DOCSLIB.ORG

Green Mamba Peptide Targets Type-2 Vasopressin Receptor Against Polycystic Kidney Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Green Mamba Peptide Targets Type-2 Vasopressin Receptor Against Polycystic Kidney Disease Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease Justyna Cioleka,1, Helen Reinfrankb,1,2, Lo¨ıc Quintonc, Say Viengchareund, Enrico A. Sturaa, Laura Veraa,3, Sabrina Sigismeaua, Bernard Mouillace,Hel´ ene` Orcele, Steve Peigneurf, Jan Tytgatf, Laura Droctove´ a, Fabrice Beaua, Jerome Nevouxd, Marc Lombes` d, Gilles Mouriera, Edwin De Pauwc, Denis Serventa, Christiane Mendree,4, Ralph Witzgallb,4, and Nicolas Gillesa,4 aService d’Ingenierie´ Moleculaire´ des Proteines,´ Institut des Sciences du Vivant Fred´ eric´ Joliot, Commissariat a` l’Energie Atomique, Universite´ Paris-Saclay, F-91191 Gif sur Yvette, France; bInstitute for Molecular and Cellular Anatomy, University of Regensburg, 93053 Regensburg, Germany; cLaboratoire de Spectrometrie´ de Masse, Unite´ de Recherche Molecular Systems, Universite´ de Liege,` Liege` 4000, Belgium; dINSERM U1185, Universite´ Paris Sud, Universite´ Paris-Saclay, F-94276, Le Kremlin-Bicetre,ˆ France; eInstitut de Genomique´ Fonctionnelle, CNRS, INSERM, Universite´ Montpellier, F-34094 Montpellier, France; and fLaboratory of Toxicology, University of Leuven, Leuven B-3000, Belgium Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved April 13, 2017 (received for review December 17, 2016) Polycystic kidney diseases (PKDs) are genetic disorders that can therapeutic approach, the use of V2R antagonists has certain cause renal failure and death in children and adults. Lowering advantages (7, 8). Most renal ADPKD cysts develop within the cAMP in cystic tissues through the inhibition of the type-2 vaso- vasopressin-sensitive tubular parts of the nephron, where vaso- pressin receptor (V2R) constitutes a validated strategy to reduce pressin is also the main hormonal regulator of adenylyl cyclase disease progression. We identified a peptide from green mamba and thus a stimulator of cAMP production. Moreover, increased venom that exhibits nanomolar affinity for the V2R without any levels of circulating vasopressin and elevated expression of V2R activity on 155 other G-protein–coupled receptors or on 15 ionic have been observed in human ADPKD and in animal models. channels. Mambaquaretin-1 is a full antagonist of the V2R acti- Finally, in contrast to somatostatin receptors, V2R has kidney- vation pathways studied: cAMP production, beta-arrestin interac- specific expression. tion, and MAP kinase activity. This peptide adopts the Kunitz fold Among the orally bio-available vasopressin antagonists, orig- known to mostly act on potassium channels and serine proteases. inally licensed for short-term treatment of heart failure and Mambaquaretin-1 interacts selectively with the V2R through its hyponatraemia, tolvaptan has been proved to be beneficial for first loop, in the same manner that aprotinin inhibits trypsin. the long-term treatment of ADPKD in adult patients (9). Tolvap- Injected in mice, mambaquaretin-1 increases in a dose-dependent tan is an aquaretic agent that inhibits V2R and reduces cAMP manner urine outflow with concomitant reduction of urine osmo- production in principal cells of the collecting tubules (10). In lality, indicating a purely aquaretic effect associated with the in vivo blockade of V2R. CD1-pcy/pcy mice, a juvenile model of Significance PKD, daily treated with 13 µg of mambaquaretin-1 for 99 d, developed less abundant (by 33%) and smaller (by 47%) cysts Polycystic kidney diseases (PKDs) are genetic disorders in than control mice. Neither tachyphylaxis nor apparent toxicity has which multiple cysts grow in kidneys, leading to end-stage been noted. Mambaquaretin-1 represents a promising therapeutic renal failure. Vasopressin antagonists (vaptans) currently used agent against PKDs. to treat PKDs have side effects due