therapeutic applications of pomegranate {punka granatum … applications of pomegranate... ·...

Alternative Medicine Review Volume 13, Number 2 2008

Therapeutic Applications ofPomegranate {Punka granatum L*)Î

A ReviewJulie Jurenka,MT (ASCP)

Abstract

The pomegranate, Púnica granatum L, is an ancient, mystical,

uniquefruitborneonasmall.long-livingtreecultivated throughout

the Mediterranean region, as far north as the Himalayas, in

Southeast Asia, and in California and Arizona in the United

States. In addition to its ancient historical uses, pomegranate

is used in several systems of medicine for a variety of ailments,

The synergistic action of the pomegranate constituents appears

to be superior to that of single constituents. In the past decade,

numerous studies on the antioxidant. anticarcinogenic, and

anti-inflammatory properties of pomegranate constituents

have been published, focusing on treatment and prevention

of cancer, cardiovascular disease, diabetes, dental conditions,

erectile dysfunction, bacterial infections and antibiotic

resistance, and ultraviolet radiation-induced skin damage.

Other potential applications include infant brain ischemia,

male infertility, Alzheimer's disease, arthritis, and obesity.

{Altern Med Rev 2008;13(2):128-144)

IntroductionTiie pomegranate, Púnica granatum L,, an an-

cient, mystical, and highly distinctive fruit, is the pre-dominant member ot two species comprising the Pu-nicaceae family. It was lauded in ancient times in theOld Testament oí the Bible, the Jewish Torah, and theBabylonian Talmud as a sacred fruit conferring powersot tertility, abundance, and good luck. It also featuresprominently in the ceremonies, art, and mythology ofthe Egyptians and Greeks and was the personal emblemot the Holy Roman Emperor, Maximilian. Pomegranateis the symbol and heraldic device of the ancient city ofGranada in Spain - from which the city gets its name.

The genus name. Púnica, was the Roman name forCarthage, where the best pomegranates were known togrow. Pomegranate is known by the French as grenade,the Spanish as granada, and literally translates to seeded("granatus") apple ("ponium").'

The pomegranate tree typically grows 12-16feet, has many spiny branches, and can be extremely longlived, as evidenced by trees at Versailles, France, knownto be over 200 years old. Tlie leaves are glossy and lance-shaped, and the bark of the tree turns gray as the treeages. Tiie flowers are large, red, white, or variegated andhave a tubular calyx that eventually becomes the truit.The ripe pomegranate fruit can be up to five inches widewith a deep red, leathery skin, is grenade-shaped, andcrowned by the pointed calyx. The fruit contains manyseeds (arils) separated by white, membranous pericarp,and each is surrounded by small amounts of tart, redjuice. Tlie pomegranate is native from the Himalayasin northern India to Iran but has been cultivated andnaturalized since ancient times over the entire Mediter-ranean region. It is also found in India and more aridregions of Southeast Asia, the East Indies, and tropicalAfrica. The tree is also cultivated tor its fruit in the drierregions of California and Arizona.^

In addition to its ancient historical uses, pome-granate is used in several systems of medicine for a vari-ety of ailments. In Ayurvedic medicine the pomegranateis considered "a pharmacy unto itself" and is used as anantiparasitic agent,' a "blood tonic,"' and to heal aph-thae, diarrhea, and ulcers.^ Pomegranate also serves as

Julie Jurenka, MT (ASCP) - Associate Editor, Alternative Medicine Review.technical assistant, Thoffie ResearchCorrespondence adöress: Thorne Research, PO Box 25, Dover, ID 83825Email: [email protected]

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Alternative Medicine Review Voiume 13, Number 2 2008

a remedy for diabetes in the Unani system of medicinepraetieed in the Middle East and India.'' The eurrentexplosion of interest in pomegranate as a medieinal andnutritional product is evidenced by a MedLine searchfrom 2000 to present, revealing over 130 new scientificpapers pertaining to its health effeets. Between 1950 and1999 only 25 sueh publications appear on MedLine.'The potential therapeutic properties of pomegranateare wide-ranging and include treatment and preventionof cancer, cardiovascular disease, diabetes, dental con-ditions, erectile dysfunction, and protection from ul-traviolet (UV) radiation. Other potential applicationsinelude infant brain isehemia, Alzheimers disease, maleinfertility, arthritis, and obesity.

The following abbreviations for various pome-granate extraets will be used throughout the article:

O Pomegranate juiee - PJO Pomegranate by-produet - PBP0 Fermented pomegranate juice - FPJO Cold-pressed seed oil — CPSOO Pomegranate peel extract - PPE

o Pomegranate pulp juice - PPJO Pomegranate fruit extract - PFEO Pomegranate flower extract - PFLEO Hydroalcoholic extract of pomegranate - HAEPO Gel-based pomegranate extract - GPBE

Biochemical ConstituentsOver the past decade, significant progress has

been made in establishing the pharmacological mecha-nisms of pomegranate and the individual constituentsresponsible for them. Extraets of all parts of the fruitappear to have therapeutic properties,^ and some stud-ies report the bark, roots, and leaves of the tree havemedicinal benefit as well.' Current research seems toindicate the most therapeutically beneficial pomegran-ate constituents are ellagie acid ellagitannins (includingpunicalagins), punicie aeid, flavonoids, anthocyanidins,anthocyanins, and estrogenic flavonols and flavones.Table 1 lists the principal constituents of the Punicagranatum tree and fruit. Figure 1 depicts the structureof ellagie aeid.

Table 1. Pomegranate Fruit Parts and Constituents^"^^

PUNT COMPONENT

Pomegranate juice

mPomegranate seed oil

Pomegranate pericarp ^ ^ ^ H(peel, rind) ^Ê

Pomegranate leaves

Pomegranate flower ^ ^ ^ B

Pomegranate roots and bark

CONSTITUENTS

anthocyanins;^ glucose, ascorbic acid;'' ellagie acid, gallic acid,caffeic acid;'° catechin, EGCG;" quercetin, rutin;'^ numerousminerals, particularly iron;'' amino acids'

95-percent punicic acid;''' other constituents, including ellagieacid;'" other fatty acids;''' sterols'''

phenolic punicalagins; gallic acid and other fatty acids;'"catechin, EGCG;" quercetin, rutin, and other flavonols;'Mlavones,flavonones;^^ anthocyanidins"

tannins (punicalin and punicafolin); and flavone glycosides,including luteolin and apigenin'^

gallic acid, ursolic acid;'^ triterpenoids, including maslinic andasiatic acid;'^ other unidentified constituents

ellagitannins, including punicalin and punicalagin;^" numerouspiperidine alkaloids^'

