6,786
Views
51
CrossRef citations to date
0
Altmetric
Reviews

Fatalities caused by novel opioids: a review

ORCID Icon
Pages 95-110 | Received 05 Dec 2017, Accepted 09 Mar 2018, Published online: 07 May 2018

References

  • World Drug Report 2017. Vienna: United Nations; 2017 [cited 2017 September 16]. Available from: http://www.unodc.org
  • Pichini S, Solimini R, Berretta P, et al. Acute intoxications and fatalities from illicit fentanyl and analogues: an update. Ther Drug Monit. 2018;40:38–51.
  • Armenian P, Vo KT, Barr-Walker J, et al. Fentanyl, fentanyl analogs and novel synthetic opioids: a comprehensive review. Neuropharmacology. 2017. doi: 10.1016/j.neuropharm.2017.10.016
  • Ventura L, Carvalho F, Dinis-Oliveira RJ. Opioids in the frame of new psychoactive substances network: a complex pharmacological and toxicological issue. Curr Mol Pharmacol. 2018:11:97–108.
  • Henderson GL. Fentanyl-related deaths: demographics, circumstances, and toxicology of 112 cases. J Forensic Sci. 1991;36:422–433.
  • Schumann H, Erickson T, Thompson TM, et al. Fentanyl epidemic in Chicago, Illinois and surrounding Cook County. Clin Toxicol (Phila). 2008;46:501–506.
  • Denton JS, Donoghue ER, McReynolds J, et al. An epidemic of illicit fentanyl deaths in Cook County, Illinois: September 2005 through April 2007. J Forensic Sci. 2008;53:452–454.
  • Algren DA, Monteilh CP, Punja M, et al. Fentanyl-associated fatalities among illicit drug users in Wayne County, Michigan (July 2005–May 2006). J Med Toxicol. 2013;9:106–115.
  • Tamburro LP, Al-Hadidi JH, Dragovic LJ. Resurgence of fentanyl as a drug of abuse. J Forensic Sci Med. 2016;2:111–114.
  • Lee D, Chronister CW, Broussard WA, et al. Illicit fentanyl-related fatalities in Florida: toxicological findings. J Anal Toxicol. 2016;40:588–594.
  • Okic M, Cnossen L, Crifasi JA, et al. Opioid overdose mortality in Kansas, 2001-2011: toxicologic evaluation of intent. J Anal Toxicol. 2013;37:629–635.
  • Smialek JE, Levine B, Chin L, et al. A fentanyl epidemic in Maryland 1992. J Forensic Sci. 1994;39:159–164.
  • Hull MJ, Juhascik M, Mazur F, et al. Fatalities associated with fentanyl and co-administered cocaine or opiates. J Forensic Sci. 2007;52:1383–1388.
  • Thompson JG, Baker AM, Bracey AH, et al. Fentanyl concentrations in 23 postmortem cases from the hennepin county medical examiner's office. J Forensic Sci. 2007;52:978–981.
  • Krinsky CS, Lathrop SL, Crossey M, et al. A toxicology-based review of fentanyl-related deaths in New Mexico (1986–2007). Am J Forensic Med Pathol. 2011;32:347–351.
  • Martin TL, Woodall KL, McLellan BA. Fentanyl-related deaths in Ontario, Canada: toxicological findings and circumstances of death in 112 cases (2002-2004). J Anal Toxicol. 2006;30:603–610.
  • Kronstrand R, Druid H, Holmgren P, et al. A cluster of fentanyl-related deaths among drug addicts in Sweden. Forensic Sci Int. 1997;88:185–193.
  • Increases in fentanyl drug confiscations and fentanyl-related overdose fatalities [cited 2017 November 13]. Available from: https://www.cdc.gov/drugoverdose/opioids/fentanyl.html
  • Rodda LN, Pilgrim JL, Di Rago M, et al. A cluster of fentanyl-laced heroin deaths in 2015 in Melbourne, Australia. J Anal Toxicol. 2017;41:318–324.
  • Henderson GL. Designer drugs: past history and future prospects. J Forensic Sci. 1988;33:569–575.
  • Lust EB, Barthold C, Malesker MA, et al. Human health hazards of veterinary medications: information for emergency departments. J Emerg Med. 2011;40:198–207.
