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.

The pharmaco-toxicological conundrum of oleander: Potential role of gut microbiome.

Nerium oleander L., commonly known as oleander, is a toxic shrub and also a medicinal plant. All parts of oleander are rich in cardiac glycosides that inhibits Na+/K+-ATPase and induce inotropic effect on the cardiomyocytes. Several pre-clinical and clinical reports indicate acute toxicity due to intentional, accidental and suicidal oleander consumption. Contrarily, oleander is used for the treatment of diverse ailments in traditional medicinal practices around the globe and several evidence-based pre-clinical studies indicated metabolic and immunological health benefits of polyphenol-rich oleander extracts. Thus, the current review aims to address this pharmaco-toxicological conundrum of oleander by addressing the possible role of gut microflora in the differential oleander toxicity. Additionally, a comprehensive account of ethnopharmacological usage, metabolic and immunological health benefits has been documented that supplement the conflicting arguments of pharmaco-toxicological properties of oleander. Finally, by addressing the gap of knowledge of ethnomedicinal, pharmacological and toxicological reports of oleander, the current review is expected to pave the way to address the differential pharmaco-toxicological effects of oleander.

An In Vivo Study on Intoxicating Effects of Nerium oleander Water Based Extract on Multiorgans of Wistar Rat.

This study was aimed to find histological changes in the extrahepatic organs, hepatic iron deposition, and gene expression of some iron regulatory proteins in rats after sterile muscle abscess during the acute intoxication of Nerium oleander leaves decoction. 10 ml/kg of the leaves extract was injected intramuscularly in Wistar rats (200-225 g, n = 4). Control animals received saline injection of matched volume. Animals were anesthetized and sacrificed after 3, 6, 12, and 24 h after administration of decoction. Lungs, kidney, spleen, and liver were extracted and processed for histopathological examination while portion of liver tissue was proceeded for iron regulatory gene expression quantification. Sections of all studied organs were found with signs of cellular dysfunction with infiltration of variety of leucocytes. In the lungs section at 3 h time point mononuclear cell infiltrates were observed while in alveolar tissue at 24 h time point dilation and even collapse in some of the alveoli were evident. In kidney sections distortion of renal tubules and epithelial cells with shrinkage of glomeruli was noted at all studied time points. In the splenic section of 12 h time point, degeneration, depopulation, and shrinkage of white pulp have been noted. Distension of the red pulp along with activation of splenic follicles was evident after 24 h onset of APR. Significant changes in the expression of acute phase cytokine and iron regulatory genes were noted. IL-6 and Hepc gene expression were strongly upregulated up to 12 h whereby Tf gene expression showed an early upregulation at 3 h time point followed by downregulation on later points while Hjv gene expression showed an overall downregulation at all study time points compared to control. It is concluded that inherent toxins present in the N. oleander can induce acute phase response and cause severe histological changes in the organs and marked changes in the regulation of iron regulatory proteins thus cannot be practiced routinely.

Improved method for diagnosis of Nerium oleander poisoning in necropsy tissues / Método aprimorado para diagnóstico da intoxicação por Nerium oleander em tecidos de necropsia

Nerium oleander is an ornamental cardiotoxic plant found in tropical and subtropical areas of the World. Its toxicity is related to the content of cardioactive glycosides, mainly oleandrin, found throughout the plant. The present study aimed to describe a new and improved method for oleandrin detection in tissue samples. The determination of oleandrin was made after extraction with a modified QuEChERS technique and measurement by UFLC-MS/MS. A total of 36 guinea pigs (Cavia porcellus) were distributed into 3 groups (n=12): control group that received only water orally (CON), and two treated groups that received hydroalcoholic oleander extract at doses of 150mg.kg-1 (OLE 150) and 300mg.kg-1 (OLE 300) in single oral dose. After three hours, fragments of heart, kidneys, liver and brain were collected for determination of oleandrin levels. The extraction and chromatographic procedures were effective for oleandrin detection and quantification in tissues, with retention time of 1.2 min and detection limit of 0.001μg g-1. The chromatographic analysis of treated guinea pigs indicated that oleandrin is distributed equally among the analyzed tissues. The developed methodology is a reliable, effective and rapid form of diagnosis of N. oleander poisoning based on necropsy tissue samples.(AU)

