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Veratrum Album

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Veratrum Album

Veratrum album (commonly known as false helleborine, white hellebore, European white hellebore, or white veratrum; syn. Veratrum lobelianum Bernh)[1] is a poisonous medicinal plant[2][3] of the Liliaceae or Melanthiaceae. It is native to Europe and parts of western Asia (western Siberia, Turkey, Caucasus).[4] In Persian and Arabic, its name in traditional medicine is خربق ابیض.

Plant description

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Veratrum album is a tall perennial herb with alternate, pleated leaves. The flowers are white, marked with green on the top portion of the stalk. The fruit is a small pod containing winged seeds. The stout, simple stems are 50 to 175 cm tall. They are commonly mistaken for Yellow Gentian, Gentiana lutea, which is used in beverages, resulting in poisoning.[5][6][7] All part of the plant are poisonous, including its aroma.[8] The plants have an estimated lifespan of several centuries and often achieve dominance in wild areas as they are unpalatable to grazing herbivores.[9]

Toxicity

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Protoveratrine A

Veratrum album contains over fifty steroidal alkaloids called 'Veratrum alkaloids', including O-acetyljervine, cevadine, cryptenamine, cyclopamine (11-deoxojervine), cycloposine, germitrine, germidine, jervine, muldamine, protoveratrine (A&B), veratramine, veratridine, and veriloid.[10][11][12] Some of the principal toxins have a modified steroid template while others differ in their esterified acid moieties.[13] In general, Veratrum alkaloids act by increasing the permeability of the sodium channels of nerve cells, causing them to fire continuously. Increased stimulation, associated with the vagal nerve, results in the Bezold-Jarisch reflex: hypotension, bradycardia and apnoea.[13]

 
Protoveratrine B

Symptoms

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Symptoms of Veratrum alkaloid poisoning typically occur within thirty minutes to four hours of ingestion,[13] and include:[14]

  • vomiting
  • abdominal pain
  • hypotension
  • bradycardia
  • nausea
  • drowsiness
  • dizziness
  • dilated pupils

Treatment

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Treatment for Veratrum alkaloid poisoning include supportive care and symptomatic treatments, such as fluid replacement and anti-emetics. Atropine and vasopressors act to combat bradycardia and hypotension. Duration of illness can last up to ten days but full recovery is possible within a few hours depending on dose and treatment.[13]

Mechanism of Action

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Sodium ion channel

The neurotoxicity of Veratrum alkaloids derives from their effect on the sodium ion channels of nerve cells. They activate receptor site 2 of the voltage-dependent Na+ channel in excitable membranes by prolonging its open state.[15] The alkaloids depolarize nerves by enhancing exchange of Na+ and K+ across the membrane.[16]

Studies on the effect of local anesthetics on lipid monolayers of nerve membranes show that, at pharmacologically relevant concentrations, veratridine and cevadine cause an "interfacial dissolution": instability of films where both the alkaloid and stearate leave the monolayer upon compression, or as an increase of the rate of monooctadecyl phosphate desorption. Procaine and veratramine also penetrate into the lipid monolayer but do not produce film instability. The labilizing effect of veratridine can be reversed by the presence of procaine, Ca2+ and low pH.[16]

Uses

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The first proposal to use Veratrum Album to manage the effects of hypertension was made in 1859 by Baker,[17] who used the crude plant extracts in his experiments. Inconsistent and non-reproducible results limited the therapeutic use of the plant as the dose of the active compounds was unknown and accidental poisoning could easily occur. In 1890, Salzberger first isolated and named the alkaloid protoveratrine and its crystalline form became clinically available.[18] Later investigation found that protoveratrine is a mixture of two closely related alkaloids, protoveratrine A and protoveratrine B.[19] During the 1940s and 1950s, Veratrum Album was used as a hypotensive agent in treatment against essential hypertension, hypertension during renal dysfunction, and pre-eclampsia.[20][21] The use of Veratrum alkaloids for medicinal benefits has fallen out of practice due to the prevalence of more effective drugs and the fact that the alkaloid composition varies wildly in each plant extract.[22]