  • Vardanyan RS, Hruby VJ. Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications. Future Med Chem. 2014;6:385–412.
  • Vuckovic S, Prostran M, Ivanovic M, et al. Fentanyl analogs: structure-activity-relationship study. Curr Med Chem. 2009;16:2468–2474.
  • Labroo RB, Paine MF, Thummel KE, et al. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos. 1997;25:1072–1080.
  • Goromaru T, Matsuura H, Yoshimura N, et al. Identification and quantitative determination of fentanyl metabolites in patients by gas chromatography–mass spectrometry. Anesthesiology. 1984;61:73–77.
  • Van Rooy HH, Vermeulen MP, Bovill JG. The assay of fentanyl and its metabolites in plasma of patients using gas chromatography with alkali flame ionisation detection and gas chromatography-mass spectrometry. J Chromatogr. 1981;223:85–93.
  • Coopman V, Cordonnier J, Pien K, et al. LC-MS/MS analysis of fentanyl and norfentanyl in a fatality due to application of multiple Durogesic transdermal therapeutic systems. Forensic Sci Int. 2007;169:223–227.
  • Marinetti LJ, Ehlers BJ. A series of forensic toxicology and drug seizure cases involving illicit fentanyl alone and in combination with heroin, cocaine or heroin and cocaine. J Anal Toxicol. 2014;38:592–598.
  • Sutter ME, Gerona RR, Davis MT, et al. Fatal fentanyl: one pill can kill. Acad Emerg Med. 2017;24:106–113.
  • Lotsch J, Walter C, Parnham MJ, et al. Pharmacokinetics of non-intravenous formulations of fentanyl. Clin Pharmacokinet. 2013;52:23–36.
  • Anderson DT, Muto JJ. Duragesic® transdermal patch: postmortem tissue distribution of fentanyl in 25 cases. J Anal Toxicol. 2000;24:627–634.
  • Bakovic M, Nestic M, Mayer D. Death by band-aid: fatal misuse of transdermal fentanyl patch. Int J Legal Med. 2015;129:1247–1252.
  • Kuhlman JJ Jr., McCaulley R, Valouch TJ, et al. Fentanyl use, misuse, and abuse: a summary of 23 postmortem cases. J Anal Toxicol. 2003;27:499–504.
  • Prosser JM, Jones BE, Nelson L. Complications of oral exposure to fentanyl transdermal delivery system patches. J Med Toxicol. 2010;6:443–447.
  • Serghini I, Qamouss Y, Zoubir M, et al. Fatal intoxication caused by the application of the multiple transdermals patchs of fentanyl. Pan Afr Med J. 2015;20:21.
  • Higashigawa Y, Suzuki S. Studies on 1-(2-phenethyl)-4-(N-propionylanilino)piperidine (fentanyl) and its related compounds. VI. Structure–analgesic activity relationship for fentanyl, methyl-substituted fentanyls and other analogues. Forensic Toxicol. 2008;26:1–5.
  • Helander A, Backberg M, Beck O. Intoxications involving the fentanyl analogs acetylfentanyl, 4-methoxybutyrfentanyl and furanylfentanyl: results from the Swedish STRIDA project. Clin Toxicol (Phila). 2016;54:324–332.
  • Dwyer JB, Janssen J, Luckasevic TM, et al. Report of increasing overdose deaths that include acetyl fentanyl in multiple counties of the southwestern region of Pennsylvania in 2015–2016. J Forensic Sci. 2017;63:195–200.
  • McIntyre IM, Trochta A, Gary RD, et al. An acute acetyl fentanyl fatality: a case report with postmortem concentrations. J Anal Toxicol. 2015;39:490–494.
  • Takase I, Koizumi T, Fujimoto I, et al. An autopsy case of acetyl fentanyl intoxication caused by insufflation of ‘designer drugs’. Leg Med (Tokyo). 2016;21:38–44.
  • Maryanoff BE, Simon EJ, Gioannini T, et al. Potential affinity labels for the opiate receptor based on fentanyl and related compounds. J Med Chem. 1982;25:913–919.