Nerium oleander é uma planta cardiotóxica ornamental encontrada em áreas tropicais e subtropicais do mundo. Sua toxicidade é relacionada á presença de glicosídeos cardioativos, principalmente a oleandrina, encontrada em toda a planta. O presente estudo objetiva descrever um novo e aprimorado método para detecção da oleandrina em amostras de tecido. A determinação da oleandrina foi feita após extração utilizando técnica modificada de QuEChERS e mensuração por UFLC-MS/MS. Um total de 36 cobaios (Cavia porcellus) foi distribuído em três grupos (n=12): grupo controle que recebeu apenas água por via oral (CON), e dois grupos tratados que receberam extrato hidroalcóolico de oleander nas doses de 150mg.kg-1 (OLE 150) e 300mg.kg-1 (OLE 300) em uma única dose oral. Após três horas, fragmentos do coração, rins, fígado e cérebro foram coletados para determinação dos níveis de oleandrina. A extração e procedimentos cromatográficos foram eficientes na detecção e quantificação da oleandrina nos tecidos, com tempo de retenção de 1,2min e limite de detecção de 0,001μg g-1. A análise cromatográfica dos animais tratados indicou que a oleandrina é distribuída de forma equalizada pelos tecidos analisados. A metodologia desenvolvida representa uma forma de diagnóstica segura, efetiva e rápida da intoxicação por N. oleander a partir de amostras de tecidos de necropsia.(AU)

Successful use of digoxin-specific immune Fab in the treatment of severe Nerium oleander toxicosis in a dog.

OBJECTIVE: To describe a case in which digoxin-specific immune Fab was used successfully in a dog with severe oleander toxicosis secondary to ingesting plant material. CASE SUMMARY: A 6-year-old intact female Rhodesian Ridgeback mixed breed dog was presented for severe oleander toxicosis and was refractory to all antiarrhythmic therapies and supportive care. Digoxin-specific immune Fab was successful in treating this dog. The dog recovered but suffered ischemic injuries, the long-term effects of which are unknown. NEW OR UNIQUE INFORMATION PROVIDED: This report describes the successful use of digoxin-specific immune Fab in the treatment of oleander toxicosis in a dog, which has not previously been published in veterinary literature. Oleander poisoning can be associated with permanent cardiac arrhythmias due to the ischemic damage.

Fatal Oleander Toxicosis in Two Miniature Horses.

Two young American miniature horses from the same farm were evaluated by a veterinarian due to presence of lethargy, anorexia, and cardiac arrhythmias. Both horses were treated aggressively with IV fluids and other supportive measures. The first horse died approximately 72 hr after the start of clinical signs and the second horse was humanely euthanized due to poor response to treatment. Oleander toxicosis was suspected based on the types of clinical signs present and due to several oleander plants and dried leaves present on the property. Oleander toxicosis was confirmed by the presence of oleandrin in gastrointestinal contents and digoxin in the serum of second horse.

Atrial Fibrillation in Eight New World Camelids.

BACKGROUND: There is limited information on the incidence of clinical signs, concurrent illness and treatment options for atrial fibrillation (AF) in New World Camelids (NWC). OBJECTIVE: Describe clinical signs and outcome of AF in NWC. ANIMALS: Eight New World Camelids admitted with AF. METHODS: A retrospective observational study of camelids diagnosed with AF based on characteristic findings on electrocardiogram (ECG). RESULTS: All animals had an irregularly irregular heart rhythm detected on physical examination and 4 cases had obtunded mentation on admission. Three camelids were diagnosed with AF secondary to oleander intoxication, 3 animals had underlying cardiovascular disease, 1 was diagnosed with lone AF and 1 had AF diagnosed on examination for a urethral obstruction. Five of eight animals survived to discharge and nonsurvivors consisted of animals which died or were euthanized as a result of cardiovascular disease (2/8) or extra-cardiac disease unrelated to the AF (1/8). CONCLUSIONS AND CLINICAL IMPORTANCE: Atrial fibrillation occurs in NWC in association with cardiovascular disease, extra-cardiac disease or as lone AF. Amiodarone and transthoracic cardioversion were attempted in one llama with lone AF, but were unsuccessful. Atrial fibrillation was recorded in 0.1% of admissions.

[Irritant contact dermatitis caused by direct contact with oleander (Nerium oleander)]. / Dermatite irritative par contact direct avec du laurier rose (Nerium oleander).

