Green Tea, the "Asian Paradox,"and Cardiovascular Disease Bauer E Sumpio, MD, PhD, FACS, Alfredo C Cordova, MD, David W Berke-Schlessel, BS, Feng Qin, MD,Quan Hai Chen, MD Archeologic findings have revealed that infusions of 75% to 80%of the 140 million cups of tea consumed leaves from various wild plants, including the tea plant, might have been consumed for more than 500,000 Next to green tea, one of the most highly consumed yLegends from China and India indicate that use products in Asia is cigarettes. Evidence strongly associates of tea occurred as far back as 2,737 years BC when the cigarette smoking with cardiovascular events, including Chinese Emperor Shen Nung, "Divine Healer," found myocardial infarction, stroke, peripheral vascular disease, himself with a beverage harboring a pleasant aroma and aggravation of stable angina pectoris, vasospastic angina, refreshing taste after dried leaves accidentally blew into rethrombosis after thrombolysis, restenosis after angio- hot boiling waterThis ancient practice associated with plasty, and even sudden death, and medicinal purposes, lifestyle customs, and nutritional These pathologic conditions occur as a result of a num- beliefs was progressively introduced to countries world- ber of detrimental effects leading to atherogenesis, in- wide by tradesmen and travelers Tea was used to cluding an increase in levels of fatty acids, LDL, and very reduce inflammation, improve blood flow, treat infec- LDL, and a decreased turnover of HDL cholesterol.
tious diseases, purify the body, and maintain mental Smoking has also been correlated with aggravation of The people of Japan, China, India, and hypertension, promotion of platelet aggregation, and England elevated tea from a simple beverage to a social modulation and proliferation of vascular endothelial custom, bestowing tea consumption a preferential place cells (EC) and smooth muscle cells Using a bovine aortic vascular SMC scrape injury model, as Scientific validation has slowly accumulated and shown by our laboratorya mitogen-activated protein green tea has attracted more followers as the word has kinases p38 and p44/42 mediated SMC migration spread about its health and medicinal properties. A re- would result as a consequence of nicotine exposure.
cent survey conducted in the US among cancer patients Despite the high consumption of tobacco, Asia and using herbal remedies revealed that green tea was the Japan in particular have among the lowest incidences of most common herb used in 54% of Tea is the arteriosclerosis and lung cancer per capita It has most widely consumed beverage in the world, second been postulated that this paradox, the "Asian Paradox," ex- only to water,with a worldwide per capita consump- ists as a result of the high consumption of green tea in tion of 40 L per yearApproximately 3 billion kilograms this region, and most benefits occur when approxi- of tea are produced and consumed annually and this mately 1.2 L of green tea are consumed every day. For number is growing at a rate of 2.1% per yearIn the example, a Japanese epidemiologic involving Western World, black tea is preferred, and in the Asian 1,371 men older than 40 years of age reported the asso- countries green tea is the primary drink. The practice of ciation between the consumption of ⬎ 10 cups (1,500 drinking iced tea is spreading from the US, where it mL) of green tea a day with a decreased serum concen- began during the early 20th century. It now accounts for tration of total cholesterol, LDL, and triglycerides, andwith an increased HDL concentration. A recent meta-involving 10 cohort studies and 7 case-control Received October 31, 2005; Revised December 7, 2005; Accepted January studies, reported an 11% decrease in myocardial infarc- tion when 3 cups of tea (tea type not specified) were From the Department of Vascular Surgery, Yale University School of Medi-cine, New Haven, CT.
consumed daily. Risk of myocardial infarction was seen Correspondence address: Bauer E Sumpio, MD, PhD, FACS, Department of to be reduced by 44% in individuals drinking ⱖ 1 cup Surgery, Vascular Surgery Section, Yale University School of Medicine, 333Cedar St, New Haven, CT 06520-8062. email: [email protected] (237 mL) of tea per day compared with nondrinkers, in 2006 by the American College of Surgeons ISSN 1072-7515/06/$32.00 Published by Elsevier Inc.