  • Guerrieri D, Rapp E, Roman M, et al. Acrylfentanyl: another new psychoactive drug with fatal consequences. Forensic Sci Int. 2017;277:e21–e29.
  • Helander A, Backberg M, Signell P, et al. Intoxications involving acrylfentanyl and other novel designer fentanyls — results from the Swedish STRIDA project. Clin Toxicol (Phila). 2017;55:589–599.
  • Ujvary I, Jorge R, Christie R, et al. Acrylfentanyl, a recently emerged new psychoactive substance: a comprehensive review. Forensic Toxicol. 2017;35:232–243.
  • European drug report: European monitoring centre for drugs and drug addiction; 2016 [cited 2017 October 26, 2017]. Available from: http://www.emcdda.europa.eu/edr2016
  • Butler DC, Shanks K, Behonick GS, et al. Three cases of fatal Acrylfentanyl Toxicity in the United States and a review of literature. J Anal Toxicol. 2018;42:e6–e11.
  • McIntyre IM, Trochta A, Gary RD, et al. An acute butyr-fentanyl fatality: a case report with postmortem concentrations. J Anal Toxicol. 2016;40:162–166.
  • Staeheli SN, Baumgartner MR, Gauthier S, et al. Time-dependent postmortem redistribution of butyrfentanyl and its metabolites in blood and alternative matrices in a case of butyrfentanyl intoxication. Forensic Sci Int. 2016;266:170–177.
  • Hikin L, Smith PR, Hudson S, et al. Multiple fatalities in the North of England associated with synthetic fentanyl analogue exposure; detection and quantitation in a case series from early 2017. Forensic Sci Int. 2018;282:179–183.
  • Cole JB, Dunbar JF, McIntire SA, et al. Butyrfentanyl overdose resulting in diffuse alveolar hemorrhage. Pediatrics. 2015;135:e740–e7433.
  • Backberg M, Beck O, Jonsson KH, et al. Opioid intoxications involving butyrfentanyl, 4-fluorobutyrfentanyl, and fentanyl from the Swedish STRIDA project. Clin Toxicol (Phila). 2015;53:609–617.
  • George AV, Lu JJ, Pisano MV, et al. Carfentanil–an ultra potent opioid. Am J Emerg Med. 2010;28:530–532.
  • Riches JR, Read RW, Black RM, et al. Analysis of clothing and urine from Moscow theatre siege casualties reveals carfentanil and remifentanil use. J Anal Toxicol. 2012;36:647–656.
  • Papsun D, Isenschmid D, Logan BK. Observed carfentanil concentrations in 355 blood specimens from forensic investigations. J Anal Toxicol. 2017;41:777–778.
  • Swanson DM, Hair LS, Strauch Rivers SR, et al. Fatalities involving carfentanil and furanyl fentanyl: two case reports. J Anal Toxicol. 2017;41:498–502.
  • Mohr AL, Friscia M, Papsun D, et al. Analysis of novel synthetic opioids U-47700, U-50488 and furanyl fentanyl by LC-MS/MS in postmortem casework. J Anal Toxicol. 2016;40:709–717.
  • Guerrieri D, Rapp E, Roman M, et al. Postmortem and toxicological findings in a series of Furanylfentanyl-related deaths. J Anal Toxicol. 2017;41:242–249.
  • Milroy CM, Kepron C. Two deaths associated with Furanylfentanyl toxicity. Forensic Sci Int. 2017; IAFS special issue:88.
  • Martucci HFM, Ingle EA, Hunter MD, et al. Distribution of furanyl fentanyl and 4-ANPP in an accidental acute death: a case report. Forensic Sci Int. 2018;283:e13–e17.
  • Papsun D, Hawes A, Mohr AL, et al. Case series of novel illicit opioid-related deaths. Acad Forensic Pathol. 2017;7:477–486.
  • Martin M, Hecker J, Clark R, et al. China white epidemic: an eastern United States emergency department experience. Ann Emerg Med. 1991;20:158–164.
  • Gillespie TJ, Gandolfi AJ, Davis TP, et al. Identification and quantification of alpha-methylfentanyl in post mortem specimens. J Anal Toxicol. 1982;6:139–142.
