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Nerium oleander and Oleandrin Amanda Rouse

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  • 1.Why Oleandrin? Many everyday natural substances are toxic Some have been harnessed for medicine N. oleander is greatly known to be fatally toxic withexposure 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 Neriumoleander

2. 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 westernmedicine 3. Where is Oleandrin found? In Nerium oleander plants In leaves, stems, flowers, and nectar Also found in Nerium oleander are Digitoxigenin, Neriin, and Oleondroside (cardiacglycosides) 4. Nerium oleander Lance shaped leaves, summer flower Dogbane/Apocynaceae Family: many cardio toxic andblood 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: Laurierrose, rosebay,desert rose, and many 5. 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 containshigh amounts (relative to toxicity) of Oleandrin, and other toxins Symptoms of toxicity after ingestion or inhalation of smoke: Blurred vision - Tachyarrhythmia Vomiting/Diarrhea- Confusion Bradyarrhythmia- Death by heart attack 6. Oleandrin Structure 5,20(22)-Cardenolide-3,14,16-triol-3-([2,6-dideoxy-3-O-methyl--L-arabinohexopyranosyl]oxy) 16-acetate C32H48O9 7. Oleandrin Action Is a Cardiac Glycoside (most potent in N. oleander) Inhibits the alpha-3 subunit of Na+/K+-ATPasepump - Binds reversibly to the alpha-3 subunit causing 1) Intracellular sodium increase 2) Calcium ions increase in muscle cells of the heart 3) Irregular muscle contraction 4) May have an effect of signaling pathways 5) May inhibit protein assembly Other effects: Cytochrome C release from mitochondria Apoptosis: activates caspases 6 and 8 8. extracellularintracellular1) Intracellular sodium increase Oleandrin inhibits the alpha 3 subunit of Na+/K+ATPase pumps Na+ unable to leave cell Inner cell Na+ increases 9. 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+exchangerIncreases intracellular Ca2+ Calcium imbalance affects muscle contraction May have an effect of signaling pathways May inhibit protein assembly 10. Metabolism of Oleandrin Half life longer for ingested oleandrin than for intravenousacquisition 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 11. 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 afteraccidental ingestion 12. 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 13. Oleander use in Folk Remedies Known for ~3500 years that ingestion is fatal, but external application showsno 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: snakebitetreatment, external parasite remover, musclecramps, asthma, coma, menstrual pain, epilepsy, cancer, paralysis, skindisease, cardiac problems (traditionalChinese), insecticide, eczema, psoriasis, herpes, malaria, leprosy, used inboth ancient and more recent times for suicide Today: many websites detail how to make homeopathic cancer fightingoleander soup at home (does that scare you too?) 14. Recent Folk Medicine use Gone Bad Topical aphrodisiac in New York 4 men died after exposure to an oleander based productmarketed as topical aphrodisiac Digoxin like compound was found in all 4, though none hadtaken digoxin Later found that thedigoxin like substance in their blood wasoleandrin*Take home message: even topical therapeutic applicationscan have strong effects 15. Western Medical Developments1. Cardiac failure and atrial fibrillation medicine Resembles digitalis (digoxin makes digitalis: a cardiac medicine)1. Cancer treatment (Anvizrel) Not supported by FDA1. Anti-aging Skin treatment (NeriumAD) Not supported by FDA1. Neural protection from ischemic stroke being investigatedFor all medicinal developments, issues with narrow therapeutic rangeMany known and theoretical drug interactions 16. 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 3:1 subunit ratio in cancer cells makes them more susceptible to oleandrin Overexpression of the 3 subunit in tumor cells correlates with proliferation Blocks activation of NF-kproliferation 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 trial http://www.neriumbiotech.com/cancer_research.htm 17. Protectant Against Ischemic Stroke Promising results Oleander has been shown to have neural protectiveeffects against electric shocks Oleander has been shown to have anticonvulsant effectson rat models 18. 