468/0LEOCANTHAL PDR FOR NUTRITIONAL SUPPLEMENTS

INDICATIONS AND USAGE premium extra-virgin contains about nine milli- Olecocanthal, an olive polyphenol, has reported antioxida- grams of oleocanthal. The potency of oleocanthal and tive and antiinflammatory activity. One report stirred wide ibuprofen is approximately the same. Therefore, nine milli- interest in the substance by claiming it has ibuprofen-like grams of oleocanthal is approximately equal to nine milli- activity. In common with what has been claimed for other grams of ibuprofen, which is about 10% percent of a low olive polyphenols (see and ), it dose (l00 milligrams) of ibuprofen. may have some cardioprotective and anticancer activity, as Dietary supplements of oleocanthal are currently well, although clinical evidence for this is lacking. unavailable. RESEARCH SUMMARY LITERATURE A brief communication in the journal Nature excited interest Andrewes p, Busch JL, de Joode T, et al. Sensory properties of in oleocanthal when researchers reported that this substance, virgin olive oil polyphenols: identification of deacetoxy- derived from newly pressed extra-virgin olive oil, has some ligstroside aglycon as a key contributor to pungency. Agric characteristics in common with the anti-inflammatory drug Food Chem. 2003;51(5):1415-1420. ibuprofen. They noted that both induce very similar stinging Beauchamp GK, Keast RS, Morel D, et al. Phytochemistry: sensations in the throat and thereafter determined that the ibuprofen-like activity in extra-virgin olive oil. Nature. two substances have structural and pharmacological similari- 2005;437(7055):45-46. ties. They found that oleocanthal, like ibuprofen, is an Fini L, Hotchkiss E, Fogliano V, et al. Chemopreventive inhibitor of the COX-I and COX-2 enzymes in a dose- properties of pinoresinol-rich olive oil involve a selective dependent manner. Thus they hypothesized that, through activation of the ATM-p53 cascade in colon cancer cell lines. consistent long-term consumption of extra-virgin olive oil, Carcinogenesis. 2oo8;29( I): 139-46. some ibuprofen-like relief from inflammation and pain might Fogliano V, Sacchi R. Oleocanthal in olive oil: between myth be realized in some individuals. Others, however, have and reality. Mol Nutr Food Res. 2006;50(1):5-6. questioned whether plasma levels of the polyphenol could Impellizzeri J, Un J. A simple high-performance liquid thus ever be high enough to have a meaningful effect. chromatography method for the determination of throat-burning Research is needed to see whether supplements of this oleocanthal with probated antiinflammatory activity in extra substance could safely and effectively be used in the same virgin olive oils. J Agric Food Chem. 2006;54(9):3204-3208. way that ibuprofen is used. If so, it might have application in Joshi K, Hankey. A, Patwardhan B. Traditional phytochemistry: a number of situations since there are data suggesting that identification of drug by 'taste'. Evid Based Complement ibuprofen, apart from providing pain relief, may, when used Alternat Med. 2007;4(2): 145-148. long-term, have some inhibiting effect on various inflamma- tory processes, including Alzheimer's disease. Smith AB 3rd, Sperry 18, Han Q. Syntheses of (-)-oleocanthal, a natural NSAID found in extra virgin olive oil, the (-)- CONTRA INDICATIONS, PRECAUTIONS, ADVERSE REACTIONS deacetoxy-oleuropein aglycone, and related analogues. J Org CONTRA INDICA TIONS Chem. 2007;72(18):6891-6900. Oleocanthal is contraindicated in those hypersensitive to any Smith AB 3rd, Han Q, Breslin PA, et al. Synthesis and component of an oleocanthal-containing product. Hypersen- assignment of absolute configuration of (-)-oleocanthal: a potent, sitivity to oleocanthal is probably very rare. naturally occurring non-steroidal anti-inflammatory and anti- oxidant agent derived from extra virgin olive oils. Org Lett. PRECAUTIONS 2005;7(22):5075-5078. Those who wish to use oleocanthal for health reasons should first discuss this with his or her physician.