BACKGROUND: Although the oleander plant is practically ubiquitous throughout the Mediterranean area, very few publications refer to its cutaneous toxicity. PATIENTS AND METHODS: Herein, we report two cases of irritant contact dermatitis caused by oleander. The patients in question were twins who had oleander leaves applied directly to their face for 20minutes. The initial lesions consisted of periorbital erythema, followed by the emergence of papules and macules. Vesicles and crusts appeared over the ensuing 24hours. Treatment included withdrawal of the toxic agent, prescription of oral antihistamines, and the topical application of dermocorticoids to the lesions for two weeks. The outcome on the 9th day was slightly hypochromic and atrophic. Complete restitutio ad integrum of the skin was observed after 30 days. DISCUSSION: In our patients, a joint effect of ultraviolet radiation (phytophotodermatitis) and chlorine from the swimming pool cannot be ruled out. Although the substances present in oleanders (irritant saponins and glycosides) can cause chemical irritant dermatitis, immunological reactions cannot be excluded. The lack of signs of systemic toxicity observed is the result of the factors governing transdermal diffusion of the toxic glycosides found in oleander. CONCLUSION: These two cases provide a timely reminder, both for the general public and for healthcare professionals, of the potential biohazards of oleander, not only because of its systemic toxicity but also because of the risks associated with cutaneous exposure.

Hypoglycemia associated with oleander toxicity in a dog.

Oleander poisoning typically results in cardiac arrhythmias, hyperkalemia, and gastrointestinal irritation, and can be fatal. Oleander extracts have also been studied experimentally as hypoglycemic agents. Here, we describe a dog with confirmed oleander toxicosis presenting with classical symptoms and also hypoglycemia. After excluding other likely causes of hypoglycemia, the finding was attributed to oleander toxicosis, which has not been previously reported in dogs. A 7-year-old female spayed Maltese was presented to the emergency service after ingesting oleander leaves. Toxicosis was confirmed by measurement of digoxin using a competitive binding immunoassay, patient level 0.7 ng/mL (0.9 nmol/L) 24-h post-ingestion. Clinical symptoms included vomiting, cardiac arrhythmia, mild hyperkalemia, and hypoglycemia. Treatment was successful with aggressive supportive care, and the dog was discharged from the hospital after 48 h and made a full recovery. This case reviews the presentation and treatment of oleander toxicity but also highlights possible effects of oleander on blood sugar in dogs. Hypoglycemia in this dog, attributed to oleander poisoning, is interesting as it supports experimental research into hypoglycemic properties of oleander extracts.

Toxicity in goats caused by oleander (Nerium oleander).

Cases of poisoning by oleander (Nerium oleander) were observed in several species, except in goats. This study aimed to evaluate the pathological effects of oleander in goats. The experimental design used three goats per group: the control group, which did not receive oleander and the experimental group, which received leaves of oleander (50 mg/kg/day) for six consecutive days. On the seventh day, goats received 110 mg/kg of oleander leaves four times at one-hourly interval. A last dose of 330 mg/kg of oleander leaves was given subsequently. After the last dose was administered, clinical signs such as apathy, colic, vocalizations, hyperpnea, polyuria, and moderate rumen distention were observed. Electrocardiogram revealed second-degree atrioventricular block. Death occurred on an average at 92 min after the last dosing. Microscopic evaluation revealed renal necrosis at convoluted and collector tubules and slight myocardial degeneration was observed by unequal staining of cardiomyocytes. Data suggest that goats appear to respond to oleander poisoning in a manner similar to other species.

Intoxicación por Nerium oleander / Nerium oleander poisoning

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Molluscicidal activity of Nerium indicum Mill, Pterocarya stenoptera DC, and Rumex japonicum houtt on Oncomelania hupensis.

OBJECTIVE: To evaluate the molluscicidal activities of three Chinese plants N. indicum Mill, R stenoptera DC, and R. japonicum Houtt, and to clarify the molluscicidal mechanism. METHODS: N-butanol extracts and water extracts of the three plants were obtained. The reactions of EST isozyme, glycogen and total protein of snails to the plant extracts were studied. RESULTS: EST electrophoresis showed that EST was an important antidotal enzyme system and reacted strongly to environment. EST changed greatly during the whole exposure period so that it could be viewed as a pathological index of toxicity. Extracts decreased the glycogen content of the snails' soft tissues greatly, and also the protein content. CONCLUSION: All extracts show strong molluscicidal activity. The LD50 value of the water extract of N. indicum Mill is as low as 13.2 mg/L. EST can be viewed as a pathological index of toxicity. The energy metabolism abnormity is the key reason for the molluscicidal activities. The biochemical mechanism needs further research.

