DOCSLIB.ORG

|H|||||||||| USOO5278143A United States Patent 19 11 Patent Number: 5,278,143 Shepro Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
|H|||||||||| USOO5278143A United States Patent 19 11 Patent Number: 5,278,143 Shepro Et Al |H|||||||||| USOO5278143A United States Patent 19 11 Patent Number: 5,278,143 Shepro et al. (45) Date of Patent: Jan. 11, 1994 (54) PROPHYLACTIC AND THERAPEUTIC OTHER PUBLICATIONS METHODS FOR TREATING NTER LEUKIN-MEDIATED EDEMAS Rudinger, Peptide Hormones, Parsons (Ed.) U. Park t Press, Baltimore, pp. 1-7 (1976). (75) Inventors: David Shepro, Boston, Mass.; J. Doukas et al., Blood, vol. 69, No. 6 pp. 1563-1569 (Jun. Steven Alexander, Nashville, Tenn. 1987). Frimmer, Chem. Abstracts, vol. 71, No. 99937m (1969). 73) Assignee: Trustees of Boston University, Wieland et al., Crit. Rev. Biochem. vol. 5, pp. 185-260 Boston, Mass. (1978). (21) Appl. No.: 807,668 Welbournet al., J. Appl. Physiol 70: 1364-1368 (1991). 22 illed: Dec. 16, 1991 Primary Examiner-Y. Christina Chan 22 Filed ec. 10, Attorney, Agent, or Firm-David Prashker Related U.S. Application Data 57 ABSTRACT m 63 continuation of ser. No. 416,905, Oct. 4, 1989, aban- Unique methods for treating interleukin-mediated ede doned, which is a continuation-in-part of Ser. No. mas in living subjects are provided comprising adminis 47,121, Oct. 4, 1989, abandoned, and a continuation- tering an effective amount of a composition selected in-part of Ser. No. 185,650, Apr. 25, 1988, abandoned. from the group consisting of phallotoxins, phallotoxin analogues, antamanide, or an antananide analogue to 51 Int. Cl. ........................ A61K 37/02; CK /6 the subject. The methods offer prophylactic and thera 52 576.5/35567; 17,353 peutic modes of treatment for both localized and sys s s 8 temic interleukin-mediated edemas. The compositions 58) Field of Search .................... 530/317,321; 514/9, of choice may be applied topically or given parenter 514/11, 870, 922; 424/85.2 ally; and may be employed with other diverse agents for (56) References Cited treatment of both inflammatory and non-inflammatory edemas. U.S. PATENT DOCUMENTS 4,690,915 9/1987 Rosenberg .............................. 514/2 7 Claims, 3 Drawing Sheets U.S. Patent Jan. 11, 1994 Sheet 1 of 3 5,278,143 ** 3: SIG. OIFF. FROM CONTROL SALINE (P<0.5, P<0.0) RESPECTIVELY ) ava SIG. DIFF. FROM IL-2 106 U/M 1 (P<0.05, PCO,O RESPECTIVELY) E at m - - a de e C C UMd a UM (V) MD GMD N. a. N N N a N. Cn N. cn (N ad - - ON t C l - - ad 3 - A. a with P O sed - n - a 5 MD Mo CM) N EA. S SQ s -N Nup CN NN CN and a 22 - b A. a es Ee S2 U.S. Patent Jan. 11, 1994 Sheet 2 of 3 5,278,143 3,3:3: SIG. DIFF. FRON CONTROL SALINE (P<0.05, P & O. O. RESPECTIVELY ) -- ~ SIC. DIFF. FRON IL-2 IO 6U/M (P<0.05, PCOO RESPECTIVELY i FIG. 3 i F G. 4. U.S. Patent Jan. 11, 1994 Sheet 3 of 3 5,278,143 %,3+ SIG. DIFF. FROM CONTROL SALINE (P<0.05, PCOO RESPECTIVELY ) ava SIG. Diff. FROM IL-20 6U/M (P<0.05, P&O.O RESPECTIVELY ) 5 a r 4 s 2250 2000 750 500 250 000 d ae CSS C S CC C C C CC S.C 750 C C S. O C C C C3 CC SS C 500 O C C SSC C 250 C 33. C 3. 3. SALNE SNE pRobinS SSs froE CONTROL IL-2 L-2 IL-2 FIG.6 TREATMENT 5,278,143 1 2 ter "nm') in radius or by slits about 8 nm wide. There is PROPHYLACTIC AND THERAPEUTICMETHODS also believed to be a system of larger sized pores about FOR TREATING INTERLEUKIN-MEDIATED 25 nm in radius which accounts for the small quantities EDEMAS of protein and other large solutes that normally cross the endothelial wall barrier. GOVERNMENTAL SUPPORT A variety of different disturbances can induce a con Research support for the present invention was pro dition of edema. These include: an elevated venous vided by a grant from the Community Technology hydrostatic pressure which may be