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Threat by Nerve Agents: Update of Diagnostic and Therapeutic Strategies! Threat by nerve agents: Update of diagnostic and therapeutic strategies! H. Thiermann and F. Worek Bundeswehr Institute of Pharmacology and Toxicology, 80937 Munich, Germany Congress of the European Society of Emergency Hot Topic Lecture Wednesday 12th September 2018 Glasgow, United Kingdom Scenarios of an Attack with Chemical Warfare Agents – Attack on Civilian Population 1 Scenarios of an Attack with Chemical Warfare Agents – Targeted Homicidal Attack Nerve Agents and other Organophosphorus Compounds G - Agents Tabun (GA), Sarin (GB), Cyclosarin (GF), Soman (GD) (and Analogs) R R X V - Agents VX, Russian VX (VR), Chinese VX (CVX) (and Analogs) OP- Pesticides Diethyl-type, Dimethyl-type, hundreds of other compounds! 2 Characteristics of Poisoning by Nerve Agents Generally assumed: patients exposed up to 5x LD50 Inhalative G-Type Nerve Agent Poisoning - Immediate onset of cholinergic crisis - Short persistence of nerve agent in the body Percutaneous V-type Nerve Agent Poisoning - Prolonged onset of cholinergic crisis - Persistence of nerve agent over several days in the body Organophosphorus Compound Threats © 2017 by InstPharmToxBw Worek et al. Arch Toxicol 2016 3 Effects of Organophosphorus Compounds Mechanism: - inhibition of AChE - accumulation of ACh - disturbance of cholinergic functions https://www.stern.de/politik/ausland/syrien--angriff-auf-klinik- mit-mutmasslichen-giftgas-opfern-7398534.html Cholinesterases – Reason of Confusion AChE (EC 3.1.1.7) • found mostly in nervous tissue and blood (red blood cells) • primates have the highest activity, rats one tenth and cats roughly 1 % compared to human RBCs Pl-ChE (EC 3.1.1.8) • synthesis in the liver • capable of splitting several cholinesters, incl. acetylcholine, highest activity with butyrylcholine Confusion Often reported: determination of AChE in human plasma with acetylcholine or acetylthiocholine as substrate: in fact activity of BChE was determined! Blum et al. unpublished 4 Clinical Challenge of Nerve Agent Poisoning Signs and symptoms Nerve agent poisoning Slight Moderate Severe Miosis / lacrimation Local fasciculations Hypersalivation / sweating Nausea Vomiting / defacation / emiction Bronchocontriction / bronchorrhoe Bradycardia / circulatory depression Respiratory depression Convulsions Coma Worek et al. Arch Toxicol 2016 Effects of Organophosphorus Compounds Mechanism: - inhibition of AChE - accumulation of ACh - disturbance of cholinergic functions Life threatening effects: - bronchoconstriction/ bronchorrhoea (muscarine receptors) - central respiratory arrest (muscarine and nicotine receptors) - peripheral respiratory arrest (nicotine receptors) 5 ChE Check Mobile for on-site Confirmation of the Clinical Diagnosis Acetylthiocholine AChE BChE AS-1397 Acetate Thiocholine + DTNB 5-Mercapto-2-nitrobenzoate + TNB- Ellman et al. Biochem Pharmacol 1961 OP-SkinDisclosure-Kit 12,5 cm 16,7 cm Weight: 20 Gramm 6 OP-SkinDisclosure-Kit: How to Use? Cup with enzyme Cup with chemicals on test tube, on test tube, Sampling Put the sampler vigorous shaking, vigorous shaking, on the skin in the test tube 1 min incubation 1 min incubation read the color OP-SkinDisclosure-Kit: Score 4 3 2 1 0 Nerve Agent No