Health Care Professional Information

Scientific Name
Nerium oleander
Common Name

Rose laurel, adelfa, rosenlorbeer, karavira

Brand Name

Anvirzel™

Clinical Summary

Nerium oleander is an ornamental shrub native to northern Africa, the eastern Mediterranean basin and Southeast Asia. It is used in traditional medicine to treat hemorrhoids, ulcers, leprosy, and as an abortifacient. The leaf of Nerium oleander is poisonous because of oleandrin. This is a cardiac glycoside with structure and actions similar to those of digoxin. They both exert their effects by inhibiting membrane enzyme Na+, K+ -ATPase (1). However, most studies have been focused on the herb’s anticancer activities because of its apoptotic effects in various cancer cell lines (2) (3) (4) (5) (6) (7) (8). It also increases the sensitivity of PC-3 human prostate cells to radiotherapy (9) and reduces gentamycin toxicity (10) In other studies oleandrin demonstrated neuroprotective activity (11) and reduced infectivity of HIV virus (24).

A hot water extract of this plant known as Anvirzel™ has been developed as a treatment for cancer, AIDS and congestive heart failure. It consists of a mixture of oleandrin and the glycone oleandrigenin. Results from an earlier study showed that it is safe in humans when injected intramuscularly although adverse effects such as injection site pain, fatigue and other GI symptoms were reported (12).

Anvirzel™ is not an approved cancer treatment in the United States. Until more data regarding its efficacy and toxicity are available, this product should not be used outside of clinical trials.

Purported Uses
  • Cancer treatment
  • Congestive heart failure
  • Hepatitis
  • AIDS
Constituents
  • Cardiac glycosides: Oleandrin, odoroside, neritaloside, aglycone oleandrigenin
  • Polysaccharides
Mechanism of Action

Oleandrin may slow tumor growth by inhibiting the membrane enzyme Na+, K+ -ATPase (1), especially in cells that have higher ratio of alpha 3 to alpha 1 isoform expression (13). It improves cellular export of fibroblast growth factor-2 (FGF-2)(4). Oleandrin induces apoptosis through Fas gene expression in tumor cells (14) and by suppressing NF-kB (2) (15). It selectively sensitizes lung cancer cells to apoptosis-inducing ligand Apo2L/TRAIL. This is accompanied by up-regulation of death receptors 4 (DR4) and 5 (DR5) at both the RNA and protein levels (16).
Other proposed mechanisms include the formation of superoxide radicals that cause tumor cell injury via mitochondrial disruption (7), inhibition of interleukin-8 that mediates tumorigenesis (17), activation of caspase-3 (9), induction of tumor cell autophagy (6) and inhibition of P-gp (8).

Pharmacokinetics

In a study of mice, oleandrin was rapidly absorbed when taken orally. Maximum plasma concentration (Cmax) was reached at 20 min with elimination half-life at 2.3 +/- 0.5 h. The oral bioavailability was approximately 30%. Oleandrin concentrated mainly in the liver in the form of the aglycone oleandrigenin. Other components of oleander extract may enhance transport of oleandrin across the blood brain barrier (18). About half of circulating oleandrin is bound to plasma proteins. Both biliary and renal elimination have been shown (7).

Warnings

Unprocessed leaves from the Nerium oleander plant are highly toxic.

Contraindications

Patients with hypercalcemia, hypokalemia, bradycardia, ventricular tachycardia, or heart failure should not use this product. (12)

Adverse Reactions
  • Common (Raw botanical)
    Consumption of even one Nerium oleander leaf can be fatal (25). Onset of toxicity occurs several hours following consumption. Symptoms include vomiting, abdominal pain, cyanosis, hypotension, hypothermia, vertigo, respiratory paralysis and death. These symptoms can occur at a serum oleandrin level between 1.0 and 2.0 ng/ml (19).
  • Reported (Anvirzel™)
    Pain at injection site, fatigue, transient erythema, nausea, vomiting and diarrhea. Consumption of oleander leaves resulted in the death of an adult diabetic male. The oleandrin levels in the blood were roughly 10 ng/ml (20).
  • Case Report
    Daily intramuscular injections of Nerium oleander extract for two months are suspected as probable cause of death of a 43-year-old patient with Metastatic Synovial Sarcoma of the knee. Her symptoms included nausea, vomiting, severe stomach pain and bloating followed by a gradual reduction in liver enzymes, and cardiopulmonary arrest (21).
Herb-Drug Interactions
  • Digoxin: Theoretically, the cardiac glycosides in Nerium oleander may have an additive effect with digoxin, causing toxicity.
  • P-glycoprotein (P-gp) substrates: Oleander leaf extract inhibits P-gp and may increase the blood levels of substrate drugs. (8)
Herb Lab Interactions

Digoxin and digitoxin immunoassays: Oleandrin is structurally similar to digoxin and digitoxin, and is known to cross react in various immunoassays. (22) (23)

Literature Summary and Critique

Studies are underway to determine the antitumor effects of Oleandrin.  