Green Tea and Cardiovascular Disease J Am Coll Surg to 7 years later in women who drank ⱖ 10 cups per day Acronyms and Abbreviations compared with those who drank ⱕ 3. In the case of the ⫽ endothelial cells men, there was also a delay, but of only 3 years. Epide- EGCG ⫽ (-)-epigallocatechin-3-gallate miologists from Japan have also reported in a case- MMP ⫽ matrix metalloproteinase control based on 139 cases of newly diagnosed ⫽ reactive oxygen species ⫽ smooth muscle cells gastric cancer and 278 gender-matched and year ofbirth-matched controls, a decreased risk of gastric canceramong subjects with green tea consumption ⬎ 10 cups a study involving 340 patients with age-, gender-, and community-matched contrIn a prospective cohort In the US and other Western countries, arteriosclero- studywhich involved 1,935 patients with a history of sis and its clinical sequelae, such as myocardial infarc- myocardial infarction, age- and gender-adjusted mortal- tion, stroke, and peripheral vascular disease, account for ity was lower among moderate tea (green or black tea) almost 40% of all mortalityConcomitant evidence is drinkers (⬍ 14 cups of tea/wk) presenting a relative risk emerging from Western nations that green tea, primarily of 0.69, and in heavy drinkers (14 cups of tea/wk) with because of the high concentration of polyphenolic fla- a relative risk of 0.61, when compared with nondrinkers.
vonoids, is a potential tool in the prevention of arterio- Another prospective cohort studyincluding 8,552 sclerosis. Hollman and assessed the associa- Japanese men and women, revealed a decreased relative tion between flavonol intake and cardiovascular disease risk for cardiovascular disease of 0.52 for men, 0.82 for through six prospective epidemiologic studies. In the women, and 0.72 for both genders for those consuming Seven Countries Studythe Zutphen Elderly S ⬎ 10 cups of green tea per day compared with those and in a Finnish cohora clear inverse correlation with consuming ⬍ 3 cups. This same study demonstrated a mortality rates from coronary heart disease was ob- decreased relative risk for cancer of 0.54 for men, 0.57 served. In vitro indicate that the polyphenol for women, and 0.59 for both genders, again for those (-)-epigallocatechin-3-gallate (EGCG) and, to a lesser consuming ⬎ 10 cups of green tea per day compared extent, other catechins in green tea, decrease oxidation with those drinking ⬍ 3 cups per day. Among cancer of LDL and inhibit SMC and EC proliferation, poten- patients, there was a delayed cancer onset for those who tially reducing the risk of arteriosclerosis. These vascular drank larger quantities of green tea. Cancer appeared up effects of EGCG are thought to be a result of its antiox- Table 1. Lifestyle Factors and Mortality from Cardiovascular Disease and Lung Cancer* *Source: World Health Organization, Global Market Information. Database (Euromonitor), †Percentage of total population who smoked at least one cigarette a day.
‡Data refers to estimates of apparent consumption based on cigarette production, imports, and exports during the most recent 3-y moving average between 1992and 2000.
§1 kg ⫽ approximately 311 cups (60⫺70 lb leaves ⫽ 20 lb dry tea ⫽ 2,800 cups tea).
CAD, coronary artery disease.
Vol. 202, No. 5, May 2006 Green Tea and Cardiovascular Disease idant properties.EGCG has also been reported to pre- and black tea is the result of a 60- to 90-minute reaction vent angiogenesis and tube formation, causing cessation of cancer growthand preventing certain types of tu- Polyphenols are bonded benzene rings with multiple mors from Angiogenesis inhibition is hydroxyl groups Polyphenols are categorized by thought to be due primarily to specific receptor block- structure into flavonoids and nonflavonoids, with the age, which alters certain cell regulatory functions, in- chemicals found in tea being mainly flavonoids. All cluding apoptosis of SMC and EC.Vascular endo- three types of teas contain compounds called catechins; thelial growth factor binding to its receptors can be which are currently thought to be primarily responsible reduced by EGCG, affecting downstream signaling.
