Death of Socrates: a likely case of poison hemlock (Conium maculatum) poisoning.

INTRODUCTION: The death of Socrates in 399 BCE is described in Plato's dialogue, the Phaedo, written an unknown time afterwards from accounts by others. THE EVIDENCE: Socrates' death has almost always been attributed to his drinking an extract of poison hemlock, Conium maculatum, despite apparent discrepancies between the clinical features described in classical translations of the Phaedo and general clinical experience of poisoning with the toxic alkaloids it contains. EVALUATION: Recent acute philological analysis of the original Greek text has resolved many of the discrepancies by showing that the terms used in the classical translations were misinterpretations of the clinical signs described. It is also likely that the unpleasant clinical effects, such as vomiting, abdominal pain, diarrhoea and muscle fasciculation commonly described in modern reports of poison hemlock poisoning, were not mentioned to present the death of Socrates in a way consistent with his philosophical ideals and those of his pupil Plato. CONCLUSIONS: Seen in this way, the death of Socrates can be accepted as a limited case report of Conium maculatum poisoning. Even after reaching that conclusion, intriguing scientific questions remain about the toxicity of the coniine alkaloids and the mechanisms of their effects.

Lantana camara poisoning in cattle that took refuge during a storm in a forest invaded by this plant.

An outbreak of poisoning by Lantana camara occurred in cattle when a herd sought refuge in a Eucalyptus forest heavily infested by this plant. The animals showed apathy, elevated serum activities of hepatic enzymes, severe photosensitivity, jaundice, hepatomegaly and nephrosis. After a clinical manifestation period of 2-15 days, 74 out of 170 heifers died. The main histological changes were random hepatocellular necrosis, cholestasis, biliary proliferation and, in one animal, centrilobular necrosis. Immunostaining for Caspase 3 detected scattered apoptotic hepatocytes.

A toxic shrub turned therapeutic: The dichotomy of Nerium oleander bioactivities.

Nerium oleander L. is a medicinal plant, used for the treatment of cancers and hyperglycemia across the world, especially in Indian sub-continent, Turkey, Morocco, and China. Although clinical studies supporting its pharmacological effects remain critically underexplored, accidental and intentional consumption of any part of the plant causes fatal toxicity in animals and humans. While the polyphenolic fraction of oleander leaves has been attributed to its pre-clinical pharmacological activities, the presence of diverse cardiac glycosides (especially oleandrin) causes apoptosis to cancer cells in vitro and results in clinical signs of oleander poisoning. Thus, the dual pharmacological and toxicological role of oleander is a perplexing dichotomy in phytotherapy. The current investigative review, therefore, intended to analyze the intrinsic and extrinsic factors that likely contribute to this conundrum. Especially by focusing on gut microbial diversity, abundance, and metabolic functions, oleander-associated pharmacological and toxicological studies have been critically analyzed to define the dual effects of oleander. Electronic databases were extensively screened for relevant research articles (including pre-clinical and clinical) related to oleander bioactivities and toxicity. Taxonomic preference was given to the plant N. oleander L. and synonymous plants as per 'The World Flora Online' database (WCSP record #135196). Discussion on yellow oleander (Cascabela thevetia (L.) Lippold) has intentionally been avoided since it is a different plant. The review indicates that the gut microbiota likely plays a key role in differentially modulating the pharmacological and toxicological effects of oleander. Other factors identified influencing the oleander bioactivities include dose and mode of treatment, cardiac glycoside pharmacokinetics, host-endogenous glycosides, plant material processing and phytochemical extraction methods, plant genotypic variations, environmental effects on the phytochemical quality and quantity, gene expression variations, host dietary patterns and co-morbidity, etc. The arguments proposed are also relevant to other medicinal plants containing toxic cardiac glycosides.

[Colchicum poisoning by confusion with wild garlic (Allium ursinum)]. / Intoxication au colchique par confusion avec l'ail des ours.

INTRODUCTION: Colchicine poisoning is a life-threatening intoxication. CASE REPORT: We report a case of food poisosing with Colchicum autumnale by confusion with wild garlic. The clinical presentation is the same as that of colchicine drug intoxication. The evolution can be fatal in case of massive ingestion. The proximity of the place of growth and their similar appearance in spring make Colchicum and wild garlic plants that can easily be confused. CONCLUSION: Physicians have to be vigilant in case of dysenteric syndrome and biological disturbances in spring and look for the consumption of perennial plant preceding symptoms.

