEXIDINE HYDROCHLORIDE ALLANTOIN ALLOPURINOL ALMOTRIPTAN ALOIN ALPRENOLOL ALTRETAMINE ALVERINE CITRATE AMANTADINE HYDROCHLORIDE AMBROXOL HYDROCHLORIDE AMCINONIDE AMIKACIN SULFATE AMILORIDE HYDROCHLORIDE 3-AMINOBENZAMIDE gamma-AMINOBUTYRIC ACID AMINOCAPROIC ACID N- (2-AMINOETHYL)-4-CHLOROBENZAMIDE (RO-16-6491) AMINOGLUTETHIMIDE AMINOHIPPURIC ACID AMINOHYDROXYBUTYRIC ACID AMINOLEVULINIC ACID HYDROCHLORIDE AMINOPHENAZONE 3-AMINOPROPANESULPHONIC ACID AMINOPYRIDINE 9-AMINO-1,2,3,4-TETRAHYDROACRIDINE HYDROCHLORIDE AMINOTHIAZOLE AMIODARONE HYDROCHLORIDE AMIPRILOSE AMITRIPTYLINE HYDROCHLORIDE AMLODIPINE BESYLATE AMODIAQUINE DIHYDROCHLORIDE AMOXEPINE AMOXICILLIN AMPICILLIN SODIUM AMPROLIUM AMRINONE AMYGDALIN ANABASAMINE HYDROCHLORIDE ANABASINE HYDROCHLORIDE ANCITABINE HYDROCHLORIDE ANDROSTERONE SODIUM SULFATE ANIRACETAM ANISINDIONE ANISODAMINE ANISOMYCIN ANTAZOLINE PHOSPHATE ANTHRALIN ANTIMYCIN A (A1 shown) ANTIPYRINE APHYLLIC
    [Show full text]
  • Effect of Atropine on Denervated Rabbit Ear Blood Vessels
    http://www.paper.edu.cn Effect of Atropine on Denervated Rabbit Ear Blood Vessels *Shu-Qin Liu, *Wei-Jin Zang, *Zeng-Li Li, *Xiao-Jiang Yu, and †Bao-Ping Li similar to those of atropine and scopolamine. Henbane drugs Abstract: Surgical denervation of rabbit ear blood vessel beds was might exert multiple advantages in shock patients, but the va- combined with the isolated perfused rabbit ear technique to investi- sodilator effect is undoubtedly the main mechanism. Although gate the mechanism of atropine’s vasodilator action. Intramuscular many studies have been done throughout the world, the mecha- injection of atropine 0.2 mg/kg dilated the denervated blood vessels in the rabbit ear like innervated ones in vivo. Atropine at the maximal nisms of henbane drugs’ vasodilator action remain unclear. concentration (C )of3×10−6 to3×10−4 M did not increase ef- Atropine usually activates the central nervous system at max 8,9 fluent flow of the isolated perfused denervated rabbit ear under con- high doses. Scopolamine, in general, inhibits the central ner- −6 10–13 stant perfusion pressure, but chlorpromazine at a Cmax of 10 M and vous system at any dose. Anisodine slightly inhibits the acetylcholine (ACh) at 2.5 × 10−7 M significantly increased it and central nervous system compared with scopolamine.12,13 An- noradrenaline (NA) at 10−7 M significantly decreased it. Atropine at isodamine is so difficult to pass through the blood–brain bar- −7 −6 Cmax of3×10 M did not affect, but at3×10 M it abolished the rier that it might neither activate nor inhibit the central nervous −7 increase of the effluent flow induced by ACh 2.5 × 10 M.
    [Show full text]
  • GPCR/G Protein
    Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com GPCR/G Protein G Protein Coupled Receptors (GPCRs) perceive many extracellular signals and transduce them to heterotrimeric G proteins, which further transduce these signals intracellular to appropriate downstream effectors and thereby play an important role in various signaling pathways. G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a GPCR. Upon receptor stimulation by a ligand, G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. These effects include activating the MAPK and PI3K pathways, as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels. Most human GPCRs can be grouped into five main families named; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin, forming the GRAFS classification system. A series of studies showed that aberrant GPCR Signaling including those for GPCR-PCa, PSGR2, CaSR, GPR30, and GPR39 are associated with tumorigenesis or metastasis, thus interfering with these receptors and their downstream targets might provide an opportunity for the development of new strategies for cancer diagnosis, prevention and treatment. At present, modulators of GPCRs form a key area for the pharmaceutical industry, representing approximately 27% of all FDA-approved drugs. References: [1] Moreira IS. Biochim Biophys Acta. 2014 Jan;1840(1):16-33.
