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OLEANDER: AS PROTAGONIST AND ANTAGONIST
Aaeen Alchi1, Kalpesh Solanki
1 and Dr. Himanshu A. Pandya*
2
1Research Scholar Department of Biochemistry and Forensic Science, Gujarat University.
2Head, Department of Biochemistry and Forensic Science, Gujarat University.
ABSTRACT
Herbal products have been utilized by populations to cure and prevent
diseases throughout history; however, the quality and safety of these
herbal products has now become a serious issue because several cases
of intentional self-harm and accidental ingestion have been reported
from across the world. Due to scarcity of well documented case
reports, cardiac toxicity is a statistically uncommon phenomenon.
Oleander plant is draught tolerant ornamental plant. It contains
polysaccharides, glycosides and titerpenoids. The parts of plant are
used as traditional remedy in various diseases. This species also
produces secondary metabolites some of which are of pharmacological
interests. This review paper is evidence based information regarding
the toxicity and pharmacological activity of this plant.
KEY WORDS: Herbal products; poison; cardiac glycosides; oleander; cardiac toxicity.
INTRODUCTION
From the past few decades there has been a dramatic increase in use of plant product in
preparations throughout the industrialized world. According to World Health Organization
70-80% of the populations rely on non-conventional medicinal sources such as herbal in their
primary health care, there has increased growth of popularity of medicinal products or other
natural sources.[1]
Medicinal plants have been used by human beings from time immemorial
for healing different ailments. This practice still continues, even after the advent of modern
allopathic medicine.[2]
It is essential to take cognizance of the fact that overuse or abuse of
medicinal constituents of plants can cause danger.[3]
Plants containing glucosides, acids or
alkaloids are used as medicines, and the latex white or colored sap found in families of
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 6.647
Volume 6, Issue 8, 2446-2461 Review Article ISSN 2278 – 4357
Article Received on
19 June 2017,
Revised on 10 July 2017, Accepted on 31 July 2017,
DOI: 10.20959/wjpps20178-9907
*Corresponding Author
Dr. Himanshu A.
Pandya
Head, Department of
Biochemistry and
Forensic Science, Gujarat
University.
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Himanshu et al. World Journal of Pharmacy and Pharmaceutical Sciences
Apocynaceae, Asclepiadaceae, Sapolaceae, Euphorbiaceae and Papaveraceae, if used in
excess always act as poison.[4-10]
A poison is a substance which, when administered, inhaled or ingested, is capable of acting
deleteriously on human body. Thus, there is a very thin limit, for a medicine in a large dose is
a poison and a poison in a small dose may be a medicine means, it depends on dose/quantity
only. In law, real difference between a medicine and a poison is the intent with which it is
given. If the substance is given with the intention for betterment of life, it is a medicine but if
it is given with the intention to cause bodily harm, it is a poison.[11]
It is fact that almost any
substances can be harmful at high concentration- as Paracelsus (1493-1541), the father of
toxicology, “Everything is a poison and there is poison in everything, only dose makes a
thing not a poison.”[12]
Throughout the human history, intentional application of poison has been used as a method of
assassination, murder, suicide and execution. Poison includes both naturally produced
compounds and chemicals manufactured by humans. Natural poisons are produced by species
of bacteria, fungi, protists, plants and animals. Poisonous plants are those which cause serious
problems, even death occur, if a small quantity of its stem, leaves, seeds, fruits and roots are
ingested.[13]
Other plants are normally harmless but they may become toxic if preparative
from them are taken in excess in strong doses or for a long period of time.[14]
Poisonous
plants have played so large part, in romance as well as crime, that the subject is one which
claims the attention of even student of human nature.[15]
Ancient Egyptians and Romans first used plants containing cardiac glycosides medicinally as
emetics for heart ailments. Therapeutic use of herbal cardiac glycosides continues to be a
source of toxicity today. It has been also found in Chinese and Asian herbal products being a
source of human toxicity. But the growing series of case reports indicate that cardiotoxicity is
an important factor in morbidity and mortality associated with the products.[16]
An analysis of Johannesburg forensic database over the years 1991-1995 revealed 206 cases
where traditional remedy was either stated to be the cause of death or was found to be present
in a case of poisoning with an unknown substance. The range of toxins detected was wide,
with herbal materials being found in 43% of cases, half of these cases involved the use of
herbal cardiac glycoside.[17]
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While the clinical recognition, even quantity appraisal of congestive heart failure is a matter
of routine in practice of medicine, no precise definition of this state has been formulated
which is equally satisfactory to clinicians, physiologists and pathologists. When the
circulation is affected, it is not necessary that there is some major or primary defect is present
in cardiac function. But there may be change in cardiac output, blood volume, sodium
retention, and diastolic heart volume, mechanical efficiency of the heart, peripheral venous
pressure, intra-cardiac pressures and peripheral vasomotor reactions.[18]
Cardiac glycosides primarily affect cardiovascular, neurologic and gastrointestinal systems.