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Constituent Standardization versusSynergy

The goal of many pomegranate studies hasbeen to identify the therapeutic constituents. Common-ly found in many plants, ellagic acid exhibits powerfulanticarcinogenic'"' and antioxidant''' properties, propel-ling it to the forefront of pomegranate research. Manycommercially available pomegranate extracts are beingstandardized to contain 40-percent (or more) ellagicacid; however, Lansky, a prominent researcher on themedicinal properties of pomegranate, cautions againstfocusing on ellagic acid standardization to the exclusionof other therapeutically important pomegranate constit-uents.'' Research on ellagic acid with other flavonoidssuch as quercetin supports his contention.^^"^ Lan-sky's research confirms the synergistic action of severalpomegranate constituents is superior to ellagic acid insuppressing prostate cancer.'^'" To quote Lansky, "Therecent profusion onto the nutraceuticals marketplace ofproducts standardized to 40 percent (or even higher)ellagic acid represents a cynical, lucre-driven attempt toreplace the power of the pomegranate with the powerof ellagic acid. The pomegranate needs no such tricksor enhancements. It is rather an extraordinary, albeitmysterious (and messy), fruit with a complete medicinalpower contained within its juice, peel, and seeds."^'

Figure 1, Structure of Ellagic Acid

Biochemistry/PharmacokineticsAlthough little is known about the metabolism

and bioavailability of ellagitannins from food sources,three small human trials and one case study have inves-tigated the bioavailability, absorption, metabolism, andin vivo antioxidant effects of pomegranate. In the casestudy, consumption of 180 mL pomegranate juice (PJ)by a single subject yielded 31.9 ng/mL plasma ellagicacid at one hour, with rapid plasma clearance by fourhours post-ingestion. lTiis was the first direct evidencethat ellagic acid consumed ft"om food was absorbed inhumans."''' A study of 18 healthy volunteers by the sameresearchers confirmed the rapid absorption and plasmaclearance of ellagitannins and also confirmed urolithinmetabolites excreted in the urine can persist for 48 hoursafter pomegranate juice ingestion, thereby suggesting anexplanation of the benefits of long-term pomegranateadministration."^

In a 13-day clinical trial involving six healthysubjects (4 men and 2 women), one liter of PJ contain-ing 4.37 g/L punicalagins and 0.49 g/L anthocyaninswas consumed by all six subjects for five days. Threepomegranate juice metabolites were detected in theplasma - urolithin A, urolithin B, and a third unidenti-fied minor metabolite; urinalysis at 24 hours revealedsix metabolites - the three found in the plasma as wellas an aglycone metabolite corresponding to each of threeplasma metabolites. Maximum excretion rates occurred3-4 days after juice ingestion. Significant variability ofurinary metabolite concentrations was observed amongsubjects and may be attributable to differences in co-Ionic microHora, where the ellagitannins are believed tobe metabolized." The persistence of urolithin A and Bin the urine may be responsible for pomegranate's long-term antioxidant effects, rather than the polyphenolsfound in the juice.

In another study, 11 healthy men and womenwere placed on a polyphenol- and antioxidant-free dietfor three days prior to consuming pomegranate extract(plant parts used were not specified). Subjects weregiven 800 mg capsuled pomegranate extract daily con-taining 330.4 mg punicalagins and 21.6 mg ellagic acid(EA). C and T for plasma EA was 33.8±12.7 m/mL at one hour post-ingestion, similar to values ob-served in the case study when similar amounts of pu-nicalagins and EA were administered. This study alsodemonstrated a significant increase (31.8%) in plasma

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antioxidant capacity 30 minutes after extract adminis-tration; one and two hours post ingestion, values wereincreased 1.62- and 1.43-foId, respectively.'^

Mechanisms of ActionAlthough pomegranate's wide-ranging thera-

peutic benefits may be attributable to several mecha-nisms, most research has focused on its antioxidant,anticarcinogenic, and anti-inflammatory properties.

Antioxidant MechanismsAn in vitro assay using four separate testing

methods demonstrated pomegranate juice and seedextracts have 2-3 times the antioxidanr capacity of ei-ther red wine or green tea.'' Pomegranate extracts havebeen shown to scavenge free radicals and decrease mac-rophage oxidative stress and lipid peroxidation in ani-mals'' and increase plasma antioxidant capacity in el-derly humans.'^

Studies in rats and mice confirm the antioxi-dant properties oí a pomegranate by-product (PBP)extract made from whole fruit minus the juice, show-ing a 19-percent reduction in oxidative stress in mouseperitoneal macrophages (MPM), a 42-percent decreasein cellular lipid peroxide content, and a 53-percent in-crease in reduced glutathione levels.'"' In vitro assay of afermented pomegranate juice (FPJ) extract and a cold-pressed seed oil (CPSO) extract found the antioxidantcapacity of both are superior to red wine and similar togreen tea extract.'' A separate study in rats with CCl^-induced liver damage demonstrated pretreatment witha pomegranate peel extract (PPE) enhanced or main-tained the free-radical scavenging activity of the hepaticenzymes catalase, super oxide disniutase, and peroxi-dase, and resulted in 54-percent reduction of lipid per-oxidation values compared to controls.'^

Research in humans has shown a juice madefrom pomegranate pulp (PPJ) has superior antioxidantcapacity to apple juice. Using the FRAP assay (ferricreducing/antioxidant power), Guo ct al found 250 mLPPJ daily for four weeks given to healthy elderly sub-jects increased plasma antioxidant capacity from 1.33mmol to 1.46 mmol, while subjects consuming applejuice experienced no significant increase in antioxidantcapacity. In addition, subjects consuming the PPJ exhib-ited significantly decreased plasma carbonyl content (a

biomarker for oxidant/antioxidant barrier impairmentin various inflammatory diseases) compared to subjectstaking apple juice. Plasma vitamin E, ascorbic acid, andreduced glutathione values did not differ significantlybetween groups, leading researchers to conclude pome-granate phenolics may be responsible ior the observedresults. ̂ ^

Anticarcinogenic MechanismsIn vitro assays utilizing three prostate cancer

cell lines (DU-145, LNCaP, and PC-3) demonstratedvarious pomegranate extracts (juice, seed oil, peel) po-tently inhibit prostate cancer cell invasiveness and pro-liferation, cause cell cycle disruption, induce apoptosis,and inhibit tumor growth. These studies also demon-strated combinations of pomegranate extracts fromdifferent parts of the fruit were more effective than anysingle extract.'"''