    [Show full text]
  • Analytical Reference Standards
    Cerilliant Quality ISO GUIDE 34 ISO/IEC 17025 ISO 90 01:2 00 8 GM P/ GL P Analytical Reference Standards 2 011 Analytical Reference Standards 20 811 PALOMA DRIVE, SUITE A, ROUND ROCK, TEXAS 78665, USA 11 PHONE 800/848-7837 | 512/238-9974 | FAX 800/654-1458 | 512/238-9129 | www.cerilliant.com company overview about cerilliant Cerilliant is an ISO Guide 34 and ISO 17025 accredited company dedicated to producing and providing high quality Certified Reference Standards and Certified Spiking SolutionsTM. We serve a diverse group of customers including private and public laboratories, research institutes, instrument manufacturers and pharmaceutical concerns – organizations that require materials of the highest quality, whether they’re conducing clinical or forensic testing, environmental analysis, pharmaceutical research, or developing new testing equipment. But we do more than just conduct science on their behalf. We make science smarter. Our team of experts includes numerous PhDs and advance-degreed specialists in science, manufacturing, and quality control, all of whom have a passion for the work they do, thrive in our collaborative atmosphere which values innovative thinking, and approach each day committed to delivering products and service second to none. At Cerilliant, we believe good chemistry is more than just a process in the lab. It’s also about creating partnerships that anticipate the needs of our clients and provide the catalyst for their success. to place an order or for customer service WEBSITE: www.cerilliant.com E-MAIL: [email protected] PHONE (8 A.M.–5 P.M. CT): 800/848-7837 | 512/238-9974 FAX: 800/654-1458 | 512/238-9129 ADDRESS: 811 PALOMA DRIVE, SUITE A ROUND ROCK, TEXAS 78665, USA © 2010 Cerilliant Corporation.
    [Show full text]
  • Rapid Screening for 61 Central Nervous System Drugs in Plasma
    African Journal of Pharmacy and Pharmacology Vol. 5(6), pp. 706-720, June 2011 Available online http://www.academicjournals.org/ajpp DOI: 10.5897/AJPP10.292 ISSN 1996-0816 ©2011 Academic Journals Full Length Research Paper Rapid screening for 61 central nervous system drugs in plasma using weak cation exchange solid-phase extraction and high performance liquid chromatography with diode array detection Yin Zhang1*, Wei-Ping Xie2, Chong-Hong Chen3 and Ling Lin4 1Department of Pharmacy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, People’s Republic of China. 2Department of Physical and Chemical Analysis, Quanzhou Center for Disease Control and Prevention, Quanzhou 362000, People’s Republic of China. 3Department of Pharmacology, College of Pharmacy, Fujian Medical University, Fuzhou 350004, People’s Republic of China. 4Department of Immunology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, People’s Republic of China. Accepted 8 March, 2011 Rapid and accurate screening for toxicants/chemicals in a broad range is an important element in systematic toxicological analysis (STA). Herein, we report a novel method for the rapid screening of 61 central nervous system (CNS) drugs in plasma, using a solid-phase extraction (SPE) column termed, weak cation exchange (WCX) and high performance liquid chromatography with a diode array detector (HPLC-DAD). The SPE column was preconditioned sequentially with 3 ml of acetonitrile, 1 ml of water and, 2 ml of buffer solution. The pretreated plasma was loaded onto the column, which was then washed with 2 ml of water, followed by 2 ml of acetonitrile, and the acetonitrile elution was collected as the neutral/acid fraction.
    [Show full text]
  • Spectrum-Effect Relationships Between High
    Jiang et al Tropical Journal of Pharmaceutical Research February 2017; 16 (2): 379-386 ISSN: 1596-5996 (print); 1596-9827 (electronic) © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights reserved. Available online at http://www.tjpr.org http://dx.doi.org/10.4314/tjpr.v16i2.17 Original Research Article Spectrum-effect relationships between high performance liquid chromatography fingerprint and analgesic property of Anisodus tanguticus (Maxim) Pascher (Solanaceae) roots Yun-Bin Jiang1, Mei Zhong2, Ming-Xun Hu1, Ling Chen1, Yan Gou3, Juan Zhou3, Pi-E Wu3 and Yu-Ying Ma1* 1College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, 2Analytical Chemistry Department, West China Frontier Pharmatech Co., Ltd/National Chengdu Center for Safety Evaluation of Drugs, Chengdu 610041, 3Laboratory for Traditional Chinese Medicine and Ethnic Medicine, Sichuan Institute for Food and Drug Control, Chengdu 610079, PR China *For correspondence: Email: [email protected] Received: 10 September 2016 Revised accepted: 11 January 2017 Abstract Purpose: To investigate the spectrum-effect relationships between high performance liquid chromatography with photodiode array detection (HPLC-DAD) fingerprint and analgesic activity of Anisodus tanguticus (Maxim.) Pascher (Solanaceae) (AT) roots. Methods: Analgesic activity of AT roots was evaluated by acetic acid-induced writhing test in mice. Fingerprint of AT roots was established by HPLC-DAD. After oral administration of AT roots extract, intra-gastric contents of caffeoylputrescine, anisodine, fabiatrin, scopolin, scopolamine, anisodamine and atropine in mice were determined by HPLC-DAD. Spectrum-effect relationships between HPLC- DAD fingerprint and analgesic activity were investigated using bivariate correlation analysis. Results: Following treatment with different batches of AT roots extract, acetic acid-induced writhing responses in mice were inhibited significantly (p < 0.05 or 0.01), with inhibitions of 26.62 - 55.13 %, relative to the control group.