Isolated steroidal compounds from Veratrum Album, including protoveratrine, germidine, and jervine, have been reported to influence arterial pressure responses, decrease mean aortic pressure, cause renal, femoral and mesenteric vasodilation, and decrease the heart rate.[23][24][25]

O-acetyljervine has been reported to have beta-agonist activity.[26]

Extracts from dried rhizomes of Veratrum Album were briefly used as a pesticide against the Colorado potato beetle.[27]

Various Veratrum alkaloids were present in a German sneezing powder in 1982, resulting in the accidental poisoning of those who used it.[28]

Poisonings

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Sneezing powders are commonly used to prank others. In 1983, there were nine cases of accidental poisoning as a result of these pranks due to the presence of Veratrum alkaloids in the sneezing powders.[29] The victims were nine boys aged between 11 and 18 years old in Scandinavian countries who used supplies imported from the Federal Republic of Germany. All boys had inhaled the powder and six had ingested it. Symptoms typically presented within an hour, after which calls were made to authorities. After sneezing, the victims began to develop gastrointestinal disturbances such as vomiting in all cases and epigastric pain in two. Three of the children collapsed due to low blood pressure prior to being admitted to hospital. Seven of the children had significantly decreased blood pressure and five have cases of sinus bradycardia with no other irregularities. Half of those who had ingested the powder were treated with gastric lavage. Four of the boys were given atropine to combat bradycardia and one was given activated charcoal. Atropine normalised their heart rates within minutes but did little to assist with low blood pressure. In all cases, the patients recovered within twenty-four hours.[28]

 
Yellow Gentian

In 1985, five cases of acute accidental poisoning were reported.[30] Symptoms in all cases presented within minutes of drinking a homemade gentian wine. Yellow Gentian and White Hellebore often grow close together in fields and can be easily confused. Analysis showed that all wines ingested contained Veratrum alkaloids, causing vomiting, abdominal pain, hypotension, and bradycardia. Four patients showed sinus bradycardia and one patient had a complete atrioventricular block. All patients were treated with atropine and recovered within a few hours.

Two lethal cases of Veratrum poisoning were reported in France in 2001.[31] The deceased men were recovered from a lake one month after their deaths. Postmortem examination of the bodies revealed the presence of many black seeds in their stomachs. The circumstances of ingestion are unknown. The seeds were found to contain the alkaloids veratridine and cevadine, and the seeds were determined to be from the Veratrum Album plant. Authorities theorised that the men either knew of the plant's poisonous properties and intentionally poisoned themselves or hoped that the plant would have psychoactive properties, which have never been shown to be present.[14]

In 2005 and 2008, there were three reported cases of accidental poisoning from White Hellebore, two men in 2005[32] and one man in 2008.[33] Similar to the 1985 poisonings, the men had consumed beverages containing Yellow Gentian.

In 2005, the men presented with nausea and vomiting, preceded by headaches developed within one hour after ingestion, and followed by diarrhoea in one of the patients. The men's vital signs were normal except for their heart rates, which had dropped to 42 and 45 beats per minute respectively. Activated charcoal and antiemetics were administered and symptoms subsided withing eight hours.

In 2008, a 49-year-old man presented with nausea, vomiting, and oral paraesthesia after ingesting two classes of his poisoned beverage. He suffered severe bradycardia and hypotension. He was treated with activated charcoal, antiemetics, atropine, and intravenous electrolytic solution. Analysis of his drink confirmed the presence of protoveratrine A and protoveratrine B.[33]

In 2009, eleven children, aged 8 to 12 years old, accidentally ingested Veratrum Album at a youth camp where they'd prepared homemade tea using fresh herbs. Two children remained asymptomatic, nine developed mild gastrointestinal symptoms, six presented neurological symptoms, and three showed bradycardia. After medical care, all patients recovered within four hours of ingestion.[34]

Four cases of accidental poisoning were reported in 2010 after Veratrum Album was mistaken for Allium Ursinum (wild garlic) and used in self prepared-salad and soups.[35] All victims developed nausea, vomiting, abdominal pain, sinus bradycardia, and hypotension. Complete recovery took between twenty-four and forty-eight hours.