caused by thrombo Foundation of Boston, University. sis of a vein or any other venous obstruction; hypopro This application is a continuation of application Ser. 10 teinemia with reduced plasma oncotic pressure result No. 416,905, filed Oct. 4, 1989, now abandoned; which ing from either inadequate synthesis or increased loss of is a continuation-in-part of U.S. patent application Ser. albumin; increased osmotic pressure of the interstitial No. 185,650 filed Apr. 25, 1988 now abandoned; and a fluid due to abnormal accumulation of sodium in the continuation-in-part of copending U.S. patent applica body because renal excretion of sodium cannot keep tion Ser. No. 417,121, filed Oct. 4, 1989, now aban 5 pace with the intake; failure of the lymphatics to re doned. move fluid and protein adequately from the interstitial space; an increased capillary permeability to fluids and FIELD OF THE INVENTION proteins as occurs in the inflammatory response to tissue The present invention is concerned with inflamma injury; an increased mucopolysaccharide content tory and non-inflammatory (hydraulic) associated ede 20 within the interstitial spaces; and an iatrogennic induced mas and is particularly directed to prophylactic and or mediated increase or accumulation of fluid and pro therapeutic methods for treating localized and systemic tein resulting from the administration of a pharmacolog edemas caused or mediated by interleukins. ically active lymphokine during the course of treatment BACKGROUND OF THE INVENTION by a physician or surgeon. This last-identified distur 25 bance merits a more detailed examination in view of Edema is the term generally used to describe the recent developments in immunotherapy. accumulation of excess fluid in the intercellular (inter Lymphokines comprise a broad class of biologically stitial) tissue spaces or body cavities. Edema may occur active substances which are secreted by various types of as a localized phenomenon such as the swelling of a leg lymphocytes in-vivo and in-vitro, especially by differ. when the venous outflow is obstructed; or it may be 30 ent populations of T-cell lymphocytes. Perhaps the systemic as in congestive heart failure or renal failure. When edema is severe and generalized, there is diffuse most controversial presently is the family of interleu swelling of all tissues and organs in the body and partic kins, which presently comprises: Interleukin-1 (“IL-1") ularly pronounced areas are given their own individual involved in the activation of resting T-cells; Interleukin names. For example, collection of edema in the perito 35 2 ("IL-2') which mediates the proliferation of T-cells neal cavity is known as "ascites'; accumulations of fluid and induces cytotoxic activity in T-cells; Interleukin-3 in the pleural cavity are termed "hydrothorax'; and ("IL-3') which causes the proliferation of mast cells edema of the pericardial sac is termed "pericardial effu and granulocytes; Interleukin-4 ("IL-4') which medi sion' or "hydropericardium'. Non-inflammatory ates the proliferation, activation, and differentiation of edema fluid such as accumulates in heart failure and B-cells, T-cells, and natural killer cells; and Interleukin renal disease is protein poor and referred to as a "transu 6 ("IL-6”) which induces the growth and differentiation date'. In contrast, inflammatory edema related to in of B-cells and T-cells Spits et al., J. Immunol. 139:1142 creased endothelial permeability is protein rich and is (1987); Kawakami et al., J. Exp. Med 168:2183 (1988); caused by the escape of plasma proteins (principally Spits et al., J. Immunol. 141:29 (1988); and Tartakovsky albumin) and polymorphonuclear leukocytes (hereinaf 45 et al., J. Immunol. 