to liver toxicity. We report the characterization of Mambaquaretin-1, a Kunitz-fold j j polycystic kidney disease Kunitz peptide snake toxin polypeptide isolated from mamba venom that selectively and fully inhibits three major signaling pathways of the vaso- olycystic kidney diseases (PKDs) are potentially life-threat- pressin type-2 receptor. Mambaquaretin-1 induces a purely Pening genetic disorders that are characterized by the pres- aquaretic effect on mice and reduces cyst development in a ence of multiple fluid-filled cysts in the kidney. In PKDs, cyst for- mouse model. We produced mambaquaretin-1 by peptide syn- mation and enlargement progressively compromise normal renal thesis and determined its X-ray structure, its binding mode, parenchyma functions and with time severely distort the entire and functional properties. With high selectivity and without kidney, leading to end-stage renal failure (1). With an estimated toxic metabolic byproducts associated with its peptidic nature, prevalence of 1 in 1,000, autosomal-dominant PKD (ADPKD), mambaquaretin-1 could become the preferential treatment caused by mutations in either the polycystin-1 or polycystin-2 for these disorders. gene, is one of the most common monogenetic disorders affect- ing millions of people worldwide (2, 3). Autosomal-recessive Author contributions: E.A.S., B.M., C.M., R.W., and N.G. designed research; J.C., H.R., L.Q., PKD caused by mutations in the fibrocystin gene is 20 times less S.V., E.A.S., L.V., S.S., B.M., H.O., S.P., J.T., L.D., F.B., J.N., M.L., G.M., C.M., R.W., and N.G. performed research; J.C., H.R., L.Q., S.V., E.A.S., L.V., S.S., B.M., H.O., S.P., J.T., L.D., F.B., common than ADPKD and affects children in the first year of life J.N., M.L., G.M., C.M., R.W., and N.G. analyzed data; and J.C., L.Q., E.A.S., B.M., S.P., J.T., with a high mortality rate. No satisfactory therapy for PKDs has M.L., E.D.P., D.S., C.M., R.W., and N.G. wrote the paper. yet been developed despite huge efforts for more than 30 y. All of The authors declare no conflict of interest. the strategies, from microtubule stabilization with the antitumor This article is a PNAS Direct Submission. drug paclitaxel to the inhibition of either epidermal growth factor Data deposition: The atomic coordinates and structure factors have been deposited in receptor or B-Raf, MAPK/ERK, and mTOR kinases have failed the Protein Data Bank, www.pdb.org (PDB ID code 5M4V). to significantly improve the pathological state (4). A key advance 1 in ADPKD treatment has been the observation that in the poly- J.C. and H.R. contributed equally to this work. 2 cystic kidneys a pathogenic cAMP accumulation stimulates cell Present address: Department of Nephrology, University Hospital of Regensburg, 93053 Regensburg, Germany. proliferation and chloride-driven fluid secretion into cyst lumen 3Present address: Laboratory of Biomolecular Research, Division of Biology and Chem- (5, 6). The cAMP level can be reduced in two ways: through istry, Paul Scherrer Institute, 5232 Villigen, Switzerland. Gi-protein activation by the somatostatin SSTR2 receptor or, 4To whom correspondence may be addressed. Email: [email protected], christiane. alternatively, through type-2 vasopressin receptor (V2R) inhibi- [email protected], or [email protected]. tion that decreases Gs-protein signaling. Although both strate- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. gies appear to be effective in humans and constitute an efficient 1073/pnas.1620454114/-/DCSupplemental. 