for the beneficial effects of tea.Green tea has the Data collected from the World Health Organization highest concentration of catechins per gram of dried on lifestyle factors and mortality from cardiovascular leaves compared with black and oolong teas and is the disease and lung cancer, shown in reveal in- best dietary source of this compound. In green tea, cat- creased levels of mortality in countries such as Ireland echins represent 80% of flavonoids, although in black and the United Kingdom, where, in fact, black tea, and tea they only represent 20% to 30% Each tea not green tea, is heavily consumed. Asian countries such contains primarily four different types of catechins including: as Japan and Korea, where green tea is consumed exclu- sively, on the other hand, have lower mortality rates, and (-)-epigallocatechin-3-gallate (EGCG).Other impor- suggesting beneficial properties. In this article, the most tant dietary sources of catechins are red wine, black grapes, recent and relevant data associated with green tea's pu- apples, and chocolate.The most important flavonols in tative cardiovascular protective effects will be reviewed tea are quercetin, kaempferol, and rutin. They are more to provide insight on the clinical significance of its widely distributed and can also be found in red wine, black grapes, apples, onions, cherries, berries, grape-fruits, and cruciferous vegetables.Tea also contains COMPOSITION OF GREEN TEA phenolic acids, including mainly caffeic, gallic, and Tea derives from the leaves of the plant Camellia sinensis, quinic acids, and is an excellent source of methylxan- and is reported to contain nearly 4,000 bioactive chem- thines, containing approximately one-third the amount of ical compounds, one-third of which are polyphenols.
caffeine compared with coffee.A cup of tea contains 40 to EGCG, the major catechin in tea, accounts for 10% of 55 mg of caffeine, and a cup of coffee contains 125 to 150 the total weight Camellia sinensis is indigenous to India and the Far East countries, primarily China andJapan.Three different types of tea: green (no "fermen- METABOLISM AND BIOAVAILABILITY tation"), oolong (moderate "fermentation"), and black In healthy volunteers, drinking green tea resulted in a cat- (complete "fermentation") tea can be derived from this echin concentration in plasma between 0.2% to 2% of the When tea leaves at harvest are withered and im- ingested amount, with a maximal concentration after 1.4 to mediately steamed or heated, the polyphenol oxidase 2.4 hours after consumption.The half-life of EGCG is that is present in the leaves is inactivated, yielding green about 5 hours, although that for (-)-epigallocatechin and tea. If the leaves are harvested, withered, rolled, and epicatechin are shorter, between 2.5 and 3.4 hours.The crushed, the polyphenol oxidase is liberated and is bio- latter two can be partly recovered in urine, although EGCG chemically oxidized, which in turn leads to polymeriza- cannot. In humans, a studyusing radioactively labeled tion of the polyphenols. Polyphenols are converted to catechins demonstrated the efficient metabolism of this fla- dimers and polymers, mainly theaflavins and thearubi- vonoid. Little is known about the bioavailability of theafla- gins. These products are responsible for the characteris- vins and thearubigins, the black tea polyphenols; they both tic yellowish-orange to reddish-brown color of these teas appear to be absorbed. Adding milk to the beverage, as and for physiologic and biochemical properties compa- customized in Great Britain, does not reduce polyphe- rable with those of catechins, but with considerably less nols' bioavailability as this produces no change in the antioxidant effects This process is stopped by blood polyphenol On the other hand, drying the product in a stream of hot air. Oolong tea is milk has been reported to reduce the antioxidant activity produced when this reaction time is about 30 minutes, of tea in vivoThe effects of green tea might be less

Green Tea and Cardiovascular Disease J Am Coll Surg Figure 1. Biochemical composition of green tea. (Reprinted from: Dufresne CJ, Farnworth ER. A review of latest research findings on thehealth promotion properties of tea, J Nutr Biochem 2001;12:405, with permission).
