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The Peas Are Red, the Crocus Are Blue. Have a Colorful Meal, Mulple 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, posion, 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 powder from ricin beans Injected himself with the powder Called 911 Immediate pain, then voming, weakness 4 hrs later SBP 90/40 pulse 120 voming, acidemic, creat 2.2

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23 March 2014

Ricinus communis

Southern US and NE and West coast

Mediterranean basin East Africa India

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Abrus precatorius – jequirity, rosary pea

Jatropha curcas Black locust

Chinese cucumber, Trichosanthes American mistletoe

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history

Georgi Markov September 11, 1978

Bloomberg, Obama Shannon Richardson – May 29, 2013

Lecns – that binds carbs Toxalbumins – ricin and Ribosomal Inacvang Protein II (RIP II) A part and B part Ricin – powder or crystal; in liquid

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Stops making , etc.1 Chain B – Binds galactose Chain A – Aacks, inhibits 28s subunit of 60S ribosome

Ricin communis agglunin2 RBC agglunaon, hemolysis IV injecon Ricinine – seizure in animals3

1Day, Biochemistry, 2002 2Balint, Toxicol, 1974 3Darby, J Forensic Sci, 2001

Abrin – toxalbumin like ricin RIP II Not weaponized

Ingeson – 30mg/kg LD50 in mice Few grains of salt IV or inhaled – 1000x lower dose Humans 1-20 mcg/kg (8 beans?)

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Clinical findings

Decontaminaon • PPE

Toxic effects

GI, hypotension, liver-renal failure Cough sob, fever, respi distress w/in 4-6 hrs but can be < 10 hrs allergic response; within 8 hrs

Cardiac, heme, hepac, renal Delayed – failure to make a protein

Local ssue, weak; delayed voming, fever, MOF, w/in 10-12 hrs

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Syndrome

Bacterial, chemical, foodborne gastroenteris

Rapid severe resp illness in 12-24 hrs

Pseudomembranous conjuncvis1

Urcaria – 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 Instute Infecous Disease CDC

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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

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JAMA November 2005

Medical Toxicologists

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The Peas Are Red, the Crocus Are Blue. Have a Colorful Meal, Mulple 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

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DISCLOSURE:

I have no relevant financial interest/ arrangement or affiliaon with any organizaons related to commercial products or services to be discussed at this program

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Learning Objecves

Aer compleng this acvity, parcipants 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

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Historical Perspecve

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Colchicine

• Listed in the Egypan medical papyrus (ca. 1500 B.C.) • Used by a number Greek physicians • Prior to ****, colchicine was an unapproved drug with no prescribing informaon, dosage recommendaons, or drug interacon warnings

Environmental Consideraons

Colchicine Alkaloids

• Colchicum autumnale • Gloriosa superba • Sandersonia auranaca • Kreysigia mulflora (Tripladenia cunninghamii, Bush lily)

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Colchicum autumnale

• Autumn crocus, Meadow saffron, Star of Bethlehem, gowri gedde • Ferle meadows, oen 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 • Naonal flower of Zimbabwe • Tubers mistaken for sweet potatoes or yams

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Gloriosa superba

Courtesy Adrian Sington: Poison Diaries

Sandersonia auranaca

• 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 auranaca

Courtesyhttp://www.pacificbulbsociety.org/ M. Gastil-Buhl: Pacific Bulb Society

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Plantakinecs

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Plantakinecs

• Data following acute ingesons of plants containing colchicine alkaloids are limited • Current data are primarily based upon case reports, with co-ingestants oen confounding the kinecs

Plantakinecs

• Rapidly absorbed • Metabolized by the liver – limited renal clearance • Significant biliary excreon and enterohepac recirculaon • Peak plasma levels occur in 30 minutes to 2 hours • Volume of distribuon (10-12 L/kg) • Eliminaon half-life 1.7-32 hours • 50% protein bound • High concentraons in breast milk

Sabouraud A, Rochdi M, Urtizberea M, et al. Z Gastroenterol. 1992;30:35–39

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Mechanisms

Mechanisms

• Intracellular transport via the muldrug 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 depolymerizaon and dynamic instability

Hastie SB. Pharmacol Ther. 1991;51(3):377-401

Microtubule

β α β α β α β α β α β α β α β α β α β α α β α β α β α β α β α β

Lu Y1, Chen J, Xiao M, et al.Pharm Res. 2012 Nov;29(11):2943-71 45

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CBS Mechanisms

β α β α α β α β β β α α β α β α β α β α β α β α β α β α β α β α

CBS: Colchicine Binding Site 46

Mechanisms

• Eight idenfied β-tubulin isotypes in humans • Known mutaons 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

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Range of Toxicity

• Colchicine levels are highest at the beginning of the growth season • Plant concentraons average approximately 0.1-0.06% • Each seed contains approximately 3.5 mg of colchicine • Ingeson of 10 to 12 flowers has been fatal in adults

Range of Toxicity

• Ingesons < 0.5 mg/kg – gastrointesnal distress • Ingesons 0.5-0.8 mg/kg – Myelosuppression – 10% fatality rate • Ingesons of > 0.8 mg/kg – cardiovascular collapse – death within 72 hours

Clinical Manifestaons

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Clinical Manifestaons

• Latent period of 4–12 hours. • First phase (12-24 hours) – peripheral leukocytosis, gastrointesnal symptoms with fluid losses and hypovolemic shock. • Second phase (24–72 hours) – heart failure, arrhythmias, renal failure, hepac 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 paents between 27 and 90 years • All paents developed diarrhea and/or voming aer a latency period of between 2 and 24 h • Paents 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 oen 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

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Management

• Early intensive support measures • Granulocyte-directed growth factors • Biliary drain? • Colchicine-specific Fab fragments

Summary

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Summary

• Two primary colchicine alkaloid producing plants are Autumn crocus and Gloriosa superba • Colchicine binds to β-subunit on microtubules prevenng assembly • Disnct phases of toxicity • High fatality rate • Early intensive support measures

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The Peas Are Red, the Crocus Are Blue. Have a Colorful Meal, Mulple 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

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