Several animal studies have elucidated pome-granate's potential anticancer mechanisms. Two studiesin mice implanted with the prostate cancer PC-3 cellline demonstrated pomegranate fruit extract (PFE; ed-ible parts of the fruit, excluding the peel) inhibits cellgrowth and induces apoptosis via modulation of pro-teins regulating apoptosis.'^'*^

In an open-label, phase II clinical trial in 46men with recurrent prostate cancer, 16 patients (35%)showed a significant decrease in serum prostate specificantigen (PSA) levels (average=27%) during treatmentwith eight ounces of pomegranate juice. Correspondingin vitro assays using patient plasma and scrum dem-onstrated significant decreases in prostate cancer cellline proliferation and increased apoptosis. Nitric oxidepreservation via ingestion of pomegranate polyphenolssignificantly correlated with lower PSA values. Theseresults indicate pomegranate may affect prostate cancerbecause of antiproliferative, apoptotic, antioxidant, andpossibly anti-inflammatory effects.""'

Recent research also indicates pomegranateconstituents inhibit angiogenesis via downregulation ofvascular endothelial growth factor in MCF-7 breast can-cer and human umbilical vein endothelial cell lines.""

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Anti'inßammatory MechanismsCold pressed pomegranate seed oil has been

shown to inhibit both cyclooxygenase and lipoxygenaseenzymes in vitro. Cyclooxygenase, a key enzyme in the con-version of ar,-ichidonic acid to prostaglandins (importantinflammatory mediators), was inhibited by 37 percent bya CPSO extract. Lipoxygenase, which catalyzes the con-version of anichidonic acid to leukotrienes, also key me-diators of inflammation, was inhibited by 75 percent by aCPSO extract. By comparison, an FPJ extract resulted ina 23.8-percent inhibition of lipoxygenase IM i'fíro.'''

Another in vitro study that may have far-reachingimplications tor those suffering irom osteoarthritis (OA)demonstrated PFE has a significant and broad inhibitoryeffect on matrix metalloproteinases (MMPs), a subgroupoí collagenase enzymes expressed in high levels in arthriticjoints and involved in the turnover, degradation, and ca-tabolism of extracellular joint matrix. In pretreated hu-man femoral OA chondrocytes, PFE Inhibited IL-lbeta-induced destruction of proteoglycan, expression of MMPsat the cellular level, and phosphorylation and activation ofmitogen-activated protein kinases (signal transductionmolecules involved in MMP expression). The suppres-sion of MMP expression in OA chondrocyte cultures byPFE suggests pomegranate constituents prevent collagendegradation and may inhibit joint destruction in OA pa-tients.''42

Other MechanismsA pilot study in type 2 diabetic patients with hy-

perlipidemia found concentrated PJ decreased cholesterolabsorption, increased fecal excretion of cholesterol, had abeneficial effect on enzymes involved in cholesterol me-tabolism, significantly reduced total and LDL cholesterol,and improved total/HDL and LDL/HDL cholesterolratios.'^

PJ consumption by hypertensive patients inhib-its serum angiotensin converting enzyme (ACE; a cata-lyst for the conversion of angiotensin I to angiorensin II, apotent vasoconstrictor) activity, thereby reducing systolicblood pressure"" and potentially protecting against car-diovascular disease.

Animal studies have revealed three possible hy-poglycémie mechanisms for Púnica granatum extracts.Pomegranate flower extract (PFLE) improved insulinsensitivity and lowered glucose levels in rats as early as 30minutes post-glucose loading. PFLE also inhibited alpha-

glucosidase in vitro, thereby decreasing the conversion ofsucrose to glucose.''̂ PPE demonstrates significant hypo-glycémie activity in diabetic rats, via enhanced insulin lev-els and regeneration of pancreatic beta cells.'"'

Numerous in vitro studies'•'*'••*" and two humantrials'̂ '̂ '̂ " demonstrate the antimicrobial activity of pome-granate extracts. The growth of Staphylococcus aureus,Streptococcus pyogenes, Diplococcus pneumoniae, Escheri-

chia coli O157:H7, and Gandida albicaijs was inhibited

via direct bacteriocidal or fungicidal activity.

Clinical ApplicationsProstate Cancer

Among males in the United States and otherWestern countries, prostate cancer is the second-lead-ing cause of cancer-related death. In vitro studies showseveral PFEs inhibit prostate cancer cell growth, induceapoprosis of several prostate cancer cell lines (includinghighly aggressive PC-^3 prostate carcinoma cells), sup-press invasive potential of PC-3 cells, and decrease pro-liferation of DU-145 prostate cancer cells.̂ '̂̂ '̂ ^ Lanskyet al found combining equal amounts of FPJ, PPE, andCPSO extracts resulted in a 99-percent suppression ofDU-145 prostate cancer cell invasion across a Matrigelmatrix. CPSO extract or FPJ extract alone resulted in60-percent suppression of invasion, and comhitiing anytwo extracts induced 90-percent suppression. Studiesin mice have also demonstrated PFE inhibits prostatetumor growth and decreases PSA levels."'''^

These promising results led some of the sameresearchers to conduct a two-stage phase II clinical trialin men with recurrent prostate cancer and rising PSAlevels. AU eligible patients had previous surgery or ra-diation therapy for prostate cancer, Gleason scores (agrading system for predicting the behavior of prostatecancer) <7, rising PSA value of 0.2-5.0 ng/mL, noprior hormonal therapy, and no evidence of métastases.Baseline PSA doubling times were established for 22participants who were then started on eight ounces PJ(570 mg total polyphenol gallic acid equivalents) dailyuntil meeting disease progression endpoints. Endpointsmeasured were: effect on PSA levels, serum lipid per-oxidation and nitric oxide levels, in vitro induction ofproliferation and apoptosis of LNCaP cells in patientserum containing pomegranate constituents, and over-all safety of extract administration.''^'

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Alternative IVIedicine Review Volume 13, Number 2 2008

Based on preliminary results achieved in phaseI, 24 additional patients were enrolled and 46 patientswere evaluated over 13 months in both stages of thetrial. Of these, 35 percent (n=16) demonstrated de-creased PSA levels, the primary trial endpoint - averagedecrease=27%; median decrease=18%; range 5-85%.Four of 46 parients (8.7%) mer objective response cri-teria and exhibited > 50-percent reduction in PSA val-ues, meeting criteria tor a phase III trial. In addition, anaverage 40-percent reduction in serum oxidative statewas observed in patients accompanied by a significantreduction in serum lipid peroxidation compared tobaseline. Nitric oxide serum metabolites measured atnine months atter study initiation revealed an average23-percent increase, which significantly correlated withbaseline PSA levels.""