ADVERSE REACTIONS No reports. Oleuropein and Oleuropein

INTERACTIONS Aglycone No reports. DESCRIPTION Olive oil is the principal fat component in the Mediterranean OVERDOSAGE diet, and the consumption of olive oil by those who live in There are no reports of overdosage. the Mediterranean basin has been associated with a lower DOSAGE AND ADMINISTRATION incidence of coronary heart disease (CHD), some cancers, The concentration of oleocanthal in extra-virgin olive oil is including prostate, breast and colorectal cancer, and other variable. Premium extra-virgin olive oil contains up to 200 chronic degenerative diseases. A large number of phenolic micrograms of oleocanthal per milliliter. Fifty grams of compounds are found in olive oil, and it is thought that some SUPPLEMENT MONOGRAPHS OLEUROPEIN AND OLEUROPEIN AGLYCONE 1469 of these compounds might help to confer those health 4. OJeuropein is represented by the following chemical benefits. structure.

The phenolic compounds found in olive oil can be broken down into simple phenols (eg, , hydroxytyrosol and elenolic acid), lignans (eg, pinoresinol and acetoxypinoresi- no!) and secoiridoids (eg, oleuropein aglycone, deacetoxy oleuropein aglycone, and ligstroside aglycone).

Oleuropein aglycone is the most abundant polyphenol in olive oil and is responsible for the characteristic bitter, pungent taste of the oil. Oleuropein (oleuropein glycoside) is found in olive fruit, in the leaves and bark of the olive tree (Olea europaea L.), and in olive mill wastewater. Oleuropein Oleuropein is also found in the fruits and leaves of the Japanese privet tree (Ligustrum japonicum) and the Chinese privet tree Oleuropein is moderately soluble In water; oleuropein (Ligustrum lucidum). Oleuropein, known as the bitter aglycone is much less so. principle of the olive tree, is present in high amounts in the leaves. It is a secondary metabolite of the olive tree and ACTIONS AND PHARMACOLOGY ACTIONS confers resistance to disease and to insect infestation. Olive Oleuropein has antioxidant actiVity. It may also have leaf extracts, mainly oleuropein, were used by the ancient anticancer, anti-inflammatory, antimicrobial, antithrombotic, Egyptians to mummify their pharaohs and, in the 1800s, by cardioprotective and rejuvenating/anti aging activities. the British to treat tropical diseases, including malaria. MECHANISM OF ACTION The types of phenols in extra-virgin olive oil are different Anticancer activity: Oleuropein was shown to inh'ibit the from those of the olive fruit. The olives mainly contain the proliferation and migration of advanced-grade human tumor polar glycosides oleuropein and ligstroside. Oleuropein is the cell lines dose-dependently. The tumor cell lines included ester of elenoic acid with 3,4/-dihydroxyphenylethanol LN-18, poorly differentiated glioblastoma, TF-la, erythro- (hydroxytyrosol), and ligstroside is the ester of elenolic acid leukemia, 786-0, renal cell adenocarcinoma, T-47D, infiltrat- with 4-hydroxyphenylethanol (tyrosol). Oleuropein and lig- ing ductal carcinoma of the breast-pleural effusion, MCF-7, stroside are the parent compounds of the less polar oleuro- mammary gland adenocarcinoma, pleural effusion, RPMI- pein aglycone and ligstroside aglycone. Oleuropein aglycone 7952, malignant melanoma of the skin, node metastasis, and and ligstroside aglycone are formed during ripening by removal of the glucose moiety from the oleuropein- and LoV0, colorectal adenocarcinoma and suprascapular region metastasis. ligstroside-glycosides via the enzyme, beta-glucosidase. Those aglycones and their various derivatives are the most Oleuropein was shown to induce the production of irrever- abundant phenols in olive oil. Hydroxytyrosol is mainly sibly rounded cells, preventing their replication, motility and formed from the hydrolysis of the secoiridoid oleuropein invasiveness. No viable cells could be recovered from those aglycone (see Hydroxytyrosol). tumors. Oleuropein directly disrupted actin filaments in cells and in a cell-free system. Only very high doses of the olive The name "oleuropein" refers to the glycoside form and i~ polyphenol caused growth inhibition in normal fibroblasts. sometimes called oleuropein glycoside; the aglycone form is always called, or should always be called, oleuropein In order to see if the glucose moiety in oleuropein affected aglycone. These names are not always used correctly. its biological activity, it was removed with beta-glucosidase to produce oleuropein aglycone. Beta-glucosidase treated Oleuropein is chemically described as methyl (4S,5E,6S)-4- oleuropein was less effective in inhibiting cell proliferation [2-[2-(3,4-dihydroxypheny!)ethoxy]- 2-oxoethyl]-5- ethyli- than the nontreated phenol. Possibly, the glucose transporters dene-6- [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymeth- (GLUTs) were necessary to facilitate the diffusion of yl)oxan-2-yl]oxy-4H-pyran-3-carboxylate. It is also known oleuropein into the cells, and they didn't work as well for as [2S-(2alpha,3E,4beta)]- 3-ethylidene- 2-(beta- D-glucopyra- oleuropein aglycone. The mechanism of this interesting nosyloxy)- 3,4-dihydro- 5-(methoxycarbony 1)-2H-pyran-4-a- anticancer activity of oleuropein is unclear. Continued cetic acid 2-(3,4-dihydroxyphenyl)ethyl ester. research in this promising area is needed and warranted.

