International Journal of Advanced Academic Studies 2022; 4(3): 23-32

E-ISSN: 2706-8927
P-ISSN: 2706-8919
www.allstudyjournal.com Nerium oleander toxicity: A review
IJAAS 2022; 4(3): 23-32
Received: 27-04-2022
Accepted: 30-05-2022 Shridhar NB
Shridhar NB
Principal Investigator and Abstract
Head, Obscure Disease Nerium oleander is a plant that is commonly seen in gardens and public spaces. N. oleander was
Research Center, Karnataka originally found in subtropical Asia, but it is now spread all over the world, including the United
Veterinary Animal and States, Australia, China, and Middle Eastern nations. It is also an attractive plant that is popular in
Fisheries Sciences University, tropical and subtropical climates and is becoming more frequent in temperate regions. Poisoning from
Veterinary College Campus, oleander can occur in both animals and humans. Poisoning in animals is documented on an infrequent
Shivamogga, Karnataka, India basis, particularly as a result of the consumption of poisonous cardiac glycoside-containing leaves
(primarily oleandrin). The toxic effects of plants or their active alkaloids caused infiltration of cells
with haemorrhage and severe negative changes in the lungs, infiltration of inflammatory cells into
portal spaces with scattered necrosis of hepatocytes in the liver, and cardiac toxicity of the plant in the
heart, which caused varying degrees of haemorrhage, myocardial degeneration, and necrosis. In
electrocardiographic recordings, it also caused arrhythmia, sinus bradycardia, and a prolonged P-R
interval. Oleandrin was detected in blood, serum, liver, heart, milk, and cheese samples using ultra-
high-performance liquid chromatography-tandem mass spectrometry. The most prevalent clinical
manifestations were severe sadness, anorexia, ruminal atony, diarrhea, serous nasal discharge,
tachycardia, and irregular pulse. N. oleander's toxicity is mostly due to its inhibitory effects on the
Na+-K+ ATPase pump in the cellular membrane. The identification of the plant leaf in the feces will be
diagnostically important with the measurement of oleandrin in the serum. Toxins are treated
symptomatically. TLC, HPLC, and LCMS-MS techniques can all be used to detect oleandrin.

Keywords: Nerium oleander, toxicity, animals, mechanism, pathology

Introductions
Thevetia peruviana (Yellow oleander), which is native to tropical America, and Nerium
oleander (Common oleander), which is found in the Mediterranean basin and Asia, are the
two most common species of oleander in the globe (Oryan et al., 1996; Shepherd, 2004) [24,
29]
. Since the dawn of time, people have been aware of the shrub's toxicity. In India, before
the birth of Christ, it was known as Kajamaraka, or "the plant that kills the horse" (Ceruti et
al., 1993; Ceci et al., 2020) [12, 11]. Oleander has the potential to be lethal for people, animals,
and even some insects (Langford and Boor, 1996) [20]. As a result of the presence of various
non-digitalis cardiac glycosides, collectively known as cardenolides, including oleandrin,
nerin, digitoxigenin, and olinerin, all portions of the plant are indeed extremely hazardous.
The primary active molecule is oleandrin, which has relatively high lipophilicity that causes
it to be rapidly and thoroughly absorbed via the gastrointestinal tract and excreted slowly
through the urine system (Praveen et al., 2012) [27]. The Na+-K+-ATPase pump in
cardiomyocytes is inhibited, which raises the intracellular Na+ content, as part of the
hazardous mode of action. This has an impact on the Na+/Ca2+ exchange channels, causing
an increase in intracellular Ca2+ levels that determines a favorable inotropic effect and a rise
in the resting membrane potential. Oleander-related deaths in people mostly result from the
voluntarily ingesting of decoctions or pieces of the vegetable for suicide intentions (Azzalini
et al., 2019) [5]. Nevertheless, unintentional poisonings have been reported, especially in
youngsters, and one leaf can be fatal (Langford and Boor, 1996; Bandara et al., 2010) [20, 6].
According to Caloni et al. (2013), Renier et al. (2013), Botha and Penrith (2008) [10, 28, 9],
Corresponding Author:
Shridhar NB
accidental poisonings have regularly been reported in a variety of animal species, including
Principal Investigator and cattle (Galey et al., 1996; Ozdemir et al., 2011; Soto-Blanco et al., 2006; Varga and
Head, Obscure Disease Puschner, 2012; Rubini et al., 2019; Ceci et al., 2020) [11, 16-17, 25, 30, 32, 49].
Research Center, Karnataka In dry regions or during the dry season when there is a shortage of feed, grazing animals may
Veterinary Animal and consume sections of the plant even though oleander is unappealing due to a bitter and
Fisheries Sciences University,
Veterinary College Campus,
pungent flavour. However, when oleander is mistakenly mowed, crushed, and combined
Shivamogga, Karnataka, India with feed, poisoning can also be attributable to human administrative faults.