An in vitro arm of the trial using patient seruminvestigated whether PJ consumption had any effect ongrowth rates or apoptosis of LNCaP prostate cancercells in culture. Serum collected at nine months afterstudy initiation and incubated with LNCaP decreasedcell growth by an average of 12 percent in 84 percentof patients compared to baseline. An average 17.5-per-cent increase in apoptosis in 75 percent ot patients wasalso noted. This study indicates PJ or PJ constituentsmay have promise as a therapy for prostate cancer, par-ticularly recurrent type with rising PSA levels; phase IIIstudies are currently underway.'"'

Other Cancer TypesNumerous in vitro studies have investigated the

therapeutic effect of pomegranate extracts against sev-eral other cancer cell lines. In HT-29 colon cancer cells,cyclooxygenase-2 (COX-2) expression is increased viaactivation of nuclear factor kappa-B ( N F K B ) by tumornecrosis factor-alpha (TNF-Ot), an inflammatory cellsignaling process that may be a cause of cancer initia-tion and progression. Treatment of HT-29 colon can-cer cells with PJ, total pomegranate tannins, or concen-trated pomegranate punicalagin induced a significantdecrease in COX-2 expression. PJ treatment resultedin the highest level of COX-2 suppression (79%) com-pared to treatment with single constituents. Tlie etfectswere attributed to synergistic activity of the bioactiveconstituents thought to be necessary for pomegranate'santi-intlammatory and anticarcinogenic

Another in vitro study investigated the etîectsof punicalagin, ellagic acid, total pomegranate tannins,and PJ on several cell lines. Although all preparationsdecreased viable cell numbers in KB and CAL-27 oralcancer cell lines, as well as in HT-29 and HCT-116colon cancer cell lines, a higher degree of suppressionwas obtained with pure PJ, an atfect attributed to thesynergy of its bioactive constituents.^'

Research utilizing breast cancer cell linesMCF-7 and MB-MDA-231 demonstrates pomegran-ate constituents effectively inhibit angiogenesis,'" tumorgrowth,'^ proliferation, and invasiveness,''' and induceapoptosis.^^ To examine the effect at FPJ and CPSOextracts, and an HPLC-isoIated peak B (from the fruitextract), Mehta and Lansky used the mouse mammaryorgan culture, an animal model of breast cancer having>75-percent accuracy ot predicting in vivo carcinogen-esis. They found cancerous glands treated with eachpomegranate compound exhibited decreased lesionincidence - 37 percent for FPJ, and 75-90 percent forboth peak B and CPSO. Seed oil is comprised mainly ofpunicic acid, a trienoic acid with anticarcinogenic prop-erties and etfective at very low doses (1 flg/mL in organculture). Peak B is believed to be a phenolic compoundwith potent chemopreventative properties.^'

Research in mice has shown PFE inhibits tum-origenesis in lung cancer and skin cancer models. In thelung cancer study, mice given daily oral dosages ot PFEcomparable to what humans could reasonably consume(exact dosages were not available) exhibited significantlyless lung tumor growth than mice not receiving PFE.''*'In mice treated with skin-cancer-inducing 12-O-tet-radecanoylphorboI-13-acetate (TPA), animals treatedtopically with PFE had significantly reduced incidenceof skin tumors. In the PFE-treated group, only 30 per-cent of mice exhibited tumors compared to 100 percentof mice treated with TPA and no PFE. Tliis result wasattributed to suppression of inflammation (COX-2,MAPKs, N F K B ) and the tumor proliferation markerornithine decarboxylase."'

Lansky and Kuwaii investigated the effect offïavonoid-rich PJ and FPJ and pomegranate pericarpextracts on HL-60 human leukemia cell difîerentia-tion (the ability of cancer cells to revert to normal cells)and proliferation. Because of the structural similaritybetween plant flavonoids and retinoids (the latter be-

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ing established pro-differentiating agents), it washypothesized that flavonoid-rieh pomegranate extraetsmight have a similar effect on differentiation, ¡n vitroassays confirmed both the FPJ and pericarp extractsstrongly promoted cellular differentiation and inhibitedproliferation in HL-6Ü cell cultures; the effect of PJ oncellular differentiation was less significant. This studysuggests another mechanism by which pomegranateconstituents impart an anticareinogenic effect.̂ ^

AtherosclerosisIn vitro, animal, and human trials have exam-

ined the effects of various pomegranate constituents onprevention and attenuation of atherosclerosis. One ofthe preeminent researchers in endothelial fianction andnitric oxide {NO) biochemistry, Louis J. Ignarro, PhD,investigated the effects of pomegranate juice and otherfi uit juiecs on endothelial function, eomparing propen-sities to protect N O from destruction by reaetive oxy-gen speeies in vitro. Results of the antioxidant portionof the study demonstrate pomegranate Juiee possessessignificantly greater antioxidant capacity at much lowerconcentrations (>1000-fbId dilutions) than either grapeor blueberry juice, which was attributed to the high an-thoeyanin Havonoid content and higher total Havonoidcontent in PJ than the other Juices.''*

Because impaired endothelial function is anearly indicator of atherosclerosis, this study examinedthe effect of PJ on proliferation of rat aortic smoothmuscle cells in culture. PJ proved superior to otherjuices, significantly enhancing NO's effect on cardiacL-ndothelium even at 2,000-fold dilutions. PJ did notinfluence endothelial nitrie oxide synthase (eNOS)expression, leading Ignarro et al to conclude the anti-oxidant properties of PJ protect N O from free radicaldestruction and augment the antiproliferative action ofN O on rat aortic smooth muscle cells.̂ ^

In early-stage atherosclerosis, elevated plasmaeholesterol, increased oxidative stress, and increasedcholesterol esterification rates are factors contributingto foam cell formation and development of athero-sclerotic lesions.*''̂ ^- Research in atheroselerotie apoli-poprotein-H defieient (E") miee by Avirani et al at theLipid Research Laboratory in Haifa, Israel, has focusedon the ability of pomegranate extracts to inhibit athero-genesis."'''' Two months oí PJ to E" mice with advancedatherosclerosis redueed MPM lipid peroxide content by