Oleuropein's empirical formula is C2sH32013, its molecular Human epidermal growth factor receptor 2 (HER2) is an weight is 540.51 and its CAS Registry Number is 32619-42- important prognostic and predictive marker of treatment 470/0LEUROPEIN AND OLEUROPEIN AGLYCONE PDR FOR NUTRITIONAL SUPPLEMENTS

response in women with breast cancer in the adjuvant setting the progression (invasion and metastasis) of human breast and advanced disease. An oncogene is a protein encoding cancer. gene, which when deregulated, participates in the onset and development of cancer. The HER2 gene, also known as However, there are many questions to answer regarding this HER2/neu or c-erbB2, an oncogene, is amplified and the important work. Oleuropein aglycone, following ingestion, is HER2 protein is overexpressed in about 20% to 35% of mainly converted to hydroxytyroso.l. The anticancer activity breast cancers, with resulting poor prognosis and shortened of hydroxytyrosol was lower than that of oleuropein in the overall survival. The gene encodes a transmembrane tyrosine study. The mechanism of action of the anticancer effect of kinase growth factor receptor, which mediates signaling for oleuropein aglycone is far from being understood. The cell proliferation and survival. HER2 gene amplification and authors themselves state "caution must be applied when resultant protein overexpression are associated with a more extrapolating in vitro results into clinical practice." This aggressive clinical course. Trastuzumab (Herceptin) is a research is potentially very important and, before it can be put into clinical practice, much work needs to be done, humanized monoclonal antibody that binds to the HER2 including human pharmacokinetic studies (via oral and receptor. The combination of trastuzumab with chemothera- py has significantly improved the outlook of women with parenteral routes), safety studies and large, prospective, placebo-controlled and randomized clinical trials to investi- HER2-positive tumors. However, many women who achieve gate the possible anticancer effects of oleuropein aglycone an initial response to trastuzumab-based therapy acquire and to determine the optimal dosage of the olive oil phenol resistance to the drug within one year. for these possible effects.

