1.1_Bebarta_DaubertACMT toxalbumin-cytotoxic

3/26/14 The Peas Are Red, the Crocus Are Blue. Have a Colorful Meal, Mul?ple Organ Failure will ensue Lt Col Vik Bebarta, MD FACEP, FACMT Medical Toxicology, San Antonio Military Medical Center G. Patrick Daubert, MD, FACMT Kaiser Permanente, Northern California Regional Toxicology Service Disclosure My opinions and comments do not reflect official policy, posi?on, or product endorsement of Department of the Air Force Department of Defense, US Government Funding – Federal NIH, USAF, Army, Joint DoD, UTHSCSA No industry support 20 yo M extracted ricin powder from ricin beans Injected himself with the powder Called 911 Immediate pain, then vomi?ng, weakness 4 hrs later SBP 90/40 pulse 120 vomi?ng, acidemic, creat 2.2 1 3/26/14 23 March 2014 Ricinus communis Southern US and NE and West coast Mediterranean basin East Africa India 2 3/26/14 Abrus precatorius – jequirity, rosary pea Jatropha curcas Chinese cucumber, Trichosanthes Black locust American mistletoe 3 3/26/14 history Georgi Markov
September 11, 1978 Bloomberg, Obama
Shannon Richardson – May 29, 2013 Lec?ns – protein that binds carbs Toxalbumins – ricin and abrin Ribosomal Inac?va?ng Protein II (RIP II) A part and B part Ricin – powder or crystal; in liquid 4 3/26/14 Stops making proteins, etc.1 Chain B – Binds galactose Chain A – A(acks, inhibits 28s subunit of 60S ribosome Ricin communis agglu?nin2 RBC agglu?na?on, hemolysis IV injec?on Ricinine – seizure in animals3 1Day, Biochemistry, 2002 3Darby, J Forensic Sci, 2001 2Balint, Toxicol, 1974 Abrin – toxalbumin like ricin Abrus precatorius RIP II Not weaponized Inges?on – 30mg/kg LD50 in mice Few grains of salt IV or inhaled – 1000x lower dose Humans 1-­‐20 mcg/kg (8 beans?) 5 3/26/14 Clinical findings Decontamina?on •  PPE Toxic effects GI, hypotension, liver-­‐renal failure w/in 4-­‐6 hrs but can be < 10 hrs Cough sob, fever, respi distress allergic response; within 8 hrs Cardiac, heme, hepa?c, renal Delayed – failure to make a protein Local ?ssue, weak; delayed vomi?ng, fever, MOF, w/in 10-­‐12 hrs 6 3/26/14 Syndrome Bacterial, chemical, foodborne gastroenteri?s Rapid severe resp illness in 12-­‐24 hrs Pseudomembranous conjunc?vi?s1 Ur?caria – IgE mediated Allergic2 1Grant WM, 1993 2Kennedy DM, Clin Allergy, 1981 Blood or urine ricin or ricinine (< 48 hrs) GCMS or LC MS/MS US Army Med Research Ins?tute Infec?ous Disease CDC 7 3/26/14 Electrolytes No dialysis but follow for renal failure inhaled/vent therapies If no symptoms for 12 hrs – then likely fine Progresses over 4-­‐36hrs Inhaled – delay of 20-­‐24 hrs Dermal – likely safe ,but 12 hr obs Ricin vaccine In development November 2013 8 3/26/14 JAMA November 2005 Medical Toxicologists 26 The Peas Are Red, the Crocus Are Blue. Have a Colorful Meal, Mul?ple Organ Failure Will Ensue: The Toxicology Behind Cyctoxic Plant Poisoning Lt Col Vik Bebarta, MD, FACEP, FACMT Medical Toxicology, San Antonio Military Medical Center G. Patrick Daubert, MD, FACEP, FACMT Kaiser Permanente, Northern California Regional Toxicology Service 9 3/26/14 DISCLOSURE: I have no relevant financial interest/
arrangement or affilia?on with any organiza?ons related to commercial products or services to be discussed at this program 28 Learning Objec?ves Aler comple?ng this ac?vity, par?cipants will be able to: •  Describe those plants that contain colchicine alkaloids •  Illustrate the intracellular binding site for colchicine alkaloids •  Explain the phases of toxicity seen with cytotoxic plant poisoning 29 Historical Perspec?ve 10 3/26/14 Colchicine •  Listed in the Egyp?an medical papyrus (ca. 1500 B.C.) •  Used by a number Greek physicians •  Prior to ****, colchicine was an unapproved drug with no prescribing informa?on, dosage recommenda?ons, or drug interac?on warnings Environmental Considera?ons Colchicine Alkaloids • 
• 
• 
• 
Colchicum autumnale Gloriosa superba Sandersonia auranBaca Kreysigia mulBflora (Tripladenia cunninghamii, Bush lily) 33 11 3/26/14 Colchicum autumnale •  Autumn crocus, Meadow saffron, Star of Bethlehem, gowri gedde •  Fer?le meadows, olen at the edges of woods in the western, central, and southern Europe •  Mistaken for wild garlic (Aliium ursinum) Colchicum autumnale Courtesy David J. Slater: DJS Photography