Neurological and gastrointestinal manifestations of spontaneous poisoning by Ricinus communis in goats.

An outbreak of Ricinus communis poisoning in goats with neurological and digestive changes was related to the ingestion of different vegetative parts of the plant. Two poisoned animals died within 5 h of the plant intake showing necrotic gastroenteritis and hepatocytes degeneration and necrosis. Toxicological analysis by HPLC-DAD assay demonstrated 21.1-25.1 µg/g of ricinine in samples of ruminal fluids and 10.1-10.9 µg/g in the liver of poisoned goats.

Mineral-salt supplementation to ameliorate larkspur poisoning in cattle.

Larkspurs (Delphinium spp.) are native forbs that are poisonous to cattle and cost livestock producers millions of dollars in losses each year. Macro and micro minerals are required for normal functioning of essentially all metabolic processes in ruminants. The role that mineral status may play in larkspur poisoning in cattle is not clear. In this study, we seek to determine the effects a mineral-salt supplement, commonly used by cattle producers, to potentially reduce cattle losses to larkspur. The ability of mineral-salt supplementation to alter susceptibility to larkspur toxicosis was evaluated in a pen study. Animals supplemented with mineral-salt were found to be less susceptible to larkspur poisoning than the non-supplemented animals. A separate group of animals were then grazed on larkspur infested rangelands. One group was supplemented with a mineral-salt mix and the other group did not receive any mineral-salt. Supplementing cattle with the mineral-salt mix did not alter larkspur consumption (P > 0.05). However, overall larkspur consumption was low and averaged 3 ± 1.0% and 2 ± 1.1% for cattle supplemented with mineral and non-supplemented, respectively. Serum was collected from animals once a week during the grazing study. Average and maximum serum concentrations of toxic larkspur alkaloids were numerically higher in mineral-salt supplemented cattle compared with the non-supplemented animals. Results from the pen study suggest that a good mineral supplementation program will provide a protective effect for animals grazing in larkspur-infested ranges. The mineral-salt supplemented steers, in the grazing study, were not observed to consume less larkspur than the non-supplemented animals; however, the mineral-salt supplemented animals had higher concentrations of larkspur alkaloids in their serum indicating they may be able to tolerate higher larkspur consumption. The data also indicate that mineral-salt supplementation must be continuous throughout the time the animals are grazing these rangelands as the positive effects can be lost within 30 d post supplementation.

Larkspurs (Delphinium spp.) are native forbs poisonous to cattle and cost livestock producers millions of dollars in losses each year. The role mineral status may play in larkspur poisoning in cattle is unclear. The ability of mineral-salt supplementation to alter susceptibility to larkspur toxicosis was evaluated in a pen and grazing study. In the pen study, animals supplemented with mineral-salt were found to be less susceptible to larkspur poisoning than non-supplemented animals. A separate group of animals grazed on larkspur infested rangelands. One group was supplemented with a mineral-salt mix and the other group did not receive any mineral-salt. Supplementing cattle with the mineral-salt mix did not alter larkspur consumption of grazing cattle. However, overall larkspur consumption was low. Results from the pen study suggest that a good mineral supplementation program will provide a protective effect for animals grazing in larkspur-infested ranges. The mineral-salt supplemented steers, in the grazing study, had higher concentrations of larkspur alkaloids in their blood serum indicating they may be able to tolerate higher larkspur consumption. The data also indicate that mineral-salt supplementation must be continuous throughout the time the animals are grazing as the positive effects can be lost within 30 days after supplementation.

Evaluation of diazepam as a drug treatment for water hemlock (Cicuta species) poisoning in Spanish goats.