141:3863 (1983)). ter "PMNs') to form an exudate. Of particular interest is Interleukin-2 ("IL-2') and its Edena, whether inflammatory or non-inflammatory analogues whose isolation, chemical formulation and in nature, is thus an abnormality in the fluid balance structure, and synthesis by conventional wet chemis within the microcirculation which includes the small tries and by recombinant DNA techniques have been arterioles, capillaries, and post-capillary venules of the 50 intensively pursued see for example U.S. Pat. Nos. circulatory system. Normal fluid balance and exchange 4,490,289; 4,138,927; 4,569,790; 4,578,335; 4,761,375; is critically dependent on the presence of an intact and 4,518,584; 4,604,377; 4,564,593; and the references cited metabolically active endothelium within the vascula therein). The use of Interleukin-2 as a therapeutic com ture. Normal endothelium is a thin, squamous epit position has followed two very different approaches. belium adapted to permit free, rapid exchange of water 55 The first line of development is exemplified by the IL-2 and small molecules between plasma and interstitium; immunotherapy technique for treating cancers origi but one which limits the passage of plasma proteins with nated by Dr. Steven A. Rosenberg Rosenberg, S.A., increases in protein size. Immuno. Today 9:58-62 (1988) and the references cited The endothelial lining of all arterioles and venules, therein). That approach involves the removal of lym and most capillaries in the body, is of the continuous phoid cells from a tumor-bearing host; an in-vitro ex type, having an unbroken cytoplasmic layer with pansion of the host's cells by culture in Interleukin-2 closely apposed intercellular junctions. Physiological containing culture media to produce lymphokine studies Renkin, E., Circ. Res. 41:735-743 (1977); Ren activated killer ("LAK') cells; and a re-introduction of kin, E., ACTA Physiol. Scand. (Suppl.) 463:81 (1979); the LAK cell culture into the living host accompanied Bottaro et al., Microvasc.
Load more

Recommended publications
  • Thesis Is Presented for the Degree of Doctor of Philosophy of Curtin University of Technology
    School of Biomedical Sciences Analysis of Candidate Genes within the 3p14-p22 Region of the Human Genome for Association with Bone Mineral Density Phenotypes Benjamin H Mullin This thesis is presented for the Degree of Doctor of Philosophy of Curtin University of Technology February 2011 To the best of my knowledge and belief this thesis contains no material previously published by any other person except where due acknowledgment has been made. This thesis contains no material which has been accepted for the award of any other degree or diploma in any university. Preface The experimental work contained within this thesis was performed in the Department of Endocrinology & Diabetes at Sir Charles Gairdner Hospital under the supervision of Doctor Cyril Mamotte, Associate Professor Scott Wilson, and Professor Richard Prince. All experimental work in this thesis was performed by myself unless otherwise stated. Benjamin H. Mullin, B.Sc. Publications arising from this thesis Mullin, B. H., Prince, R. L., Dick, I. M., Hart, D. J., Spector, T. D., Dudbridge, F. & Wilson, S. G. 2008. Identification of a role for the ARHGEF3 gene in postmenopausal osteoporosis. American Journal of Human Genetics , 82 , 1262-9. Mullin, B. H., Prince, R. L., Mamotte, C., Spector, T. D., Hart, D. J., Dudbridge, F. & Wilson, S. G. 2009. Further genetic evidence suggesting a role for the RhoGTPase-RhoGEF pathway in osteoporosis. Bone , 45 , 387-91. Research grants received during completion of this thesis Wilson, S. G., Prince, R. L., Mamotte C., Mullin B. H. 2008. Influence of the ARHGEF3 gene on bone phenotypes. Arthritis Australia Project Grant ($14,500).