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Animals that consume water that has fallen and macerated Scrophulariaceae). Although all parts of oleander are
leaves in it may also get inebriated. Fortunately, the known to contain lipophilic cardenolides, the concentration
presence of saponins, which in monogastric may cause follows the order of leaf < fruit < root = seed. The steroidal
vomiting and aid in the removal of the consumed hazardous nucleus of these cardenolides, especially the 5p, 14p-
plants, reduces the danger of poisoning (Mack, 1984) [21]. androstane-3p, and 14-diol skeleton is considered the key
Depending on the animal type, different dried Nerium bioactive domain and has similar binding properties as
oleander leaves have different lethal doses (LD). The LD is digitalis glycosides. Several cytotoxic pregnane compounds
50 mg/kg for cattle, 110 mg/kg for goats, and 250 mg/kg for such as neridienone A and B were isolated from the bark
sheep, suggesting that bovines are more susceptible than and twigs. Twocoumaryloxy triterpenoids neriucoumaric
small ruminants (Oryan et al., 1996; Adam et al., 2001; and isoneriucoumaric acid, and two cardiac glycosides
Aslani et al., 2007) [24, 3]. kaneroside and neriumoside were isolated from oleander
leaves. Ursolic acid, oleanolic acid, betulinic acid, botulin,
Toxic properties of N. oleander and three new triterpenes with anti-inflammatory and
It has long been known that N. oleander is poisonous. cytotoxic properties were isolated from oleander leaves
Cardiotoxic glycosides are present in all plant sections, but (Dey, 2020) [60]. Different cardenolides including
particularly in the seeds and roots. The digitoxin of the neridiginoside, nerizoside, neritaloside, and odoroside-H
foxglove plant is structurally related to cardiac glycosides. with central nervous system depressant activities were
Numerous research has suggested that N. oleander may identified in the oleander leaf methanolic extract. Adynerin,
have antibacterial, insecticide, pesticide, and rodenticide hemidesmin-2, adynergenin, odoroside A and odoroside B
properties. Five N. oleander leaves can result in fatal with potent cytotoxic and anti-proliferative activity were
poisoning. However, it was reported that one N. oleander isolated from oleander methanolic stem extract. Nerigoside
leaf had severe toxic effects in children. Controversially, limits ERK/GSK3p/p-catenin signaling pathway to suppress
ingestion of three leaves of N. oleander by a 7 years old HT29 and SW620 cell growth and metastatic potential
child caused moderate poisoning with no complication. (Repke, 1985; Dey, 2020) [59, 60].
Mild toxicity was observed in an adult woman following Pharmacokinetic studies in mice showed that oleandrin is
consumption of five leaves of N. oleander, without severe rapidly absorbed after oral administration with a
symptoms. Thus, the determination of the fatal dose for N. bioavailability of about 30% and biotransformed to
oleander toxicity has not been fully understood and more oleandrigenin, probably through an enzymatic process.
studies should be done to find the lethal doses of the plant. Oleandrin is readily absorbed and arrives at the heart,
The severity of N. oleander toxicity is related to several causing immediate damage to cardiomyocytes. It was shown
factors including the concentration of toxin in ingested part also that oleandrin can cross the blood brain barrier (BBB)
of the plant, age, and health condition of the subject who and accumulate in the CNS. Elimination occurs mainly
consumed the plant (Bandara et al., 2010:Farkhondeh et al., through faces, suggesting hepatobiliary excretion, but there
2020) [6, 15]. is also some urinary excretion (Ni et al., 2002) [23]. One
Oleander includes oleandrin and neriine, two powerful important characteristic of oleander is its low palatability, so
cardiac glycosides or cardenolides, in all parts of the plant that it is responsible for only small numbers of poisonings
(Langford and Boor, 1996; Begum et al., 1999) [20]. The (Cheeke, 1998; Knight and Walter, 2001) [13, 19]. Cases of
kind with red flowers is the most dangerous, and even the poisoning are, as a rule, due to the lack of information
dried leaves are still poisonous. A single oleander leaf regarding the toxicity of the plant, possibly because it is
consumed by a youngster has been known to cause death used as an ornamental plant and therefore may be
(Langford and Boor, 1996) [20]. considered harmless. In the cases reported here, most were
The predominant glycosides in white and pink flowered due to deficit of forage promoted by drought and presence
oleander are oleandrin, adynerin, and digitoxigenin, the less of residual oleander parts on the grazing land, but inten-
common yellow-flowered oleander contains thevetin A, tional administration of oleander mixed with food also
thevetin B, neriifolin, peruvoside, and ruvoside. The key occurred.
toxic component of oleander has been recognized to be
oleandrin. It only accounts for 0.08% of total cardenolides Clinical signs
and has a bioavailability of 30%. However, due to its highly Ceci et al. (2020) [11] reported that, on day 0 of consumption
lipotoxic nature, slow urinary excretion, and rapid of the plant leaves, in the lactating animals displayed
gastrointestinal absorption, oleandrin results in fatal discomfort with depression, anorexia, lack of rumination,
poisoning (Bandara et al., 2010) [6]. and hypogalaxia. At day 1, some cows showing diarrhea,
The LD50 of oleander for mice is 4 g/kg, according to severe depression, and prolonged sternal decubitus. On days
research conducted by others. While several research came 2 and 3 of consumption of the plant leaves, there as
to the semi-quantitative conclusion that 3-10 oleander leaves pedaling, convulsive movements, increased frequency of
could be deadly, the LD50 of oleander leaves for cattle is 50 bellowing, and coma.
mg/kg. According to reports, the LD50 of oleander for At the herd general clinical examination, almost all animals
sheep is 250 mg/kg. Although there is disagreement on the showed, as a predominant sign, varying degrees of
oleander lethal dose, overall, the clinical signs of oleander depression and weakness; many subjects were in sternal
toxicity are essentially the same in all species (Bandara et decubitus with lowered ears, and some were soporous. The
al., 2010) [6]. other observable symptoms were highly variable in the
Oleander is well-known for the presence of cardiac different subjects. Some cows showed evident nasal and
glycosides such as oleandrin, adynerin, and digitoxigenin, lacrimal discharge with dense yellowish mucous-fibrinous
with potent cytotoxic activities and structural similarity with exudate, while others were mildly dehydrated, with dry
digitoxin from Digitalis purpurea L. (Foxglove; family mucous membranes and muzzle, and slightly sunken eyes

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Several animals showed ptyalism. In some cases, the rumen to the damage to the central nervous system (Aslani et al.,
was atonic with mild meteorism, and most of the animals 2007) [3].