Alexander the Great

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A debate amongst historians is centred around the cause of death of Alexander the Great. Some believe the Greek king died of natural causes and others believe he was poisoned. The Romance suggests that his inner circle conspired to assassinate him upon his return to Babylon.[36] A theory proposed by Schep in 2013 suggests that Veratrum Album was used to kill Alexander the Great.[37] Schep argues that the usual suspects thought to be the culprit, such as arsenic and strychnine, would have acted too quickly to correlate with historical accounts. Alexander was ill for twelve days and suffered symptoms synonymous with Veratrum Album poisoning. Notably, the theory is furthered by the proposal that Alexander drank wine poisoned with Veratrum Album. Accounts from Diodorus detail that the king was struck with pain after drinking a large bowl of unmixed wine in honor of Hercules.[38]

References

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  1. ^ "Pfaf Plant Search". www.pfaf.org. Retrieved 2018-05-05.
  2. ^ "Veratrum Album. | Henriette's Herbal Homepage". www.henriettes-herb.com. Retrieved 2018-05-05.
  3. ^ "Veratrum Album.—White Hellebore. | Henriette's Herbal Homepage". www.henriettesherbal.com. Retrieved 2018-05-05.
  4. ^ "World Checklist of Selected Plant Families: Royal Botanic Gardens, Kew". apps.kew.org. Retrieved 2018-05-05.
  5. ^ Grobosch, T.; Binscheck, T.; Martens, F.; Lampe, D. (November 2008). "Accidental intoxication with Veratrum album". Journal of Analytical Toxicology. 32 (9): 768–773. ISSN 0146-4760. PMID 19021933.
  6. ^ Zagler, Bernhard; Zelger, Anton; Salvatore, Carmen; Pechlaner, Christoph; De Giorgi, Franco; Wiedermann, Christian J. (February 2005). "Dietary poisoning with Veratrum album--a report of two cases". Wiener Klinische Wochenschrift. 117 (3): 106–108. ISSN 0043-5325. PMID 15773425.
  7. ^ Garnier, R.; Carlier, P.; Hoffelt, J.; Savidan, A. (1985). "[Acute dietary poisoning by white hellebore (Veratrum album L.). Clinical and analytical data. A propos of 5 cases]". Annales De Medecine Interne. 136 (2): 125–128. ISSN 0003-410X. PMID 4073696.
  8. ^ "Handbook of Poisonous and Injurious Plants". 2007. doi:10.1007/978-0-387-33817-0. {{cite journal}}: Cite journal requires |journal= (help)
  9. ^ Kleijn, David; Steinger, Thomas (2002-04). "Contrasting effects of grazing and hay cutting on the spatial and genetic population structure of Veratrum album, an unpalatable, long-lived, clonal plant species". Journal of Ecology. 90 (2): 360–370. doi:10.1046/j.1365-2745.2001.00676.x. ISSN 0022-0477. {{cite journal}}: Check date values in: |date= (help)
  10. ^ Chen, K. K.; Henderson, F. G.; Anderson, R. C. (August 1950). "The cardiac action of Helleborus glycosides and their aglycones". The Journal of Pharmacology and Experimental Therapeutics. 99 (4:1): 325–400. ISSN 0022-3565. PMID 15437315.