    [Show full text]
  • Peptide Chemistry up to Its Present State
    Appendix In this Appendix biographical sketches are compiled of many scientists who have made notable contributions to the development of peptide chemistry up to its present state. We have tried to consider names mainly connected with important events during the earlier periods of peptide history, but could not include all authors mentioned in the text of this book. This is particularly true for the more recent decades when the number of peptide chemists and biologists increased to such an extent that their enumeration would have gone beyond the scope of this Appendix. 250 Appendix Plate 8. Emil Abderhalden (1877-1950), Photo Plate 9. S. Akabori Leopoldina, Halle J Plate 10. Ernst Bayer Plate 11. Karel Blaha (1926-1988) Appendix 251 Plate 12. Max Brenner Plate 13. Hans Brockmann (1903-1988) Plate 14. Victor Bruckner (1900- 1980) Plate 15. Pehr V. Edman (1916- 1977) 252 Appendix Plate 16. Lyman C. Craig (1906-1974) Plate 17. Vittorio Erspamer Plate 18. Joseph S. Fruton, Biochemist and Historian Appendix 253 Plate 19. Rolf Geiger (1923-1988) Plate 20. Wolfgang Konig Plate 21. Dorothy Hodgkins Plate. 22. Franz Hofmeister (1850-1922), (Fischer, biograph. Lexikon) 254 Appendix Plate 23. The picture shows the late Professor 1.E. Jorpes (r.j and Professor V. Mutt during their favorite pastime in the archipelago on the Baltic near Stockholm Plate 24. Ephraim Katchalski (Katzir) Plate 25. Abraham Patchornik Appendix 255 Plate 26. P.G. Katsoyannis Plate 27. George W. Kenner (1922-1978) Plate 28. Edger Lederer (1908- 1988) Plate 29. Hennann Leuchs (1879-1945) 256 Appendix Plate 30. Choh Hao Li (1913-1987) Plate 31.
    [Show full text]
  • Phalloidin, Amanita Phalloides
    Phalloidin, Amanita phalloides sc-202763 Material Safety Data Sheet Hazard Alert Code EXTREME HIGH MODERATE LOW Key: Section 1 - CHEMICAL PRODUCT AND COMPANY IDENTIFICATION PRODUCT NAME Phalloidin, Amanita phalloides STATEMENT OF HAZARDOUS NATURE CONSIDERED A HAZARDOUS SUBSTANCE ACCORDING TO OSHA 29 CFR 1910.1200. NFPA FLAMMABILITY1 HEALTH4 HAZARD INSTABILITY0 SUPPLIER Company: Santa Cruz Biotechnology, Inc. Address: 2145 Delaware Ave Santa Cruz, CA 95060 Telephone: 800.457.3801 or 831.457.3800 Emergency Tel: CHEMWATCH: From within the US and Canada: 877-715-9305 Emergency Tel: From outside the US and Canada: +800 2436 2255 (1-800-CHEMCALL) or call +613 9573 3112 PRODUCT USE Toxic bicyclic heptapeptide (a member of the family of phallotoxins) isolated from the green mushroom, Amanitra phalloides Agaricaceae (the green death cap or deadly agaric). Binds to polymeric actin, stabilising it and interfering with the function of endoplasmic reticulum and other actin-rich structures. NOTE: Advice physician prior to working with phallotoxins. Prepare Emergency procedures. SYNONYMS C35-H48-N8-O11-S, phalloidine, "Amanita phalloides Group I toxin", "Amanita phalloides Group I toxin", "mushroom (green death cap/ deadly agaric) phallotoxin/ peptide", "cyclopeptide/ bicyclic bioactive heptapeptide" Section 2 - HAZARDS IDENTIFICATION CANADIAN WHMIS SYMBOLS EMERGENCY OVERVIEW RISK Very toxic by inhalation, in contact with skin and if swallowed. POTENTIAL HEALTH EFFECTS ACUTE HEALTH EFFECTS SWALLOWED ■ Severely toxic effects may result from the accidental ingestion of the material; animal experiments indicate that ingestion of less than 5 gram may be fatal or may produce serious damage to the health of the individual. ■ At sufficiently high doses the material may be hepatotoxic(i.e.
