Hikers poisoned: Veratrum steroidal alkaloid toxicity following ingestion of foraged Veratrum parviflorum.

INTRODUCTION: Steroidal alkaloids are found in plants of the genus Veratrum. Their toxicity manifests as gastrointestinal symptoms followed by a Bezold-Jarisch reflex: hypopnea, hypotension, and bradycardia. Some Veratrum steroidal alkaloids are also teratogens interfering with the hedgehog-2 signaling pathway, which causes cyclopsia and holoprosencephaly. We present a case of accidental poisoning from Veratrum parviflorum mistaken for the edible Allium tricoccum (ramps, wild leek). CASE HISTORY: A 27-year-old man and his 25-year-old wife presented to the emergency department with nausea, vomiting, hypotension, and bradycardia after foraging and ingesting plants that they believed to be a local native species of wild leek. METHODS: We collected and analyzed the implicated fresh plant material and both patients' serum/plasma. We used liquid chromatography-mass spectroscopy and high-resolution electrospray ionization time of flight tandem mass spectrometry to extract and characterize steroidal alkaloids from the foraged plant and patients' serum. RESULTS: Our V. parviflorum samples contained verazine, veratramine, veratridine, and cyclopamine. DISCUSSION: Steroidal alkaloids have been previously isolated from Veratrum viride and Veratrum album and toxicity has been reported mainly from V. album species. CONCLUSION: V. parviflorum toxicity manifests with gastrointestinal and cardiac symptoms. Treatment is symptomatic and supportive as with previous case reports of toxicity with other Veratrum species.

Was the death of Alexander the Great due to poisoning? Was it Veratrum album?

OBJECTIVE: To investigate the death of Alexander the Great to determine if he died from natural causes or was poisoned and, if the latter, what was the most likely poison. METHODS: OVID MEDLINE (January 1950-May 2013) and ISI Web of Science (1900-May 2013) databases were searched and bibliographies of identified articles were screened for additional relevant studies. These searches identified 53 relevant citations. Classical literature associated with Alexander's death. There are two divergent accounts of Alexander's death. The first has its origins in the Royal Diary, allegedly kept in Alexander's court. The second account survives in various versions of the Alexander Romance. Nature of the terminal illness. The Royal Diary describes a gradual onset of fever, with a progressive inability to walk, leading to Alexander's death, without offering a cause of his demise. In contrast, the Romance implies that members of Alexander's inner circle conspired to poison him. The various medical hypotheses include cumulative debilitation from his previous wounds, the complications of alcohol imbibing (resulting in alcohol hepatitis, acute pancreatitis, or perforated peptic ulcer), grief, a congenital abnormality, and an unhealthy environment in Babylon possibly exacerbated by malaria, typhoid fever, or some other parasitic or viral illness. Was it poisoning? Of all the chemical and botanical poisons reviewed, we believe the alkaloids present in the various Veratrum species, notably Veratrum album, were capable of killing Alexander with comparable symptoms to those Alexander reportedly experienced over the 12 days of his illness. Veratrum poisoning is heralded by the sudden onset of epigastric and substernal pain, which may also be accompanied by nausea and vomiting, followed by bradycardia and hypotension with severe muscular weakness. Alexander suffered similar features for the duration of his illness. CONCLUSION: If Alexander the Great was poisoned, Veratrum album offers a more plausible cause than arsenic, strychnine, and other botanical poisons.

Low-dose exposure to Veratrum album in children causes mild effects--a case series.

INTRODUCTION: White or false hellebore (Veratrum album) has a toxicological relevance because of the potential for misidentification of this plant as yellow gentian (Gentiana lutea). CASE SERIES: We report a retrospective case series of 11 children (8-12 years) with accidental intake of V. album at a youth camp where they had collected herbs for preparing fresh herb tea. Two children (18%) remained asymptomatic. Nine (82%) developed mild gastrointestinal symptoms, six (55%) presented neurological symptoms, and three (27%) showed bradycardia. All children recovered completely within 10 h of ingestion. The plant was identified at the emergency department; however, detection of veratridine and cevadine by means of high-performance liquid chromatography-Mass spectrometry from the blood of the child with the most severe symptoms was negative (limit 0.01 ng/mL). DISCUSSION: Veratrum species contain more than 200 different alkaloids, which are the principal toxins and are responsible for most clinical symptoms. There are likely multiple mechanisms of toxicity and some of them are only partially understood. The opening of voltage-gated sodium channels is probably one of the most relevant pathophysiological mechanisms. CONCLUSIONS: Veratrum album intoxication in children demonstrated the same clinical course as observed in adults. Accidental ingestion of a low dose of the plant had a favorable outcome with supportive care.

Accidental intoxication with Veratrum album.