42 percent compared with placebo-treated miee; MPMlipid peroxide content in PJ-treated mice was 20-per-eent lower than in four-mo nth-old eontrol mice. In ad-dition, MPM harvested from PJ-treated miee exhibited80-pereent lower rates of cholesterol esterifieation thanplaeebo-treated mice. In PJ-treated mice atheroscleroticlesion size in the aorta was 17-percent smaller than inthe age-matched placebo group. PJ and an isolated tan-nin fraction from PJ were also given to young E° miceprior to development of significant atherosclerosis.Researchers found 25- and 17-pereent reductions inplasma lipid peroxide concentrations with the isolatedtannin fraction and PJ, respectively."^

Aviram et al also investigated the anti-ath-erosclerotic effects of a PBP extract after the Juiee wasremoved. Four-month-old E° mice with significant ath-erosclerosis were given PBP extract {containing 51.5fig gallic aeid equiv/kg/day) with an eight-fold higherpolyphenol eoneentration than PJ for three months.This resulted in a signifieant reduction in MPM oxida-tive status as evidenced by a 27-pereent decrease in to-tal macrophage peroxide levels, a 42-percent decrease incellular lipid peroxide levels, and a 19-pereent deereasein peritoneal macrophage uptake of oxidized LDL.̂ **

To further identify the most potent anti-athero-genic pomegranate components, Aviram et al analyzedseveral more pomegranate extraets from all parts of tlieplant. Atherosclerotic E" mice were given six difîcrentpomegranate preparations with varying amounts of to-tal polyphenols and gallic acid content for three months,Antioxidanr activity, atherosclerotic lesion size, MPMoxidative status, blood sugar, and Hpid profiles were ex-amined. Confirming earlier results, this study demon-strated PFLE more significantly affects atheroselerotielesion size {Figure 2), lipid profiles, and blood sugar lev-els than other extraets tested; two PPEs demonstratedthe most potent antioxidant effeets. Meehanisms associ-ated with the anti-atherogenie effects of pomegranate inthis study inelude increased MPM uptake of oxidizedLDL, decreased lipid peroxidation, and decreased eho-lesterol levels.̂ ^

The effect of PJ consumption on lipid per-oxidation in plasma and HDL- and LDL-lipoproteinswas examined in a double-armed human trial. In thefirst study, 13 healthy, nonsmoking men {ages 20-35)were given 50 mL PJ daily {containing 1.5 mmol totalpolyphenols) for two weeks. In the second study (dura-tion <10 weeks), three healthy men {same age range)

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Figure 2, Atherosclerotic Lesion Size with Various Pomegranate Extracts

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Size

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Atfifam M, Volkova N, Coleman R, et al. Pomegranaîe phenolics from ttie peels, arils, and flowers are antiatherogenic: studies

in vivo in aüierosclerotic apolipoprotein E-deficient (E°J mice and in vitro cultured macrophages and lipoproteins. JAgric

Food Chem 2008:56:1148-1157.

were given increasing doses of PJ ranging from 20-80mL daily (0.54-2.16 mmol total polyphenols). Fastingblood samples were drawn from participants pt'e-studyand after one and two weeks of PJ supplementation.No significant effect was observed in either study onplasma lipid profile or lipoprotein patterns. Tlie resultsdid show, however, for the first time in humans, that PJhas an inhibitory effect on lipid peroxidation in plasmaand in lipoproteins, with the middle dose (50 mL daily)being the most effective, yielding a 32-percent decreasein plasma lipid peroxidation. PJ (in a dose-dependentmanner) also demonstrated up to 90-percent inhibi-tion of collagen-induced platelet aggregation in humanplatelets ex

HyperlipidemiaPomegranate flowers have been used in both

the Unani and Ayurvedic systems of medicine as aremedy for diabetes. Based on historical use, a study indiabetic rats explored the effects of PFLE on cardiac

iipid metabolism in 13-to 15-week old Zuckerdiabetic rats. Animalswere given 500 mg/kgPFLE or placebo for sixweeks, and total choles-terol, triglycéride, andnonesterified free fattyacids (NEFA) were de-termined prior to treat-ment (nonfasting), atweek 4 (nonfasting), andweek 5 (fasting) in bothrat plasma and cardiactissue. PFLE was shownto activate peroxisomeproliféra tor-activatedreceptor (PPAR-a), acardiac transcription fac-tor involved in myocar-dial energy productionvia fatty acid uptake andoxidation. PPAR-a acti-vation decreased cardiacuptake and circulationof Iipids. Decreases wereobserved in cardiac tissuetriglycéride content at the

end of the study and in plasma total cholesterol andNEFA after four weeks of treatment.''^

A pilot study involving 22 type 2 diabetic pa-tients (8 men and 14 women) investigated the choles-terol-lowering effects of 40 g concentrated PJ for eightweeks. Statistically significant decreases were observedin total cholesterol (from 202.4±27.7 mg/dL at baselineto 191.4±21 mg/dL at study conclusion), LDL choles-terol (124.4±31.9 mg/dL at baseline to 112.9±25.9mg/dL at study conclusion), total/HDL cholesterol ra-tio (5.5±1.3 at baseline to 5.1 ±1.1 at study conclusion),and LDL/HDL ratio (3.4+1.2 at baseline to 3.0±0.9 atstudy conclusion). The authors attributed these effectsto decreased absorption and increased fecal excretion ofcholesterol, as well as possible affects on HMG-CoAreductase and sterol O-acyltransferase, two enzymeskey to cholesterol metabolism/^

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Alternative Medicine Revievií Volume 13, Number 2 2008

Table 2. Antioxidant Activity of Pomegranate Juice Extract in Patientswith Carotid Artery Stenosis

ANALYSIS BASELINE 1 MONTH 3 MONTHS lYEAR 3 YEARS

Total Antioxidant Status(nmol/liter)

Serum Antibodies againstLDL Oxidation (EU/mL)

AAPH-induced Serum LípíPeroxidation (nmol/mL)

Serum Paraoxonase1 (PONÍ) AryiesteraseActivity (Units/mL)

Lipid Peroxide Content ofCarotid Lesions (nmol/mgof lesion protein)

0.95 ±0.12

2670 ± 61 1563 ± 69 1670 ± 52

1670 ± 66

56 ±5

2.20 ± 0.23

691 ± 43(•&59%)

97 ±10(U73%)

^75%

107 ± 10{{ï83%)

061% 044%

EU = Enzyme unitsAAPH = 2.2'-azobis, 2-amidinopropane hydrochloride

HypertensionA small clinical tiial demonstrated PJ inhib-

its serum ACE and reduces systolic blood pressure inhypertensive patients. Ten hypertensive subjects (ages62-77; seven men and three women) were given 50 mL/day PJ containing 1.5 mmol total polyphenols for twoweeks. Two of seven patients were also diabetic and twowere hyperhpidemic. Seven of 10 subjects (70%) expe-rienced a 36-percent average decrease in serum ACE ac-tivity and a small, but significant, five-percent decreasein systolic blood pressure.'*''