    [Show full text]
  • Rapid, Sensitive, and Accurate Point-Of-Care Detection of Lethal Amatoxins in Urine
    toxins Article Rapid, Sensitive, and Accurate Point-of-Care Detection of Lethal Amatoxins in Urine Candace S. Bever 1 , Kenneth D. Swanson 2, Elizabeth I. Hamelin 2 , Michael Filigenzi 3 , Robert H. Poppenga 3, Jennifer Kaae 4, Luisa W. Cheng 1,* and Larry H. Stanker 1 1 Foodborne Toxin Detection and Prevention Research Unit, Western Regional Research Center, Agricultural Research Service, United States Department of Agriculture, 800 Buchanan Street, Albany, CA 94710, USA; [email protected] (C.S.B.); [email protected] (L.H.S.) 2 Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA; [email protected] (K.D.S.); [email protected] (E.I.H.) 3 California Animal Health and Food Safety Laboratory System, University of California, 620 West Health Sciences Drive, Davis, CA 95616, USA; msfi[email protected] (M.F.); [email protected] (R.H.P.) 4 Pet Emergency and Specialty Center of Marin, 901 E. Francisco Blvd, San Rafael, CA 94901, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-510-559-6337 Received: 30 January 2020; Accepted: 12 February 2020; Published: 15 February 2020 Abstract: Globally, mushroom poisonings cause about 100 human deaths each year, with thousands of people requiring medical assistance. Dogs are also susceptible to mushroom poisonings and require medical assistance. Cyclopeptides, and more specifically amanitins (or amatoxins, here), are the mushroom poison that causes the majority of these deaths. Current methods (predominantly chromatographic, as well as antibody-based) of detecting amatoxins are time-consuming and require expensive equipment. In this work, we demonstrate the utility of the lateral flow immunoassay (LFIA) for the rapid detection of amatoxins in urine samples.
    [Show full text]
  • Poisonous Mushrooms; a Review of the Most Common Intoxications A
    Nutr Hosp. 2012;27(2):402-408 ISSN 0212-1611 • CODEN NUHOEQ S.V.R. 318 Revisión Poisonous mushrooms; a review of the most common intoxications A. D. L. Lima1, R. Costa Fortes2, M. R.C. Garbi Novaes3 and S. Percário4 1Laboratory of Experimental Surgery. University of Brasilia-DF. Brazil/Paulista University-DF. Brazil. 2Science and Education School Sena Aires-GO/University of Brasilia-DF/Paulista University-DF. Brazil. 3School of Medicine. Institute of Health Science (ESCS/FEPECS/SESDF)/University of Brasilia-DF. Brazil. 4Institute of Biological Sciences. Federal University of Pará. Brazil. Abstract HONGOS VENENOSOS; UNA REVISIÓN DE LAS INTOXICACIONES MÁS COMUNES Mushrooms have been used as components of human diet and many ancient documents written in oriental coun- Resumen tries have already described the medicinal properties of fungal species. Some mushrooms are known because of Las setas se han utilizado como componentes de la their nutritional and therapeutical properties and all over dieta humana y muchos documentos antiguos escritos en the world some species are known because of their toxicity los países orientales se han descrito ya las propiedades that causes fatal accidents every year mainly due to medicinales de las especies de hongos. Algunos hongos misidentification. Many different substances belonging to son conocidos por sus propiedades nutricionales y tera- poisonous mushrooms were already identified and are péuticas y de todo el mundo, algunas especies son conoci- related with different symptoms and signs. Carcino- das debido a su toxicidad que causa accidentes mortales genicity, alterations in respiratory and cardiac rates, cada año, principalmente debido a errores de identifica- renal failure, rhabidomyolisis and other effects were ción.