Water hemlocks (Cicuta spp.) are toxic members of the Apiaceae plant family. The best drug treatment for the convulsions associated with acute water hemlock poisoning in livestock and humans has not been determined experimentally. This work compared the therapeutic actions of benzodiazepines (diazepam) and barbiturates (phenobarbital) on water hemlock poisoning in a goat model. C. maculata tubers were orally dosed to goats. Experimental groups consisted of; control saline; 20 mg/kg phenobarbital; 1.0 mg/kg diazepam; 10 mg/kg diazepam; and 1.0 mg/kg diazepam administered as needed to moderate convulsions by intravenous (i.v.) infusion. Diazepam provided nearly instant control of convulsions. Clinical signs of poisoning were completely controlled for the duration of the experiment in the goats that received the 10 mg/kg diazepam dose. These results suggest that diazepam is effective at managing the clinical signs of water hemlock poisoning in goats. We speculate that diazepam can be used as a potential treatment for water hemlock poisoning in other livestock species and humans.

A suicide attempt by ingestion of oleander leaves and treatment with digoxin-specific Fab antibody fragments.

Natural cardiac glycosides have positive inotropic heart effects but at high, toxic doses they can cause life-threatening cardiac arrhythmias. Here we present the first Croatian case of a 16-year-old girl who attempted suicide by eating dried oleander leaves, which contain natural cardiac glycosides, and her treatment with a specific antidote. The girl presented with an oedema of the uvula indicating local toxicity, severe bradycardia, first-degree atrioventricular block, drowsiness, and vomiting. Having taken her medical history, we started treatment with atropine, intravenous infusion of dextrose-saline solution and gastroprotection, but it was not successful. Then we introduced digoxin-specific Fab antibody fragments and within two hours, the patient's sinus rhythm returned to normal. Cases of self-poisoning with this oleander are common in South-East Asia, because it is often used as a medicinal herb, and digoxin-specific Fab fragments have already been reported as effective antidote against oleander poisoning there. Our case has taught us that it is important to have this drug in the hospital pharmacy both for digitalis and oleander poisoning.

La Digitalis. Una planta ligada al arte / Digitalis. A plant linked to art

Resumen La Digitalis purpúrea ha sido utilizada por sus propiedades terapéuticas desde la antigüedad hasta nuestros días. Su difundido uso, tanto como la diversidad de indicaciones que tuvo, permitió que también se conociese desde antaño los riesgos a la salud para quien recibiese una dosis excesiva. La toxicología actual conoce y maneja perfectamente la intoxicación digitálica, sin embargo, muchas historias relacionadas con su uso son poco conocidas. Se presentan algunas de estas historias, muchas de ellas relacionadas con el mundo del arte.

Abstract Digitalis purpurea has been used because of its therapeutic properties since ancient times up to our days. Its wide- spread use as well as the variety of indications that it covered allowed to know the risks for health in case of overdose. Present toxicology is aware and knows perfectly well how to treat digitalic poisoning. However, many stories about digitalis are little known. Here, we show you some of them, specially the ones related with arts.

Investigation of cardiac glycosides from oleander in a human induced pluripotent stem cells derived cardiomyocyte model.

The ingestion of Nerium oleander and Thevetia peruviana are common causes for poisoning in Southeast Asia. All parts of the oleander shrub contain cardiac glycosides of the cardenolide type. These glycosides act via inhibition of a Na+/K+-ATPase which might cause severe arrhythmia and subsequent death in oleander-poisoned patients. The current study uses human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CM) in a microelectrode array (MEA) system to assess the cardiac effects of neriifolin, oleandrin, digitoxigenin, peruvoside and thevetin A from the oleander plant. Digoxin was used as established reference compound. All tested compounds showed a corrected field potential duration (FPDc) shortening and was the lowest for 600 nM digitoxigenin with -36.9 ± 1.2 %. Next to the dose-dependent pro-arrhythmic potential, a complete beat arrest of the spontaneously beating hiPSC-CM was observed at a concentration of 300 nM for neriifolin, 600 nM for oleandrin and 1000 nM for digitoxigenin and peruvoside. Thevetin A did not cause arrhythmia up to a final concentration of 1000 nM. Thus, it was possible to establish a cardiac effect rank order of the tested substances: neriifolin > oleandrin > digitoxigenin = peruvoside > digoxin > thevetin A.

Endemic Xanthium strumarium poisoning in cattle in flooded areas of the Araguari River, Minas Gerais, Brazil.