7154–7159 j PNAS j July 3, 2017 j vol. 114 j no. 27 www.pnas.org/cgi/doi/10.1073/pnas.1620454114 Downloaded by guest on September 24, 2021 a large randomized phase III clinical trial, tolvaptan was found A B 0,7 3 to slow down cyst development and renal insufficiency (8). B Since 2014, marketing authorization has been granted in Japan, 0,6 [AU] 0,5 2 NaCl [M] Canada, and four European countries (France, Germany, the 0,4 A C DEF United Kingdom, and Switzerland) and only more recently in the nm 280 0,3 J K 1 0,2 G H I United States, delayed because of concerns regarding its harm- Abs 0,1 ful effects on liver function. Indeed, tolvaptan degradation by 0 0 cytochrome P450 generates hepatotoxic metabolites (9). Addi- 0 2 4 6 8 10 12 14 16 tionally, because vaptans bind at a highly conserved orthosteric Time [min] site, common to all vasopressin-sensitive receptors, they have C D weak selectivity. 0,6 100 0,3 B 100 C Acetonitrile [%] 0,5 80 Acetonitrile [%] Venoms constitute a reservoir of millions of disulfide-rich D 80 [AU] 0,4 60 0,2 peptides, which are biochemically stable with particular phar- 0,3 60 [AU] 280 nm 280 B E 40 A nm 280 40 macological properties. Due to their high affinity and selectiv- 0,2 0,1 F 20 ity, polypeptides derived from venom of different animals are Abs 0,1 G A 20 Abs interesting alternatives to small nonpeptidic compounds for drug 0 0 0 0 development (11). Mamba snake venom contains toxins, such as 0 10203040506070 25 30 35 40 45 MT7, ρ-Da1b, and ρ-Da1a specific for GPCRs, able to modulate E Time [h] F Time [min] their functions in unique ways. MT7 acts as a negative allosteric 0,6 50 120 modulator of the M1 muscarinic receptor (12), ρ-Da1b is a hV1aR 0,5 46 Acetonitrile [%] 100 hOTR noncompetitive antagonist of the α2A-adrenoreceptor (13), and coinjecon hV1bR [AU] 0,4 42 80 ρ-Da1a is able to antagonize in an insurmountable way the α1A- 280 nm 280 0,3 synthec 60 38 hV2R adrenoreceptor (14). Marine cone snails are currently the only 0,2 40 Abs nave species known to secrete toxins active on vasopressin receptors. 0,1 34 20 These toxins mimic vasopressin with weak activity against the 0 30 0 V1a and V1b receptors (15, 16). Here we report the identifica- 17 18 19 20 21 -11 -10 -9 -8 -7 -6 -5 H-AVP bound (% of control) of (% bound H-AVP tion, 3D structure, and properties of mambaquaretin-1 discov- Time [min] 3 Log (ligand), M ered by screening green mamba venom.
Load more

Recommended publications
  • US EPA, Pesticide Product Label, A335.06,09/21/2020
    [Note to reviewer: [Text] in brackets denotes optional or explanatory language [Note to reviewer: {Text} in braces denotes where in the final label text will appear {BOOKLET FRONT PANEL LANGUAGE} S-METOLACHLOR GROUP 15 HERBICIDE METRIBUZIN GROUP 5 HERBICIDE FOMESAFEN GROUP 14 HERBICIDE A335.06[™] [Alternate Brand Name: Statler] [Herbicide for preemergent control of certain grasses and broadleaf weeds in Soybeans] ACTIVE INGREDIENTS: (% by weight) S-Metolachlor*………………………………………….……………………………………………………………………………..…………………… 36.29% Metribuzin**………………………………………….……………………………………………………………………………..………………………. 8.05% Fomesafen***………………………………………….……………………………………………………………………………..……………………... 7.16% OTHER INGREDIENTS: ……………………………………………………..…………………………………………………………………………….. 48.5% TOTAL …………………………………………………………………………………………………………….……………………………………………. 100.0% *contains 3.39 Ib of S-metolachlor per gallon **contains 0.75 Ib of metribuzin per gallon ***contains 0.67 Ib of fomesafen acid per gallon KEEP OUT OF REACH OF CHILDREN CAUTION Si usted no entiende la etiqueta, busque a alguien para que se la explique a usted en detalle. (If you do not understand the label, find someone to explain it to you in detail.) See [below] [inside label booklet] for [additional] [First Aid,] [Precautionary Statements] and [Directions for Use]. EPA Reg. No.: 91234-201 EPA Est. No.: Net Weight: Manufactured for: Atticus, LLC 5000 CentreGreen Way, Suite 100 Cary, NC 27513 1 {LANGUAGE INSIDE BOOKLET} FIRST AID If on skin or Take off contaminated clothing. clothing: Rinse skin immediately with plenty of water for 15-20 minutes. Call a poison control center or doctor for treatment advice. If swallowed: Call a poison control center or doctor immediately for treatment advice. Have person sip a glass of water if able to swallow. Do not induce vomiting unless told to do so by the poison control center or doctor.
