Nerium oleander and

Oleandrin Amanda Rouse

Why Oleandrin?

• Many everyday natural substances are toxic– Some have been harnessed for medicine

• N. oleander is greatly known to be fatally toxic with exposure to very low doses, BUT– Has been used in folk medicine– Under investigation for uses in Western Medicine

• Oleandrin is the main active compound in Nerium oleander

Overview of Oleandrin

• Most potent of ~30 glycosides found in Oleander

• Most commonly known for its fatal cardiotoxicity

• Used in folk medicine for thousands of years

• Currently under investigation for uses in western medicine

Where is Oleandrin found?

• In Nerium oleander plants– In leaves, stems, flowers, and nectar

• Also found in Nerium oleander are– Digitoxigenin, Neriin, and Oleondroside (cardiac

glycosides)

Nerium oleander

– Lance shaped leaves, summer flower– Dogbane/Apocynaceae Family: many cardio toxic and

blood pressure effecting plants– Native to Mediterranean, Southeast Asia, and Africa

- Thrives in almost all warm climates- Fast growing - evergreen

- Commonly used In landscaping worldwide- Also known as: Laurier rose,

rosebay, desert rose, and many other names

Oleander: known to be toxic• Cardiotoxic: due to Cardiac glycosides like Oleandrin

• Toxic mostly to mammals– Children and animals at higher risk for ingestion– Highly toxic in low doses

• Single leaf can kill an adult human in hours• Even honey from bees that take pollen and nectar from oleander contains

high amounts (relative to toxicity) of Oleandrin, and other toxins

• Symptoms of toxicity after ingestion or inhalation of smoke:– Blurred vision– Vomiting/Diarrhea– Bradyarrhythmia

- Tachyarrhythmia- Confusion- Death by heart attack

Oleandrin Structure

• 5β,20(22)-Cardenolide-3β,14,16β-triol-3-([2,6-dideoxy-3-O-methyl-α-L-arabinohexopyranosyl]oxy) 16-acetate

• C32H48O9

Oleandrin Action• Is a Cardiac Glycoside (most potent in N. oleander)

• Inhibits the alpha-3 subunit of Na+/K+-ATPase pump

• Other effects:– Cytochrome C release from mitochondria– Apoptosis: activates caspases 6 and 8

- Binds reversibly to the alpha-3 subunit causing1) Intracellular sodium increase2) Calcium ions increase in muscle cells of the heart3) Irregular muscle contraction4) May have an effect of signaling pathways5) May inhibit protein assembly

1) Intracellular sodium increase– Oleandrin inhibits the alpha 3 subunit of

Na+/K+ ATPase pumps– Na+ unable to leave cell• Inner cell Na+ increases

intracellular

extracellular

2) Calcium ions increase in muscle cells of the heart

• Na+ unable to move in against gradient• Ca2+ unable to move out of cell via Na+/

Ca2+ exchanger• Increases intracellular Ca2+

• Calcium imbalance affects muscle contraction• May have an effect of signaling pathways• May inhibit protein assembly

Metabolism of Oleandrin• Half life longer for ingested oleandrin than for intravenous acquisition

• Oleandrin and metabolites travel throughout the body, – Oleandrin rapidly accumulates in liver, brain, and kidneys

• Crosses the blood brain barrier

• Oleandrin converted to Oleandrinogen – Happens in plasma of mice, but only in organs of humans– Happens within 5-15 minutes of delivery– Highest amounts of oleandrinogen found in liver, other (yet unidentified)

metabolites also found (only) in the liver– To a lesser extent occurs in heart and kidney

• Excretion within 24 hours of delivery – via mainly feces, and partially urine

Medical and Veterinary Importance

• Medical:– Poisoning of people• Via accidental ingestion (mostly children)