A 49-year-old man consumed two glasses (approximately 2 x 20 mL) of a beverage containing yellow gentian (Gentiana lutea). Shortly after ingestion, he developed nausea, vomiting, and oral paraesthesia. On admission to the hospital he suffered from severe bradycardia (35 beats/min) and hypotension (50/30 mm Hg), and he was treated with activated charcoal, antiemetics (metoclopramide, ondansetron), atropine, and intravenous electrolytic solution. The initial suspicion of Veratrum poisoning could be confirmed by identifying protoveratrines A (ProA) and protoveratrine B (ProB) in a sample from the beverage as well as in the patients serum by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS-MS). The yellow-colored beverage contained 25% ethanol (by headspace gas chromatography), 20.4 mg/L ProA, and 13.7 mg/L ProB. The serum concentration of ProA was 1162 ng/L and ProB was 402 ng/L. Veratridine, cevadine, and jervine were not detected, neither in the beverage nor in the serum sample. The lower limits of quantitation for all compounds is 10 microg/L (S/N > 10, beverage) and 100 ng/L (S/N > 10, serum). After treatment, the patient completely recovered from the symptoms within 24 h and was discharged from the hospital. The analytical method described was developed for the simultaneous identification and quantitation of five Veratrum alkaloids. The method is based on a liquid-liquid extraction followed by LC-MS-MS analysis. The time needed for analysis was 6 min.

Veratrum poisoning.

Several species of the Veratrum genus are associated with toxicity in humans and animals. The principal toxins are steroid alkaloids; some have a modified steroid template, whereas others differ in their esterified acid moieties. These 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 a reflex that causes the triad of responses known as the Bezold-Jarisch reflex: hypotension, bradycardia and apnoea. Clinically, various Veratrum extracts were marketed for clinical use as antihypertensive drugs, but because of their narrow therapeutic index were withdrawn from the market. Following the ingestion of Veratrum alkaloids, expected signs and symptoms include vomiting and abdominal pain, followed by cardiovascular effects such as bradycardia, hypotension and cardiac conduction abnormalities and death. Similar symptoms arise in other mammalian species ingesting these alkaloids; teratogenic effects may occur to the fetuses of animals that have grazed on Veratrum californicum. Treatment consists of supportive care, with an emphasis on haemodynamic stability with fluid replacement, atropine and vasopressors. The onset of symptoms occurs between 30 minutes and 4 hours, and the duration of the illness can range from 1 to 10 days; however, with prompt supportive care, patients typically make a full recovery within 24 hours.

Biomedical applications of poisonous plant research.

Research designed to isolate and identify the bioactive compounds responsible for the toxicity of plants to livestock that graze them has been extremely successful. The knowledge gained has been used to design management techniques to prevent economic losses, predict potential outbreaks of poisoning, and treat affected animals. The availability of these compounds in pure form has now provided scientists with tools to develop animal models for human diseases, study modes of action at the molecular level, and apply such knowledge to the development of potential drug candidates for the treatment of a number of genetic and infectious conditions. These advances are illustrated by specific examples of biomedical applications of the toxins of Veratrum californicum (western false hellebore), Lupinus species (lupines), and Astragalus and Oxytropis species (locoweeds).

Development of an enzyme-linked immunosorbent assay for the veratrum plant teratogens: cyclopamine and jervine.

Veratrum californicum was responsible for large losses of sheep grazing high mountain ranges in central Idaho in the 1950s. Veratrum induces various birth defects including the cyclopic-type craniofacial defect (monkey-faced lambs) that is specifically induced in lambs after pregnant ewes grazed the plant on the 14th day of gestation. The steroidal alkaloids cyclopamine (1) and jervine (2) were isolated from Veratrum and shown to be primarily responsible for the malformations. Cyclopamine (1) and jervine (2) are potent teratogens that inhibit Sonic hedgehog (Shh) signaling during gastrulation-stage embryonic development, producing cyclopia and holoprosencephaly. Although losses to the sheep industry from Veratrum are now relatively infrequent, occasional incidents of toxicoses and craniofacial malformations are still reported in sheep and other species. However, the benefits to biomedical research using cyclopamine (1) as a tool to study human diseases have greatly expanded. A competitive inhibition enzyme-linked immunosorbent assay (ELISA) to detect and measure cyclopamine (1) and jervine (2) was developed using polyclonal antibodies produced in ewes. The limits of detection of the assay were 90.0 and 22.7 pg for cyclopamine (1) and jervine (2), respectively. This assay was used for the detection and measurement of cyclopamine (1) spiked into sheep blood. The simple extraction-ELISA methods developed in this study demonstrate the potential of using these techniques for the rapid screening of biological samples to detect the presence and concentration of cyclopamine (1) and jervine (2) and will be beneficial to pharmacological studies and livestock diagnostics.

Prolonged cardiotoxicity from poison lilly (Veratrum viride).

A 51-y-o otherwise healthy male presented to the emergency department 45 min after ingesting a soup made with boiled "leeks". Physical examination was significant for severe vomiting depressed mental status, and sluggishly reactive 2-3 mm pupils. Heart rate was 30 bpm and bp was 40/p mmHg requiring atropine and fluid resuscitation. After 60 min substernal chest pressure was noted and an ECG showed new V2-V6 ST segment depression. Recurrent hypotension required the use ofa dopamine infusion. At this time, the regional poison control center botanist identified a sample of the ingested material as Veratrum viride. The patient improved slowly over the next 24 hours, although bradycardia and heart block persisted for approximately 48 hours.

[A case of Veratrum poisoning]. / Un caso di avvelenamento da Veratro.