Oleuropein aglycone was reported, to reverse acquired Anti-inflammatory activity: Oleuropein is discussed in this autoresistance to trastuzumab in HER2-overexpressing - section. However, oleuropein aglycone has similar breast cancer. Among extra-virgin olive oil polyphenols, properties. oleuropein aglycone was the most potent one in decreasing breast cancer viability. An up to 50-fold increase in the Oleuropein was assessed in experimental sepsis in rabbits efficacy of trastuzumab occurred in the presence of oleuro- caused by the bacteria Pseudomonas aeruginosa. Oleuropein pein aglycone. A preclinical model of acquired autoresis- was found to significantly prolong the survival of the tance to trastuzumab completely recovered trastuzumab animals. Rabbits administered oleuropein intravenously had sensitivity when co-cultured in the presence of oleuropein lower levels of the inflammatory cytokine, tumor necrosis aglycone. Oleuropein aglycone significantly reduced HER2 factor-alpha (TNF-alpha). It was thought that the positive ECD (extracellular domain) cleavage and subsequent HER2 result with the olive phenol could be explained, at least in autophosphorylation, while it dramatically enhanced trastuz- part, by an anti-inflammatory mechanism. Promotion of umab-induced downregulation of HER2 expression. Hydrox- phagocytosis by oleuropein was another possibility. ytyrosol slightly, but significantly, reduced' cell viability at Oleuropein was demonstrated to have protective effects on the highest concentrations tested. Oleuropein glycoside was bone mass in an ovariectomy/inflammation experimental rat ineffective at inducing any significant cytostatic or cytotoxic model of bone loss induced by talc granulomatosis. Castra- effect, regardless of the HER2 status of breast cancer cells. tion in the animals was associated with decreased mineral density. Inflammation, as characterized by an increase in In the first study mentioned above, oleuropein had more spleen weight and plasma fibrinogen levels, exacerbated the effective anticancer activity against a number of advanced- bone loss. Oleuropein was found to reduce bone loss and to grade human cancer cell lines than did oleuropein aglycone. improve the biomarkers of inflammation, such as fibrinogen This is very different than the present study under consider- and spleen weight. The mechanism of action of the possible ation. In the present study, a significantly higher cytotoxic anti-inflammatory effect of oleuropein is not clear. An activity of the aglyconic form compared with the glycosidic antioxidant mechanism was ruled out. This research should form of oleuropein w,asobserved in all the breast cancer cell continue, since these preliminary results suggest that oleuro- lines employed in the study. The authors speculated that the pein might play a role in the treatment and prevention of difference possibly derived, from the greater lipophilicity of osteoporosis. the aglyconic form, a property that, they suggest, should allow better cell membrane incorporation and/or interaction There are a couple of reports of oleuropein inhibiting the with other lipids. proinflammatory 5-lipoxygenase (5-LOX) enzyme. The inhibition of 5-LOX interferes with eicosanoid metabolism, The above study suggests that oleuropein aglycone, through thereby reducing leukotriene B4 production in leukocytes. the specific inhibition of the HER2 oncogene, may exert The exact mechanism of action of the possible anti-inflam- protective effects not only in the promotion (risk) but also in matory effects of oleuropein is unclear. SUPPLEMENT MONOGRAPHS OLEUROPEIN AND OLEUROPEIN AGL YCONE /471

Antimicrobial: Phenols have long been known to have malondialdehyde (MDA, a marker of oxidative stress) and antimicrobial activity, including antibacterial, antiviral and blood glucose as well as alteration in enzymatic and non- antifungal activities. The antimicrobial action of phenols is enzymatic antioxidants in the diabetic animals. Essentially, related to their ability to denature proteins, and they are all of this was attributed to oxidative stress. When the generally classified as surface-acting agents. They act by animals were treated with the antioxidant oleuropein, the causing leakage of cytoplasmic constituents. High concentra- levels of MDA and blood glucose, as well as the levels of tions precipitate proteins, while lower concentrations inacti- both the non-enzymatic and enzymatic antioxidants, were vate enzymes. restored to near normal levels.

Oleuropein and its aglycone (oleuropein aglycone) have been Antithrombotic activity: Oleuropein is discussed in this found to possess antibacterial activity against both gram- section. However, oleuropein aglycone has similar negative and gram-positive strains of bacteria, including properties. Pseudomonas sp., Enterococcus sp. Salmonella sp., Bacillus sp., Vibrio sp. and Staphylococcus sp. They have also been Inhibition of platelet aggregation by oleuropein was found in shown to inhibit various mycoplasma strains, including a recent study that examined a few olive oil phenols, their Mycoplasma hominis and Mycoplasma fermentans. The effect on platelet aggregation, and the role cyclic adenosine antimicrobial effect of plant secondary metabolites, such as monophosphate phosphodiesterase (cAMP-PDE) inhibition the olive phenolics, represents the plant's defense against may play in the effect. Oleuropein was found to inhibit microbes, insects and an occasional omnivore that might platelet aggregation, but in contrast to hydroxytyrosol, which injure it. Continued research in this area is necessary in order turned out to be a less potent inhibitor of platelet aggrega- to determine the role oleuropein and oleuropein aglycone tion, oleuropein inhibited (cAMP-PDE), while hydroxytyro- might have in the treatment and prevention of bacterial and sol did not. other microbial infections in humans. It is not clear whether Phosphodiesterase inhibitors possess anti-aggregatory ac- either oleuropein or its aglycone retains its antimicrobial tivity. properties in vivo.