    [Show full text]
  • Foto M. Illice
    A.M.B. Centro Studi Micologici (Foto M. Illice) 1 A.M.B. Centro Studi Micologici Comitato di Gestione: Direttore: Carlo Papetti Segretario: Mario Manuzzato A.M.B. FondazioneA.M.B. - Fondazione Bibliotecario: Mario Mariotto Curatore dell'Erbario: Gianfranco Centro Studi Micologici Medardi Rapporti con il C.S.N.: P.O. Box n° 292 - IT - 36100 VICENZA Emanuele Campo c.s.m. Vicedirettore: Gianfranco Gasparini Associazione Micologica Bresadola - via A. Volta, 46 - IT 38123 Trento. www.ambbresadola.it - E-mail: [email protected] 6° Convegno Internazionale di Micotossicologia I Funghi: sicurezza alimentare, alimenti, integratori Associazione Micologica Bresadola “Fondazione Centro Studi Micologici” Commissione Micotossicologia 6° Convegno Internazionale di Micotossicologia 23-24 novembre 2018 Hotel Quattro Torri - Via Corcianese, 260 - Perugia SEGRETERIA SCIENTIFICA 2 PAGINE DI MICOLOGIA K. Kob - Gruppo AMB di Bolzano E-mail: [email protected] O. Tani - Gruppo AMB di Cesena E-mail: [email protected] N. Sitta - Gruppo AMB di Pergine Valsugana (TN) E- mail: [email protected] P. Davoli E-mail: [email protected] G. Antenhofer E-mail: [email protected] O. Petrini E-mail: [email protected] SEGRETERIA ORGANIZZATIVA G. Visentin - Segretario AMB E- mail: [email protected] C. Papetti - Direttore Centro Studi Micologici dell’AMB E-mail: [email protected] COMMISSIONE MICOTOSSICOLOGIA CSM-AMB K. Kob - E-mail: [email protected] O. Tani - E-mail: [email protected] N. Sitta - E-mail: [email protected] P. Davoli - E-mail: paolo- [email protected] G. Visentin - E-mail: [email protected] 3 A.M.B. Centro Studi Micologici 6° Convegno Internazionale di Micotossicologia la commestibilità dei funghi: miti e malintesi DeniS r BenjaMin B.SC., M.B., B.Ch.
    [Show full text]
  • The Effect of a High-Resolution Accurate Mass Spectrometer On
    GÜFBED/GUSTIJ (2020) 10 (4): 878-886 Gümüşhane Üniversitesi Fen Bilimleri Enstitüsü Dergisi DOI: 10.17714/gumusfenbil.680816 Araştırma Makalesi / Research Article The Effect of A High-Resolution Accurate Mass Spectrometer On Simultaneous Multiple Mushroom Toxin Detection Yüksek Çözünürlüklü Kütle Spektrometrenin Eşzamanlı Çoklu Mantar Toksin Tayinleri Üzerindeki Etkisi Yasemin NUMANOĞLU ÇEVİK*1,2,a 1MoH, Turkish Public Health General Directorate, Microbiology Reference Laboratory, Adnan Saygun Street 55, 06100 Sıhhıye, Ankara, TURKEY 2Separation Science Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 S4-Bis, 9000 Gent, Belgium • Geliş tarihi / Received: 29.01.2020 • Düzeltilerek geliş tarihi / Received in revised form: 17.06.2020 • Kabul tarihi / Accepted: 02.07.2020 Abstract Amatoxins are deadly wild mushroom toxins that cause severe poisoning in humans, from diarrhea to organ dysfunction. Mortality can be as high as 80% if no specific treatment is applied. In this study, separation and determination methods were developed for the simultaneous determination of 7 toxins belonging to Amanita phalloides. After extraction and purification of Amanita phalloides (death cap) wild mushrooms, toxins were detected using HPLC- ESI MS and exact mass with time of flight MS (TOF-MS) in positive ionization mode. In addition, it was observed that the toxins of α- and β-amanitine could be differentiated from each other thanks to HR-MS detection in case of their close retention (Rt) in LC. The presence of two toxins at the same retention point in the chromatogram was detected by differentiating the molecular ion mass (920.3514 DA) of the α-amanitine with the HR-MS (920.3696 DA).
    [Show full text]
  • Amanita Phalloides Poisoning: Mechanisms of Toxicity and Treatment
    Food and Chemical Toxicology 86 (2015) 41–55 Contents lists available at ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox Review Amanita phalloides poisoning: Mechanisms of toxicity and treatment Juliana Garcia a,∗, Vera M. Costa a, Alexandra Carvalho b, Paula Baptista c,PaulaGuedesde Pinho a, Maria de Lourdes Bastos a, Félix Carvalho a,∗∗ a UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua José Viterbo Ferreiran° 228, 4050-313 Porto, Portugal b Department of Cell and Molecular Biology, Computational and Systems Biology, Uppsala University, Biomedical Center, Box 596, 751 24 Uppsala, Sweden c CIMO/School of Agriculture, Polytechnique Institute of Bragança, Campus de Santa Apolónia, Apartado 1172, 5301-854 Bragança, Portugal article info abstract Article history: Amanita phalloides, also known as ‘death cap’, is one of the most poisonous mushrooms, being involved Received 10 April 2015 in the majority of human fatal cases of mushroom poisoning worldwide. This species contains three main Received in revised form 8 September 2015 groups of toxins: amatoxins, phallotoxins, and virotoxins. From these, amatoxins, especially α-amanitin, Accepted 10 September 2015 are the main responsible for the toxic effects in humans. It is recognized that α-amanitin inhibits RNA Available online 12 September 2015 polymerase II, causing protein deficit and ultimately cell death, although other mechanisms are thought Keywords: to be involved. The liver is the main target organ of toxicity, but other organs are also affected, especially Amanita phalloides the kidneys. Intoxication symptoms usually appear after a latent period and may include gastrointestinal Amatoxins disorders followed by jaundice, seizures, and coma, culminating in death.