Carotid Artery StenosisIn a small, long-term study, 19 subjects (ages

65-75) with severe carotid artery stenosis (70-90%stenosis of internal carotid arteries) were randomizedto receive either 50 mL PJ daily containing L5 mmolestotal poiyphenols (n-10) or no treatment (n=9) forone year; five subjects continued PJ for an additional

two years. Study participants were treated with similarhypocholesterolemic and antihypertensive medicationsand no dietary or lifestyle changes occurred in eithergroup. Blood samples were collected and echo Doppleranalysis was performed at baseline and at 3, 6, 9, 12,22, 28, and 36 months. Control subjects demonstrateda mean nine-percent increase in intima-media thick-ness (IMT) of left and right carotid arteries during thefirst year. Conversely, those consuming PJ had reducedIMT at 3, 6, 9, and 12 months ranging from 13 percentat three months to 35 percent at one year compared tobaseline values.''''

Most serum biochemistry parameters re-mained unchanged by Pj consumption over the firstyear, with the exception of triglycéride concentrations,which increased 16 percent but remained in the normalrange. Serum lipid peroxidation in subjects consum-ing PJ was significantly reduced by 59 percent afterone year, and levels of LDL-associated lipid peroxides

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were also decreased by as much as 90 percent after sixmonths of supplementation. Body mass index did notchange in treated subjects but systolic blood pressurewas reduced an average of 16 percent during the three-year study.*" In addition to previous reports of reducedsystolic blood pressure''' and inhibition of lipid peroxi-dation,^' this study demonstrated that PJ consumption(via antioxidative mechanisms) significantly reducesvarious aspects of IMT in patients with severe carotidartery stenosis (Table 2).

Myocardial PerfusionIn a double-blind, randomized, placebo-con-

trolled trial, 39 patients were given either 240 mL PJ(polyphenol content not specified) (n=23) or a sportsbeverage of similar color, flavor, and caloric contentdaily for three months (n=16). Although both controland treatment patients demonstrated similar levels ofstress-induced ischemia at baseline, at three monthsstress-induced ischemia increased in the placebo group(from 5.9+4.3 to 7.1±5.5) but decreased in the treat-ment group (from 4.5±3.1 to 3.7±3.7). In addition, an-gina episodes increased 38 percent in the placebo groupbut decreased 50 percent in the treatment group (a netchange of 88 percent). These results demonstrate a re-duction in myocardial ischemia and improved myocar-dial perfusion (as measured by stress-induced ischemia)in patients consuming pomegranate juice.^"

DiabetesIn an animal model of diabetes, Huang et al dem-

onstrated the favorable effect of PFLE on lipid profiles"'and cardiac fibrosis'** of Zucker fatty diabetic rats. Rosen-blat et al investigated the effect of 50 mL/day PJ for threemonths on oxidative stress, blood sugar, and lipid profilesin 10 type 2 diabetic patients (history of diabetes for 4-10years) and 10 healthy controls (ages 35-71).̂ '* In diabeticpatients, triglycéride levels were 2.8 times greater, HDLcholesterol was 28-percent lower, and hemoglobin AlC(HbAlC) values were 59-percent higher than in controlpatients. Insulin was only slightly lower in patients thancontrols, and C-peptÍde (a proinsulin metabolite markerfor endogenously secreted insulin) was slightly higher indiabetic patients than in healthy controls at baseline (indi-cating slight hyperinsulinemia). Consuming PJ for threemonths did not significantly affect triglycéride, HDL

cholesterol, HbAlC, glucose, or insulin values, but didlower serum C-peptide values by 23 percent compared tobaseline in diabetic patients - a sign of improved insulinsensitivity.

PJ consumption also significantly reduced oxi-dative stress in the diabetic patients as evidenced by a56-percent reduction in lipid peroxides and a 28-percentreduction in TBARS compared to baseline serum levels.In addition, a 39-percent decrease in uptake of oxidizedLDL by human monocyte-derived macrophages (an earlydevelopment in foam cell formation and atherogenesis)was observed in diabetic patients after PJ consumption.Researchers concluded that despite the sugars naturallypresent in pomegranate juice, consumption did not ad-versely affect diabetic parameters but had a significant ef-fect on atherogenesis via reduced oxidative stress.'̂ '̂

Dental ConditionsTopical applications of pomegranate prepara-

tions have been found to be particularly effective forcontrolling oral inflammation, as well as bacteria andfungal counts in periodontal disease and Candida-asso-ciated denture stomatitis.

Dental PlaqueA hydroalcoholic extract oí Púnica granatum

fruit (HAEP) was investigated for antibacterial effecton dental plaque microorganisms. Sixty healthy patients(33 femaIes/27 males; ages 9-25) with fixed orthodon-tic appliances were randomized to three groups of 20:(1) control group who rinsed with 15 mL distilled wa-ter; (2) a group who rinsed with 15 niL chlorbexidine,a standard antiplaque mouth rinse; and (3) a group whorinsed with a 15-mL HAEP solution. Rinsing durationwas one minute and dental plaque material was collectedfrom each patient prior to and afi:er rinsing. Samples werediluted and plated on Meuller-Hinton agar and incuba-ted at 37° C for 48 hours. HAEP decreased the numberof colony forming units (CFU) of dental plaque bacteria84 percent, comparable to chlorhexidine (79-percent in-hibition) but significantly better than the control rinse(11-percent inhibition). Both HAEP and chlorhexidinewere effective against Staphylococcus, Streptococcus,Klebsiella, and Proteus species, as well as E. coli. Theellagitannin, punicalagin, is thought to be tlie fractionresponsible for pomegranates antibacterial activity.''^

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Periodontal DiseaseA preliminary and follow-up study by a group

of Tliai researchers investigated the effect of biodegrad-able chips impregnated with Centella asiática and P. gra-natum pericarp on periodontal disease in 20 patientswith gum pocket depths of 5-8 mm. A baseline examwas performed and followed by root planing and scal-ing of target teeth. Subgingival placement of the medi-cated chips (treatment group) anci non-medicated chips(placebo/control group) followed, and pocket depth,attachment level, bleeding, and gingival and plaque in-dexes were measured at baseline and after three and sixmonths. All treatment sites demonstrated a trend to-ward decreasing plaque and significant improvementswere noted in pocket depth and attachment level atthree months compared to placebo.'"