variable than black tea in this respect, as milk is not used can reduce lipid, starch, and protein digestibility, affect for green tea in Japan or other Asian countries.
insulinemic and glycemic responses, increase excretion Polyphenols have an especially strong affinity for pro- of fats, and reduce absorption of cholesterTea poly- line rich proteins such as casein, milk, gelatin, and saliva, phenols have an important interaction with transition and also interfere with the absorption of other com- metal ions, strongly inhibiting nonhaem iron absorption pounds in the The most effective binding capacity in the gastrointestinal tract by forming insoluble com- is held by the large, flexible, and poorly water soluble plexes with this With a varied diet, iron By binding to digestive enzymes, tannins absorption is unaffected; in vegetarian diets, it is advised Vol. 202, No. 5, May 2006 Green Tea and Cardiovascular Disease Table 2. Tea Biochemical Compounds Responsible for structure and contributes to atherogenesis in several Taste, Flavor, and Color ways. First, oxidized LDL has cytotoxic properties that Biochemical compounds can promote endothelial injury. It can also act as a che- moattractant for circulating monocytes, leading to their increased accumulation within plaques. Oxidized LDL Slight astringency and ashyness has also been reported to inhibit the egression of macro- Bitterness and briskness phages from plaques. Lipid and protein oxidation have been correlated with an increase in arteriosclerosis, dia- Phenyl ethanol, Benzaldehyde, betic complications, and a reduction in the immune Nerolidol, Methyl salicylate Linalool, Linalool oxide To prevent cell injury, free radicals can be inhibited by antioxidants and by compartmentalization. The detoxi- fication process occurs through a multistage enzyme sys- tem, where molecules activated by phase I enzymes such as NADPH, p450, and cytochrome, are converted into Flavonol glycosides electrophilic water soluble compounds. They are then conjugated for their inactivation to detoxifying mole- cules, such as glutathione and UDP-glucoronosyl, be- fore their excretion.Antioxidants from nutrients such as tocopherol, ascorbic acid, and carotenoids, which in- cludes lycopenes and polyphenols, contribute to theoverall protection of cell integrity and the immune func- that green tea be consumed between meals to avoid a tion, in conjunction with the cell's constitutive enzy- reduction in the already limited amount of available matic and nonenzymatic protection against RO irIn rats, zinc absorption inhibition has been ob- Polyphenols' antioxidant activity can prevent DNA served, although results for copper remain unclear. Poly- lipid hydroperoxide f phenols also affect the bioavailability of sodium and alu- photograph-enhanced lipid peroxidation.They present minum; it does not interfere with that of calcium, scavenging activity against free superoxide radicals,and peroxynitrite.They also altermany catalytic activities of enzymes, notably the oxida- POLYPHENOL ANTIOXIDANT ACTIVITY tive ones,and can modify the process of protein phos- Free radicals are molecules or atoms with an unpaired phorPolyphenols can inhibit the formation of electron. The unpaired electron results in a high level of the harmful N-nitroso compound, which is the result of reactivity because the free radical "seeks" another elec- the reaction of endogenous or exogenous nitrosating tron to fulfill a pair. Free radicals are a natural byproduct agents when exposed to nitrogen-containing com- of cellular metabolism, but are also generated by the They prevent formation of metal-catalyzed external action of ultraviolet radiation, toxic substances, free radicals by chelating iron and copper.Flavonoids ozone, cigarette smoke, microbial attacks, and even in- can contribute to cells overall antioxidant protection tensive exercise.These free radicals include: hydroxyl mechanism by sparing ␤-carotene, urate, and vitamins radical, nitric oxide, hypochlorous acid, peroxynitrite, singlet oxygen, and alkoxyl radical, among others.