References
  1. Lin Y, Ho DH, Newman RA. Human tumor cell sensitivity to oleandrin is dependent on relative expression of Na+, K+ -ATPase subunitst. Journal of experimental therapeutics & oncology. 2010;8(4):271-286.
  2. Manna SK, Sah NK, Newman RA, et al. Oleandrin suppresses activation of nuclear transcription factor-kappaB, activator protein-1, and c-Jun NH2-terminal kinase. Cancer research. Jul 15 2000;60(14):3838-3847.
  3. Pathak S, Multani AS, Narayan S, et al. Anvirzel, an extract of Nerium oleander, induces cell death in human but not murine cancer cells. Anti-cancer drugs. Jul 2000;11(6):455-463.
  4. Smith JA, Madden T, Vijjeswarapu M, et al. 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. Aug 15 2001;62(4):469-472.
  5. Felth J, Rickardson L, Rosen J, et al. Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs. Journal of natural products. Nov 2009;72(11):1969-1974.
  6. Newman RA, Kondo Y, Yokoyama T, et al. Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid-soluble cardiac glycoside. Integrative cancer therapies. Dec 2007;6(4):354-364.
  7. Newman RA, Yang P, Hittelman WN, et al. Oleandrin-mediated oxidative stress in human melanoma cells. Journal of experimental therapeutics & oncology. 2006;5(3):167-181.
  8. Turan N, Akgun-Dar K, Kuruca SE, et al. Cytotoxic effects of leaf, stem and root extracts of Nerium oleander on leukemia cell lines and role of the p-glycoprotein in this effect. Journal of experimental therapeutics & oncology. 2006;6(1):31-38.
  9. Nasu S, Milas L, Kawabe S, et al. Enhancement of radiotherapy by oleandrin is a caspase-3 dependent process. Cancer letters. Nov 28 2002;185(2):145-151.
  10. Emanuele E, Olivieri V, Aldeghi A, et al. Topical administration of oleandrin could protect against gentamicin ototoxicity via inhibition of activator protein-1 and c-Jun N-terminal kinase. Medical hypotheses. 2007;68(3):711.
  11. Dunn DE, He DN, Yang P, et al. In vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke models. Journal of neurochemistry. Nov 2011;119(4):805-814.
  12. Mekhail T, Kaur H, Ganapathi R, et al. Phase 1 trial of Anvirzel in patients with refractory solid tumors. Investigational new drugs. Sep 2006;24(5):423-427.
  13. Yang P, Menter DG, Cartwright C, et al. Oleandrin-mediated inhibition of human tumor cell proliferation: importance of Na,K-ATPase alpha subunits as drug targets. Molecular cancer therapeutics. Aug 2009;8(8):2319-2328.
  14. Sreenivasan Y, Raghavendra PB, Manna SK. Oleandrin-mediated expression of Fas potentiates apoptosis in tumor cells. Journal of clinical immunology. Jul 2006;26(4):308-322.
  15. Afaq F, Saleem M, Aziz MH, et al. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion markers in CD-1 mouse skin by oleandrin. Toxicology and applied pharmacology. Mar 15 2004;195(3):361-369.
  16. Frese S, Frese-Schaper M, Andres AC, et al. Cardiac glycosides initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5. Cancer research. Jun 1 2006;66(11):5867-5874.
  17. Manna SK, Sreenivasan Y, Sarkar A. Cardiac glycoside inhibits IL-8-induced biological responses by downregulating IL-8 receptors through altering membrane fluidity. Journal of cellular physiology. Apr 2006;207(1):195-207.
  18. Ni D, Madden TL, Johansen M, et al. Murine pharmacokinetics and metabolism of oleandrin, a cytotoxic component of Nerium oleander. Journal of experimental therapeutics & oncology. Sep-Oct 2002;2(5):278-285.
  19. Pietsch J, Oertel R, Trautmann S, et al. A non-fatal oleander poisoning. International journal of legal medicine. Jul 2005;119(4):236-240.
  20. Wasfi IA, Zorob O, Al katheeri NA, et al. A fatal case of oleandrin poisoning. Forensic science international. Aug 6 2008;179(2-3):e31-36.
  21. Altan E, Bitik B, Kalpakci Y, et al. Probable hepatotoxicity related to Nerium oleander extract in a patient with metastatic synovial sarcoma of the knee. Journal of alternative and complementary medicine. Feb 2009;15(2):113.
  22. Datta P, Dasgupta A. Interference of oleandrin and oleandrigenin in digitoxin immunoassays: minimal cross reactivity with a new monoclonal chemiluminescent assay and high cross reactivity with the fluorescence polarization assay. Therapeutic drug monitoring. Aug 1997;19(4):465-469.
  23. Dasgupta A, Risin SA, Reyes M, et al. Rapid detection of oleander poisoning by Digoxin III, a new Digoxin assay: impact on serum Digoxin measurement. American journal of clinical pathology. Apr 2008;129(4):548-553.
  24. Singh S, Shenoy S, Nehete PN, et al.Nerium oleander derived cardiac glycoside oleandrin is a novel inhibitor of HIV infectivity. Fitoterapia. 2013 Jan;84:32-9.
  25. Papi L, Luciani AB, Forni D, Giusiani M. Unexpected double lethal oleander poisoning. Am J Forensic Med Pathol. 2012 Mar;33(1):93-7.