  11. ^ Freis, E. D.; Stanton, J. R.; Moister, F. C. (February 1950). "Assay in man of the chemical fractions of Veratrum Viride, and identification of the pure alkaloids germitrine and germidine as potent hypotensive principles derived from the drug". The Journal of Pharmacology and Experimental Therapeutics. 98 (2): 166–173. ISSN 0022-3565. PMID 15422510.
  12. ^ Marchetti, G. (January 1954). "[Effect of two new alkaloids of Veratrum viride on the circulatory apparatus]". Archivio Italiano Di Scienze Farmacologiche. 4 (1): 15–27. PMID 13159580.
  13. ^ a b c d Schep, Leo J.; Schmierer, David M.; Fountain, John S. (2006-06-01). "Veratrum Poisoning". Toxicological Reviews. 25 (2): 73–78. doi:10.2165/00139709-200625020-00001. ISSN 1176-2551.
  14. ^ a b "Veratrum album, white hellebore - THE POISON GARDEN website". www.thepoisongarden.co.uk. Retrieved 2018-05-05.
  15. ^ Ujvary, Istvan; Eya, Bryan K.; Grendell, Richard L.; Toia, Robert F.; Casida, John E. (October 1991). "Insecticidal activity of various 3-acyl and other derivatives of veracevine relative to the veratrum alkaloids veratridine and cevadine". Journal of Agricultural and Food Chemistry. 39 (10): 1875–1881. doi:10.1021/jf00010a039. ISSN 0021-8561.
  16. ^ a b "Studies on the mechanism of action of local anesthetics with phospholipid model membranes". Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes. 265 (2): 169–186. 1972-04-18. doi:10.1016/0304-4157(72)90001-9. ISSN 0304-4157.
  17. ^ Saksena, Anil K.; McPhail, Andrew T. (January 1982). "Structure of protoveratrine C, a new alkaloid from provoveratrine". Tetrahedron Letters. 23 (8): 811–814. doi:10.1016/s0040-4039(00)86955-5. ISSN 0040-4039.
  18. ^ Stoll, A.; Seebeck, E. (1953). "Über Protoveratrin A und Protoveratrin B. 6. Mitteilung über Veratrum-Alkaloide". Helvetica Chimica Acta (in German). 36 (3): 718–723. doi:10.1002/hlca.19530360326. ISSN 0018-019X.
  19. ^ GLEN, WILLIAM L.; MYERS, GORDON S.; BARBER, RICHARD; MOROZOVITCH, PAUL; GRANT, GORDON A. (1952). "Hypotensive Alkaloids of Veratrum album". Nature. 170 (4335): 932–932. doi:10.1038/170932a0. ISSN 0028-0836.
  20. ^ Barrow, J. G.; Sikes, C. R. (May 1951). "The use of purified veratrum viride alkaloids in the treatment of essential hypertension". American Heart Journal. 41 (5): 742–748. ISSN 0002-8703. PMID 14829406.
  21. ^ Stearns, N. S.; Ellis, L. B. (1952-03-13). "Acute effects of intravenous administration of a preparation of Veratrum viride in patients with severe forms of hypertensive disease". The New England Journal of Medicine. 246 (11): 397–400. doi:10.1056/NEJM195203132461102. ISSN 0028-4793. PMID 14910826.
  22. ^ Meilman, Edward; Krayer, Otto (1950-02-01). "Clinical Studies on Veratrum Alkaloids: I. The Action of Protoveratrine and Veratridine in Hypertension". Circulation. 1 (2): 204–213. doi:10.1161/01.CIR.1.2.204. ISSN 0009-7322. PMID 15409589.
  23. ^ Korol, B.; Zuber, A. V.; Miller, L. D. (August 1970). "Carotid sinus pressure reflex bioassay for Veratrum viride". Journal of Pharmaceutical Sciences. 59 (8): 1110–1113. ISSN 0022-3549. PMID 5457326.
  24. ^ Roesch, E. (1954). "[Effect of cevadine, veratridine and Veratrum viride extract on blood pressure and respiration in dog]". Naunyn-Schmiedebergs Archiv Fur Experimentelle Pathologie Und Pharmakologie. 222 (1–2): 209–212. PMID 13176492.