Nerven Agent present present Worek et al. Toxicol. Lett 2880: 190 -194, 2017 7 Peculiarities in Treatment of Chemical Agent Poisoning Self – Protection; Working under aggravated conditions; Protection of medical units; Latency period. Decontamination of victims with signs and symptoms ouvry.com Tu, 2002 Compare: Thiermann et al. Chem Biol Interact 2013; Rosman et al. Annal Intern Med 2014 Med C- Special Diagnostics/ Reconnaissance / Verification and Analysis Biomedical verification of exposure to chemical agents ► chemical warfare agents ► degradation products ► metabolites and adducts 8 Atropine for Nerve Agent Poisoning Military doctrine: autoinjectors for self and buddy aid Enhanced first aid and clinical care by medical personnel) Aggressive atropine dosing Recommended German regimen 2 mg, i.m. followed by consecutive doubling the dose (4 – 8 – 16 - 32 mg) and finally infusion at field hospital Criteria Clear chest on auscultation; heart rate >80 beats/min; pupils no longer pinpoint; dry skin (axilla); systolic blood pressure >80 mmHg Thiermann et al. Chem Biol Interact, 2013; according to Eddleston et al. Crit Care 2004 and J Toxicol ClinToxicol 2004. For review see: Thiermann et al. Treatment of Nerve Agent poisoning In:Chemical Warfare Toxicology, Volume 2: Management of Poisoning, © The Royal Society of Chemistry 2016 Development of Oximes Synthesis of thousands 2018 of oximes since the Oximes in use or in early 1950ies advanced development - Monopyridinium oximes 2-PAM 1955 - Bispyridinium oximes TMB-4 1958 - Asymmetric oximes MMB-4 1959 - Substituted pyridinium oximes Obidoxime 1959 - Uncharged oximes HI-6 1968 9 Effects of Obidoxime in a Patient with Parathion Poisoning Patient: 56-year old, female Emergency situation: Unconscious, cardiovascular resuscitation Clinical course: As the clinical course situation remained critical for about 4 days without obidoxime, the regimen was started AChE activity of red blood cells Neuromuscular transmission prior to Obidoxime 600 Obidoxime 500 RBC-AChE in vivo 400 RBC-AChE in vitro 300 200 mU/µmol Hb after Obidoxime 100 0 0 12 24 36 48 Hours Reactions Occurring at AChE with an OP and an Oxime OP enzyme leaving group inhibited enzyme X + AChE-OH X + ACHE RNOH H2OH2O AChE-OH CH3-CH2OH AChE-OH + + + R ACHE oxime induced aging spontaneous reactivation reactivation 10 Effects of Obidoxime in a Patient with Parathion Poisoning Patient: 56-year old, female Emergency situation: Unconscious, cardiovascular resuscitation Clinical course: As the clinical course situation remained critical for about 4 days without obidoxime, the regimen was started AChE activity of red blood cells Neuromuscular transmission prior to Obidoxime 600 Obidoxime 500 RBC-AChE in vivo 400 RBC-AChE in vitro 300 200 mU/µmol Hb after Obidoxime 100 0 0 12 24 36 48 Hours Kinetic-Based Computer Model ki (1) [E] + [OP] [EP] 1000 ka 150 Toxicokinetics (2) [EP] + H2O [EP'] Pharmacokinetics 100 100 10 ks VX (nM) VX (3) [EP] + H2O [E] + [P] (µM) 6 HI 50 1 0.1 0 KD kr 0 100 200 300 400 500 0 100 200 300 400 500 (4) [EP] + [OX] [EPOX] [E] + [POX] min min kr * [OX] kobs = KD + [OX] d[E] ki * [OP] * [E] ks * [EP] kobs * [EP EPOX] dt d[EP] ki * [OP] * [E] ks * [EP] kobs * [EP EPOX] ka * [EP] dt Worek et al. TAP 2005 11 The Use of Kinetic Constants, Pharmacokinetic and Toxicokinetic Data for Prediction of AChE-Activity in Human Poisoning 20 100 Patient: Obidoxime Paraoxon 80 [nM]Paraoxon A 45-year old, male 15 60 Emergency situation: 10 40 Unconscious, severe signs and 5 symptoms of cholinergic crisis. [µM] Obidoxime 20 1.5 mg of atropine, intubation and initiation of artificial ventilation. 