  • Hibbs J, Perper J, Winek CL. An outbreak of designer drug–related deaths in Pennsylvania. JAMA. 1991;265:1011–1013.
  • Ojanpera I, Gergov M, Rasanen I, et al. Blood levels of 3-methylfentanyl in 3 fatal poisoning cases. Am J Forensic Med Pathol. 2006;27:328–331.
  • Ojanpera I, Gergov M, Liiv M, et al. An epidemic of fatal 3-methylfentanyl poisoning in Estonia. Int J Legal Med. 2008;122:395–400.
  • Coopman V, Cordonnier J, De Leeuw M, et al. Ocfentanil overdose fatality in the recreational drug scene. Forensic Sci Int. 2016;266:469–473.
  • Dussy FE, Hangartner S, Hamberg C, et al. An acute ocfentanil fatality: a case report with postmortem concentrations. J Anal Toxicol. 2016;40:761–766.
  • Kronstrand R, Thelander G, Lindstedt D, et al. Fatal intoxications associated with the designer opioid AH-7921. J Anal Toxicol. 2014;38:599–604.
  • Vorce SP, Knittel JL, Holler JM, et al. A fatality involving AH-7921. J Anal Toxicol. 2014;38:226–230.
  • Karinen R, Tuv SS, Rogde S, et al. Lethal poisonings with AH-7921 in combination with other substances. Forensic Sci Int. 2014;244:e21–e24.
  • Elliott S, Bodenschaft C, Beran D. AH-7921: critical review report. Geneva: World Health Organization; 2014. p. 22.
  • Fels H, Krueger J, Sachs H, et al. Two fatalities associated with synthetic opioids: AH-7921 and MT-45. Forensic Sci Int. 2017;277:e30–e35.
  • Elliott S, Bodenschatz C, Beran D. AH-7921. Critical review report. Geneva: United Nations; 2014.
  • Katselou M, Papoutsis I, Nikolaou P, et al. AH-7921: the list of new psychoactive opioids is expanded. Forensic Toxicol. 2015;33:195–201.
  • Evans-Brown E, Cunningham A, Gallegos A, et al. MT-45 risk assessment. Lisbon: EMCDDA; 2014.
  • Helander A, Backberg M, Beck O. MT-45, a new psychoactive substance associated with hearing loss and unconsciousness. Clin Toxicol (Phila). 2014;52:901–904.
  • Papsun D, Krywanczyk A, Vose JC, et al. Analysis of MT-45, a novel synthetic opioid, in human whole blood by LC-MS-MS and its identification in a drug-related death. J Anal Toxicol. 2016;40:313–317.
  • Uchiyama N, Matsuda S, Kawamura M, et al. Identification of two new-type designer drugs, piperazine derivative MT-45 (I-C6) and synthetic peptide Nooppet (GVS-111), with synthetic cannabinoid A-834735, cathinone derivative 4-methoxy-alpha-PVP, and phenethylamine derivative 4-methylbuphedrine from illegal products. Forensic Toxicol. 2014;32:9–18.
  • Elliott SP, Brandt SD, Smith C. The first reported fatality associated with the synthetic opioid 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and implications for forensic analysis. Drug Test Anal. 2016;8:875–879.
  • Coopman V, Blanckaert P, Van Parys G, et al. A case of acute intoxication due to combined use of fentanyl and 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700). Forensic Sci Int. 2016;266:68–72.
  • Ellefsen KN, Taylor EA, Simmons P, et al. Multiple drug toxicity involving novel psychoactive substances, 3-fluorophenmetrazine and U-47700. J Anal Toxicol. 2017;41:765–770.
  • Rohrig TP, Miller SA, Baird TR. U-47700: a not so new opioid. J Anal Toxicol. 2017;42:e12–e14.
  • Domanski K, Kleinschmidt KC, Schulte JM, et al. Two cases of intoxication with new synthetic opioid, U-47700. Clin Toxicol (Phila). 2017;55:46–50..
  • Jones MJ, Hernandez BS, Janis GC, et al. A case of U-47700 overdose with laboratory confirmation and metabolite identification. Clin Toxicol (Phila). 2017;55:55–59.