  25. ^ Zupko, A. G.; Edwards, L. D. (November 1950). "A study of a depressor principle of Veratrum viride". Journal of the American Pharmaceutical Association. American Pharmaceutical Association. 39 (11): 610–615. PMID 14794527.
  26. ^ Gilani, Anwar H.; Aftab, Khalid; Saeed, S. A.; Ali, Rahat A.; Rahman, Atta-ur (1995-04-01). "O-Acetyljervine: A new β-adrenoceptor agonist fromVeratrum album". Archives of Pharmacal Research. 18 (2): 129–132. doi:10.1007/BF02979146. ISSN 0253-6269.
  27. ^ Aydin, Tuba; Cakir, Ahmet; Kazaz, Cavit; Bayrak, Neslihan; Bayir, Yasin; Taşkesenligil, Yavuz (2014). "Insecticidal Metabolites from the Rhizomes ofVeratrum albumagainst Adults of Colorado Potato Beetle,Leptinotarsa decemlineata". Chemistry & Biodiversity. 11 (8): 1192–1204. doi:10.1002/cbdv.201300407. ISSN 1612-1872.
  28. ^ a b Carlier, P.; Efthymiou, M-L.; Garnier, R.; Hoffelt, J.; Fournier, E. (April 1983). "Poisoning with Veratrum-containing Sneezing Powders". Human & Experimental Toxicology. 2: 321–325.
  29. ^ Fogh, Anne; Kulling, Per; Wickstrom, Elsa (1983). "Veratrum Alkaloids in Sneezing-Powder a Potential Danger". Journal of Toxicology: Clinical Toxicology. 20.
  30. ^ Garnier, R.; Carlier, P.; Hoffelt, J.; Savidan, A. (1985). "[Acute dietary poisoning by white hellebore (Veratrum album L.). Clinical and analytical data. A propos of 5 cases]". Annales De Medecine Interne. 136 (2): 125–128. ISSN 0003-410X. PMID 4073696.
  31. ^ Gaillard, Yvan; Pepin, Gilbert (September 2001). "LC-EI-MS Determination of Veratridine and Cevadine in Two Fatal Cases of Veratrum album Poisoning" (PDF). Journal of Analytical Toxicology. 25: 481–485.
  32. ^ Zagler, Bernhard; Zelger, Anton; Salvatore, Carmen; Pechlaner, Christoph; De Giorgi, Franco; Wiedermann, Christian J. (February 2005). "Dietary poisoning with Veratrum album--a report of two cases". Wiener Klinische Wochenschrift. 117 (3): 106–108. ISSN 0043-5325. PMID 15773425.
  33. ^ a b Grobosch, T.; Binscheck, T.; Martens, F.; Lampe, D. (November 2008). "Accidental intoxication with Veratrum album". Journal of Analytical Toxicology. 32 (9): 768–773. ISSN 0146-4760. PMID 19021933.
  34. ^ Rauber-Luthy, Christine (February 2010). "Low-dose exposure to Veratrum album in children causes mild effects – a case series". Clinical Toxicology. 48.
  35. ^ Gilotta, Irene; Brvar, Miran (November 2010). "Accidental poisoning with Veratrum album mistaken for wild garlic (Allium ursinum)". Clinical Toxicology (Philadelphia, Pa.). 48 (9): 949–952. doi:10.3109/15563650.2010.533675. ISSN 1556-9519. PMID 21171854.
  36. ^ Pseudo-Callisthenes. (1991). The Greek Alexander romance. Stoneman, Richard. London, England: Penguin Books. ISBN 0140445609. OCLC 24810739.
  37. ^ Schep, Leo (August 2013). "Was the death of Alexander the Great due to poisoning? Was it Veratrum album?". Clinical Toxicology. 54.
  38. ^ "Mystery of Alexander the Great's death solved? Ruler was 'killed by". The Independent. 2014-01-12. Retrieved 2018-05-05.
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