EGCG and a variety of other polyphenols are antioxi- Reactive oxygen species (ROS) deleterious effects on cel- dants and have the ability to neutralize free radicals. The lular membranes and internal structures might contrib- antioxidant potential of EGCG is far greater than vita- ute to the onset of cardiovascular disease, cancer, and mins E and which, along with glutathione and super- impairment of the immune function by altering the me- oxide dismutase, are the cell's main internal defense.
tabolism. DNA, LDL, and other intracellular and extra- EGCG and other antioxidants have the ability to prevent cellular molecules are susceptible to damage by free rad- and protect against oxidative damage occurring on LDL icals. When a free radical attacks LDL, it changes its molecules, and have an antiatherosclerotic eEGCG Green Tea and Cardiovascular Disease J Am Coll Surg inhibition of oxidative damage is dose-dependent. A low reported to affect phospholipase A2 activity and the an- concentration of EGCG of 0.25 ␮M resulted in an antiox- tithrombotic reaction of platelets. This data suggest that idant protective effect of 13%, although a concentration of green tea polyphenols have antithrombotic action ex- 10.00 ␮M had a 68% effect. EGCG is a potent antioxi- plained primarily by antiplatelet activity, with relative dant because it has three polyphenolic benzene rings, sparing of the coagulation function.
yielding eight hydroxyl hydrogens per molecule. Eachhydroxyl hydrogen enhances the ability of EGCG to be POLYPHENOL EFFECTS ON VASOMOTOR TONE a potent antioxidant because the polyphenolic hydro- Hypertension is an important risk factor for develop- gens will attract free radicals displacing LDL and other ment of cardiovascular complications.Antioxidants, biologic Catechin's scavenging activity is like those found in green tea, are very useful in protect- associated with the number of o-dihydroxy and ing and restoring endothelial function.The balance in o-hydroxyketo groups, the number of C2-C3 double the endothelium between vasodilators, such as nitric ox- bonds, the concentration, the solubility, accessibility to ide and ROS, and vasoconstrictors, such as thrombox- the antioxidant by the active group, and the stability of ane and isoprostane, contributes to vascular resistance the reaction product.In green tea, EGCG has the and endothelium-dependent contraction.There is most potent antioxidant effects because of its four dihy- clinical and experimental evidence that tea phytochemi- droxy groups.
cals can also improve endothelial function.In an ep-idemiologic study, tea consumption was shown to be POLYPHENOL MODULATION OF inversely associated with systolic blood pressure.In a PLATELET AGGREGATION clinical involving 1,507 men and women from Cardiovascular disease can be the result of numerous Taiwan ages 20 years and older, researchers found that stimuli, one being platelet aggregation. Platelets will ag- the habitual consumption of ⱖ 120 mL/d of moderate gregate in blood vessels for a variety of reasons, including strength green or oolong tea for at least 1 year, consider- vessel damage and disease. The primary purpose of ably reduced risk of hypertension developing. After ad- platelets is to aid in the repair of the damaged blood justing for different confounding factors, such as age, vessel by forming clots that plug holes in the vessel wall gender, personal and family medical history, dietary and preventing additional blood loss. Platelet aggregation lifestyle factors, they observed that compared with non- can sometimes lead to adverse consequences, including habitual tea drinkers, risk of hypertension developing strokes and myocardial infarctions.
decreased by 46% for those who drank 120 to 599 EGCG can act on platelets and other cells to prevent mL/d, and was reduced by 65% for those who drank ⱖ platelet aggregation. It can inhibit platelet-activating 600 mL on a daily basis.
factor, decreasing the "stickiness" of platelets and de- Several animal studies have also reported a consistent creasing the probability of platelet aggregation.Kang hypotensive effect on rats exposed to green tea and investigated the effects of EGCG on mu- In precontracted aortic rings in rats, puri- rine pulmonary thrombosis in vivo, human platelet aggre- fied catechins evoked endothelium-dependent va- gation ex vivo and in vitro, and on coagulation parameters.
