Colorful - American College of Medical Toxicology

The$Peas$Are$Red,$the$Crocus$Are$Blue.$
Have$a$Colorful$Meal,$Mul9ple$Organ$
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$policy,$posi9on,$or$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$vomi9ng,$weakness$4$hrs$later$
SBP$90/40 $pulse$120 $vomi9ng,$acidemic,$creat$2.2$
23$March$2014$
Ricinus'communis'
Southern$US$and$NE$
and$West$coast$
Mediterranean$basin$
East$Africa$
India$
Abrus'precatorius'–'jequirity,'rosary'pea'
Jatropha$curcas$
Chinese$cucumber,$Trichosanthes$
Black$locust$
American$mistletoe$
history$
Georgi$Markov
$September$11,$1978$
Bloomberg,$Obama
$Shannon$Richardson$–$May$29,$2013$
Lec9ns$–$protein$that$binds$carbs$
Toxalbumins$–$ricin$and$abrin$
Ribosomal$Inac9va9ng$Protein$II$(RIP$II)$
$A$part$and$B$part$
Ricin$–$powder$or$crystal;$in$liquid$$
Stops$making$proteins,$etc.1$$
Chain$B$–$Binds&galactose$
Chain$A$–$A(acks,$inhibits$
28s$subunit$of$60S$ribosome$
Ricin$communis$agglu9nin2$
$$$RBC$agglu9na9on,$hemolysis$$
$$$IV$injec9on$
Ricinine$–$seizure$in$animals3$
1Day,$Biochemistry,$2002$
3Darby,$J'Forensic'Sci,$2001$
$2Balint,$Toxicol,$1974$
Abrin$–$toxalbumin$like$ricin$
$Abrus'precatorius'
RIP$II$
Not$weaponized$
Inges9on$–$$30mg/kg$LD50$in$mice$
$Few$grains$of$salt $$
$IV$or$inhaled$–$1000x$lower$dose$$
Humans$1f20$mcg/kg$(8$beans?)$
Clinical$findings$
Decontamina9on$
•  PPE$
Toxic$effects$
GI,$hypotension,$liverfrenal$failure$
$w/in$4f6$hrs$but$can$be$<$10$hrs$
Cough$sob,$fever,$respi$distress$
allergic$response;$within$8$hrs$$
Cardiac,$heme,$hepa9c,$renal$
Delayed$–$failure$to$make$a$
protein$
Local$9ssue,$weak;$delayed$vomi9ng,$
fever,$MOF,$w/in$10f12$hrs$
Syndrome$
Bacterial,$chemical,$
foodborne$gastroenteri9s$
Rapid$severe$resp$illness$
in$12f24$hrs$
Pseudomembranous$
conjunc9vi9s1$
Ur9caria$–$IgE$mediated$
$Allergic2$
1Grant$WM,$1993$$$$2Kennedy$DM,$Clin'Allergy,$1981$$
Blood$or$urine$ricin$or$ricinine$(<$48$hrs)$
GCMS$or$LC$MS/MS$
US$Army$Med$Research$Ins9tute$Infec9ous$Disease$
CDC$
Electrolytes$$
No$dialysis$but$follow$for$
renal$failure$
inhaled/vent$therapies$
If$no$symptoms$for$12$hrs$–$then$likely$fine$
Progresses$over$4f36hrs$
Inhaled$–$delay$of$20f24$hrs$
Dermal$–$likely$safe$,but$12$hr$obs$$
Ricin$vaccine$
In$development$
November$2013$
JAMA$
Medical$Toxicologists$
$November$2005$
26$
The$Peas$Are$Red,$the$Crocus$Are$
Blue.$Have$a$Colorful$Meal,$Mul9ple$
Organ$Failure$Will$Ensue:$The$
Toxicology$Behind$Cyctoxic$Plant$
Poisoning$$
Lt$Col$Vik$Bebarta,$MD,$FACEP,$FACMT$
Medical$Toxicology,$San$Antonio$Military$Medical$Center$
G.$Patrick$Daubert,$MD,$FACEP,$FACMT$
Kaiser$Permanente,$Northern$California$Regional$Toxicology$Service$
DISCLOSURE:$
I$have$no$relevant$financial$interest/
arrangement$$
or$affilia9on$with$$
any$organiza9ons$related$to$$
commercial$products$or$services$$
to$be$discussed$at$this$program$
28$
Learning$Objec9ves$
Aler$comple9ng$this$ac9vity,$par9cipants$will$be$
able$to:$
•  Describe$those$plants$that$contain$colchicine$
alkaloids$
•  Illustrate$the$intracellular$binding$site$for$
colchicine$alkaloids$
•  Explain$the$phases$of$toxicity$seen$with$
cytotoxic$plant$poisoning$
29$
Historical$Perspec9ve$
Colchicine$
•  Listed$in$the$Egyp9an$medical$papyrus$$(ca.$
1500$B.C.)$
•  Used$by$a$number$Greek$physicians$
•  Prior$to$****,$colchicine$was$an$unapproved$
drug$with$no$prescribing$informa9on,$dosage$
recommenda9ons,$or$drug$interac9on$
warnings$
Environmental$Considera9ons$
Colchicine$Alkaloids$
• 
• 
• 
• 
Colchicum'autumnale'
Gloriosa'superba'
Sandersonia'auranBaca'
Kreysigia'mulBflora$(Tripladenia'cunninghamii,$
Bush$lily)$
33$
Colchicum'autumnale'
•  Autumn$crocus,$Meadow$saffron,$Star$of$
Bethlehem,$gowri$gedde$$
•  Fer9le$meadows,$olen$at$the$edges$of$woods$
in$the$western,$central,$and$southern$Europe$$
•  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,$9ger$claw,$and$fire$lily$
•  Occurs$in$semifshade$areas$among$bush$on$
hillsides$in$Southern$Asia$and$Tropical$Africa$$