A rare cause of complete heart block after transdermal botanical treatment for psoriasis.

We report the case of a 59-year-old man with a new 3 degrees AV block with a history of psoriasis. After implantation of a definitive DDDR pacemaker, the patient reported a transdermal self-medication with an extract of Nerium oleander for the treatment of his psoriasis. The pharmacological, epidemiological, and clinical features are discussed in brief.

Clinical and pathological aspects of experimental oleander (Nerium oleander) toxicosis in sheep.

Dried Nerium oleander leaves at single lethal dose of 110 mg/kg body weight were administered orally to six native male sheep. Clinical signs of toxicosis in sheep began to appear about 30 min after receiving the oleander and included decrease of the heart rate followed by cardiac pauses and tachyarrhythmias; ruminal atony, mild to moderate tympany, abdominal pain, polyuria and polakiuria. Electrocardiography revealed bradycardia, atrio-ventricular blocks, depression of S-T segments, ventricular premature beats and tachycardia, and ventricular fibrillation. Five sheep died within 4-12 h and one survived. At necropsy there were varying degrees of haemorrhages in different organs and gastroenteritis. Histopathological examination of tissue sections revealed myocardial degeneration and necrosis, degeneration and focal necrosis of hepatocytes, necrosis of tubular epithelium in kidneys, oedema in the lungs, and ischemic changes in the cerebrum.

Control of common freshwater predatory fish, Channa punctatus, through Nerium indicum leaf extracts.

The diethyl ether, chloroform, acetone and methanol extract of Nerium indicum leaf were evaluated for their piscicidal activity against common freshwater air breathing predatory fish Channa punctatus. The rank of order of toxicity (LC50) of the leaf extract was, diethyl ether extract (17.34 mg/l)>acetone (40.01 mg/l)>chloroform (40.61 mg/l)>and methanol (106.37 mg/l). There was a significant negative correlation between LC50 values and exposure periods. Thus increase in exposure period, LC50 decreases from 17.34 mg/l (24 h) to >13.58 mg/l (96 h) in the diethyl ether extract. Similar trends were also observed in acetone, chloroform and methanol extracts. Exposure of sub-lethal doses (40% and 80% of LC50) of the diethyl ether extract of N. indicum leaf (which has maximum piscicidal activity) for 24 or 96 h caused significant alteration in the level of total protein, total free amino acid, nucleic acid, glycogen, pyruvate, lactate and activity of enzyme protease, phosphatases, alanine aminotransferase, aspartate aminotransferase and acetylcholinesterase in liver and muscle tissue. The alterations in all the above biochemical parameters were significantly (P<0.05) time and dose dependent. There was a significant recovery in all the above biochemical parameters, in both liver and muscle tissues of fish after the seventh day of the withdrawal of treatment. Thus, the leaf extracts of N. indicum have potent piscicidal activity against fish C. punctatus and also significantly affect both aerobic and anaerobic pathway of respiration in fish.

Toxic potential of oleander derived compost and vegetables grown with oleander soil amendments.

California recycles 50% of previously disposed trash. Increased use of yardwastes and composts has raised concern about toxic materials in these products. Oleander is a toxic shrub common to CA landscapes and is frequently clipped and disposed of in greenwaste containers, resulting in concerns about the toxicity of oleander-contaminated yardwastes and composts from these wastes. Information about breakdown of oleandrin (one of the glycoside toxicants of oleander) during composting or the ability of plants to absorb this molecule has not been reported. In separate experiments, we documented the apparent first-order disappearance of oleandrin from composts of pure oleander, with a disappearance half-life of 15 d. Within 50 d, 90% of the oleandrin was removed during aerobic composting in a turned pile. In an amendment study with fresh uncomposted oleander, no oleandrin was detected in tomato and zuchinni fruit, snap beans, carrot tubers, or green lettuce. Oleandrin was found in red leaf lettuce growing in soils mulched with oleander, but oleandrin concentrations were near the detection limit of the assay. Soil from oleander mulched and amended plots contained low levels of oleandrin at the time of harvest.