Glycosides are sugar derivatives and aglycones or genins, the nonsugar complement, are
generated when the sugar moiety is detached; in cardiac glycosides, or cardenolides, which
bear a structural resemblance to steroid saponins, the aglycones are distinguished from other
steroids by structural features that impart cardiotoxic properties.[19]
Cardenolides are composed of an aglycone that stems from plants terpenoid metabolism and
may or may not be glycosidically bound to one or more sugars. The aglycone has a typical
steroid structure comprising a four membered ring system while the sugars may often be
idiosyncratic for specific cardenolides.[20]
Cardenolides are members of a larger group, the cardiac glycosides, that comprises two
classes of compounds which differ in the structure of their aglycone: cardenolides have a five
membered lactone group in β position at c17,[21]
cardenolides occur in total of 12 families.[22]
They are most prominent in the Apocynaceae (now including the Asclepiadaceae;[23]
yet the
occurrence in the genus Digitalis among the Scrophulariaceae is for medical reason very
renowned.[22,24]
Being mostly polar compounds, cardenolides are predominantly stored in the
cell vacuole[25]
and may occur in all plant tissues.[22]
Given the widespread yet erratic
distribution in just some genera per plant family (with exception of the Apocynaceae) cardiac
glycosides are a convergent evolution.[20]
Although mostly recognized as a typical plant compounds cardinolides may also be produced
via the cholesterol pathway in animal tissues.[21,26,27]
Over the last 3 decades, evidence has
accumulated that cardiac glycosides are actually mammalian hormones found in blood
plasma, the adrenal cortex and the hypothalamus. They regulate blood pressure, cardiac,
kidney function, salt mechanism, also cell proliferation and cell half-life. Structurally these
endogenous cardiac glycosides comprise two cardenolides, ouabin and digoxin, that are
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identical to plant produced compounds. [28]
This suggests that plant producing cardenolides
are actually synthesizing hormone analogs.[20]
To humans cardenolides are bitter tasting compounds depending on their polarity and
structure. In mammals, a chemoreceptor trigger zone in medulla is responsible for induction
of vomiting at concentrations below toxic doses. Other effects including headache, altered
vision, psychosis and hormonal effects have also been described in humans.[24]
While the
mechanisms leading to these symptoms are still hard to trace, the immediate toxic effect of
ingested cardenolides is simple and well understood. The primary mode of action of
cardenolides is the inhibition of Na+/K
+ - ATPase, or sodium pump. This transmembrane ion-
motive ATPase is responsible for the maintenance of membrane potentials that drive
secondary transport mechanisms and enable the generation of action potentials in nerve cells.
During each cycle of Na+/K
+ -ATPase one molecule of ATP is hydrolysed and the energy is
used to translocate three Na+ ions to extracellular side in exchange for two K
+- ions that are
shuffled into the cystol.[29-31]
The structure of heterodimeric Na+/K
+ -ATPase is highly conserved in animal kingdom: a
catalytic α-subunit with ten transmembrane domains forming five extracellular loops interacts
with a small heavily glycosylated β-subunit that crosses the membrane only once. In addition
a regulatory γ-subunit may or may not be present. Cardenolides reversibly bind to the α-
subunit from extracellular side and lock it in its phosphorylated E2-P conformation, thereby
disrupting ion translocation.[29]
The pharmacological effect of cardenolides in humans used in
the treatment of heart insufficiencies is an increased level of intracellular Na+ that secondarily
leads to elevated intracellular Ca2+
levels by Na+/Ca
2+ exchange. This increased intracellular
Ca2+
concentration triggers the release of excess Ca2+
from the sarcoplasmic reticulum by a
cascade presumably involving the inositol-triphosphate receptor the Ca2+
-ATPase and finally
results in an increased strength of heart contraction.[28]
Even before the existence of
endogenous cardiac glycosides in mammals could be proven it had been speculated that this
kind of regulation of blood pressure and heart contraction may be the true reason for the
highly conserved cardenolide binding site and that endogenous cardenolide like substances
await discovery.[32]
By now the existence of endogenous cardiac glycosides is firmly
established[33-35]
and evidence for additional signaling cascades triggered by the docking of
endogenous cardiac glycosides to the Na+/K
+ - ATPase have emerged.