0 0 Clinical course: 400 2 bolus doses of obidoxime together 300 with an atropine infusion at the local hospital. Transfer to the ICU of 200 Technical University, Munich. AChE: measured The patient recovered uneventfully. 100 AChE (mU/µmol Hb) (mU/µmol AChE AChE: calculated 0 Worek et al. TAP 2005 0 24 48 72 96 120 144 Time p.i. (h) Reactions Occurring Between Phosphoryl-AChE and Oxime During Reactivation Inhibition kI E-OH + OP E-OP Association KD E-OP + Oxime Oxime-E-OP Reactivation kr Oxime-E-OP Oxime-OP + E-OH 12 Which Oximes Should We Use? Compare: Thiermann et al. Chem Biol Interact 2013 and Tox Lett 1999; modified by using data from Aurbek et al. Toxicolgy 2006; Bartling et al. Toxicolgy 2007 Worek et al. Tox Lett 2011 Translation of Clinical Findings from Human Poisoning to an Animal Model Poisoning by dimethoate (oral) and treatment with 2-PAM 100 ACHE in vivo 75 ACHE calc 50 ACHE (%) 25 0 100 200 300 400 500 600 700 800 time (min) 50 80 40 60 30 40 20 2-PAM (µM) 2-PAM 10 Omethoate (µM) Omethoate 20 2-PAM Omethoate 0 100 200 300 400 500 600 700 800 0 100 200 300 400 500 600 700 800 time (min) time (min) Worek et al. Chem Biol Interact. 2010 13 Translation of Findings from OP-Pesticide- Poisoning to Nerve Agent-Poisoning Male York-Landrace cross swine (about 20 kg) Poisoning: 3 x LD50 VX, p.c. Treatment: HI-6 (12.7 mg/kg) / Atropine sulfate (0.05 mg/kg) i.m., according to signs and symptoms Field laboratory diagnosis: AChE activity on-site Plasma sampling for laboratory analysis: HI-6, VX RBC-AChE Activity - Signs and Symptoms of a VX-Poisoned Swine Treatment according to signs and symptoms breathing problems dysrhythmias / hypotension salivation miosis fasciculation / mastication seizure apnoe / manual ventilation 30 % AChE activity On-site analysis On-site analysis of VX 3x LD50 14 RBC-AChE Activity, HI-6 and VX Concentrations in Plasma of a VX-Poisoned Swine Treatment according to signs and symptoms Treatment when 100 signs and symptoms 80 occurred 60 - salivation / bronchorrhea, 40 - breathing problems AChE (% ) with HI-6 and atropine, i.m., 20 subsequent treatment 0 according to fixed 0 60 120 180 240 300 360 schedule time [min] 100 10000 80 1000 60 100 40 VX [pM] HI 6 [µM] 6 HI 10 20 VX(+) (pM) VX(-) (pM) 0 1 0 60 120 180 240 300 360 0 60 120 180 240 300 360 time [min] time [min] Is there a Correlation between RBC-AChE- Activity and Clinical Status? A parathion poisoned patient was treated with obidoxime. The cholinesterase status and NMT were monitored during treatment at the ICU. 600 RBC-AChE in vivo Reactivatability 400 86.4 h mU/µmol Hb 200 0 0 24 48 72 96 Hours 93.7 h 60 40 20 94.6 h Obidoxime (µmo/l) Obidoxime 0 0 24 48 72 96 Hours Eyer et al. Clincal Toxicology 2009 15 Cholinesterase Status Blood sampling Blood dilution Plasma 1. AChE 2. BChE activity activity Incubation of blood dilution with Incubation of plasma with obidoxime (100 µM, 30 min, 37°C) AChE standard (60 min, 37°C) AChE activity AChE activity 3.
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