    [Show full text]
  • BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available
    BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on September 26, 2021 by guest. Protected copyright. BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from Treatment of stable chronic obstructive pulmonary disease: a protocol for a systematic review and evidence map Journal: BMJ Open ManuscriptFor ID peerbmjopen-2018-027935 review only Article Type: Protocol Date Submitted by the 15-Nov-2018 Author: Complete List of Authors: Dobler, Claudia; Mayo Clinic, Evidence-Based Practice Center, Robert D.
    [Show full text]
  • Download Product Insert (PDF)
    PRODUCT INFORMATION Anisodamine Item No. 19650 CAS Registry No.: 17659-49-3 Formal Name: αS-(hydroxymethyl)-benzeneacetic acid, 6-hydroxy-8-methyl-8- azabicyclo[3.2.1]oct-3-yl ester O Synonym: 6-hydroxy Hyoscyamine N HO MF: C17H23NO4 O FW: 305.4 Purity: ≥98% OH Supplied as: A crystalline solid Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Anisodamine is supplied as a crystalline solid. A stock solution may be made by dissolving the anisodamine in the solvent of choice. Anisodamine is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide (DMF), which should be purged with an inert gas. The solubility of anisodamine in ethanol and DMF is approximately 25 mg/ml, and approximately 20 mg/ml in DMSO. Further dilutions of the stock solution into aqueous buffers or isotonic saline should be made prior to performing biological experiments. Ensure that the residual amount of organic solvent is insignificant, since organic solvents may have physiological effects at low concentrations. Organic solvent-free aqueous solutions of anisodamine can be prepared by directly dissolving the crystalline solid in aqueous buffers. The solubility of anisodamine in PBS, pH 7.2, is approximately 5 mg/ml. We do not recommend storing the aqueous solution for more than one day. Description Anisodamine is a natural tropane alkaloid shown to be a weak antagonist of α1-adrenoceptors, blocking WB-4101 and clonidine (Item No. 15949) binding in brain membrane preparations with pKi values of 2.63 and 1.61, respectively.1 Anisodamine also has antioxidant effects that may protect against free radical-induced cellular damage.2 Anisodamine is predominantly found in the roots of A.
    [Show full text]
  • An in Vitro Study on Interaction of Anisodine and Monocrotaline With
    Chinese Journal of Natural Chinese Journal of Natural Medicines 2019, 17(7): 04900497 Medicines An in vitro study on interaction of anisodine and monocrotaline with organic cation transporters of the SLC22 and SLC47 families CHEN Jia-Yin1, Jürgen Brockmöller2, Mladen V. Tzvetkov2, WANG Li-Jun1, CHEN Xi-Jing3* 1 Department of Pharmacy, Peking University Shenzhen Hospital, Shenzhen 518036, China; 2 Institute for Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen 37075, Germany; 3 Clinical Pharmacokinetics Lab, China Pharmaceutical University, Nanjing 211198, China; Available online 20 July, 2019 [ABSTRACT] Current study systematically investigated the interaction of two alkaloids, anisodine and monocrotaline, with organic cation transporter OCT1, 2, 3, MATE1 and MATE2-K by using in vitro stably transfected HEK293 cells. Both anisodine and monocro- −1 taline inhibited the OCTs and MATE transporters. The lowest IC50 was 12.9 µmol·L of anisodine on OCT1 and the highest was 1.8 −1 −1 mmol·L of monocrotaline on OCT2. Anisodine was a substrate of OCT2 (Km = 13.3 ± 2.6 µmol·L and Vmax = 286.8 ± 53.6 pmol/mg −1 protein/min). Monocrotaline was determined to be a substrate of both OCT1 (Km = 109.1 ± 17.8 µmol·L , Vmax = 576.5 ± 87.5 −1 pmol/mg protein/min) and OCT2 (Km = 64.7 ± 14.8 µmol·L , Vmax = 180.7 ± 22.0 pmol/mg protein/min), other than OCT3 and MATE transporters. The results indicated that OCT2 may be important for renal elimination of anisodine and OCT1 was responsible for monocrotaline uptake into liver. However neither MATE1 nor MATE2-K could facilitate transcellular transport of anisodine and monocrotaline.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2009/0269772 A1 Califano Et Al