In this paper, we describe poisoning outbreaks of Xanthium strumarium in cattle on the borders of the Araguari River, Southeastern Brazil. In this region, several hydroelectric plants promote transient flooding, which creates a favorable environment for the invasion of X. strumarium in extensive areas, often as the predominant species in those areas. The outbreaks occurred between July and September (dry season). Bovines of all ages were affected, including suckling animals. Mortality varied from 2% to 5.5%. The animals exhibited ataxia, weakness, loss of balance, recumbency, and the majority were found dead. Laboratory results showed a marked increase in the serum activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase. Histological and ultrastructural changes in the liver consisted of centrilobular necrosis and hemorrhage. On toxicological evaluation, the dicotyledons contained 0.30 µg/mg of atractyloside and 0.37 µg/mg of carboxyatractyloside. Considerable economic loss has occurred in this region due to the lack of knowledge regarding X. strumarium as a toxic plant and its adaptation to the environmental and climatic conditions of the region, which have made the condition endemic.

Poisonous delicacy: Market-oriented surveys of the consumption of Rhododendron flowers in Yunnan, China.

ETHNOPHARMACOLOGICAL RELEVANCE: Plants from the family Ericaceae, and in particular those in the genus Rhododendron are frequently reported to contain grayanotoxins. Plant products such as honey and herbal medicines made from these plants occasionally contain grayanotoxins, and in turn may lead to intoxication. The balance between the benefits and risk of poisoning from Rhododendrons is of concerns. This study explores the ethnobotanical knowledge of the people in Yunnan, China as regards the consumption of Rhododendron flowers, and gives special focus to their assessment of the benefit-risk balance. MATERIALS AND METHODS: An ethnobotanical survey was conducted across 14 county-level local markets in north and central Yunnan province, during which a total of 82 stalls selling Rhododendron flowers were visited and 204 people were interviewed. Voucher specimens were obtained under the guidance of collectors, and details about local practices and knowledge were recorded using semi-structured interviews and participatory observations. RESULTS: The consumption of the corollas of Rhododendron decorum Franch. Flowers (RDf) or Rhododendron pachypodum Balf. f. & W.W. Sm. Flowers (RPf) as a seasonal delicacy is a long-standing tradition in the study area. RDf are widely consumed in northwest and northeast Yunnan, while RPf are more prevalent in the central regions of Yunnan, and there is a high consistency in the knowledge of the process for detoxification or palatability for each species. The main reasons for eating the flowers were listed as health benefits (mostly clear heat), wild collected, tradition and good flavor. All RPf consumers stated that the corolla from this species is not toxic, while 67.4% of the RDf consumers claim that the corolla from RDf is toxic. We compared the two species and analyzed their process intensities, poisoning cases and cautions, market trade forms and existing toxicity studies, which agreed well and consistently that the corolla of RDf deserve more toxicity attention than RPf. CONCLUSION: Our study provides a window to look into the ways, beyond honey and herbal medicine, by which Rhododendron species have influenced human wellbeing. The local culture can justify eating Rhododendron flowers, and meanwhile, has developed a series of skills to avoid the side effects of eating them, and therefore the study also provides a good case to answer more general questions about the rationality of eating any plant products by assessing the trade-off between benefits and side effects.

Poisonous medicinal plants used in the popular pharmacopoeia of the Rif, northern Morocco.

Popular herbal medicine has served as a unique health provider for human beings for thousands of years. In the present study, we document the toxic plants used as medicines in the Rif, intending to assess the knowledge of indigenous people on the toxicity of the natural products used. Ethnobotanical survey was conducted in the Rif, northern Morocco between June 2016 and June 2018 using semi-structured questionnaires and focus groups. An investigation of the scientific literature was conducted to sustain or verify the claimed toxicological information. A total of 84 species of plants belonging to 67 genera and 30 families were reported as being used in the prevention and treatment of diseases. The families reported to be most representatives of these kinds of plants are Asteraceae and Fabaceae (7 species). However, the highly toxic plant prescribed was Rosmarinus officinalis L. Leaf was the most commonly used plant part, and the majority of herbal remedies were prepared from a decoction (40.6%). The results of this investigation showed that the local people in the Rif are still dependent on herbal medicine. These species used for remedial purposes are noted to have a potential toxic impact associated with their irrational consumption. Therefore, we recommend that attention should be observed when using them as medicinal sources.