showed a lack of rumination. There were varying degrees of
abdominal pain (colic) and false kyphosis. Diarrhea was ECG pattern
present in most of the animals with different characteristics The ECG test corroborated the abnormalities in the cardiac
aqueous, translucent liquid with fibrin and rusty blood rhythm noticed during the heart auscultation. There was a
traces, and pasty stools with blood streaks.In some cattle, first-degree atrioventricular block with a frequency ranging
the perianal area was smeared with hemorrhagic stools. from 99 to 113 beats per minute, as well as a paroxysmal
Some animals showed tachypnea, cough, and mainly ventricular tachycardia with ventricular arrhythmias with a
abdominal discordant breathing. Other cows displayed frequency of 122 beats per minute (Ceci et al., 2020) [11].
pollakiuria, bruxism, and muscular fibrillations. The body An earlier study conducted by Aslani et al.(2004) [2] on the
temperature was always normal. A careful check of the cardiotoxicity impact of N. oleander (110 mg/kg, orally,
remaining feed ration that was removed by the farmer single dose) in male sheep indicated that sinus bradycardia
revealed the presence of intact and fragmented oleander was seen as the first symptom in electrocardiogram (ECG)
leaves mixed into the hay. At the clinical examination of the 0.5 h after receiving this plant. Then, the sinus arrhythmia
four animals with the most severe symptoms, depression was observed. The second cardiac effect was moderate and
(drowsiness, dizziness, prolonged sternal decubitus, slow consists of blockage of arterial/ventricular (AV) valve, sinus
and staggering gait), sero-fibrinous nasal and lacrimal tachycardia, ST-segment depression, AV dissociation,
discharge, slight colic pain, ruminal atony, and watery ventricular tachycardia, and fibrillation. Histopathological
diarrhea with blood streaks were present. Heart auscultation examination indicated degeneration and necrosis in the
showed splitting of the first tone in two animals and myocardium (Aslani et al., 2004) [2].
different arrhythmias in the other two. At auscultation of Two large retrospective studies had found that at
lungs, strengthened vesicular murmur and slight rattles were presentation, 50% had features of AV block while ST-T
detected. The temperature of the body was normal. A abnormalities were noted in 10%–25% of their
thorough examination of the animal's residual feed ration cohort. Another large study of 170 patients had found that a
revealed the presence of entire and fragmented oleander similar 40% had presented with AV conduction
leaves intermingled within the hay. Depression (drowsiness, abnormalities with a mortality of 18%. Sinus rhythm was
dizziness, prolonged sternal decubitus, slow and staggering the most common rhythm at presentation, however, sinus
gait), sero-fibrinous nasal and lacrimal discharge, slight bradycardia and second-degree heart blocks were the most
colic pain, ruminal atony, and watery diarrhoea with blood common arrhythmias followed by Junctional arrhythmias
streaks were all present during the clinical examination of (Carfora et al., 2021; Thomas et al., 2022) [53, 56].
the four animals with the most severe symptoms. In two of
the animals, heart auscultation revealed a splitting of the Mechanism of toxicity
first tone, as well as distinct arrhythmias in the other two. Cardiac glycosides component in N. oleander inhibits the
Lung auscultation revealed a stronger vesicular murmur and “Na+-K+ ATPase pump” in the membrane of
minor rattling. mal. The milk was discarded for 15 days as a cardiomyocytes, resulting in an increase in intracellular Na+
precautions. concentration. Additionally, this increase changes the shift
Oleander poisoning is characterised by a variety of of Na+-Ca2+ channels, resulting in an elevation in
symptoms, the onset and severity of which varies according intracellular Ca2+ and contraction force and also cardiac
to the amount of active ingredients consumed (Galey et al., automaticity. “Na+-K+ ATPase pump” inhibition changes the
1996) [16-17]. The symptoms will appear within the first 24 shift of K+, resulting in increased level of K+.12
hours of consumption of the plant, followed by the death of Hyperkalemia indicates the severity of toxicity in acute
the first animal within 48 hours. The remaining 12 animals cardiac glycosides poisoning (Blum and Rieders,1987) [8].
died over the next four days. The principal clinical
indicators are associated with cardiac, gastrointestinal, and Toxic effects of N. oleander on lungs
neurological system diseases. Accordingly, the animals Intramuscularly (IM) administration of N. oleander leaves
showed depression, sero-fibrinous nasal and ocular extract (10 ml/kg) in both hind limbs of rats showed
discharge, slight colic pain, ruminal atony, and diarrhea. It mononuclear cell infiltrates in the lung tissue section, most
should be noted that the clinical presentation varied among frequently around the blood vessel 3, 12, and 24 h after
individual members of the herd regarding the type and administration. Dilation and even collapse in some alveoli
severity of toxicity. We believe this may be related to were observed in alveolar tissue 24 h after administration.
variation inthe dose of the ingested poison. Massive infiltration along with hemorrhage and
When ruminants' GI tracts are affected, they often have extravasation of blood cells and severe negative changes
abdominal pain, atony, and tympanism. However, diarrhea were also observed in the study group. Alveoli, alveolar
has been seen in cattle and other animals that have been sacs, and bronchus were observed in sections of the control
accidentally poisoned by oleander (Ozdemir et al., 2011; lung tissue. The aqueous decoction of leaves extract of N.