In the follow-up study, 15 patients who hadcompleted srandard periodontal therapy but still hadpocket depths of 5-8 mm were implanted with the samemedicated chips. The same parameters were measuredagain at baseline and after three and six months, butresearchers also measured inflammatory markers inter-leukin-lß (IL-lfí) and IL-6. Significant improvementwas noted in all re-measured parameters and confirmedby significant decreases in IL-lß and IL-6 at three andsix months compared to baseline/'

Denture StomatitisThe primary etiologic factors for denture stom-

atitis are poor oral hygiene, inflammation from ill-fittingdentures, and Candida infection,'' ' which manifest asswelling, pain, burning in the mouth, and aphthous ul-cers/'' In a randomized, double-blind study of 60 sub-jects (ages 19-62) with candidiasis confirmed via myco-logie examination, the efîect of a gel-based P. granatumbark extract (GPBE) was evaluated for its effect on heal-ing of oral lesions and direct fungicidal effect. Patientswere randomized into two groups of 30: one receivedmiconazole oral gel (a standard therapy) and the otherused GPBE, both three times daily for 15 days. Gelswere applied to oral surfaces, dentures were removedand cleaned nightly, then brushed with the correspond-ing oral gels. All subjects reported an improvement insymptoms and general oral health. Clinical symptoms ofthose using miconazole were slightly better (27/30 sat-isfactory improvement) compared to GPBE (21/30 sat-isfactory improvement). Clearing of Candida infection

was approximately the same in both groups (25/30 in themiconazole group and 23/30 in the GPBE group).'"

Interestingly, despite randomized subject place-ment, there were three times more subjects with goodoral hygiene scores in the miconazole group comparedto the GPBE group, possibly accounting for the superiorresults observed by miconazole therapy. Also, becausethe initial step in the development of Candida denturestomatitis is adherence of organisms to dentures and themiconazole gel was stickier than GPBE, contact dura-tion of miconazole was longer. A stickier GPBE mightresult in improved clinical response.^"

Bacterial InfectionsThe only human trials examining the antibac-

terial properties of pomegranate extracts have focusedon oral bacteria.'*'̂ '̂ "™'̂ However, several in vitro assaysdemonstrate its bacteriocidal activity against severalhighly pathogenic and sometimes antibiotic-resistantorganisms. Brazilian researchers evaluated the synergis-tic effect of a P. granatum methanolic extract with fiveantibiotics on 30 clinical isolates of methiciilin-resistantStaphylococcus aureus (MRSA) and methicillin-sensitiveS. iiuretis.'•" Antibiotics tested were chloramphenicol, gen-tamicin, ampicillin, tetracycline, and oxacillin. Althoughsynergistic activity between the pomegranate extractand all five antibiotics was noted in the S. aureus isolates,synergy with ampicillin was the most pronounced. Acombination of the two increased the lag time to bacter-ial growth by three hours (over that of ampicillin alone)and was also bacteriocidal as evidenced by a 72.5-per-cent reduction in methicillin-sensitive organisms and a99.9-percent reduction in MRSA. Based on earlier re-search'^ and the results of this study, the ellagitannin,punicalagin. Is thought to be the primary constituentresponsible tor the observed antibacterial effects.

Another organism that can cause significant dis-ease in humans is enterohemorrhagic Escherichia coli (£.coli O157:H7), which can present with diarrhea, hem-orrhagic colitis, thrombocytopenic purpura, and hemo-lytic uremic syndrome. P. granatum and seven other Thaimedicinal plant extracts were tested for in vitro activityagainst E. coli O157:H7. An ethanolic PPE, one of thetwo most effective extracts against E. coli O157:H7, wasshown to be both bacteriostatic and bacteriocidal, indi-cating PPE may be an effective adjunct treatment for E.i-o/i0157;H7 infection.'"

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Ultraviolet RadiationIn vitro studies using normal human epidermal

keratinocytes and PFE demonstrate PFE incubationwith cell cultures ameliorates ultraviolet A and B radia-tion-induced cell damage in a dose- and time-dependentmanner, providing evidence at a cellular level that PFEmay be an effective photo-chemopreventive agent/^™

A double-blind, placebo-controlled trial eval-uated the protective and ameliorative properties ofpomegranate extract and its EA constituent on UV-induced skin pigmentation. An ethanolic PPE was pre-pared containing 89.5 percent EA, confirmed by HPLCanalysis. Thirty-nine healthy women (ages 20-49) wererandomly assigned to one of three groups: (1) high-dose (200 mg/day) EA tablets; (2) low-dose (100 mg/day) EA tablets; and (3) placebo (0 mg EA) tablets forfour weeks. Prior to the first dose, subjects received a1.5 minimum erythema dose (MED) oi UV radiationon the inside upper right arm. Melanin, luminance, anderythema values were measured at baseline and at theend of each of the next four weeks. A questionnairewas completed by subjects to evaluate PPE's effective-ness on improvement of UV-induced slight sunburn.Rate of change for luminance, melanin, and erythemavalues was not significantly different for subjects receiv-ing either EA dose compared to placebo or comparedto baseline values. However, analysis of the question-naire results demonstrated a trend toward ameliorationof UV-induced damage in both EA groups comparedto placebo.'^

Erectile DysfunctionA study using a rabbit model of arteriogenic

erectile dysfunction (ED) measured the effect of PJconcentrate on intracavernous blood flow and penileerection. Azadzoi et al found eight weeks administra-tion of 3.87 mL PJ concentrate (112 \xmol polyphenols)daily significantly increased intracavernous blood flowand smooth muscle relaxation, probably via its antioxi-dant effect on enhanced N O preservation and bioavail-ability.«"

A randomized, double-blind, placebo-con-trolled, 10-week crossover trial in 53 men (mean age46) investigated PJ's therapeutic effect on mild-to-moderate ED. Subjects with other medical conditions

that might contribute to ED were excluded, and sub-jects were asked to refrain from taking ED medicationfor the duration of the study. The trial consisted of twofour-week treatment periods separated by a two-weekwashout. During the first four weeks, subjects weregiven PJ (1.5 mmol polyphenols daily) or placebo bev-erage, followed by washout and crossover to the othergroup. Although assessment via the International hidexof Erectile Function and Global Assessment Question-naires demonstrated a trend toward improvements inED, statistical significance was not achieved. This maybe attributable to small sample size, short study dura-tion, subject compliance with beverage consumption, ormay indicate the PJ dosage did not have an appreciableeffect on ED.«'