Keratouveitis caused by Euphorbia milii sap: case report and overview / Ceratouveíte causada pela seiva de Euphorbia millii: relato de caso e visão geral

ABSTRACT Objective: To report a case of anterior uveitis caused by Euphorbia milii sap and review all reported cases of keratouveitis related to this species. Methods: A 64-year-old male patient presented with a 10-day history of reduced visual acuity, pain, and photophobia in the left eye after an accidental contact with Euphorbia milii sap. Best-corrected visual acuity was initially 20/200. Upon examination, ciliary injection, mild corneal edema; fine keratic precipitates, and significant anterior chamber reaction. There was no vitritis, and fundoscopy was unremarkable. The patient initiated on topical steroid and tropicamide. Results: Best-corrected visual acuity in left eye improved to 20/20 after using eyedrops for 3 weeks, associated with complete resolution of anterior uveitis. Over the following 6 months, best-corrected visual acuity remained stable, and no evidence of recurrent inflammation was observed. Conclusion: To the best of our knowledge, this is the third reported case of keratouveitis caused by Euphorbia milii sap. As observed in other cases of keratouveitis caused by sap of this species, the clinical course is benign and characterized by moderate reaction of the anterior chamber, and corneal involvement of variable intensity.

RESUMO O objetivo foi relatar um caso de uveíte anterior induzida pela seiva da Euphorbia milii e revisar todos os casos relatados de ceratouveíte causados por essa espécie. Paciente do sexo masculino, 64 anos, apresentou história de 10 dias de evolução com redução da acuidade visual, dor e fotofobia no olho esquerdo, após contato acidental com a seiva da planta Euphorbia milii. A acuidade visual com melhor correção era inicialmente 20/200. O exame revelou injeção ciliar, edema de córnea leve, precipitados ceráticos finos e reação de câmara anterior significativa. Não havia vitreíte, e a fundoscopia não exibia alterações. Foram iniciados colírios de esteroides e tropicamida. A acuidade visual no olho esquerdo melhorou para 20/20 em 3 semanas com a utilização dos colírios, além de se ter alcançado a resolução completa da uveíte anterior. Nos 6 meses seguintes, a acuidade visual permaneceu estável, e não foi observada evidência de recorrência da inflamação. Até então, este é o terceiro caso relatado de ceratouveíte pela seiva da Euphorbia milii. Como visto nos demais casos de ceratouveíte induzidos pela seiva dessa espécie, o curso clínico é benigno e caracterizado por reação moderada da câmara anterior, com envolvimento corneano de intensidade variável.

Rumen and Serum Metabolomes in Response to Endophyte-Infected Tall Fescue Seed and Isoflavone Supplementation in Beef Steers.

Fescue toxicosis impacts beef cattle production via reductions in weight gain and muscle development. Isoflavone supplementation has displayed potential for mitigating these effects. The objective of the current study was to evaluate isoflavone supplementation with fescue seed consumption on rumen and serum metabolomes. Angus steers (n = 36) were allocated randomly in a 2 × 2 factorial arrangement of treatments including endophyte-infected (E+) or endophyte-free (E-) tall fescue seed, with (P+) or without (P-) isoflavones. Steers were provided a basal diet with fescue seed for 21 days, while isoflavones were orally administered daily. Following the trial, blood and rumen fluid were collected for metabolite analysis. Metabolites were extracted and then analyzed by UPLC-MS. The MAVEN program was implemented to identify metabolites for MetaboAnalyst 4.0 and SAS 9.4 statistical analysis. Seven differentially abundant metabolites were identified in serum by isoflavone treatment, and eleven metabolites in the rumen due to seed type (p < 0.05). Pathways affected by treatments were related to amino acid and nucleic acid metabolism in both rumen fluid and serum (p < 0.05). Therefore, metabolism was altered by fescue seed in the rumen; however, isoflavones altered metabolism systemically to potentially mitigate detrimental effects of seed and improve animal performance.