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 19. Industrial Uses Gunpowder As Poison: Organic Insecticide Rodent poison 20. 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 21. For the Future Legal control of use for landscaping Agricultural areas: protect food supply and animals Near schools More research on adverse effects and specificmechanisms of other toxins present in N. oleander More research on specific effects of interactionswith drugs, supplements, and herbal treatments 22. Sources Cited IDeaths Associated with a Purported Aphrodisiac -- New York City, February 1993-May 1995. [Internet] 1995 November[cited 2013 February 28] MMWR Weekly. 44(46): 853-855. Available from:www.cdc.gov/mmwr/preview/mmwrhtml/00039633.htmDunn, D.E., He, D.N., Yang, P., Johansen, M., Newman, R.A., Lo, D.C. 2011. In vitro and in vivo neuroprotectiveativity of thecardiac glycoside oleandrin from the Nerium oleander in brain slice-based stroke models. Journal of Neurochemistry.119: 805-814Goyder, D. Plants & Fungi: Nerium oleander (oleander) - Species profile. [Internet] 2013 February [cited 2013 February 26]Kew Royal Bontanic Gardens. Available from: http://www.kew.org/plants-fungi/Nerium-oleander.htmHallbook, H., Feith, J., Eriksson, A., Fryknas, M., Bohlin, L., Larsson, R., Gullbo, J. 2011. Ex vivo activity of cardiac glycosides in acute leukaemia. Plos One 6(1): e15718Jortani, S.A., Helm, R.A., and Valdes, R. Jr. 1996. Inhibition of Na, K-ATPase by oleandrin and oleandrigenin, and their detection by digoxin immunoassays. Clinical Chemistry. 42(10): 1654-1658M.D. Anderson Cancer Center. Oleandrin (Nerium Oleander) in combination with carboplatin and docetaxel in treatingpatients with advanced non-small cell lung cancer [Internet]. Clinical Trials.gov. November 2012 [cited 2013 February 2]Available from http://clinicaltrials.gov/show/NCT01562301Nerium Biotechnology, Inc. 2013. Unique Partnership Launches breakthrough skincare line [Internet]. PRWeb [cited 2013February 23] Available from: http://www.prweb.com/releases/2011/8/prweb8755747.htm 23. Sources Cited IINewman, R.A., Yang, P., Hittelman, W.N., Lu, T., Ho, D.H., Dan, N., Chan, D., Vijjeswarapu, M., Cartwright, C., Dixon, S., Felix, E., and Addington, C. 2006. Oleandrin-mediated oxidative stress in human melanoma. Journal of Experimental Therapeutics and Oncology. 5:167-181Ni, D., Madden, T. L., Johansen, M., Felix, E., Ho, D. H. and Newman, R. A. (2002), Murine pharmacokinetics and metabolism of oleandrin, a cytotoxic component of Nerium oleander. Journal of Experimental Therapeutics and Oncology, 2: 278 285. doi: 10.1046/j.1359-4117.2002.01052.xOleander Poisoning. Medicine Plus. [cited 2013 February 25]. Accessed from:http://www.nlm.nih.gov/medlineplus/ency/article/002884.htmOleander. WebMD. [cited 2013 February 24]. Accessed from:http://www.webmd.com/vitamins-supplements/ingredientmono-789- OLEANDER.aspx?activeIngredientId=789&activeIngredientName=OLEANDERPerne, A., Muellner, M.K., Steinrueck, M., Craig-Mueller, N., Maverhofer, J.,Schwarzinger, I., Sloane, M., Uras, I.Z., Hoermann, G., Nijman, S.M., and Maverhofer, M. 2009. Cardiac glycosidesinduce cell death in human cells by inhibiting general protein synthesis. Plos One. 4(12): e8292Prassas, I., and Diamandis, E.P. 2008. Novel therapeutic applications of cardiac glycosides. Nature Reviews Drug Discovery. 7:926-935.Rakhshandeh, H., Boroushaki, M.T., Sadeghian, A., Parasee, H. 2004. Antimicrobial effect of different extracts of Neriumoleander L on standard and clinically isolated microorganism. Koomesh Journal. 6(1): 37-42 24. Sources Cited IIISinghal, K. G., and Gupta, G. D. 2011. Some central nervous system activities of Nerium oleander Linn (Kaner) Flower Extract.Tropical Journal of Pharmaceutical Research. 10(4): 455-461Smith, J.A., Madden, T., Vijjeswarapu, M., and Newman, R.A. 2001. Inhibition of export of fibroblast growth factor-2 (FGF-2)from the prostate cancer cell lines PC3 and DU145 by anvirzel and its cardiac glycoside component, oleandrin.Biochemical Pharmacology. 62(4): 469-472