sorelaxation by means of nitric oxide release from the In mice, they observed that EGCG prevented death caused endothelium.EGCG acts as a natural activator of by pulmonary thrombosis in a dose-dependent manner endothelial nitric oxide synthase in EC by increasing and considerably prolonged bleeding time. Ex vivo, aden- its phosphorylation by a phosphatidylinositol-3-OH- osine diphosphate- and collagen-induced rat platelet aggre- kinase-, cAMP-dependent protein kinase-, and Akt- gation was inhibited. EGCG also inhibited adenosine dependent pathway, leading to endothelial-dependent va- diphosphate-, collagen-, epinephrine-, and calcium iono- sorIn an in vivo involving stroke-prone phore A23187-induced human platelet aggregation with- spontaneously hypertensive rats, green and black tea effects out changing the activated partial thromboplastin time, on blood pressure were assessed. The amounts of poly- prothrombin time, or thrombin time. EGCG has also phenols used for this experiment correspond to those been demonstrated to block tyrosine phosphorylation present in approximately 1 L of tea. Systolic and dia- and reduce gene expression of platelet-derived growth stolic pressures were observed to be substantially lower factor-␤ receptor. In diabetic green tea has been in both groups compared with the control group. Green Vol. 202, No. 5, May 2006 Green Tea and Cardiovascular Disease and black tea considerably decreased phosphorylated can also prevent obesity and a fatty liver by enhancing myosin light chains that were measured in the aorta noradrenaline-induced lipolysis and inhibiting pancreatic using Western blotting. Protein expression of catalase lipase activity, as observed in high-fat diet obese was also studied, and was found elevated only in thegreen tea group. 2-amino-5-(N-ethylcarboxyamido)-pentoic acid, a nynhydrin-positive compound from un- POLYPHENOL INHIBITION OF CELL processed tea leaves, has been observed to be a potent PROLIFERATION AND MIGRATION inhibitor of thrombin-stimulated thromboxane forma- Green tea has been shown to inhibit SMC invasion tion.This compound has been reported to be inhibited through the basement barrier, a key event involved in in rats taking green tea, but not in those given processed development and progression of arteriosclerosis and tea extracts. Theanin given at high doses to spontane- injury-induced vascular remodeling. Matrix metallopro- ously hypertensive rats has also been reported to mark- teinases (MMP) are considered important in migration edly decrease blood pressure.
and growth of EC and and in vitro indicate that EGCG reduces expression of MMP. In bo- POLYPHENOL EFFECTS ON CHOLESTEROL vine aortic SMC, EGCG has been found to inhibit con- In hypercholesterolemic rats, green tea considerably re- canavalin A-induced pro-MMP-2 activation and the duced serum and liver cholesterol, the atherogenic in- gelatinolytic activity of EGCG also inhibits dex, and liver weight by lowering the deposition of lip- SMC invasion through the basement membrane barrier, ids.The levels of HDL-cholesterol and triglycerides in in a dose-dependent manner. In a rat carotid artery bal- this study remained unchanged. Other inv loon injury vascular remodeling was assessed reported that consumption by rats of tea plant leaves for when green tea extracts were added. Green tea reduced the a long period of time decreased serum levels of triglyc- area of the intima in the injured arteries by 30%, and the eride and total cholesterol, produced superoxide dis- intimal to the medial area ratio by 36.2% compared with mutase enhancement, and increased the activity of phase controls in vessels after 14 days of injury. Green tea cat- II enzymes in the liver. In hamsters fed a normal or a echins administration substantially increased expression high cholesterol diet, green tea, and black tea exhibited of tissue inhibitor of MMP-2, and reduced the levels of improved plasma lipid profiles, and reduction in LDL active MMP-2 and of the gelatinolytic net activity. This and very LDL oReduction of blood choles- evidence suggests to some extent an association between terol levels might be explained by precipitation of lipids the antiatherogenic action of catechins and the anti- and their fecal A study in sug- invasive and antimetalloproteinase activity.
gested that squalene epoxidase, a rate-limiting enzymefound in tea and involved in cholesterol biogenesis, For new blood vessels to form, angiogenesis, EC, and might also be responsible for this effect.