Soto-Blanco et al., 2006) [25, 30]. Aslani et al. (2004) [2] say oleander leaves extract (10 ml/kg) induced histopatholo-
that these symptoms in humans are likely caused by the gical changes in the Wistar rat’s lung tissues including
direct contact of oleander toxins with the mucosa, not by alterations in the pulmonary tissue with disruption of
involvement of the nervous or circulatory systems (Katzung bronchus mucosal folds. Also, alveolar cells with extreme
and Parmley, 1998) [18]. In the same way, neurodegenerative widening of lumen of the bronchiole and vascular lesions
diseases are directly caused by toxins that are able to cross have been observed. Inflammatory cells, especially
the blood-brain barrier. But damage to the vascular neutrophils, were frequently found in the bronchoalveolar
endothelium and acute heart failure are likely to contribute region. In addition, lung sections of the control group

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showed normal histological architecture and numerous clear heart muscles, while 200 mg of N. oleander showed focal
alveoli with thin interalveolar septa and alveolar sacs marked inter-fascicular edema with congested vessels and
(Abbasi et al., 2014) [42]. moderately degenerated myocytes with vacuolation of the
The aqueous extracts of N. oleander flowers (11, 22, and 33 muscle (Abdou et al., 2019) [33].
mg/kg) induced severe congestion in blood vessels and Oral administration of aqueous leaf extract of N. oleander
edema around the esophagus in albino male mice, especially for 28 days induced pathomorphological changes in the
at the high dose of extract (Majeed, 2012) [22]. The aqueous heart in male rabbits. Mild granular degeneration of
leaves extract of N. oleander (10 mg/kg) on healthy male myocytes, coagulative necrosis, fragmentation in the cardiac
New Zealand rabbits for 4-week treatment showed muscle, and loss of striations were observed in heart by
pathological changes, such as interstitial pneumonia, photomicrograph. In addition, intra-sarcoplasmic vacuoles
alveolar space hemorrhage, the disappearance of pulmonary with myocytolysis were also observed in the heart samples
alveolus, thickening of the lung matrix, and alveolar septa, in treated animals compared to the control group (Taheri et
while in the control group, there were no significant al., 2013) [31]. N. oleander flowers aqueous extracts (22 and
abnormalities observed in the lung tissue (Taheri et al., 33 mg/kg, b.w.) showed congestion and hemorrhage,
2013) [31] Orally administration of N. oleander leaves at especially in the myocardium regions. In addition, varying
lethal dose (110 mg/kg) to native female goats induced degrees of coagulative necrosis of cardiac muscle cells that
interstitial hemorrhage in the lung 1 h after receiving the were associated with the infiltration of mononuclear
oleander and also caused congestion and edema in the lung inflammatory cells in heart sections were observed (Majeed
of sheep (Aslani et al., 2007) [3]. Administration of N. et al., 2012) [22].
oleander leaves (110 mg/kg,) induced varying degrees of N. oleander (110 mg/kg) induced congestion and severe
congestion or hemorrhage in the lungs of sheep (Ozmaie et hemorrhage especially in the subendocardial regions in the
al., 2013) [26]. The results of the above studies indicated that hearts of goats. Additionally, varying degrees of coagulative
leaves or flowers of N. oleander have toxic effects on the necrosis of cardiac muscle cells associated with infiltration
lung tissue of exposed animal, such as induced congestion of inflammatory cells were also observed. The mononuclear
in blood vessels, disruption of bronchus mucosal, induced inflammatory cell infiltration into the endoneurium of nerve
inflammatory cells and neutrophils in the bronchoalveolar, fascicles and hemorrhages in the left ventricular endocard
and induced congestion or hemorrhage in the lung tissue. was observed (Aslani et al., 2013).
Administration of N. oleander leaves (110 mg/kg, b.w.)
Toxic effects of N. oleander on liver induced varying degrees of hemorrhage, myocardial
The results of Prussian blue iron-stained sections after 3,6 degeneration, and necrosis in the heart of sheep (Ozmaie et
and12 h of N. oleander leaves extract (10 ml/kg, IM) al., 2013) [26]. Botelho et al. (2017) investigated the
administration showed extensive iron accumulation but in cardiotoxic effect of N. oleander hydroalcoholic extract
section after 12 h of administration, mild deposition in (150 and 300 mg/kg) in guinea pigs. It was found that N.
sinusoidal space was also observed particularly. Distinct oleander caused death due to severe cardiac arrhythmias in
bluish granules (ferritin) within hepatocytes 6 and 12 h after some animals. In vitro studies indicated that N. oleander
onset of acute phase response were observed. (Abbasi et al., disturbed electromechanical function in the heart by sodium
2014) [42]. the extracts of N. oleander flowers (33 mg/kg) (Na+) and potassium (K+) pump inhibition, mitochondrial
induced hydropic degenerations in the liver tissue. In addi- swelling, and the sarcoplasmic Ca2+ ATPase impairment. A
tion, mononuclear cell infiltration in the portal spaces with non-blinded, placebo- controlled study was designed to
scattered necrosis of hepatocytes was induced by plant investigate the protective effect of digoxin-specific Fab
flower extract. Congestion and hemorrhage in some cases fragments (dsFab) against cardiotoxicity induced by N.
were also observed (Majeed, 2012) [22]. Dried leaves of N. oleander in dogs. N. oleander leaves (30 mg/kg, intrave-
oleander (110 mg/kg) induced lesions in the liver that nous, IV) caused dysrhythmias during 27 min of starting the
caused fatty change and infiltration of inflammatory cells administration. However, Fab reversed to normal condition
into the portal spaces with scattered necrosis of hepatocytes during the first minutes of injec- tion (Clark et al., 1991) [35].