    [Show full text]
  • Acetylcholinesterase — New Roles for Gate a Relatively Long Distance to Reach the Active Site, Ache Is One of the Fastest an Old Actor Enzymes14
    PERSPECTIVES be answered regarding AChE catalysis; for OPINION example, the mechanism behind the extremely fast turnover rate of the enzyme. Despite the fact that the substrate has to navi- Acetylcholinesterase — new roles for gate a relatively long distance to reach the active site, AChE is one of the fastest an old actor enzymes14. One theory to explain this phe- nomenon has to do with the unusually strong electric field of AChE. It has been argued that Hermona Soreq and Shlomo Seidman this field assists catalysis by attracting the cationic substrate and expelling the anionic The discovery of the first neurotransmitter — understanding of AChE functions beyond the acetate product15. Site-directed mutagenesis, acetylcholine — was soon followed by the classical view and suggest the molecular basis however, has indicated that reducing the elec- discovery of its hydrolysing enzyme, for its functional heterogeneity. tric field has no effect on catalysis16.However, acetylcholinesterase. The role of the same approach has indicated an effect on acetylcholinesterase in terminating From early to recent discoveries the rate of association of fasciculin, a peptide acetylcholine-mediated neurotransmission The unique biochemical properties and phys- that can inhibit AChE17. made it the focus of intense research for iological significance of AChE make it an much of the past century. But the complexity interesting target for detailed structure–func- of acetylcholinesterase gene regulation and tion analysis. AChE-coding sequences have recent evidence for some of the long- been cloned so far from a range of evolution- a Peripheral Choline binding site suspected ‘non-classical’ actions of this arily diverse vertebrate and invertebrate binding enzyme have more recently driven a species that include insects, nematodes, fish, site profound revolution in acetylcholinesterase reptiles, birds and several mammals, among Active site research.
    [Show full text]
  • Ce4less.Com Ce4less.Com Ce4less.Com Ce4less.Com Ce4less.Com Ce4less.Com Ce4less.Com
    Hallucinogens And Dissociative Drug Use And Addiction Introduction Hallucinogens are a diverse group of drugs that cause alterations in perception, thought, or mood. This heterogeneous group has compounds with different chemical structures, different mechanisms of action, and different adverse effects. Despite their description, most hallucinogens do not consistently cause hallucinations. The drugs are more likely to cause changes in mood or in thought than actual hallucinations. Hallucinogenic substances that form naturally have been used worldwide for millennia to induce altered states for religious or spiritual purposes. While these practices still exist, the more common use of hallucinogens today involves the recreational use of synthetic hallucinogens. Hallucinogen And Dissociative Drug Toxicity Hallucinogens comprise a collection of compounds that are used to induce hallucinations or alterations of consciousness. Hallucinogens are drugs that cause alteration of visual, auditory, or tactile perceptions; they are also referred to as a class of drugs that cause alteration of thought and emotion. Hallucinogens disrupt a person’s ability to think and communicate effectively. Hallucinations are defined as false sensations that have no basis in reality: The sensory experience is not actually there. The term “hallucinogen” is slightly misleading because hallucinogens do not consistently cause hallucinations. 1 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com How hallucinogens cause alterations in a person’s sensory experience is not entirely understood. Hallucinogens work, at least in part, by disrupting communication between neurotransmitter systems throughout the body including those that regulate sleep, hunger, sexual behavior and muscle control. Patients under the influence of hallucinogens may show a wide range of unusual and often sudden, volatile behaviors with the potential to rapidly fluctuate from a relaxed, euphoric state to one of extreme agitation and aggression.