Antioxidant activity: Oleuropein is discussed in this section. Cardioprotective activity: Rat hearts were made ischemic However, oleuropein aglycone has similar properties. and then reperfused. At different times, the coronary effluent was collected and assayed for creatine kinase activity and for It is known that compounds that share an orthodiphenolic reduced and oxidized glutathione. Lipid peroxidation was (catecholic) structure possess antioxidant activity. Oleuro- also assayed by measuring thiobarbituric acid reactive pein and oleuropein aglycone, like hydroxytyrosol, possess substances (TBARS) concentration in cardiac muscle. this type of structure. Several studies, for the most part in (TBARS is used as an assay for lipid peroxidation, a major vitro studies, have evaluated the antioxidant properties of indicator of oxidative stress.) Pretreatment of the rat hearts oleuropein. The polyphenol has scavenging activity against a with oleuropein prior to ischemia resulted in a decrease of wide range of radicals, including hydroxyl, peroxyl, peroxy- creatine kinase and reduced glutathione release in the nitrite and superoxide anion radicals. Oleuropein has been perfusate. The protective effect of oleuropein against the found to inhibit the respiratory burst of neutrophils caused by post-ischemic oxidative burst was assayed by measuring the the enzyme NADPH oxidase and the production of hypo- release in the coronary effluent of oxidized glutathione, a chlorous acid-derived radicals. sensitive marker of the heart's exposure to oxidative stress. Reflow in ischemic hearts was accompanied by prompt Prevention of free radical formation by oleuropein may release of oxidized glutathione. In ischemic hearts treated occur through its ability to chelate metal ions, such as copper with oleuropein, the release of oxidized glutathione was and ferric ions, which catalyze free radical generation significantly reduced. Membrane lipid peroxidation was also reactions. prevented by oleuropein. The mechanism by which oleuro- Oleuropein has also been found to inhibit the oxidation of pein prevents oxidative myocardial injury induced by LDL (low-density lipoprotein). Oxidized LDL is thought to ischemia and reperfusion can be explained, in part, by the be a crucial factor in the pathogenesis of atherosclerosis. antioxidant activity of oleuropein. When comparing the radical scavenging ability of oleuropein with that of hydroxytyrosol, hydroxytyrosol was found to In another study, oleuropein was demonstrated to exhibit generally have more potent antioxidant activity. anti-ischemic, antioxidative and hypolipidemic effects in anesthetized rabbits. Oleuropein reduced the infarct size, In one study, diabetes was induced in rabbits by alloxan. conferred strong antioxidant protection and reduced the After induction of diabetes, there is a significant rise in circulating lipids. Again, the mechanism of these effects can -