[28]
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Exposure of humans and different domestic animals to oleander cardenolides are common in
plant growing regions.[36-42]
Oleander poisoning is clinically well-documented, and has been
profusely used in suicide, homicide as well as abortifacient. This plant is highly toxic since
all parts contain several potent glycosides with digoxin- like activity.[43-45]
Most of the cases reported in past few decades have history of poisoning through; seeds, leaf
extract and flower poisoning were observed to be fatal,[46-51]
in few cases patients were saved
by activated charcoal,[52,53]
Digitoxin specific Fab antibody fragments[54,55]
and atropine
sulphate.[56-58]
Nerium oleander is small evergreen tree of 2-5m in height. [59]
Two common species-Nerium
oleander Linn. and Thevetia peruviana belongs to the Dogbane family, Apocynaceae are
drought tolerant evergreen plants[60,61]
Nerium oleander L. is distributed in Mediterreanean
region, subtropical Asia, South western United States, is indigenous to Indo-Pakistan
subcontinent.[62-67]
This species is often grown in gardens as ornamental plants due to its
abundant and long-lasting flowering and moderate hardiness[68,69]
and its certain parts are
used as medicinal materials in Chinese folk medicine.[64,70]
Whole plant is poisonous to
humans, animals and certain insects[63]
and in some parts of the world they are considered
noxious weeds. Oleander is an evergreen shrub or small tree; with diffusely branched and
dense-crown, it has flexible branches with green, smooth bark eventually turning grey.[60]
The
leaves are 5-20 cm long narrow, acuminated or acute in the apex, shortly petiolate, with
coriaceous dark-green and shining above, midrib stout, nerves numerous, spreading
horizontally.[71]
Leaves are linear- lanceolate, leathery and dark green to grey green, with
distinct yellowish veins. Some cultivators have white or yellow variegated leaves.[43]
Oleander shows terminal flower clusters that are available in different colors and their color
vary from deep to pale pink, lilac, carmine, purple, salmon, apricot, copper, orange, yellow
and white.[71]
Flower is about 5 cm in diameter with 5 petals, although some cultivators have
double flowers. The fruit consists of narrow follicle 7.5 to 17.5 cm long, rigid at length
separating fleshy, triangular drupe, green turning yellow and then black which opens to
disperse fluffy silky haired seeds.[72]
Calyx-lobes lanceolate, corolla-3.8 cm diameter,
filaments hairy, appendages of anthers twice as long as cells. The sap is thick, gummy and
milky white. Oleander can be propagated by seed but, being allogamous and highly
heterozygous, it shows great variability in seedling populations. Variety identification is
mainly based on flower color and shape, but other discriminating characters are presence of
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foliage variegation and growth habit. The plant is commonly known as „kaner‟ and its various
parts are reputed as therapeutic agents in treatment of swellings, leprosy, eye and skin
diseases.[44,73-75]
Although dismissed from modern pharmacopoeias, preparations of oleander
have been used for centuries as rodenticides and insecticides, as well as folk remedies for
indigestion, malaria, leprosy, mental or venereal diseases, or as abortifacients.[76]
Table 1: Studies performed on different animals.
Author
Subject
(animal)
Dose and died in
duration Symptoms Main findings
Schwartz[77]
Monkey
0.30g/kg
Died in 2-4hr
Vomiting, salivation,
polyuria, bradycardia,
vaginal hemorrhage,
abortion, anorexia,
constipation,
narcosis, restlessness,
weakness, shallow
and rapid respirations
Haemorrhages, degeneration or
necrosis were observed in heart,
gastrointestinal tract, skeletal muscles,
ovaries, adrenal glands, liver, kidneys,
pancreas. The organ weight of
pancreas were reduced. Significant
increase in weight of adrenal glands
was probably manifestation of
compensatory hyperplasia.
Reid
Hanson[78]
Horse
10 grams of leaves
Died in 1-48hr
Cholic, diarrhea,
weakness and heart
failure
Determined minimum toxic amount,
developed tests for determining
exposure to oleanderin, provided
diagnostic tool to identify previously
undiagnosed oleander poisoning in
horses, before and after death
Adam[79]
Sheep
0.25g/kg
Died in 18-24hr
Uneasiness, anorexia,
grinding of the teeth,
salivation, moaning,
frequent urination,
dyspnoea, ruminal
bloat, ataxia and
recumbency
In single dose of 0.25g/kg of oleander
leaves, congestion or haemorrhage
particularly observed on the heart,
kungs, liver, intestines, abomasums
and spleen, pulmonary emphysema
and cyanosis, hepatorenal fatty change
and necrosis were observed. No
lesions were observed in the brain or
peripheral nerves.