    [Show full text]
  • Snap-On Industrial April 23, 1014 Page 1 Item Number Description
    Snap-on Industrial April 23, 1014 Unit of Item Number Description Net Price Measure 00000072E00 TURNTABLE VTA 1 SET 2 PC 550.27 Each 00000096000 DEPRESSOR ASSY-PEDAL 35.37 Each 00000129000 ALIGNMENT WHEEL STANDS 1309.19 Each 00001260000 TURNTABLE TRUCK 1 SET OF 2 1210.66 Each 00006310000 CONE-ADAPT. SET CAN USE 110612 300.54 Each 00043102Q00 ECONO 4-POST 172 7904.23 Each 00044218Q00 4 POST CLOSED CENTER 18K LIFT 22045.54 Each 00055502000 CLAMP ASSY-WHEEL,STEER 62.31 Each 00058839000 TOOL-PDQ WEIGHT PASS CAR 34.5 Each 00060466000 DUAL WHEEL SPACER 160.5 Each 00060779000 CONE-MEDIUM 9 1/2 DEG 82.1 Each 00060873000 CONE-TRUCK GRIND 241.29 Each 00060874000 SPACER-WHEEL TRUCK 173.82 Each 00064222000 REAR SLIPPLATES 483.82 Each 00066006000 LUBE BOTTLE 24.18 Each 00090488000 TRI TIPS/SETS SCREWS- 10 44.06 Each 00110560000 CONE-CENTERING 75-110MM HAWE 79.55 Each 00110612000 TRUCK CONE KIT 261.4 Each 00110614000 ADAPTER-UNILUG SEE REMARKS 538.16 Each 00112094000 OPTIONAL HVY DTY KIT 3.5 1456.61 Each 00112109000 DAYTON WHEEL ADAPTER 24 1033 Each 00112111000 4 ARM STAR QK ADPTR 702958178 889.5 Each 00112112000 5 ARM STAR QK ADPTR 702958179 942 Each 00112113000 4 TO 5 STAR UPDATE KT70295818 412.5 Each 00112292000 220.1MM HWKA 70BE958-008 321.54 Each 00112320000 DISC-220.8MM 70BE 958 007 448.33 Each 10002MRMHCDI TORQUE WRENCH 150-1000INLB 110.36 Each 10-01085A LOCK-N-ROLL LATCH 67 IN. 3.09 Each 10-01185A LOCK N ROLL LATCH FOR KRL1099 1.83 Each 1001XL36PV SLDG TRAY 21.45 Each 10-03783A TR DR SLVR EPLS 27.99 KRSC30 2.02 Each 10059 BEARING NEEDLE THRUST
    [Show full text]
  • Ion Channels
    UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties.