472/0LEUROPEIN AND OLEUROPEIN AGLYCONE PDR FOR NUTRITIONAL SUPPLEMENTS be explained, in part, by the antioxidant activity of Oleuropein aglycone, the form found in olive oil, is poorly oleuropein. absorbed in the small intestine. Virtually no oleuropein aglycone is transferred across human Caco-2 cell monolayers Rejuvenation/anti-aging activity: Aging can be characterized or rat segments of jejunum and ileum in in vitro models of as increasing damage to the various tissues of the body and absorption. In comparison, hydroxytyrosol is efficiently increasing inability to repair the damage, thus leading to transferred across the monolayers and the intestinal seg- chronic degenerative diseases and disorders. ments. It appears that a certain amount of oleuropein Some of the deleterious changes that occur are the accumula- aglycone is hydrolyzed in the stomach to produce hydroxy- tion of damaged proteins. Proteasomes are large protein tyrosol. A much greater amount is rapidly degraded by the complexes within most of our cells, whose major function is colonic microflora, resulting in the formation of hydroxyty- to degrade unneeded or damaged proteins via proteolysis. rosol. A small amount of oleuropein aglycone may get The proteins are tagged for degradation by a small protein absorbed in the small intestine. Most of an ingested dose of called ubiquitin. In time, this repair mechanism becomes less oleuropein aglycone, however, will wind up as hydroxy tyro- efficient and damaged proteins accumulate in the cells. The sol. Oleuropein, the form found in olive leaves, has its accumulation of damaged proteins accelerates cell senes- glucose removed via a glucosidase prior to its being cence. Human fibroblasts undergo a limited number of converted to hydroxytyrosol in the stomach and colon. divisions in cell culture and progressively reach a state of Hydroxytyrosol is efficiently absorbed from the lumen of the irreversible growth arrest, a process termed replicative small intestine into the enterocytes via passive diffusion. senescence. The fibroblasts remain viable and functional, but From the enterocytes, hydroxytyrosol enters the portal they exhibit several biochemical and morphological changes. circulation, which takes it to the liver from whence it enters Oxidative distress is a major factor in the aging process. the systemic circulation. Hydroxytyrosol produced in the Oxidative distress can be defined as the accumulation of colon is absorbed and also enters the portal circulation and reactive oxygen and nitrogen species to the point where the then the systemic circulation. The systemic circulation antioxidative mechanisms of the cell are overwhelmed. In transports hydroxytyrosol to the various tissues of the body. the process, DNA, lipids and proteins are damaged. If the Hydroxytyrosol appears to cross the blood-brain barrier, proteasome has difficulty handling the damaged proteins, a entering the brain where it can mix with hydroxytyrosol that vicious cycle develops, which hastens the aging process and is produced from the catabolism of dopamine. The major all the degenerative disorders associated with it. So, what metabolites of hydroxytyrosol in humans are 4-hydroxy-3- does all of this have to do with olives? methoxyphenylethanol, also called homovanillyl alcohol, produced from hydroxytyrosol via the enzyme catechol-O- Oleuropein was demonstrated to enhance the proteasome methyltransferase (COMT), 4-hydroxy-3-methoxyphenyla- activities in vitro. At the same time, continuous treatment of cetic acid (homovanillic acid) and the glucuronide early passage human embryonic fibroblasts with oleuropein conjugates of hydroxytyrosol, as well as of homovanillyl was found to decrease the intracellular levels of reactive alcohol and homovanillic acid. Most of the ingested oxygen species, to reduce the amount of oxidized proteins hydroxytyrosol is ultimately excreted in the urine as its through increased proteasome-mediated degradation rates glucuronide conjugate. Homovanillyl alcohol and homovan- and to retain proteasome function during replicative senes- illic acid and their glucuronide conjugates and some cence. Further, oleuropein-treated cultures exhibited a delay unconjugated hydroxytyrosol are also found in the urine. in the appearance of senescence morphology and their life Glucuronidation of hydroxytyrosol appears to occur in both spans were extended by about 15%. Basically, the antioxi- the small intestine and in the liver. dant oleuropein slowed down the oxidative damage of the proteasome and the fibroblasts, leading to an increase in the Further PK studies on oleuropein and oleuropein aglycone in life span of the fibroblasts, in vitro. humans are needed in order to fill in all the details on their ADME (absorption, distribution, metabolism and excretion). There has been great interest in attempting to increase life PK studies on parenterally administered oleuropein and span in experimental animals by manipulating antioxidant oleuropein aglycone would also be valuable. mechanisms. The results to date have been mixed. INDICATIONS AND USAGE PHARMACOKINETICS Oleuropein, a polyphenol component of olive leaves, and The pharmacokinetics (PK) of oleuropein aglycone in oleuropein aglycone derived from olive oil, have antioxida- humans, as well as that of oleuropein, is incomplete, but tive and anti-inflammatory activity that may confer upon some studies are available. The following PK picture of them cardioprotective and anticancer effects. There is also oleuropein represents a composite of those studies. preliminary evidence these substances might be helpful in SUPPLEMENT MONOGRAPHS OLEUROPEIN AND OLEUROPEIN AGLYCONE /473

treating and preventing some of the complications of model of bone loss in the rat. The level of response was diabetes, protecting against UVB irradiation and preventing dose-dependent. Further research is warranted. inflammation-induced bone loss. They may have also some A gel containing oleuropein has shown some efficacy against antimicrobial effects. Clinical studies are lacking. UVB irradiation.