•  Na9onal$flower$of$Zimbabwe$
•  Tubers&mistaken&for&sweet&potatoes&or&yams&&
Gloriosa'superba$
Courtesy Adrian Sington: Poison Diaries
Sandersonia'auranBaca'
•  Christmasfbells,$Chinese$lantern$lily,$Gold$lily$
of$the$valley$
•  Grows$in$damp$grassland,$on$forests$margins$
in$the$eastern$areas$of$South$Africa$
•  Delicate,$slightly$climbing$plant$with$
pendulous$lanterns$
•  Popular$cut$flower$in$southern$hemisphere$$
Sandersonia'auranBaca'
Courtesy
M. Gastil-Buhl: Pacific Bulb Society
http://www.pacificbulbsociety.org/
Plantakine9cs$
40$
Plantakine9cs$
•  Data$following$acute$inges9ons$of$plants$
containing$colchicine$alkaloids$are$limited$$
•  Current$data$are$primarily$based$upon$case$
reports,$with$cofingestants$olen$confounding$
the$kine9cs$
Plantakine9cs$
•  Rapidly$absorbed$
•  Metabolized$by$the$liver$–$limited$renal$clearance$
•  Significant$biliary$excre9on$and$enterohepa9c$
recircula9on$
•  Peak$plasma$levels$occur$in$30$minutes$to$2$hours$$
•  Volume$of$distribu9on$(10f12$L/kg)$
•  Elimina9on$halfflife$1.7f32$hours$
•  50%$protein$bound$$$
•  High$concentra9ons$in$breast$milk$
Sabouraud A, Rochdi M, Urtizberea M, et al. Z Gastroenterol. 1992;30:35–39
Mechanisms$
Mechanisms$
•  Intracellular$transport$via$the$mul9drug$
transporter$Pfglycoprotein$(Pgp)$(ATPase$efflux$
pump)$
•  Colchicine$reversibly$binds$to$βftubulin$
•  Results$in$curved$tubulin$dimer$$
•  Prevents$a$straight$structure$due$to$a$steric$
clash$between$colchicine$and$αftubulin$
•  Loss$of$lateral$contacts$leads$to$rapid$
microtubule$depolymeriza9on$and$dynamic$
instability$
Hastie SB. Pharmacol Ther. 1991;51(3):377-401
Microtubule$
α"
β"
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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$
CBS
α"
β"
CBS: Colchicine Binding Site
Mechanisms$
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"
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β"
β"
46$
Mechanisms$
•  Eight$iden9fied$βftubulin$isotypes$in$humans$
•  Known$muta9ons$in$tubulin$and$
overexpression$of$β$IIIftubulin$isoform$
•  Overexpression$of$class$III$βftubulin$is$an$
indicator$of$resistance$to$tubulin$binding$by$
colchicine$
Range$of$Toxicity$
48$
Range$of$Toxicity$
•  Colchicine$levels$are$highest$at$the$beginning$of$the$
growth$season$
•  Plant$concentra9ons$average$approximately$
0.1f0.06%$$
•  Each$seed$contains$approximately$3.5$mg$of$
colchicine$
•  Inges9on$of$10$to$12$flowers$has$been$fatal$in$adults$
Range$of$Toxicity$
•  Inges9ons$<$0.5$mg/kg$$
–  gastrointes9nal$distress$
•  Inges9ons$0.5f0.8$mg/kg$$
–  Myelosuppression$
–  10%$fatality$rate$
•  Inges9ons$of$>$0.8$mg/kg$$
–  cardiovascular$collapse$
–  death$within$72$hours$
Clinical$Manifesta9ons$
51$
Clinical$Manifesta9ons$
•  Latent$period$of$4–12$hours.$$
•  First$phase$(12f24$hours)$
–  peripheral$leukocytosis,$gastrointes9nal$symptoms$with$
fluid$losses$and$hypovolemic$shock.$$
•  Second$phase$(24–72$hours)$
–  heart$failure,$arrhythmias,$renal$failure,$hepa9c$injury,$
respiratory$distress,$coagulopathies,$bone$marrow$
depression$and$neuromuscular$involvement$
•  Third$phase$(5–7$days)$
–  leukocytosis$and$alopecia$
Case$Review$
•  German$case$series$of$32$pa9ents$between$27$and$
90$years$
•  All$pa9ents$developed$diarrhea$and/or$vomi9ng$aler$
a$latency$period$of$between$2$and$24$h$
•  Pa9ents$with$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$
Management$
• 
• 
• 
• 
Early$intensive$support$measures$$
Granulocytefdirected$growth$factors$$
Biliary$drain?$
Colchicinefspecific$Fab$fragments$
Summary$
56$
Summary$
•  Two$primary$colchicine$alkaloid$producing$
plants$are$Autumn'crocus'and$Gloriosa'
superba'
•  Colchicine$binds$to$βfsubunit$on$microtubules$
preven9ng$assembly$
•  Dis9nct$phases$of$toxicity$
•  High$fatality$rate$
•  Early$intensive$support$measures$
57$
The$Peas$Are$Red,$the$Crocus$Are$Blue.$
Have$a$Colorful$Meal,$Mul9ple$Organ$
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$