    [Show full text]
  • M4 Muscarinic Receptors Are Involved in Modulation of Neurotransmission at Synapses of Schaffer Collaterals on CA1 Hippocampal Neurons in Rats
    Journal of Neuroscience Research 87:691–700 (2009) M4 Muscarinic Receptors Are Involved in Modulation of Neurotransmission at Synapses of Schaffer Collaterals on CA1 Hippocampal Neurons in Rats Gonzalo Sa´nchez,1 Lucas de Oliveira Alvares,2,3 Marı´a Victoria Oberholzer,1 Bruna Genro,2 Jorge Quillfeldt,2 Jaderson Costa da Costa,3 Carlos Cerven˜ansky,4 Diana Jerusalinsky,1 and Edgar Kornisiuk1* 1Laboratorio de Neuroplasticidad y Neurotoxinas, Instituto de Biologı´a Celular y Neurociencias, Facultad de Medicina, Universidad de Buenos Aires y CONICET, Buenos Aires, Argentina 2Laborato´rio de Psicobiologia e Neurocomputac¸a˜o, Dep. de Biofisica, Instituto de Biocieˆncias, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil 3Laborato´rio de Neurocieˆncias, Instituto de Pesquisas Biome´dicas, Pontificia Universidade Cato´lica do Rio Grande do Sul, Porto Alegre, Brazil 4Instituto Pasteur de Montevideo e IIBCE, Montevideo, Uruguay All five subtypes of muscarinic acetylcholine receptors Key words: muscarinic acetylcholine receptor; CA1 (mAChR; M1–M5) are expressed in the hippocampus, synapses; long-term potentiation; rat hippocampus; where they are involved both in cognitive functions and muscarinic toxin 3 in synaptic plasticity, such as long-term potentiation (LTP). Muscarinic toxins (MTs) are small proteins from All five subtypes of muscarinic acetylcholine recep- mamba snake venoms that display exquisite discrimi- tors (mAChR; M1–M5; Bonner et al., 1987) are nation between mAChRs. MT1 acts as an agonist at expressed in the hippocampus
    [Show full text]
  • Antivenin Plants Used for Treatment of Snakebites in Uganda
    Omara et al. Tropical Medicine and Health (2020) 48:6 Tropical Medicine https://doi.org/10.1186/s41182-019-0187-0 and Health REVIEW Open Access Antivenin plants used for treatment of snakebites in Uganda: ethnobotanical reports and pharmacological evidences Timothy Omara1,2* , Sarah Kagoya3,4, Abraham Openy5, Tom Omute6, Stephen Ssebulime7, Kibet Mohamed Kiplagat8 and Ocident Bongomin9 Abstract Snakebite envenomation is a serious public health concern in rural areas of Uganda. Snakebites are poorly documented in Uganda because most occur in rural settings where traditional therapists end up being the first-line defense for treatment. Ethnobotanical surveys in Uganda have reported that some plants are used to antagonize the activity of various snake venoms. This review was sought to identify antivenin plants in Uganda and some pharmacological evidence supporting their use. A literature survey done in multidisciplinary databases revealed that 77 plant species belonging to 65 genera and 42 families are used for the treatment of snakebites in Uganda. The majority of these species belong to family Fabaceae (31%), Euphorbiaceae (14%), Asteraceae (12%), Amaryllidaceae (10%) and Solanaceae (10%). The main growth habit of the species is shrubs (41%), trees (33%) and herbs (18%). Antivenin extracts are usually prepared from roots (54%) and leaves (23%) through decoctions, infusions, powders, and juices, and are administered orally (67%) or applied topically (17%). The most frequently encountered species were Allium cepa, Carica papaya, Securidaca longipedunculata, Harrisonia abyssinica, and Nicotiana tabacum. Species with global reports of tested antivenom activity included Allium cepa, Allium sativum, Basella alba, Capparis tomentosa, Carica papaya, Cassia occidentalis, Jatropa carcus, Vernonia cinereal, Bidens pilosa, Hoslundia opposita, Maytensus senegalensis, Securinega virosa, and Solanum incanum.