    [Show full text]
  • 5° Convegno Internazionale Di Micotossicologia
    PAGINE DI MICOLOGIA 5° Convegno Internazionale di Micotossicologia Funghi e salute: problematiche cliniche, igienico-sanitarie, ecosistemiche, normative e ispettive, legate alla globalizzazione commerciale Associazione Micologica Bresadola “Fondazione Centro Studi Micologici” Commissione Micotossicologia In collaborazione con: Centro Antiveleni di Milano Provincia di Milano Con il Patrocinio di: Istituto Superiore per la Protezione e la Ricerca Ambientale - ISPRA Ministero dell’Ambiente, della Tutela del Territorio e del Mare - MATTM 1 PdM 37.pmd 1 14/01/17, 11.45 A.M.B. Centro Studi Micologici 5° Convegno Internazionale di Micotossicologia 3-4 dicembre 2012 Centro Congressi Provincia di Milano Via Corridoni, 16 - Milano SEGRETERIA SCIENTIFICA L. Cocchi - Gruppo Franchi - AMB di Reggio Emilia E-mail: [email protected] C. Siniscalco - ISPRA/GMEM-AMB E-mail: [email protected] SEGRETERIA ORGANIZZATIVA G. Visentin - Segretario AMB E-mail: [email protected] P. Follesa - Comitato scientifico AMB E-mail: [email protected] C. Converso - Provincia di Milano E-mail: [email protected] COMMISSIONE MICOTOSSICOLOGIA CSM-AMB O. Tani - E-mail: [email protected] E. Borghi - E-mail: [email protected] E. Brunelli - E-mail:[email protected] L. Cocchi - E-mail: [email protected] P. Follesa - E-mail: [email protected] A. Granziero - E-mail: [email protected] K. Kob - E-mail: [email protected] C. Siniscalco - E-mail: [email protected] G. Visentin - E-mail: [email protected] 2 PdM 37.pmd 2 14/01/17, 11.45 PAGINE DI MICOLOGIA 5° Convegno Internazionale di Micotossicologia PROGRAMMA SCIENTIFICO 3 dicembre 2012 8.30 Registrazione dei partecipanti 9.00 Apertura dei lavori - saluto delle Autorità: N.U.
    [Show full text]
  • Detection of Α-, Β-, and Γ-Amanitin in Urine by LC-MS/MS Using 15 N10-Α-Amanitin As the Internal Standard
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Toxicon Manuscript Author . Author manuscript; Manuscript Author available in PMC 2019 September 15. Published in final edited form as: Toxicon. 2018 September 15; 152: 71–77. doi:10.1016/j.toxicon.2018.07.025. Detection of α-, β-, and γ-amanitin in urine by LC-MS/MS using 15 N10-α-amanitin as the internal standard Nicole L. Abbotta, Kasey L. Hillb, Alaine Garrettc, Melissa D. Carterb, Elizabeth I. Hamelinb,*, and Rudolph C. Johnsonb a.Battelle Memorial Institute at the Centers for Disease Control and Prevention, Atlanta, GA, USA b.Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA c.Oak Ridge Institute of Science and Education Fellow at the Centers for Disease Control and Prevention, Atlanta, USA Abstract The majority of fatalities from poisonous mushroom ingestion are caused by amatoxins. To prevent liver failure or death, it is critical to accurately and rapidly diagnose amatoxin exposure. We have developed an liquid chromatography tandem mass spectrometry method to detect α-, β-, and γ-amanitin in urine to meet this need. Two internal standard candidates were evaluated, 15 including an isotopically labeled N10-α-amanitin and a modified amanitin methionine sulfoxide 15 synthetic peptide. Using the N10-α-amanitin internal standard, precision and accuracy of α- amanitin in pooled urine was ≤5.49% and between 100–106%, respectively, with a reportable range from 1–200 ng/mL. β- and γ-Amanitin were most accurately quantitated in pooled urine using external calibration, resulting in precision ≤17.2% and accuracy between 99 – 105% with calibration ranges from 2.5–200 ng/mL and 1.0–200 ng/mL, respectively.