Aslani[36]
Sheep
1.10g/kg
Died in 4-12hr
Tachyarrhythmias,
ruminal atony,
tympany, abdominal
pain, polyuria,
polakiuria,
bradycardia, atrio
ventricular blocks,
depression of S-T
segments,tachycardia
and ventricular
fibrillation.
Clinical signs of toxicosis in sheep
began to appear about 30 min after
receiving the oleander, Decrease in
heart rate followed by cardiac pauses.
Histopathological examination
revealed myocardial degeneration and
necrosis, degeneration and focal
necrosis of hepatocytes, necrosis of
tubular epithilieum in kidneys,
odedema in lungs and ischemic
changes in cerebrum.
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Blanco[37]
Cattle
0.005% of
bodyweight
Died in 2-24hr
Prostration,
recumbence,
inappetence,
haemorrhagic
diarrhea, dehydration,
ataxia, staggering
gait, stretched neck,
salivation,
tachycardia, panting,
rapid breathing,
paralysis.
All reported cases occurred during dry
season. Total 92 cattels were poisoned
by oleander in 7 different heards, 57
animals died. Pharmacokinetic studies
showed that oleandrin is rapidly
absorbed after oral administration
with bioavailability of about 30% and
biotransformed to oleandrigenin,
probably through an enzymatic
process.
Barbosa[80]
Goats
1.10g/kg
Died in 4-12hr
Apathy,colic
vocalizations,
hyperpnea, polyuria
and moderate rumen
distention
Bradycardia was first clinical sign
noted, 30 min after administration.
Necrosis was found convoluted as
well as in collecting tubules. Renal
tubule necrosis is responsible for renal
failure and is due to impairment of
k+/Na+ - ATPase pump
Anna[81]
Equids
-
Died in 2-24hr Cardiac dysfunction
30 equids were reported having
medical records with detectable
concentrations of oleandrin in serum,
plasma, urine, gastrointestinal fluids
samples. Oleander toxicosis lead to
gastrointestinal tract, cardiac and renal
problems
Mizanur[82]
Earthworms
0.039g/ml
Died in 10-40 min Paralysis, death
Anthelmintic activity of yellow
oleander bark extract was determined.
Table 1 shows the reported work of studies performed on different animals their doses,
symptoms and main findings due to oleander poisoning. These reports gave diagnostic
symptoms and the postmortem findings after providing different doses of oleander extract to
the subject animals. These studies confirmed that oleander possess the cardio toxicity
Schwartz et al suggested lesions of the heart, gastrointestinal tract and liver were consistently
found in monkeys that died from effects of oleander. Reid Hanson gave presumptive and
postmortem findings for diagnostic tools for detection of oleander poisoning. Adam et al
studied the rapid death attributed to respiratory and cardiovascular failure. Aslani et al
studied that sheep are as susceptible as cattle to oleander toxicosis. Sheep may be used as a
model to study the different aspects of intoxication with cardiac glycosides in ruminants.
Blanco et al studied oleandrin is readily absorbed and arrives at the heart causing immediate
damage to cardiomyocytes, also can cross the blood-brain barrier and accumulate in CNS.
Barbosa et al suggested that brain in goats are not affected by oleander poisoning which
could be due differences in susceptibility to intoxication of different species, also kidney and
heart failure was similar to other species. Anna et al suggested that oleander intoxication
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Himanshu et al. World Journal of Pharmacy and Pharmaceutical Sciences
should be a differential diagnosis for equids with colic in geographic areas where oleander is
found, especially when azotemia or cardiac arrythymias are detected concurrently. Mizanur et
al proved the methanolic extracts of oleander possess cytotoxic properties.
In the cardiac toxicity study, various instrumentation techniques have been used.