    [Show full text]
  • Herbicide 900 Ml &
    SEE ENCLOSED PAMPHLET FOR FULL SIEN INGESLOTE PAMFLET VIR VOLLEDIGE PARTICULARS BESONDERHEDE Reg. No. L8525 (Act No. 36 of 1947) Reg. Nr. L8525 (Wet Nr. 36 van 1947) Namibian Reg No. N-AR 1572 Namibiese Reg. Nr. N-AR 1572 A suspension concentrate post- 'n Suspensie konsentraat na emergence herbicide for the control opkoms onkruiddoder vir die Herbicide of certain broadleaf and grass weeds beheer van sekere breëblaar- en A suspension concentrate post- in maize and sugarcane. grasonkruide in mielies en emergence herbicide for the suikerriet. control of certain broadleaf and grass weeds in maize and sugarcane. HERBICIDE GROUP CODE F2 ONKRUIDDODERGROEPKODE contains: Tembotrione (Triketone) and Isoxadifen-ethyl (Safener) Active ingredients: Aktiewe bestanddele: Tembotrione (Triketone)..........................420 g/l Tembotrione (Triketone).........................420 g/l Isoxadifen-ethyl (Safener).......................210 g/l Isoxadifen-etiel (Beveiliger)....................210 g/l REGISTERED BY / GEREGISTREER DEUR: Bayer (Pty) Ltd / (Edms) Bpk Reg. 1968/011192/07 P.O. Box/Posbus 143 Isando 1600 South Africa/Suid-Afrika TEL: (OFFICE HOURS) / (KANTOORURE) (011) 921 5911 IN CASE OF POISONING PLEASE PHONE / IN GEVAL VAN VERGIFTIGING SKAKEL: 0861555777 Laudis® is a registered trademark of the Bayer Group. Laudis® is ‘n geregistreerde handelsmerk van die Bayer Groep. © Bayer (Pty) Ltd Packaging / Verpakking: BATCH NUMBER: 900 ml & 5 L LOTNOMMER: See on pack DATE OF MANUFACTURE: Sien op houer HARMFUL DATUM VERVAARDIG: SKADELIK RSA/0318/Laudis 900ml/Sales Panel Code: 84951498D Herbicide WARNINGS: DO NOT GRAZE OR USE PLANTS AS FODDER FROM TREATED MAIZE WITHIN 70 DAYS OF LAST APPLICATION. DO NOT USE PLANTS AS FODDER FROM TREATED SUGARCANE WITHIN 235 DAYS OF LAST APPLICATION.
    [Show full text]
  • EMERGING DRUG TRENDS – 2014 Special Research Report • Regional Organized Crime Information Center
    EMERGING DRUG TRENDS – 2014 Special Research Report • Regional Organized Crime Information Center Emerging Drug Trends Table of Contents Opioid Abuse .................................................... 2 By ROCIC Publications Specialist Jennifer Adkins Opiate Abuse .................................................... 7 © Regional Organized Crime Information Center Synthetic Cathinones ..................................... 13 ew drugs are emerging at an unprecedented rate as manufacturers Synthetic Cannabinoids ................................. 18 of “legal high” products use new chemicals to replace those that Phenethlyamines ............................................ 22 N Party Pills ...................................................27 are banned. These new chemicals take the place of heroin, morphine, and amphetamines. These drugs are highly accessible, touted as legal, Herbal Drugs ..............................................29 Sources of Information ...............................32 and perceived as safe. This Special Research Report was supported by Grant No. 2011-RS-CX-K007, awarded by the Bureau of Justice Assistance, Office of Justice Programs, U.S. However, despite the popularity in designer drugs and legal high Department of Justice. The Office of Justice Programs also coordinates the activi- ties of the Bureau of Justice Statistics, the National Institute of Justice, the Office of products, the abuse of heroin and prescription painkiller medication Juvenile Justice and Delinquency, and the Office for Victims of Crime.