  • DEA Headquarters News. Washington (DC): Drug Enforcement Administration; 2016 [cited 2017 October 23]. Available from: https://www.dea.gov/divisions/hq/2016/hq111016.shtml
  • Helland A, Brede WR, Michelsen LS, et al. Two hospitalizations and one death after exposure to ortho-fluorofentanyl. J Anal Toxicol. 2017;41:708–709.
  • Strehmel N, Vejmelka E, Kastner K, et al. NPS-findings in forensic toxicology – three case reports. Toxichem Krimtech. 2017;84:199–204.
  • Ferslew KE, Hagardorn AN, McCormick WF. Postmortem determination of the biological distribution of sufentanil and midazolam after an acute intoxication. J Forensic Sci. 1989;34:249–257.
  • Cunningham SM, Haikal NA, Kraner JC. Fatal intoxication with acetyl fentanyl. J Forensic Sci. 2016;61 Suppl 1:S276–S280.
  • Giorgetti A, Centola C, Giorgetti R. Fentanyl novel derivative-related deaths. Hum Psychopharmacol. 2017;32:1–11.
  • Ruzycki S, Yarema M, Dunham M, et al. Intranasal fentanyl intoxication leading to diffuse alveolar hemorrhage. J Med Toxicol. 2016;12:185–188.
  • Porter R, O'Reilly H. Pulmonary hemorrhage: a rare complication of opioid overdose. Pediatr Emerg Care. 2011;27:742–744.
  • Tiscione NB, Wegner K. Validation of the Neogen(R) Fentanyl ELISA Kit for blood and urine. J Anal Toxicol. 2017;41:313–317.
  • Wang BT, Colby JM, Wu AH, et al. Cross-reactivity of acetylfentanyl and risperidone with a fentanyl immunoassay. J Anal Toxicol. 2014;38:672–675.
  • Ruangyuttikarn W, Law MY, Rollins DE, et al. Detection of fentanyl and its analogs by enzyme-linked immunosorbent assay. J Anal Toxicol. 1990;14:160–164.
  • Schueler HE. Emerging synthetic fentanyl analogs. Acad Forensic Pathol. 2017;7:36–40.
  • Pearson J, Poklis J, Poklis A, et al. Postmortem toxicology findings of acetyl fentanyl, fentanyl, and morphine in heroin fatalities in Tampa, Florida. Acad Forensic Pathol. 2015;5:676–689.
  • Van Nimmen NF, Poels KL, Veulemans HA. Highly sensitive gas chromatographic-mass spectrometric screening method for the determination of picogram levels of fentanyl, sufentanil and alfentanil and their major metabolites in urine of opioid exposed workers. J Chromatogr B Analyt Technol Biomed Life Sci. 2004;804:375–387.
  • Eckart K, Rohrich J, Breitmeier D, et al. Development of a new multi-analyte assay for the simultaneous detection of opioids in serum and other body fluids using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2015;1001:1–8.
  • Cooreman S, Deprez C, Martens F, et al. A comprehensive LC-MS-based quantitative analysis of fentanyl-like drugs in plasma and urine. J Sep Sci. 2010;33:2654–2662.
  • Sofalvi S, Schueler HE, Lavins ES, et al. An LC-MS-MS method for the analysis of carfentanil, 3-Methylfentanyl, 2-Furanyl Fentanyl, acetyl fentanyl, fentanyl and norfentanyl in postmortem and impaired-driving cases. J Anal Toxicol. 2017;41:473–483.
  • Gergov M, Nokua P, Vuori E, et al. Simultaneous screening and quantification of 25 opioid drugs in post-mortem blood and urine by liquid chromatography-tandem mass spectrometry. Forensic Sci Int. 2009;186:36–43.
  • Shaner RL, Kaplan P, Hamelin EI, et al. Comparison of two automated solid phase extractions for the detection of ten fentanyl analogs and metabolites in human urine using liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2014;962:52–58.
  • Wang L, Bernert JT. Analysis of 13 fentanils, including sufentanil and carfentanil, in human urine by liquid chromatography-atmospheric-pressure ionization-tandem mass spectrometry. J Anal Toxicol. 2006;30:335–341.
  • Shoff EN, Zaney ME, Kahl JH, et al. Qualitative identification of fentanyl analogs and other opioids in postmortem cases by UHPLC-Ion Trap-MSn. J Anal Toxicol. 2017;41:484–492.