Male InfertilityResearch in rats demonstrates PJ consumption

improves epididymal sperm concentration, spermato-genic cell density, diameter of seminiferous tubules, andsperm motility, and decreases the number of abnormalsperm compared to control animals. An improvementin antioxidant enzyme activity in both rat plasma andsperm was also

Neonatal Hypoxie-Ischémie Brain InjuryNeonatal hypoxic-ischemic (HI) brain injury

in severely preterm, very low birth-weight infants is amajor cause of infant illness and death**' and has beenassociated with an increase in reactive oxygen species."**Two studies in which pregnant mice were given PJ indrinking water revealed the neonatal offspring, whensubjected to experimentally-induced HI brain injury,had significantly less brain tissue loss (64% decrease)and significantly decreased hippocampal caspase-3 ac-tivity (84% decrease) compared to neonates with ex-perimentally-induced HI brain injury from dams whoconsumed a control beverage.**̂ '*̂ These results suggestPJ has an antioxidant-driven neuroprotective effectconferred from mother to neonate.

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Alzheitne/s Diseasellie ncuroprotectivc properties of pomegran-

ate polyphenols were evaluated in an animal model ofAlzheimer's disease. Transgenic mice with Alzheimer's-like pathology treated with PJ had 50-percent less accu-mulation of soluble amyloid-beta and less hippocampalamyloid deposition than mice consuming sugar water,suggesting PJ may be neuroprotective. Animals alsoexhibited improved learning of water maze tasks andswam faster than control animals/'

ObesityPFLE (400 or 800 mg/kg/day) given to obese

hyperlipidemic mice tor five weeks caused significantdecreases in body weight, percentage of adipose pad

weights, energy intake, and serum cholesterol, triglyc-éride, glucose, and total cholesterol/HDL ratios. De-creased appetite and intestinal fat absorption were alsoobserved, improvements mediated in part by inhibitionof pancreatic lipase activity.**"

Potential Drug InteractionsBased on pomegranate's current popularity

and research suggesting its therapeutic benefit in cancer,cardiovascular disease, and other diseases treated withprescription medications, it has been of interest to de-termine whether pomegranate extracts have any effecton cytochrome P450-3A, the hepatic enzyme systemresponsible for metabolism of many prescription medi-cations. A randomized, single-dose, crossover study in

Table 3. Ongoing Pomegranate Trials

CLINTRIALS.GOVIDENTIFIER

NCTÜ04I3530

NCT00060086

NCT00433797

J

NCT00381108

NCT00455416

NCT00336934

NCT00428532

NCT00655031

STUDY FOCUS

Rising PSA levels inmen with previousprostate cancer

Recurrent prostatecancer

Prostate cancer

Benign prostatichyperpiasia

FoKicular lymphoma

Rising PSA levels inmen with previousprostate cancer

Attierosclerosis indiabetics

Prevention ofrtiino-virus infection

SPONSOR

M.D.Anderson CancerCenter: Houston, TK

Jonsson ComprehensiveCancer Center; NationalCancer Institute

University of Oslo;Norwegian CancerSociety; The ResearchCouncil of Norway

University of California,irvine; JarrowPharmaceuticals

University of Oslo,Norway

Jonsson ComprehensiveCancer Center; NationalCancer Institute

HaEmek Medical Center,Israel

Pom Wonderful LLC

ESTIMATEDENROLLMENT

300 subjects

29-40subjects

102 subjects

20 subjects

45 subjects

250 subjects

10 males10 females

150 subjects

STUDY STARTDATE

December2006

March2003

June2007

September2005

April2007

November2005

March2007

April2008

ESTIMATEDCOMPLETION DATE

December2008

September 2004or longer

March2009

March2009

December2009

December2009

August2007

June2008

STATUS

Currentlyrecruiting

Ongoing

Currentlyrecruiting

Currentlyrecruiting

Currentlyrecruiting

Currentlyrecruiting

Completed;publicationpending

Currentlyrecruiting

From; http://www.clinicaltrials.gov

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Alternative Medicine Revievi/ Volume 13, Number 2 2008

13 healthy human volunteers demonstrated PJ pretreat-ment did not affect elimination half-life or distributionof intravenous midazolam (a benzodiazepine derivativewith anxiolytic, amnestic, hypnotic, anticonvulsant, andmuscle relaxant properties), nor did it affect the C orclearance of oral midazolam."' Tliis human study con-tradicts a rat study showing PJ has an inhibitory effecton carbamazepine pharmacokinetics, an anticonvulsantmedication also metabolized by cytochrome P450-

Safety of Pomegranate ExtractsPomegranate and its constituents have safely

been consumed for centuries without adverse effects.Studies of pomegranate constituents in animals at con-centrations and levels commonly used in folk and tradi-tional medicine note no toxic effects.'" Toxicity of thepolyphenol antioxidant punicalagin, abundant in pome-granate Juice, was evaluated in rats. No toxic effects orsignificant differences were observed in the treatmentgroup compared to controls, which was confirmed viahistopathological analysis of rat organs.'̂ '̂

Research in 86 overweight human volunteersdemonstrated the safety of a tableted PFE in amountsup to 1,420 mg/day (870 mg gallic acid equivalents)for 28 days, with no adverse events reported or adversechanges in blood or urine laboratory values observed." '̂Another study in 10 patients with carotid artery steno-sis demonstrated PJ consumption (121 mg/L EAequivalents) for up to three years had no toxic effecton blood chemistry analysis for kidney, liver, and heart

ConclusionAn explosion of interest in the numerous

therapeutic properties oí Púnica granatum over the lastdecade has led to numerous in vitro, animal, and clini-cal trials. Pomegranate is a potent antioxidant, superiorto red wine and equal to or better than green tea. Inaddition, anticarcinogenic and anti-inHammatory prop-erties suggest its possible use as a therapy or adjunctfor prevention and treatment of several types of cancerand cardiovascular disease. Because of pomegranate'santimicrobial properties, it may aid in preventing infec-tion by dental pathogens, pathogenic E. coli Oi57:H7,and antibiotic-resistant organisms such as MRSA.

Pomegranate's effect on bacterial pathogens has onlybeen tested in vitro, however, necessitating human trialsto refute or substantiate any cUnical effect. The possibil-ity that pomegranate extracts may also have an effecton several other disease processes, such as Alzheimersdisease, osteoarthritis, neonatal brain injury, male infer-tility, and obesity, underscores the need for more clinicalresearch. Currently, numerous clinical trials aie in pro-gress exploring the therapeutic potential of pomegran-ate extracts (Table S).''"*

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