– Usually advised not to plant N. oleander near schools or playgrounds

• Via inhalation of smoke from fires burning N. oleander

• Veterinary:– Quickly kills domestic animals and livestock after

accidental ingestion

Treatment for Ingestion

• Gastric Decontamination(ingestion): Charcoal • Hydration via IV saline• Electrolytes• Antiemetics: to treat nausea• Correction of Hyper or Hypokalemia• Treatment of Arrhythmias

– Bradyarrhythmia correction: • atropine or isoprenaline

– Tachyarrhymia correction: • Usually poor prognosis• Digoxin-specific antibody fragments• Lidocaine

* Same treatments for Inhalation of smoke, except charcoal

Oleander use in Folk Remedies

• Known for ~3500 years that ingestion is fatal, but external application shows no toxic symptoms

• 15 century BC: oleander and licorice combo used to treat hangovers

• 8th Century AD: cancer treatment

• Other folk remedy uses originating from Mesopotamia: snakebite treatment, external parasite remover, muscle cramps, asthma, coma, menstrual pain, epilepsy, cancer, paralysis, skin disease, cardiac problems (traditional Chinese), insecticide, eczema, psoriasis, herpes, malaria, leprosy, used in both ancient and more recent times for suicide

• Today: many websites detail how to make homeopathic cancer fighting “oleander soup” at home (does that scare you too?)

Recent Folk Medicine use Gone Bad

• Topical aphrodisiac in New York

– 4 men died after exposure to an oleander based product marketed as “topical aphrodisiac”

– Digoxin like compound was found in all 4, though none had taken digoxin

– Later found that the digoxin like substance in their blood was oleandrin

*Take home message: even topical therapeutic applications can have strong effects

Western Medical Developments

1. Cardiac failure and atrial fibrillation medicine– Resembles digitalis (digoxin makes digitalis: a cardiac medicine)

2. Cancer treatment (Anvizrel)– Not supported by FDA

3. Anti-aging Skin treatment (NeriumAD)– Not supported by FDA

4. Neural protection from ischemic stroke being investigated

• For all medicinal developments, issues with narrow therapeutic range

• Many known and theoretical drug interactions

As a Cancer Treatment

• As a cancer treatment (Anvizrel)• Anvizrel made by Nerium Biotechnology

– Same manufaturer as NeriumAD skincare• Nerium Biotechnology Claims:

– Inhibits the Na+/K+ pump in cancer cells specifically, inhibiting protien expression• Because higher α3:α1 subunit ratio in cancer cells makes them more

susceptible to oleandrin– Overexpression of the α3 subunit in tumor cells correlates with proliferation

– Blocks activation of NF-kβ proliferation signal– May cause apoptosis of cancer cells

• Did not pass FDA approval– FDA claims Nerium Biotechnology posted misleading website

information on scientific proof of efficacy in clinical trialhttp://www.neriumbiotech.com/cancer_research.htm

Protectant Against Ischemic Stroke

• Promising results– Oleander has been shown to have neural protective

effects against electric shocks– Oleander has been shown to have anticonvulsant effects

on rat models

Drug Interactions

• Usually cardiac in nature• Interactions may arise from:– Antibiotics– Digoxin (and other cardiac medicines)

• Also herbal treatments derived from plants that contain cardiac glycosides– Cardiac glycoside toxicity

– Quinine– Laxatives– Corticosteroids

• Compounds Na+ retention

– Diuretics– Calcium supplements

Industrial Uses

• Gunpowder

• As Poison:– Organic Insecticide– Rodent poison

Conclusion

• Nerium oleander is highly toxic – Mainly due to the cardiac glycoside Oleandrin

• Cardiac glycosides may be therapeutically useful– Used in folk medicine – May not be safe enough for use in western medicine

• Used currently in industry– Gunpowder, rodent and insect poisons

For the Future

• Legal control of use for landscaping– Agricultural areas: protect food supply and animals– Near schools

• More research on adverse effects and specific mechanisms of other toxins present in N. oleander

• More research on specific effects of interactions with drugs, supplements, and herbal treatments

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