in female goats and male sheep. 6, 17. In addition, mild bile Fattahi et al. (2013) [36] indicated that N. oleander (100
duct hyperplasia was observed in two goats (Aslani et al., mg/kg, orally) caused ventricular fibrillation in sheep,
2007) [3]. N. oleander leaves (110 mg/kg) induced varying leading to death in two animals. However, pretreatment with
degrees of hemorrhage, degeneration and focal necrosis of garlic extract improved arrhythmia in five sheep.
hepatocytes, necrosis of hepatocytes, fatty degeneration, and Khordadmehr et al. investigated cardiac toxicity of N.
infiltration of mononuclear inflammatory cells in liver. oleander (10, 12.5, 15, and 20 mg/kg, orally) in Wistar rats
and Balb/c mice (Khordadmehr and Nazifi, 2018) [37].
Toxic effects of N. oleander on heart Creatine kinase (CK) and troponin levels increased in mice
Oral administration of 100 mg of N. oleander ethanolic and rat received N. oleander. Hyperemia, hemorrhage, and
extract showed diffuse mild interfascicular edema with myofibroblasts were seen in the cardiac tissue of animals.
congested vessels and many fragmentations of myofibrils in
degenerated myocytes 14 days after treatment in heart Toxic effects of N. oleander on blood parameters
muscles. In addition, 200 mg of N. oleander ethanolic Oral administration of N. oleander alcoholic extract (100
extract showed moderate interfascicular edema with dilated and 200 mg of dried extract/kg) after 14 days significantly
congested vessels and few degenerated myocytes with focal changed blood parameters including increased mean
striation loss and focal vacuolar degeneration in the heart corpuscular hemoglobin (MCH) and decreased white blood
muscles; 30 days treatments animals with 100 mg of N. cells (WBCs) at 200 mg of extract and also significantly
oleander showed focal mild interfascicular edema with decreased lymphocytes (%) at two dose of extracts. In
congested vessels and very few degenerated myocytes in the addition, after 30 days of oral administration, mean

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corpuscular volume (MCV), WBCs, and platelet (PLT) different active ingredient of the plant. The time of
count significantly elevated at 200 mg of extract. The treatment was similar between different treated 28 groups.
percent of lymphocytes also significantly decreased at two Serum K+ levels after 2 weeks significantly increase in
dose of extracts (Abdou et al., 2019) [33]. summer and winter N. oleander leaf extracts compared to
The aqueous extracts from boiling air-dried leaves of N. the control group, while there were no significant
oleander in 0.9% NaCl solution (1:1, w/v) significantly differences between summer and winter groups. Increased
altered hematological parameters such as red blood cells levels of K+ were depended on the time of treatment (2 and
(RBCs), hemoglobin (Hb), hematocrit, MCV, lymphocyte, 4 weeks) (Salih and Alkhayyat, 2016) [41].
neutrophil, monocyte, and eosinophil count in the groups of Salih and Alkhayyat, (2016) [41] also informed that the
N. oleander oral intake for 3 and 7 days compared to the serum levels of ALT significantly increased between the
control group (Akhtar et al., 2014) [38]. two summer and winter N. oleander leaf extracts compared
The aqueous leaves extract of N. oleander and flowers (25 to the control, while there was no significant increase
mg/kg, b.w.) significantly increased WBCs, while decreased differences between winter and summer groups.
RBCs and Hb, after 2 and 4 weeks treatments in mice Additionally, serum levels of AST and alkaline phosphatase
compared with the control group (Altaee, 2011) [39]. were not significantly changed between the summer and
Intraperitoneal administration alkaloid extract of N. winter N. oleander leaf extracts compared to the control.
oleander leaves (20 mg/kg) per day for a period of 30 days Administration of aqueous leaves extract of N. oleander (10
decreased the body weight after 10, 20, and 30 days of mL/kg, IM) significantly enhanced total iron content in the
experience in treated female mice compared with control serum with maximum increase of 156.87% after 12 h and
group. Alkaloid extract of N. oleander also decreased 100% rise was observed after 3 h, in male Wistar rats
packed cell volume (PCV), mean platelet volume, MCH, compared to control group. The serum ferritin was declined
and Hb, while significantly increased RBC distribution with at 3 and 24 h of injection with 29% and 23%, respectively,
MCH concentration (MCHC), plateletcrit, PLT, and WBC which were not significant differences with control group.
in treated female mice compared to the control group Serum hepcidin concentration greatly increased which
(Akhtar et al., 2014) [38]. reached a peak at 12 h compared with the control group
The aqueous leaves extract of N. oleander (10 mg/kg) once while decreased 9.53% value after 24 h (Abbasi et al.,
a day for 28 days significantly increased RBC and WBC 2013). Administration of N. oleander leaves (110 mg/kg,
counts and also mean Hb value in the treated rabbits b.w.) as lethal dose decreased serum glucose and urea
compared to the control group. However, the PLTs count concentration. Serum activity of enzymes such as ALT and
was decreased significantly in the treatment group compared AST was increased in experimental group compared to the
to the control group. The percent of PCV value was control group (Ozmaie et al., 2013) [26].
