OLEANDER: AS PROTAGONIST AND ANTAGONIST · oleander Linn. and Thevetia peruviana belongs to the...

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Himanshu et al. World Journal of Pharmacy and Pharmaceutical Sciences

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.


2447


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


2453


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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