Chromatographic procedures have more seldomly employed. The autopsy samples of oral
and rectal administration of oleander poisoning was done by thin-layer
chromatography(TLC) while its quantification were performed in fluorescence
spectrophotometry on dry extracts reconstituted in water/methanol.[48]
Thermolability and
nonvolatility of cardiac glycosides were performed by using GC/MS, HPLC/MS, which
proved to be the method of choice for unequivocal identification of therapeutic compounds
such as digoxin or digitoxin.[83]
Fluorescence polarization immunoassay is been used in the
diagnosis of plant induced cardiac glycoside poisoning on livestock in southern Africa. The
diagnosis is based on circumstantial evidence of presence of plant cardiac glycosides in
animal specimens, like plasma levels in humans and dogs as well as in the rumen and organs
of dosed sheep. The positive FPIA values were obtained with bufadienolide containing plants
and negative results indicated diagnosis of cardiac glycosides.[84]
Electrospray ionization
(ESI) in combination with mass spectrometry is an efficient method to analyze the polar and
non-volatile cardiac glycosides,[85]
because gentle ionization can be achieved under
atmospheric pressure conditions. C18 reversed-phase high-performance liquid
chromatography, using bi or ternary solvent mixtures, is a convenient method to separate
cardiac glycosides.[83,86,87]
Typical mobile phases are water, methanol and acetonitrile,
buffered with formic acid and ammonium formate respectively. The preferred detection
technique is (tandem) mass spectrometry.[86-88]
The use of triple-quadruple analyzer in the
MRM (multiple reaction monitoring) mode enables the analysis of cardiac glycosides even in
complex human matrixes. The hybrid system, namely a quadruple time of flight (Q-TOF)
mass spectrometer was used to characterize the six thevetia glycosides.[89]
The multiple body fluid samples were analysed by Liquid chromatography- mass
spectrophotometry (LC-MS/MS) and concentration of oleandrin was detected.[76]
Serum
samples were assayed immunochemically for digitoxin related compounds by electro-
chemiluminiscent immunoassay, using HPLC-MS/MS analysis for oleandrin.[52]
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Medicinal importance
The main constituents of oleander are polysaccharides, cardenolides, glycosides and
titerpenoids.[90,91]
Various parts of Nerium oleander have been used medicinally, chiefly as a
heart tonic, diuretic, in treatment of swelling, leprosy and eye and skin diseases[62]
and are
reported to possess a wide range of biological activities including antinociceptive, anti-
inflammatory, cardiotonic, antibacterial, anti-cancer,[92]
cytotoxic, antiplatelet aggregation,
and central nervous system depressant activities.[44,73,93-95]
The important pharmacological activities are anti-inflammatory, anti-bacterial, anti-cancer,
antinociceptive and CNS depressant activity.[96]
The leaves and flowers are cardio tonic,
diaphoretic, diuretic, anticancer, antibacterial,[44]
antifungal[87]
and expectorant. A decoction
of the leaves has been applied externally in the treatment of scabies and to reduce swellings.
This is a very poisonous plant, containing a powerful cardiac toxin and should only be used
with extreme caution. The root is powerfully resolvant is used in the form of plasters and is
applied to tumors because of its poisonous nature it is only used externally. It is beaten into a
paste with water and applied to lesion and ulcers on penis.[97]
The bark is bitter and is used as cathartic, febrifuge and intermittent fever. Plants have an
extensive root system and are often used to stabilize soil in warmer areas. Oil prepared from
the root bark is used in treatment of leprosy and skin diseases of a scaly nature. Seeds are
poisonous, abortifacient and alternative. They are used as purgative in dropsy and
rheumatism. The whole plant is said to have anticancer properties.[90]
Oleander has also been
used in the treatment of cancer,[98]
the flowers, leaves, leaf juice or latex, bark and roots have
been used against corns, warts, cancerous ulcers, carcinoma, ulcerating or hard tumors.[4,99]
CONCLUSION
Understanding of the interactions between drugs, herbs and food is still in its infancy. People
are using herbal medicines from centuries for safety, efficacy, cultural acceptability for lesser
side effects. Plants and plant products have utilized with varying success to cure and prevent
diseases throughout history.
Major plunge by the pharmaceutical industry is focused towards design and development of
new innovative/ indigenous plant based drugs through investigation leads from traditional
system of medicine.
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The oleander plant is commonly known as „Kaner‟, its parts are used as traditional remedy in
various diseases. Oleander contains glycosides with digoxin like activity. Cardiac glycosides
blocks electric impulses by inhibiting the Na+/K
+- ATPase sodium-potassium ion pump.
Therapeutic use of herbal cardiac glycosides continues to be a source of toxicity.
There is an urgent requirement for a concerted effort to enlarge forensic and toxicological
databases to include methods for detection of poisoning by these cardiotoxic plants.
The significance of this review on such studies of plants and their toxicity will help forensic
investigators in solving the crimes and searching the poisoning- plant materials on the crime
spot. It can lead to the reason related to the poisoning- suicidal, accidental or homicidal, by
the parts of plants may or may not be found at crime spot like forest/ garden, symptoms of
poisoning can help to direct the investigation to right path. On the basis of analysis and plant
origin toxicity, forensic team can opine whether the case was suicidal, homicidal or of
accidental type.
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