    US 20090269772A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0269772 A1 Califano et al. (43) Pub. Date: Oct. 29, 2009 (54) SYSTEMS AND METHODS FOR Publication Classification IDENTIFYING COMBINATIONS OF (51) Int. Cl. COMPOUNDS OF THERAPEUTIC INTEREST CI2O I/68 (2006.01) CI2O 1/02 (2006.01) (76) Inventors: Andrea Califano, New York, NY G06N 5/02 (2006.01) (US); Riccardo Dalla-Favera, New (52) U.S. Cl. ........... 435/6: 435/29: 706/54; 707/E17.014 York, NY (US); Owen A. (57) ABSTRACT O'Connor, New York, NY (US) Systems, methods, and apparatus for searching for a combi nation of compounds of therapeutic interest are provided. Correspondence Address: Cell-based assays are performed, each cell-based assay JONES DAY exposing a different sample of cells to a different compound 222 EAST 41ST ST in a plurality of compounds. From the cell-based assays, a NEW YORK, NY 10017 (US) Subset of the tested compounds is selected. For each respec tive compound in the Subset, a molecular abundance profile from cells exposed to the respective compound is measured. (21) Appl. No.: 12/432,579 Targets of transcription factors and post-translational modu lators of transcription factor activity are inferred from the (22) Filed: Apr. 29, 2009 molecular abundance profile data using information theoretic measures. This data is used to construct an interaction net Related U.S. Application Data work. Variances in edges in the interaction network are used to determine the drug activity profile of compounds in the (60) Provisional application No. 61/048.875, filed on Apr.
    [Show full text]
  • Toxicology Reference Laboratory
    TOXICOLOGY REFERENCE LABORATORY Laboratory User Guide ROOM 708, BLOCK P PRINCESS MARGARET HOSPITAL 2-10 Princess Margaret Hospital Road Lai Chi Kok Tel: 2990 1941 Fax: 2990 1942 http://trl.home Version 6.1 Effective date: 1/July/2014 Contents Contents ..................................................................................................................................................... 2 Introduction ............................................................................................................................................... 4 Staff ............................................................................................................................................................ 5 Honorary Medical Staff .......................................................................................................................... 5 Scientific Staff ........................................................................................................................................ 5 Technical Staff ........................................................................................................................................ 5 Supportive Staff ...................................................................................................................................... 6 How to Make Laboratory Request .......................................................................................................... 7 Instruction for Referring Clinician ........................................................................................................
    [Show full text]
  • ( 12 ) United States Patent
    US010493080B2 (12 ) United States Patent (10 ) Patent No.: US 10,493,080 B2 Schultz et al. (45 ) Date of Patent : Dec. 3 , 2019 ( 54 ) DIRECTED DIFFERENTIATION OF (56 ) References Cited OLIGODENDROCYTE PRECURSOR CELLS TO A MYELINATING CELL FATE U.S. PATENT DOCUMENTS 7,301,071 B2 11/2007 Zheng (71 ) Applicants : The Scripps Research Institute , La 7,304,071 B2 12/2007 Cochran et al. Jolla , CA (US ) ; Novartis AG , Basel 9,592,288 B2 3/2017 Schultz et al. 2003/0225072 A1 12/2003 Welsh et al. ( CH ) 2006/0258735 Al 11/2006 Meng et al. 2009/0155207 Al 6/2009 Hariri et al . (72 ) Inventors : Peter Schultz , La Jolla , CA (US ) ; Luke 2010/0189698 A1 7/2010 Willis Lairson , San Diego , CA (US ) ; Vishal 2012/0264719 Al 10/2012 Boulton Deshmukh , La Jolla , CA (US ) ; Costas 2016/0166687 Al 6/2016 Schultz et al. Lyssiotis , Boston , MA (US ) FOREIGN PATENT DOCUMENTS (73 ) Assignees : The Scripps Research Institute , La JP 10-218867 8/1998 Jolla , CA (US ) ; Novartis AG , Basel JP 2008-518896 5/2008 (CH ) JP 2010-533656 A 10/2010 WO 2008/143913 A1 11/2008 WO 2009/068668 Al 6/2009 ( * ) Notice : Subject to any disclaimer , the term of this WO 2009/153291 A1 12/2009 patent is extended or adjusted under 35 WO 2010/075239 Al 7/2010 U.S.C. 154 ( b ) by 0 days . (21 ) Appl. No .: 15 /418,572 OTHER PUBLICATIONS Molin - Holgado et al . “ Regulation of muscarinic receptor function in ( 22 ) Filed : Jan. 27 , 2017 developing oligodendrocytes by agonist exposure ” British Journal of Pharmacology, 2003 , 138 , pp .
    [Show full text]