Fatal Yellow Oleander Poisoning Masquerading as Benign Candlenut Ingestion Taken for Weight Loss.

BACKGROUND: Candlenuts (Aleurites moluccana) and yellow oleander seeds (Thevetia peruviana) bear a physical resemblance to one another. Candlenuts are benign and marketed as weight loss supplements. Yellow oleander seeds, however, contain toxic cardioactive steroids; as few as 2 seeds may cause fatal poisoning. Because of their physical similarities, the potential for a lethal substitution exists. CASE REPORT: A 63-year-old woman presented to the emergency department with vomiting after ingesting 5 of what she believed to be candlenuts that were ordered online under the colloquial name "Nuez de la India" for the purpose of weight loss. She was bradycardic (nadir pulse of 30 beats/min) and hyperkalemic (serum potassium 7.3 mEq/L). Within hours of presentation she suffered a ventricular fibrillation arrest, followed by a terminal asystolic arrest. Postmortem analyses of liver tissue and the seeds were consistent with fatal T. peruviana poisoning. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: T. peruviana seeds contain toxic cardioactive steroids; their physical resemblance to candlenuts poses a risk of potentially fatal substitution. Therapy with high-dose digoxin specific immune fragments (20-30 vials) may be helpful.

Outbreak of Oleander (Nerium oleander) Poisoning in Dairy Cattle: Clinical and Food Safety Implications.

Oleander is a spontaneous shrub widely occurring in Mediterranean regions. Poisoning is sporadically reported in livestock, mainly due to the ingestion of leaves containing toxic cardiac glycosides (primarily oleandrin). In this study, 50 lactating Fleckvieh cows were affected after being offered a diet containing dry oleander pruning wastes accidentally mixed with fodder. Clinical examination, electrocardiogram, and blood sampling were conducted. Dead animals were necropsied, and heart, liver, kidney, spleen, and intestine were submitted to histological investigation. Oleandrin detection was performed through ultra-high performance liquid chromatography-tandem mass spectrometry in blood, serum, liver, heart, milk, and cheese samples. Severe depression, anorexia, ruminal atony, diarrhea, serous nasal discharge, tachycardia, and irregular heartbeat were the most common clinical signs. The first animal died within 48 h, and a total of 13 cows died in 4 days. Disseminated hyperemia and hemorrhages, multifocal coagulative necrosis of the cardiac muscle fibers, and severe and diffuse enteritis were suggestive of oleander poisoning. The diagnosis was confirmed by the presence of oleandrin in serum, liver, heart, milk, and cheese. Our results confirm the high toxicity of oleander in cattle and report for the first time the transfer into milk and dairy products, suggesting a potential risk for the consumers.

Identification of phytolaccosides in biological samples from pokeweed intoxication patients using liquid chromatography-tandem mass spectrometry.

In Phytolaccaceae family, Phytolacca americana L. (American pokeweed) and P. esculenta Van Houtte (Chinese pokeweed) are the two representative species among the genus. Pokeweeds have triterpenoid saponins as toxic compounds in every part of the plant. The saponins phytolaccoside A, B, D, E, and G were isolated from P. americana, and esculentoside H, J, L, K, M, I, and N were isolated from P. esculenta. Along with saponins, their aglycones (phytolaccagenin, phytolaccagenic acid, esculentic acid and jaligonic acid) were also isolated from P. americana and P. esculenta. Two people who unknowingly ate misidentified pokeweed plant roots were transferred to the emergency room. Urine and gastric content after irrigation were collected from the first patient (patient 1), and blood and urine were collected from the second patient (patient 2). The samples were analyzed to identify toxic substances with liquid chromatography-tandem mass spectrometry (LC-MS/MS). In the blood sample, 1.9 ng/mL of esculentoside A and 1.5 ng/mL of esculentoside C were detected, while the concentration of esculentoside B and H were below the LLOQ. In gastric contents and ingested roots, esculentoside A, B, C, and H were identified. Esculentoside A, C, and H were identified in the urine of patient 1, and esculentoside A and C were identified in the urine sample of patient 2. The developed analytical method was validated for parameters such as linearity, limit of detection, precision, accuracy, matrix effect, recovery, and process efficiency, and they showed clear and unbiased results.