SMC must migrate. EGCG has been demonstrated to Green tea reduces the levels of cholesterol and triglyc- prevent angiogenesis through several mechanisms, in- erides, inhibits the action of digestive lipase, and de- cluding inhibition of EC and SMC migration, regulat- creases fat absorption, reducing body wObe- ing EC and SMC growth and survival, and inhibiting sity increases the risk for cardiovascular disease and tube formation. EGCG induces the transcription factor cancer, and a lower body weight would reduce the risk of nuclear factor-␬B, promoting SMC death. The sum of suffering from these conditions. Through sympathetic these effects results in the cessation and potentially the activation thermogenesis, green tea plays a role in the reversal of various vascular diseases and cancer growth.
control of body composition and produces weight loss.
Vascular endothelial growth factor is a key protein in- Studies have indicated that preadipocyte apoptosis can volved in It binds to the surface of EC be induced through EGCG by demonstrating a decrease and activates various cell functions including tube for- in Cdk2 expression and an increase in caspase-3 activity.
mation. It has been demonstrated that certain catechins, The treatment of Cdk2 overexpression with caspase-3 especially EGCG, inhibit vascular endothelial growth inhibitor prevented preadipocytes apoptosis through the factor. One hundred micrometers of EGCG resulted in induction of DNA fragmentation, suggesting the EGCG a cell growth inhibition rate of 55% and prevented tube apoptotic effects of Cdk2- and Tea Green Tea and Cardiovascular Disease J Am Coll Surg CANCER AND OTHER HEALTH BENEFITS men was associated with a marked decrease in cancer Similar to atherogenesis, many factors related to diet, incidence with Cohort studies suggest a protective metabolism, and the external environment modulate the effect of green tea for esophageal, stomach, pancreatic, initiation, promotion, and progression of cancer develop- colon, and urinary bladder carcinogenesis, among other ment. Cancer pathogenesis is influenced by the modifica- tion of DNA structure, enzymatic activity, and defense It should be emphasized that although green tea ap- mechanisms, which are a result of the accumulation of pears to be widely associated with protective effects for RIn vitro studies have shown tea catechins as potent cancer, other factors such as genetic differences, geo- inhibitors of carcinogenesis at the three stages of cancer graphic regions, and lifestyles should be taken into con- development.With regard to cancer initiation, in sideration. A population-based, case-control study of vitro studies have shown that polyphenols from green tea breast cancer among Chinese, Japanese, and Filipino can prevent formation of nitrosamines, which are car- women was conducted in Los Angeles County, where cinogens also found in tobaccoPhenolics in tea 501 breast cancer patients and 594 control subjects were have also been found to inhibit heterocyclic amine for- interviewed. Detailed information on lifestyle factors, These molecules are genotoxic carcinogens including diet and the intake of black and green tea, was found in cooked meat and fish, and are associated with collected. It was found that decreased breast cancer risk pancreatic, colon, and breast cancers. EGCG exhibits was unrelated to black tea intake. On the other hand, the strongest effects against mutations, DNA scissions, green tea consumption showed a substantially reduced and nonenzymatic interception of superoxide risk. The adjusted odds ratios being 1.00, 0.71, and 0.53respectively, in association with 0.0, 0 to 85.7 and On the other hand, (-)-epicatechin-3-gallate is one of ⬎ 85.7 mL green tea per day.This study suggests that the most efficient enzymatic scavengers, directly neutral- the decreased cancer risk was irrespective of genetics, izing procarcinogens, as observed in scavenging super- geographic location, and food consumption.
oxide tests and in DNA damage With respect Green tea has also been associated with prevention to cancer promotion, EGCG inhibits the protein kinase and treatment of many other systemic disorders. Of im- activator, an enzyme involved in the cell activation pro- portance in diabetes, green tea can reduce blood glucose cess leading to promotion of tumors by blocking the levels in aged ratsand suppress the activity of glucose interaction and binding between proteins and transporters in the intestinal epithelium, reducing di- EGCG induces cellular senescence by strongly inhibit- etary glucose intake.Green tea has antiinflammatory ing telomerase activity, limiting cancer cells' lifespan in properties and EGCG has been reported to considerably leukemia and in solid Studies have also reported inhibit histamine release by 90% in rat cell culture.