noticeably higher in treated rabbits, although it was not
statistically significant (Majeed, 2012) [22]. Diagnosis
Animals exposed to oleander are often found suddenly dead
Serum biochemical parameters or they present with rapidly developing nonspecific signs
The toxic impact of N. oleander extract (100 and 200 mg of that may resemble colic. When clinical signs are observed,
dried extract/kg, orally, for 14 and 30 days) was evaluated they develop after a delay of 2-4 hours and may include
in mice. The findings indicated that interleukin 1 (IL-1), IL- abdominal pain, weakness, rumen atony, and excessive
6, tumor necrosis factor a (TNF-a), CK, and CK-MB were salivation. Cardiac alterations may include bradycardia or
significantly increased at 200 mg of N. oleander ethanolic tachycardia, weak and irregular pulse, heart blocks, and a
extract after 14 days of treatment, but C reactive protein variety of ventricular arrhythmias. Excitement, intermittent
(CRP) and lactate dehydrogenase (LDH) were significantly convulsions, dyspnea, and coma may precede death, which
increased at 100 and 200 mg of N. oleander ethanolic may occur within 2 or as late as 12-36 hours after the onset
extract. In addition, after 30 days of treatments, IL-6, TNF- of signs (Galey et al., 1996) [16-17].
a, CRP, aminotransferase (ALT), LDH, CK, and CK-MB Diagnosis in some lethal cases may be facilitated by finding
levels were significantly increased at 100 and 200 mg of leaves in the environment or in the ingesta. However, leaves
plant extract, while IL-1 was only significantly increased at may be macerated beyond identification or passed into the
200 mg extract group compared to the control group (Abdou posterior gastrointestinal tract. Thus, definitive diagnosis of
et al., 2019) [33]. oleander poisoning is often difficult.
The oral administration of aqueous extract of N. oleander Sudden death is the most common case presentation.
leaves and flowers (25 mg/kg, b.w.) significantly increased Clinical signs, if reported, are of non-specific and included
alanine aminotransferase, aspartate aminotransferase (AST), various degrees of colic, diarrhea, weakness, tachycardia,
glutamic- pyruvate transaminase (GPT), and glutamyl ataxia, and anorexia. In horses, horse will have ileus and
oxaloacetic transaminase (GOT) after 2 and 4 weeks mild colic. Cardiac arrhythmia, which was not specified,
treatments in mice compared with the saline- treated control was reported for one llama. Postmortem findings included
group [26]. These changes were depended on the time of no lesions for some peracute cases. The most common
treatments. lesions observed involved the heart. Gross lesions, when
Serum calcium levels decreased but not significantly after 2 present, included endocardial hemorrhage associated with
weeks oral administration of the N. oleander summer and increased volumes of pericardial fluid and subepicardial
winter leaf extracts compared to control rabbits, while in 4 edema around cardiac vessels. Colon and cecal contents will
weeks after treatment showed winter leaf extracts group be very fluid in some cases. Edema in the colon and/or
decreased calcium levels significantly compared to the subcutaneous tissues is also ocassionaly reported.
control group. The winter extract group was more toxic than Histologically, sites of necrosis included various cardisc
the summer group that may be due to the presence of regions, although the subendocardium seemed to be the

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most common location for lesions.Typically, the left ocassionaly reported (Galey et al., 1996; Ceci et al., 2020)
[11, 16-17]
ventricle will be of the most severely affected. Lesions also .
will be present in the walls of other portions of the heart,
including the auricles. Those lesions in the heart included Histopathological findings
subendocardial hemorrhages and multifocal myocardial The histological investigation revealed that all of the cardiac
edema, degeneration, and necrosis. Pulmonary edema, mild regions had mild multifocal hyperemia and haemorrhages,
hepatic congestion and lympholysis were also reported. as well as mild multifocal non suppurative interstitial in
Although diarrhea and gastrointestinal upset were reported flammatory infiltrates. Mild to severe multifocal
clinically, lesions in the gut were minimal (Galey et al., arteriosclerosis of tiny intramural and extramural coronary
1996) [16-17]. arteries was also found. Furthermore, the left and right
Exposure to oleander in many of the cases was indicated by papillary muscles, as well as the left and right ventricular
identification of the plant leaves in ingesta and/or the wall sections, displayed diffused hypotrophic hyper-
environment. The leaves must be distinguished from those eosinophilic shrunken muscular fibres suggesting various
of other forbs, most commonly those of Eucalyptus (gum) degrees of necrosis. The mitral and tricuspid valves have
trees. Oleander is characterized by an oblong leaf shape, moderate endocardiosis. The kidneys displayed widespread
typical parallel secondary veins, and characteristic stomata passive hyperemia and moderate, multifocal haemorrhages,
(visible under a dissecting microscope). particularly in the renal medulla. Mild, multifocal
Diagnosis in the most recent cases was supported by lymphoplasmacytic interstitial nephritis and multifocal
identifying oleandrin using TLC. Two-dimensional TLC is tubular degeneration were also seen. Perilobular non-
the best method of isolating the oleandrin. In addition to the suppurative acute hepatitis with mild diffuse hyperemia was
oleandrin, chromatography of samples of leaves and seen in the liver. Spleen revealed moderate widespread loss
fortified ingesta also revealed a consistent pattern of other of red and white pulp.
spots not found in blanks or samples spiked with oleandrin Regarding the gastrointestinal tract, the esophagus showed
alone. Fortification of diagnostic samples of stomach chronic active inflammation of the mucosa. Small intestine
contents at levels of 5, 0.25, 0.1 and 0.05 ppm all resulted in presented severe diffuse chronic enteritis characterized by
detection of oleandrin by TLC. Oleandrin was detected in hyperemia of the mucosa and
rumen contents when spiked at similar levels. Additionally, lymphoplasmacytic/eosinophilic infiltration invading the m
oleandrin spikes at 0.1 and 0.02 ppm were identified in both ucosa and partially submucosa (Galey et al., 1996; Ceci et
rumen contents and urine. No spikes at those levels failed al., 2020) [11, 16-17].