  • Alexander RT, Hedrick CW, Alexander SD, et al. Epidemic fentanyl deaths in Maryland: A public health intervention involving geographic information systems and collaboration with the drug enforcement administration. Acad Forensic Pathol. 2016;6:301–314.
  • Griswold MK, Chai PR, Krotulski AJ, et al. Self-identification of nonpharmaceutical fentanyl exposure following heroin overdose. Clin Toxicol (Phila). 2018;56:37–42.
  • Sgarlato A, deRoux SJ. Prescription opioid related deaths in New York City: a 2 year retrospective analysis prior to the introduction of the New York State I-STOP law. Forensic Sci Med Pathol. 2015;11:388–394.
  • Murphy Y, Goldner EM, Fischer B. Prescription opioid use, harms and interventions in Canada: a review update of new developments and findings since 2010. Pain Physician. 2015;18:E605–E614.
  • van Amsterdam J, van den Brink W. The misuse of prescription opioids: a threat for Europe? Curr Drug Abuse Rev. 2015;8:3–14.
  • Al-Saffar Y, Stephanson NN, Beck O. Multicomponent LC-MS/MS screening method for detection of new psychoactive drugs, legal highs, in urine-experience from the Swedish population. J Chromatogr B Analyt Technol Biomed Life Sci. 2013;930:112–120.
  • Centers for Disease Control and Prevention. Acetyl fentanyl overdose fatalities–Rhode Island, March-May 2013. MMWR Morb Mortal Wkly Rep. 2013;62:703–704.
  • Wax PM, Becker CE, Curry SC. Unexpected “gas” casualties in Moscow: a medical toxicology perspective. Ann Emerg Med. 2003;41:700–705.
  • Drummer OH. Postmortem toxicology of drugs of abuse [Review]. Forensic Sci Int. 2004;142:101–113.
  • Krinsky CS, Lathrop SL, Zumwalt R. An examination of the postmortem redistribution of fentanyl and interlaboratory variability. J Forensic Sci. 2014;59:1275–1279.
  • Lozier MJ, Boyd M, Stanley C, et al. Acetyl fentanyl, a novel fentanyl analog, causes 14 overdose deaths in Rhode Island, March-May 2013. J Med Toxicol. 2015;11:208–217.
  • Poklis J, Poklis A, Wolf C, et al. Two fatal intoxications involving butyryl fentanyl. J Anal Toxicol. 2016;40:703–708.
  • Rojkiewicz M, Majchrzak M, Celinski R, et al. Identification and physicochemical characterization of 4-fluorobutyrfentanyl (1-((4-fluorophenyl)(1-phenethylpiperidin-4-yl)amino)butan-1-one, 4-FBF) in seized materials and post-mortem biological samples. Drug Test Anal. 2017;9:405–414.
  • Yonemitsu K, Sasao A, Mishima S, et al. A fatal poisoning case by intravenous injection of “bath salts” containing acetyl fentanyl and 4-methoxy PV8. Forensic Sci Int. 2016;267:e6–e9.
  • Fort C, Curtis B, Nichols C, et al. Acetyl fentanyl toxicity: two case reports. J Anal Toxicol. 2016;40:754–757.
  • Dziadosz M, Klintschar M, Teske J. Postmortem concentration distribution in fatal cases involving the synthetic opioid U-47700. Int J Legal Med. 2017;131:1555–1556.
  • Ellefsen KN, Taylor EA, Simmons P, et al. Multiple drug-toxicity involving novel psychoactive substances, 3-Fluorophenmetrazine and U-47700. J Anal Toxicol. 2017;41:765–770.
  • McIntyre IM, Gary RD, Joseph S, et al. A fatality related to the synthetic opioid U-47700: postmortem concentration distribution. J Anal Toxicol. 2017;41:158–160.
  • Acryloylfentanyl. EMCDDA – Europol joint report on a new psychoactive substance. Lisbon: EMCDDA; 2017.
  • Shanks KG, Behonick GS. Detection of Carfentanil by LC-MS-MS and reports of associated fatalities in the USA. J Anal Toxicol. 2017;41:466–472.