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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
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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
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
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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 2Balint, Toxicol, 1974 3Darby, J Forensic Sci, 2001
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?)
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Clinical findings
Decontamina on • 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, hepa c, renal Delayed – failure to make a protein
Local ssue, weak; delayed vomi ng, fever, MOF, w/in 10-12 hrs
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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
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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, 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
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Learning Objec ves
A er 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
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Historical Perspec ve
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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 auran aca • Kreysigia mul flora (Tripladenia cunninghamii, Bush lily)
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Colchicum autumnale
• Autumn crocus, Meadow saffron, Star of Bethlehem, gowri gedde • Fer le meadows, o en 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
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Gloriosa superba
Courtesy Adrian Sington: Poison Diaries
Sandersonia auran aca
• 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 auran aca
Courtesyhttp://www.pacificbulbsociety.org/ M. Gastil-Buhl: Pacific Bulb Society
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Plantakine cs
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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 o en 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
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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
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 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
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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
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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 a er 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 o en 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 preven ng assembly • Dis nct 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, 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
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