(Galey et al., 1996) [16-17]. In horses died due to oleander poisoning, the microscopic
Diagnosis in 23 of the 37 cases benefitted by identification renal lesions, principally mild to moderate tubular changes
of oleandrin. Chemical analysis of oleandrin is the only such as hyaline cast formation, neutrophilic casts, epithelial
diagnostic evidence for many cases. Two additional cases attenuation and necrosis, as well as mineralization and
were diagnosed using the chemical test, with identification congestion, occur in horses with oleander poisoning. Most
of a source of oleander clippings only after chemical assay of these changes match the descriptions of lesions
suggested the possibility. Rumen and/or stomach contents previously noted in other species, although with less
were the most reliable diagnostic samples in most cases. frequency and severity. Similar lesions were found in horses
However, in 2 instances for horses, cecal or fecal contents that died spontaneously due to different causes or were
had oleandrin, whereas stomach contents had no evidence of euthanized. We concluded that microscopic renal lesions
the glycoside. Urine was found to have a trace of oleandrin may be detected in horses with oleander poisoning but they
in one case, yielding a spot that was similar in intensity cannot be used as a diagnostic marker that allows
(visual) to a 0.05-ppm spike. Urine had no oleandrin in 2 differentiation from other disease processes or causes of
other cases for which ingesta was found to have the toxin death (Sykes et al., 2022) [57].
(Galey et al., 1996) [16-17].
Oleandrin toxin that was recovered from the forage and Chemical analysis
rumen contents of the cattle died due to N.oleander toxicity. Oleandrin can be measured using cross-reaction of an
Oleandrin was detected and quantified by liquid immunoassay kit for digoxin, TLC, HPLC and LC/MS.
chromatography-high resolution mass spectrometry (LC- Oleandrin is thermolabile; and sometimes it is difficult to
HRMS) in rumen (Rubini et al., 2019) [49]. analyze it by GC or GC/MS, because it gives 4 peaks due to
decomposition. A method for LC/MS analysis of oleandrin
Necropsy and its metabolite d- esacetylole-andrin together with their
All of the dead animal’s necropsies revealed a generalised related compounds, such as oleandrigenin and gitoxigenin,
congestion of visceral organs, including the liver, kidneys, contained in human specimens was detected using the kits
lungs, abomasum, and intestine. There were also multifocal, (Fuke and Arao, 2005) [51].
minor haemorrhages in the ventricular endocardium. The Oleandrin was also detected by high performance liquid
lungs were edematous, and the bronchi had foamy contents. chromatography method as described by Tayoub et al.
There was also mild hydrothorax, hydropericardium, and (2014) [52].
ascites. Postmortem findings included no lesions for some Chemical examinations of blood, serum, heart, and liver
peracute cases. The most common lesions observed samples from three poisoned cows using ultra-high
involved the heart. Gross lesions, when present, included performance liquid chromatography-tandem mass
endocardial hemorrhage associated with increased volumes spectrometry (UHPL C-MS/MS) verified the theory of
of pericardial fluid and subepicardial edema around cardiac oleander poisoning. Indeed, oleandrin concentration in
vessels. Colon and cecal contents were very fluid in some blood and serum was around 1 ng/mL in all animals, while
cases. Edema in the colon and/or subcutaneous tissues was more than 10-fold higher levels were detected in heart

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(15.29 ± 0.79 ng/g) and liver (15.94 ± 0.44 ng/g). Oleandrin However, Driggers et al. (1989) [43] reported a survived 83
concentrations similar to those in blood and serum were years old woman of N. oleander poisoning who ingested for
measured also in milk (1.25 ± 0.99 ng/mL) and cheese (0.82 suicide.
± 0.02 ng/g) (Ceci et al., 2020) [11]. It was reported death of 58 years old Caucasian woman due
Oleandrin toxin was isolated from cattle feed and rumen to consumption of N. oleander for self-poisoning. The
contents due to N.oleander toxicity. Liquid pathological evaluation indicated petechiae, edema, and
chromatography-high resolution mass spectrometry (LC- congestion in tongue, gastric, and lung (Azzalini et al.,
HRMS) was used to detect and quantify oleandrin in rumen 2019) [44]. N. oleander extract comprising oleandrin, blocked
(Rubini et al., 2019) [49]. the “a-3 subunit of Na/K ATPase, FGF-2 export, Akt and
A method of detection of oleandrin was developed using p70S6K,” leading to alleviating the activity of mTOR.
liquid chromatography-tandem mass spectrometry Grade 1 atrioventricular block was observed in 10 subjects
(UHPLC-ESI-MS/MS) method for quantification of and supraventricular tachycardia (grade II) in one patient
oleandrin and other cardiac glycosides and evaluation of (Hong et al., 2019) [45].
their levels in herbs and spices from the belgian market. The N. oleander poisoning was reported in a 21 years old
method included oleandrin, digoxin, digitoxin, woman. She was admitted to hospital with vomiting, light
convallatoxin and ouabain. The LC-MS/MS method was headedness and cardiac block. Electrocardiogram indicated
used to examine 65 samples of culinary herbs and herb and P wave reversion in inferior and PR interval prolongation,
spice mixtures collected in Belgium, from supermarkets and with varying degree AV blocks (Khan et al., 2010) [46].