Consumer Information

How It Works

Bottom Line: Oleandrin can inhibit the growth of some cancer cells, but it has yet to be shown to be an effective cancer treatment.

Oleandrin is an extract from the plant, Nerium oleander, which contains substances that are similar to the active chemical found in the heart medication, digoxin. In the laboratory, Anvirzel™, a brand of oleandrin, is able to suppress growth and cause cell death in certain cancer cell lines. It also has been seen to increase the sensitivity of prostate cancer cell lines to radiation therapy. However, it is unclear whether these effects occur in the human body. Oleandrin has also been used to treat heart disease, AIDS, and hepatitis.

Purported Uses
  • To treat cancer
    Laboratory studies show some anticancer activity in cancer cell lines, but clinical trials have not evaluated the anticancer activities of oleandrin in humans.

    There is no scientific evidence to support the following claims:
  • To treat congestive heart failure
  • To treat hepatitis C
  • To treat  AIDS
Patient Warnings
  • The raw plant from which AnvirzelTM is extracted, Nerium oleander, is highly toxic. Consumption of only one Nerium oleander leaf may be fatal. The onset of toxicity occurs several hours after consumption and includes vomiting, abdominal pain, cyanosis (bluish discoloration of the skin), low blood pressure, hypothermia (low body temperature), dizziness, respiratory paralysis, and death.
Do Not Take If
  • You are taking digoxin (because Anvirzel™ contains the cardiac glycosides, the same active chemical in digoxin, the two medications may have an additive effect, causing toxicity).
  • You have hypercalcemia (high blood levels of calcium), hypokalemia (low blood levels of potassium), bradycardia (abnormally slow heart rate), ventricular tachycardia (abnormally fast ventricular heart rate), or heart failure. (Anvirzel™ contains the cardiac glycosides, the same active chemical in digoxin, and is therefore contraindicated in people with these conditions).
Side Effects
  • Nausea and vomiting
  • Diarrhea
  • Itching
  • Pain at injection site
  • Tumor pain
  • Mastalgia (breast pain)
  • Leukocytosis (abnormally high white blood cell count)
  • Tachycardia (abnormally fast heart rate)
  • Cardiac arrhythmias
  • Case Report
  • Consumption of oleander leaves resulted in the death of an adult diabetic male. The oleandrin levels in the blood were roughly 10 ng/ml.
  • Case Report
    Daily intramuscular injections of Nerium oleander extract for two months are suspected as probable cause of death of a 43-year-old patient with Metastatic Synovial Sarcoma of the Knee. Her symptoms included nausea, vomiting, severe stomach pain, and bloating followed by a gradual reduction of liver enzymes and cardiopulmonary arrest.
Special Point

Anvirzel™ is considered an “investigational new drug” in the United States and is not available for use except under approved clinical trials. Until more test results showing this product is effective and safe are published, it should not be used outside of clinical trials.

E-mail your questions and comments to aboutherbs@mskcc.org.