A poisoning from a Veratrum album infusion mistaken for Gentiana lutea is described. Confusion between these two plants can easily occur because they are very similar, although flowers and disposition of leaves allow their botanic determinat: V. album leaves are alternate and flowers are white, while G. lutea leaves are opposite and flowers yellow. The poisoning involves gastrointestinal (pyrosis, vomiting) and cardiocirculatory systems (bradyarrhy-thmias, A-V dissociation, vasodilatation) Atropine is the drug of choice.

Poisoning due to ingestion of Veratrum viride (false hellebore).

We present six cases of poisoning due to ingestion of Veratrum viride (false hellebore) and review the physiology of veratrum alkaloids. Significant bradycardia and hypotension can occur after intoxication by veratrum plants, which grow widely in swampy areas of the eastern and western United States. Nausea and vomiting also occur typically after ingestion. Atropine is the mainstay of therapy, but pressors may be required to maintain blood pressure. Cases of veratrum poisoning have not been widely reported in the emergency medicine literature.

[Electrocardiographic studies of patients with acute hellebore (Veratrum album) poisoning]. / Elektrokardiografski prouchvaniia pri bolni s ostro otraviane s chemerika (Veratrum album).

In 12 patients, 20 to 80 years of age, 6 men and 6 women, with acute hellebore (Veratrum album) intoxication the electrocardiographic changes were studied. In 10 of them a characteristic ECG pattern was found: sinus bradycardia 38-40/m, shortening of the interval PQ up to 0.12-0.08 s and QTc up to 0.36-0.32 s, slow intraventricular conduction--transitory right and incomplete left bundle-branch block, rhythm disorders--atrial and substitutional ventricular extrasystoles, nodal rhythm (I patient), disturbed ventricular repolarization--depression of ST-segment, low and (or) pointed T waves. The authors are of the opinion that the bradycardia is due to a reflexively increased vagal tonus but the other changes of the ECG are caused by the direct toxic action of the hellebore alkaloids on the myocardium. This suggestion is supported by the fact that atropine corrects the bradycardia but not the other pathological changes of the ECG. They are beneficially influenced by the fast elimination of the toxins and the application of cardiotropic means--atriphos, cocarboxylase, vitamins of the group B.

Veratrum alkaloids in sneezing-powder a potential danger.

Sneezing-powders containing pulverized root of veratrum album (white hellebore) have recently been marketed in the Scandinavian countries. The powder, imported from the Federal Republic of Germany, has caused severe intoxications.

Poisoning with Veratrum-containing sneezing powders.

1 Nine cases of accidental poisoning of children with sneezing powder are reported. Symptoms, besides sneezing, included gastrointestinal disturbances and syncope, whilst examination demonstrated bradycardia and hypotension. 2 The powder, as supplied, carried no information on its constituents but Veratrum alkaloids were identified on analysis. The signs and symptoms observed were compatible with poisoning from these compounds. 3 As a result of these observations, it was possible to trace the manufacturers and a change was made to a safer formulation. This example emphasises the value of toxic vigilance by Poison Control Centres.

[Veratrum album poisoning (author's transl)]. / Vergiftung mit Veratrum album (weisser Germer).

Ingestion of plant material rarely gives rise to manifest clinical intoxication. This is due to the relatively low toxicity of most of the poisonous plants of Central Europe. Veratrum album is an important exception on account of its highly toxic alkaloids. Seven cases of overt intoxication from veratrum album have been reported to the Austrian Poison Information Centre during the past 5 years. On the basis of these case reports toxicological and clinical aspects of this rare form of poisoning are discussed.

Cyclopamine and related steroidal alkaloid teratogens: their occurrence, structural relationship, and biologic effects.

A spontaneous congenital deformity is produced in lambs whose dams consume Veratrum californicum on the 14th day of gestation. The deformity is generally expressed as cyclopia, cebocephaly, anophthalmia, or microphthalmia. This teratogenic effect is produced by certain steroidal alkaloid teratogens from the plant - most notably the compound cyclopamine. Cyclopamine is a C-nor-D-homo steroid with fused furanopiperidine rings E and F at right angles to the plane of the steroid because of spiro attachment at C-17 of the steroid. Among veratrum alkaloids, only those with an intact furan ring E were teratogenic in sheep, whereas those in which the peperidine ring is not rigidly positioned at right angles to the steroid were not. Many ruminants and laboratory animals are susceptible to the teratogen. It has wide species and tissue specificity and appears to have a direct effect on the embryo, not as a consequence of metabolic alteration of its structure nor as an indirect effect through a maternal influence. Other plant sources, notably potatoes, tomatoes, and eggplant contain related spirosolane steroidal alkaloids. Among naturally occurring spirosolanes, solasodine is teratogenic in hamsters, but neither tomatidine not diosgenin, the non-nitrogen containing analog of solasodine, is teratogenic. Results of these and other studies suggest that a basic nitrogen positioned alpha with respect to the steroidal plane and at appropriate distance beyond the D ring confers the teratogenicity on the molecule. Potato sprouts with high alkaloid content are teratogenic in hamsters, but tubers and peels are not.