RESEARCH SUMMARY Oleuropein has been more extensively studied than some of CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS the other olive polyphenols (see Hydroxytyrosol and Oleo- CONTRA INDICA TIONS Oleuropein- and oleuropein aglycone-containing dietary canthal). It is said to have potent antioxidative effects (though, according to one review of the literature, not as supplements are contraindicated in those hypersensitive to any component of an oleuropein- or oleuropein aglycone- potent as hydroxytyrosol). In vitro and animal studies suggest that oleurpein's antioxidative and anti-inflammatory containing dietary supplement. Hypersensitivity to oleuro- pein or oleuropein aglycone is probably very rare. activities may have effects that could be cardioprotective. In

one study, oleuropein enhanced nitric oxide production in PRECAUTIONS mouse macrophages. In a study of isolated rat heart, it Those who wish to use oleuropein- or oleuropein aglycone- prevented oxidative myocardial injury induced by ischemia containing dietary supplements for a health condition should and reperfusion. Membrane lipid peroxidation was prevented first discuss this with his or her physician. by the polyphenol in this study, and reperfusion-related release of oxidized glutathione was significantly inhibited. In Because of the possible antithrombotic effect of oleuropein other research, oleuropein has demonstrated antithrombotic or oleuropein aglycone, hemophiliacs and those taking activity. In a study utilizing rabbits, oleuropein exhibited warfarin (Coumadin) should exercise caution in its use. anti-ischemic, antioxidative and hypolipidemic effects. Oleuropein- or oleuropein aglycone-containing dietary sup- Treatment for six weeks with varying doses of the polyphe- plements should be stopped a few days before any surgery nol resulted in decreases in both total cholesterol and and can be resumed following the surgery. triglyceride levels in these animals. Both hypoglycemic and antioxidant effects were observed in alloxan-induced diabet- Because of the lack of long-term studies on the safety of ic rabbits administered oleuropein. During 16 weeks of oleuropein- and oleuropein aglycone-containing dietary sup- treatment with the polyphenol, oxidative stress markers and plements, pregnant women and nursing mothers should be glucose levels were largely restored to normal. Further cautious in their use.

research is needed and warranted. ADVERSE REACTIONS Like hydroxytyrosol, oleuropein has shown some antimicro- No reports. bial activity against both gram-positive and gram-negative INTERACTIONS bacterial species of several types. In a study of acute DRUGS pyelonephritis induced in 70 rabbits, oleuropein prolonged Oleuropein aglycone was reported to reverse acquired survival through immunomodulating effects which, the autoresistance to trastuzumab in HER2-overexpressing researchers concluded, might include promotion of phagocy- breast cancer. (See Anticancer activity above.) tosis and/or inhibition of biosynthesis of proinflammatory cytokines. In other research, oleuropein has demonstrated NUTRITIONAL SUPPLEMENTS antimycoplasma effects. More research is needed before any None known. conclusions can be drawn about a possible role for this HERBS substance as a useful clinical antimicrobial agent. None known. There is some evidence of an oleuropein anticancer effect. In FOODS one study, oleuropein inhibited the proliferation and migra- None known. tion of advanced-grade human tumor cell lines in a dose-

dependent manner. In a mouse model of spontaneous tumor, OVERDOSAGE the substance was said to achieve complete tumor regression There are no reports of overdosage. in 9-12 days. One group of researchers has concluded that oleuropein may be a potent antitumor agent. These promis- DOSAGE AND ADMINISTRATION . ing results need follow-up. Oleuropein-containing dietary supplements, mainly in the form of, olive leaf extracts, are available in capsules. Doses Oleuropein reduced bone loss and several inflammatory higher than those recommended on the label should general- biomarkers in an ovariectomy/inflammation experimental ly not be exceeded. 474/0LEUROPEIN AND OLEUROPEIN AGLYCONE PDR FOR NUTRITIONAL SUPPLEMENTS