Gloriosa superba •  Flame lily, climbing lily, creeping lily, glory lily, gloriosa lily, ?ger claw, and fire lily •  Occurs in semi-­‐shade areas among bush on hillsides in Southern Asia and Tropical Africa •  Na?onal flower of Zimbabwe •  Tubers mistaken for sweet potatoes or yams 12 3/26/14 Gloriosa superba Courtesy Adrian Sington: Poison Diaries
Sandersonia auranBaca •  Christmas-­‐bells, Chinese lantern lily, Gold lily of the valley •  Grows in damp grassland, on forests margins in the eastern areas of South Africa •  Delicate, slightly climbing plant with pendulous lanterns •  Popular cut flower in southern hemisphere Sandersonia auranBaca Courtesy
M. Gastil-Buhl: Pacific Bulb Society
http://www.pacificbulbsociety.org/
13 3/26/14 Plantakine?cs 40 Plantakine?cs •  Data following acute inges?ons of plants containing colchicine alkaloids are limited •  Current data are primarily based upon case reports, with co-­‐ingestants olen confounding the kine?cs Plantakine?cs •  Rapidly absorbed •  Metabolized by the liver – limited renal clearance •  Significant biliary excre?on and enterohepa?c recircula?on •  Peak plasma levels occur in 30 minutes to 2 hours •  Volume of distribu?on (10-­‐12 L/kg) •  Elimina?on half-­‐life 1.7-­‐32 hours •  50% protein bound •  High concentra?ons in breast milk Sabouraud A, Rochdi M, Urtizberea M, et al. Z Gastroenterol. 1992;30:35–39
14 3/26/14 Mechanisms Mechanisms •  Intracellular transport via the mul?drug transporter P-­‐glycoprotein (Pgp) (ATPase efflux pump) •  Colchicine reversibly binds to β-­‐tubulin •  Results in curved tubulin dimer •  Prevents a straight structure due to a steric clash between colchicine and α-­‐tubulin •  Loss of lateral contacts leads to rapid microtubule depolymeriza?on and dynamic instability Hastie SB. Pharmacol Ther. 1991;51(3):377-401
Microtubule α
β
α
β
α
α
β
α
α
β
α
α
β
α
α
β
α
β
α
β
α
β
α
β
α
β
α
Lu Y1, Chen J, Xiao M, et al.Pharm Res. 2012 Nov;29(11):2943-71
β
β
β
β
β
45 15 3/26/14 Mechanisms CBS
α
β
α
α
α
α
α
β
β
β
β
β
α
α
α
α
α
β
β
β
β
β
α
α
α
α
α
β
β
β
β
β
46 CBS: Colchicine Binding Site
Mechanisms •  Eight iden?fied β-­‐tubulin isotypes in humans •  Known muta?ons in tubulin and overexpression of β III-­‐tubulin isoform •  Overexpression of class III β-­‐tubulin is an indicator of resistance to tubulin binding by colchicine Range of Toxicity 48 16 3/26/14 Range of Toxicity •  Colchicine levels are highest at the beginning of the growth season •  Plant concentra?ons average approximately 0.1-­‐0.06% •  Each seed contains approximately 3.5 mg of colchicine •  Inges?on of 10 to 12 flowers has been fatal in adults Range of Toxicity •  Inges?ons < 0.5 mg/kg –  gastrointes?nal distress •  Inges?ons 0.5-­‐0.8 mg/kg –  Myelosuppression –  10% fatality rate •  Inges?ons of > 0.8 mg/kg –  cardiovascular collapse –  death within 72 hours Clinical Manifesta?ons 51 17 3/26/14 Clinical Manifesta?ons •  Latent period of 4–12 hours. •  First phase (12-­‐24 hours) –  peripheral leukocytosis, gastrointes?nal symptoms with fluid losses and hypovolemic shock. •  Second phase (24–72 hours) –  heart failure, arrhythmias, renal failure, hepa?c injury, respiratory distress, coagulopathies, bone marrow depression and neuromuscular involvement •  Third phase (5–7 days) –  leukocytosis and alopecia Case Review •  German case series of 32 pa?ents between 27 and 90 years •  All pa?ents developed diarrhea and/or vomi?ng aler a latency period of between 2 and 24 h •  Pa?ents with a latency of > 9 h suffered only mild poisoning •  Worse outcome if leaves were boiled (moderate, severe or fatal poisoning) •  Age > 65 years predicted a worse outcome •  Post mortem studies olen reveal high biliary levels of colchicine Hermanns-Clausen M, Schindler F, Stedtler U, et al. MMW Fortschr Med. 2006 Mar 23;148(12):45-7.
Management 18 3/26/14 Management • 
• 
• 
• 
Early intensive support measures Granulocyte-­‐directed growth factors Biliary drain? Colchicine-­‐specific Fab fragments Summary 56 Summary •  Two primary colchicine alkaloid producing plants are Autumn crocus and Gloriosa superba •  Colchicine binds to β-­‐subunit on microtubules preven?ng assembly •  Dis?nct phases of toxicity •  High fatality rate •  Early intensive support measures 57 19 3/26/14 The Peas Are Red, the Crocus Are Blue. Have a Colorful Meal, Mul?ple Organ Failure ensue Lt Col Vik Bebarta, MD FACEP, FACMT Medical Toxicology, San Antonio Military Medical Center G. Patrick Daubert, MD, FACMT Kaiser Permanente, Northern California Regional Toxicology Service 20