Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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-3O-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 - 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 extracellular intracellular 1) Intracellular sodium increase – Oleandrin inhibits the alpha 3 subunit of Na+/K+ ATPase pumps – Na+ unable to leave cell • Inner cell Na+ increases 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) 1. Cancer treatment (Anvizrel) – Not supported by FDA 1. Anti-aging Skin treatment (NeriumAD) – Not supported by FDA 1. 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 trial http://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 Sources Cited I Deaths 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.htm Dunn, D.E., He, D.N., Yang, P., Johansen, M., Newman, R.A., Lo, D.C. 2011. In vitro and in vivo neuroprotective ativity of the cardiac glycoside oleandrin from the Nerium oleander in brain slice-based stroke models. Journal of Neurochemistry. 119: 805-814 Goyder, 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.htm Hallbook, 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): e15718 Jortani, 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): 1654-1658 M.D. Anderson Cancer Center. Oleandrin (Nerium Oleander) in combination with carboplatin and docetaxel in treating patients with advanced non-small cell lung cancer [Internet]. Clinical Trials.gov. November 2012 [cited 2013 February 2] Available from http://clinicaltrials.gov/show/NCT01562301 Nerium Biotechnology, Inc. 2013. Unique Partnership Launches breakthrough skincare line [Internet]. PRWeb [cited 2013 February 23] Available from: http://www.prweb.com/releases/2011/8/prweb8755747.htm Sources Cited II Newman, 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. 5:167-181 Ni, 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.x Oleander Poisoning. Medicine Plus. [cited 2013 February 25]. Accessed from: http://www.nlm.nih.gov/medlineplus/ency/article/002884.htm Oleander. WebMD. [cited 2013 February 24]. Accessed from: http://www.webmd.com/vitamins-supplements/ingredientmono-789OLEANDER.aspx?activeIngredientId=789&activeIngredientName=OLEANDER Perne, 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 glycosides induce cell death in human cells by inhibiting general protein synthesis. Plos One. 4(12): e8292 Prassas, 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 Nerium oleander L on standard and clinically isolated microorganism. Koomesh Journal. 6(1): 37-42 Sources Cited III Singhal, 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): 455-461 Smith, 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