    [Show full text]
  • New Addictive Drugs
    Hemmat Ali Mohammed 9th April 2020, Done on 2nd April at 8:30 AM (Voodoo & Strox Assignment) New addictive drugs Synthetic cannabinoids (SC) are a new class of psychoactive substances, it is potent agonists of cannabinoid receptors, which mimic the psychoactive effects of the principal psychoactive component of cannabis. It is a drug with properties and effects similar to a known hallucinogen or narcotic but having a slightly altered chemical structure. SC are the widest and most diffused class of Novel Psychoactive Substances. History: 2005: Synthetic cannabinoids first emerged in Europe. 2009: Appeared in the United States, where it was marketed initially as “K2” and “Spice” and inhaled via a pipe or rolled into a cigarette. 2014: Two new drugs known as Strox and Voodoo have hit the Egyptian market. Street and commercial names for SC products: K2, Spice, Barely Legal, Black Mamba, Galaxy, Mojo, and Yucatan Fire. Voodoo: Voodoo is a mixture of herbs and spices that are sprayed with a synthetic compound that mimics the effects of (Tetrahydrocannabinol) THC. Voodoo spice is marketed as an herbal incense. It is a synthetic cannabinoid that is up to 100 times as powerful as natural marijuana. The most common brand is "Mister Nice Guy", which is sold in a small bag decorated with a smiley emoticon. The bag has a warning that reads “relaxing incense, not edible”. 1 Strox: Strox is popular synthetic cannabis in Egypt that consists of smokable herbal products laced with synthetic cannabinoids (THC) analogues. Strox is the Egyptian version of the Spice in which Atropa Belladonna, Datura or Hyposymus is used as plant matrix to be enhanced with unidentified synthetic cannabinoids.
    [Show full text]
  • Health Alert Movement 2019: Detroit Electronic Music Festival Hart Plaza Downtown Detroit May 25-28, 2019
    Health Alert Movement 2019: Detroit Electronic Music Festival Hart Plaza Downtown Detroit May 25-28, 2019 In this issue Updates for 2019 .............................................................................................................. 2 Prehospital Concerns ....................................................................................................... 3 Hospital Concerns ............................................................................................................ 4 THC .................................................................................................................................. 5 THC Homologs ................................................................................................................. 5 Stimulants......................................................................................................................... 7 Opioids ........................................................................................................................... 10 GABA-B .......................................................................................................................... 12 NMDA ............................................................................................................................. 13 Inhalants ......................................................................................................................... 14 Other Hallucinogens ......................................................................................................
    [Show full text]
  • 2021: Walker Farm Specialty Container Plants
    Walker Farm 2021 Specialty Plants Flower Name Flower Variety Comment Abutilon Linda Vista Peach upright w/ peach petals & red calyx Abutilon Mobile Pink soft pink blooms, darker veining; compact & prolific Abutilon Moonchimes large yellow blooms on dwarf flowering maple Abutilon savitzii striking variegated foliage;modern art; nice form Abutilon Star Sprite brilliant orange petals, darker orange veining & red calyx Abutilon pictum variegatum 'Thompsonii green & gold speckled leaves, orange blooms Abutilon x Apricot Glow 2 1/2" pale apricot flowers, sprawling habit Abutilon x Clementine upright shubby w/ coppery orange blooms Abutilon x Snowbell pure white bell shaped blooms, upright Acalypha wilkesiana Match-Me-If-You-Can mottled copper, red, gold in psychadelic flashback pattern Acorus aurea green & yellow striped blades Acorus Variegated aquatic plant, green leaves with creamy stripes Aechmea blacheliana Hawaii glowing bronze-orange foliage 3' x 3', great accent Agapanthus Midknight Blue deep rich blue blooms Agapanthus Purple Potion dramatic deep purple blooms Agastache Kudos Gold unusual yellow blooms all summer,fragrant foliage Agastache Kudos Mandarin warm orange blooms spring to fall,aromatic foliage Agastache Poquito Orange showy dense orange blooms all summer Ageratum Artist Blue fluffy blue-lavender blooms all summer Alocasia portidora huge leaves 3' x 6' on 6' stems Alocasia calodora Persian Palm bright green leaves, lightly striped stems Alstroemeria Colorita Diana yellow blooms with orange & brown stripes Alstroemeria Colorita
    [Show full text]