Oleuropein aglycone is present in extra-virgin olive oil from Manna C, Migliardi V, Golino P, et aI. Oleuropein prevents about 23.3% to 37.7%. oxidative myocardial injury induced by ischemia and reperfusion.J Nutr Biochem. 2004;15(8):461-466. LITERATURE AI-Azzawie HF, Alhamdani MS. Hypoglycemic and antioxidant Menendez JA, Vazquez-Martin A, Colomer R, et aI. Olive oil's effect of oleuropein in alloxan-diabetic rabbits. Life Sci. bitter principle reverses acquired autoresistance to trastuzumab 2006;78(12): 1371-1377. (Herceptin)in HER2-overexpressingbreast cancer cells. BMC Cancer. 2007;7:80. Andreadou I, Sigala F, I1iodromitis EK, et aI. Acute doxorubicin cardiotoxicity is successfully treated with the Perugini P, Vettor M, Rona C, et aI. Efficacy of oleuropein phytochemical oleuropein through suppression of oxidative and against UVB irradiation: preliminary evaluation. Int J Cosmet nitrosative stress. J Mol Cell Cardio!. 2007;42(3):549-558. Sci. 2008;30(2): 1131-1120. Bianco AD, Muzzalupo I, Piperno A, et aI. Bioactive Puel C, Mathey J, Agalias A, et aI. Dose-response study of derivativesof oleuropein from olive fruits. J Agric Food Chem. effect of oleuropein, an olive oil polyphenol, in an ovariectomy/ 1999;47(9):3531-3534. inflammation experimental model of bone loss in the rat. Clin Nutr. 2006 Oct;25(5):859-868. Bitler CM, Viale TM, Damaj B, et al Hydrolyzed olive vegetationwater in mice has anti-inflammatoryactivity. J Nutr. Puel C, Quintin A, Agalias A, et aI. Olive oil and its main 2005; 135(6): 1475-1479. phenolic micronutrient (oleuropein) prevent inflammation- induced bone loss in the ovariectomised rat. Br J Nutr. 2004 Briante R, La Cara F, Febbraio F, et aI. Bioactive derivatives Jul;92(1): 119-127. from oleuropein by a biotransformation on Olea europaea leaf extracts. J Biotechno!. 2002;93(2):109-119. Sivakumar G, Briccoli Bati C, et aI. Demethyloleuropein and beta-glucosidase activity in olive fruits. Biotechnol J. 2007 Christian MS, Sharper VA, Hoberman AM, et aI. The toxicity Mar;2(3):381-385. profile of hydrolyzed aqueous olive pulp extract. Drug Chem Toxico!. 2004;27(4):309-330. Soni MG, Burdock GA, Christian MS, et aI. Safety assessment of aqueous olive pulp extract as an antioxidant or antimicrobial Ciafardini G, Marsilio V, Lanza B, et aI. Hydrolysis of agent in foods. Food Chem Toxico!. 2006;44(7):903-915. Oleuropein by Lactobacillus plantarum Strains Associated with Olive Fermentation. Appl Environ Microbiol. 1994;60(11):4142- Tsarbopoulos A, Gikas E, Papadopoulos N, et aI. Simultaneous 4147. determination of oleuropein and its metabolites in plasma by high-performance liquid chromatography. J Chromatogr B Coni E, Di Benedetto R, Di Pasquale M, et aI. Protective effect Analyt Technol Biomed Life Sci. 2003;785(1):157-164. of oleuropein, an olive oil biophenol, on low density lipoprotein oxidizability in rabbits. Lipids. 2000;35(1 ):45-54. Tuck KL, Hayball Pl Major phenolic compounds in olive oil: metabolism and health effects. J Nutr Biochem. Edgecombe SC, Stretch GL, Hayball Pl Oleuropein, an 2002; 13(II ):636-644. antioxidant polyphenol from olive oil, is poorly absorbed from isolated perfused rat intestine. J Nutr. 2000;130(12):2996-3002. Visioli F, .Bellosta S, Galli C. Oleuropein, the bitter principle of olives, enhances nitric oxide production by mouse macrophages. Fleming HP, Walter WM Jr, Etchells JL. Antimicrobial properties of oleuropein and products of its hydrolysis from Life Sci. 1998;62(6):541-546. green olives. Appl Microbiol. 1973 Nov;26(5):777-782. Visioli F, Galli C. OIeuropein protects low density lipoprotein Fumeri PM, Marino A, Saija A, et aI. In vitro antimycoplasmal from oxidation. Life Sci. 1994;55(24):1965-1971. activity of oleuropein. Int J Antimicrob Agents. 2002;20(4):293- Vissers MN, Zock PL, Roodenburg AJ, et aI. Olive oil phenols 296. are absorbed in humans. J Nutr. 2002;132(3):409-417. 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The olive Ornithine alpha-ketoglutarate, abbreviated OKG, also known constituent oleuropein exhibits proteasome stimulatory properties as ornithine 2-oxoglutarate or ornithine oxoglutarate (OGO), in vitro and confers life span extension of human embryonic is a salt formed of two molecules of the non-protein amino fibroblasts. Rejuvenation Res. 2007; 10(2):157-172. acid, L-ornithine, and one molecule of the Krebs cycle

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