local stores and found to be accurate (Malysheva et al., Shumaik et al. (1988) presented a case report about self-
2020) [50]. poisoning with N. oleander. The main symptoms were
A potential strategies for rapid detection of seed-based bradycardia and sinoatrial nodal arrest inpatient. “Digoxin-
toxins and seed mashes containing oleandrin toxin using specific Fab antibody fragments” improved cardiac
chemical signatures obtained by direct analysis in real time problems. It was also reported that a man was maleciously
mass spectrometry (DART-MS). Seven toxins administrated N. oleander roots extract for 8 weeks. The
(digoxin, digitoxin, hypaconitine, hyoscyamine, symptoms such as nausea, diarrhea, abdominal pain, and
lanatoside, oleandrin, and scopolamine) and six seeds confusion were similar to acute toxicity. His clinical signs
containing these toxins were studied by this technique were moderate at the beginning, but elevated later. “Sinus
(Sisco et al., 2022ab) [55]. tachycardia” with “diffuse ST depression” and inverted “T
wave” were observed in ECG and also elevation in the
Toxicity in wild animals levels of CK (Le Couteur and Fisher, 2002) [48].
Two 18-month-old female bison and a heifer died suddenly
in the same ranch and the PM of three animals was Management of the toxicity
conducted and it was decided that they have died due to N. In the management of cases with oleander poisoning the
oleander poisoning (Streitenberger et al., 2022) [58]. quick assessment and assessment of airway, breathing and
circulation should be performed as early as possible. The
Toxicity in humans establishment of intravenous access and continuous ECG
Human exposure to N. oleander or T. peruviana may result monitoring preferably in the setting of a high dependency
from accidental ingestion, intentional ingestion, ingestion of unit would ensure prompt treatment and detection of any
medicinal preparations, and criminal poisoning. Oleander arrhythmias.
poisonings are reported widely from locations such as
Europe, United States (including Hawaii), Australia, Gastrointestinal decontamination
Southern Africa, India, Sri Lanka, East Asia and the The activated charcoal functions to adsorb the toxin which
Solomon Islands (Langford and Boor, 1996; Eddleston and is present in the GI tract and thereby reduces the amount of
Warrell, 1999) [20, 14]. toxin being absorbed into the bloodstream. It is administered
Deliberate self-harm through ingestion of T. peruviana is a at a standard dose of 1 g/kg.
major health problem in South Asia (Eddleston et al., 1998; Multi-dose AC (MDAC) also known as “gastrointestinal
Bose et al., 1999; Fonseka et al., 2002). T. peruviana dialysis” is the repeated administration of AC to enhance the
poisonings were a rare occurrence in Sri Lanka until local elimination of toxins from the body. MDAC helps in
newspapers reported the story of two girls who committed interrupting the enterogastric and enteroenteric circulation
suicide using T. peruviana seeds in 1980. Since then, this which enhances nonrenal elimination for the drug. A 2003
method of self-harm has become very popular and several randomized control trial (RCT) in patients with yellow
thousand cases have been reported each year with a case oleander poisoning revealed a significant mortality benefit
fatality rate between 4 and 10% (Eddleston et al., 1999, with MDAC compared to standard AC (2.5% vs. 8%). The
2008a, b) [14]. study also showed a reduction in the number requiring ICU
Human poisoning due to N. oleander may be caused by care, a temporary pacemaker, or anti-digoxin Ab. The
accidental or intentional consumption, consumption for benefits of standard AC versus MDAC in poisoning with up
medicinal purpose, or criminal poisoning. Oleander to 35% of study patients with oleander poisoning and results
poisoning has been observed in some countries, including did not show any mortality benefit in either group or
Europe, United States, Asia, and Africa and also in subgroup as the previous study had. Moreover, while the
Australia (Eddleston et al., 1999) [14]. Few case report asso- administration of MDAC greater care for airway protection
ciated with N. oleander poisoning has been observed. and risk of aspiration needs to be considered. Current
In this context, a case of N. oleander poisoning was reported recommendations are unclear as to the benefit of MDAC in
by Osterloh et al. (1982). They reported a 96 years old oleander poisoning, and more studies would be required
woman who died following consumption of N. oleander. before further recommendations can be made.

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Digoxin antibodies Diuresis and hemodialysis

Due to the similarities in the biochemical structure of the Cardiac glycosides have a large volume of distribution (7-8
cardenolide group of cardiac glycosides, there has been a lot L/kg) and only 20%-25% is protein bound. The efficiency
of study into the use of digoxin Ab in oleander poisoning. of hemodialysis is even reported as low as 5% in certain
From previous studies, it is clear that serum cardiac cases. A large systematic review stated there is no role in
glycoside levels correlate with serious dysrhythmias. A cardiac glycoside toxicity (Thomas et al., 2022) [56].
previous study was conducted to test the sensitivity to detect
oleandrin with digoxin assays which is used to monitor Acknowledgement
levels with therapy. Safety analysis found that 20% had an The author is thankful to the Karnataka Veterinary Animal
allergic reaction that responded to prompt therapy (Thomas and Fisheries Sciences University, Bidar and also to
et al., 2022) [56]. Government of Karnataka for the establishment of Obscure
Indications for digoxin Ab administration are life- Disease Research Center in the premises of Veterinary
threatening dysrhythmia and serum potassium over 5 meq/l. College, Shivamogga and financial assistance in terms of
Empiric administration in situations like oleander poisoning grants.
is the recommended therapeutic approach. Limitation for
digoxin Ab use in South India is the availability and cost of Conflicts of interest
the drug. No conflicts of interest.

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