    [Show full text]
  • Identification of Forensically Relevant Oligopeptides of Poisonous Mushrooms with Capillary Electrophoresis-ESI-Mass Spectrometry
    Identification of forensically relevant oligopeptides of poisonous mushrooms with capillary electrophoresis-ESI-mass spectrometry J. Rittgen, M. Pütz, U. Pyell Abstract Over 90% of the lethal cases of mushroom toxin poisoning in man are caused by a species of Amanita. They contain the amatoxins α-, β-, γ- and ε-amanitin, amanin and amanullin together with phallotoxins and virotoxins. The identification of the named toxicants in intentionally poisoned samples of foodstuff and beverages is of significant forensic interest. In this work a CE-ESI-MS procedure was developed for the separation of five forensically relevant oligopeptides including α-, β- and γ-amanitin, phalloidin and phallacidin. The running buffer consisted of 20 mmol/l ammonium formate at pH 10.8 and 10% (v/v) isopropanol. Dry nitrogen gas was delivered at 4 l/min at 250°C. The pressure of nebulizing nitrogen gas was set at 4 psi. The sheath liquid was isopropanol/water (50:50, v/v) at a flow rate of 3 µl/min. A mass range between 600 and 1000 m/z and negative as well as positive polarity detection mode was selected. The separation of the five negatively charged analytes was achieved at 23°C within 8 min using a high voltage of + 28 kV. The method validation included the determination of the detection limits (10 – 40 ng/ml) and the repeatability of migration time (0.2 – 0.3% RSD). The CE-MS procedure was successfully applied for the identification of amatoxins and phallotoxins in extracts of fresh and dried mushroom samples. 1. Introduction Over 90% of the lethal cases of mushroom toxin poisoning in man are caused by a species of Amanita [1].
    [Show full text]
  • The Toxic Peptides from Amanita Mushrooms
    INVITED REVIEW In?. J. Peptideprotein Res. 22,1983,251-216 The toxic peptides from Amanita mushrooms THEODOR WIELAND Max-Planck-Institute for Medical Research, Heidelberg, West Germany Received 13 December 1982, accepted for publication 15 January 1983 The results of 50 years of effort in the chemistry of Amanita toxins are reviewed. The phallotoxins, fast acting components, but not responsible for fatal intoxi- cations after ingestion, are bicyclic heptapeptides. They combine with F-actin, stabilizing this protein against several destabilizing influences. The virotoxins likewise fast acting are monocyclic heptapeptides. The amatoxins which are the real toxins lead to death within several days by inhibiting the enzymatic synthesis of m-RNA. They are bicyclic octapeptides. The‘ structures of all of these com- pounds are described, as well as conformations, chemical reactions and modifi- cations, syntheses and correlations between structures and biological activities. Key words: amatoxins; cyclic peptides; peptide thioethers; phallotoxins; tryptathionine; virotoxins Heinrich Wieland (photograph), born in 1877, was one of the most productive and versatile chemists during the first part of this century. In the thirties, at his institute the Chemical Laboratory of the Bavarian Academy of Science at Munich, Germany, students and post doctorals worked on such different themes as steroids, pigments of butterflies, tocd and snake venoms, radical reacfions, strychnos alkaloids, alkaloids from _calabash curare and mechanism of biological oxidation. Natural substances that had any striking properties were of interest. 50 years of Amanita research In the early thirties, H. Wieland suggested to Hans A. Raab that he attempt the isolation of the poisonous principal of the most danger- ous mushroom Amanita phalloides, “der griine Knollenblatterpilz”, whose erroneous ingestion yearly accounted for numerous victims.
    [Show full text]