that EGCG and theaflavin-3 to 3=-digallate causes the Quercetin also produces a concentration-dependent in- blockage of activator protein-1, a signal transducer associ- hibition of histamine release, and in antigen-activated ated with development of skin cancer and other cells, provides an antiinflammatory A marked With regard to cancer progression, numerous re- reduction in the incidence of arthritis is produced by porindicate that tea polyphenols inhibit the green tea polyphenols, as demonstrated in arthritic growth of malignant cells and can induce apoptosis.
joints in mice. This is explained by a strong reduction of Theaflavin-3,3=-digallate and EGCG have antiprolifera- inflammatory mediators, neutral endopeptidase activity, tive activities on tumors through the blockage of growth and levels of type II collagen-specific IgG.In terms of factor although EGCG has also been re- renal pathology, catechins increase sodium and prosta- ported to block cell division in G1In addition, glandin E2 excretion and improve renal circulation.
EGCG inhibits urokinase, a proteolytic enzyme neces- Progression of renal failure is suppressed, and mesangial sary for cancer growth, tissue invasion, and proliferation and glomerular sclerotic lesions are atten- In animals, tea has been shown to be bioactive against uated by consumption of green tea, as shown in nephrec- carcinogenesis in liver, skin, lung, gastrointestinal tract, tomized rats.Modulation of the activity of the intes- and hormonal-dependent In humans, tinal microflora and improvement in bowel function has consumption of ⬎ 10 cups (1,800 mL, approximately also been demonstrated.Extracts from tea have been 300 to 400 mg of EGCG) per day among women and reported to inhibit the effects of Campylobacter jejuni, C Vol. 202, No. 5, May 2006 Green Tea and Cardiovascular Disease coli, Helicobacter pylori, vibrio cholerae, Salmonella, shi- Table 3. Putative Mechanisms of Green Tea's Cardioprotec- gella, clostridium, mycoplasma, pseudomona, and Cryptococcus.Tea has also been shown to have antiviral effects, strongly inhibiting rotavirus in monkey cell culture and influenza A in animal cell culture, Sparing of antioxidants (vitamins E and C, ␤ among other virIn addition, flavonoids, in- Alteration of catalytic activity of cluding EGCG and (-)-epicatechin-3-gallate, have been Modification of protein reported to inhibit reverse transcriptase and propagation Platelet aggregation modulator of the retrovirus human immunodeficiency virus.
In conclusion, epidemiologic evidence suggests that chronic diseases, such as cardiovascular disease and can- Inhibition of PDGF ␤ cer, have a lower incidence in countries with a high in- Modification of phospholipase take of tea, particularly green tea. It is possible that those who do or do not drink tea differ in some other way that affects cardiovascular disease, ie, cigarette smoking, di- eNOS activationInhibition etary, and lifestyle factors. The "Asian Paradox" refers to the very low incidence of both heart disease and cancer Enhance superoxide in Asia, even though consumption of cigarettes is greater Enhance phase II enzymes than in most other countries. This discrepancy is Precipitation and fecal elimination of thought to have occurred as a result of a voluminous Inhibition of digestive lipase activity intake of green tea, approximately 1.2 L per day. In vitro Inhibition of pancreatic lipase activity and in vivo studies have shown that the main polyphe- Inhibition of squalene nolic component of green tea, EGCG, is responsible for Reduce LDL and VLDL these protective qualities One of the reasons Enhancement of noradrenaline-induced green tea is so beneficial to our health is the result of its Inhibition of SMC proliferation and vascular hyperplasia strong antioxidant nature, being stronger than oolong and black teas. Since EGCG is an antioxidant, it is able DNA strand breakage to prevent LDL oxidation, which has been shown to play a key role in the pathophysiology of arteriosclerosis.
Another phenomenon that increases the risk of arte- riosclerosis is platelet aggregation. EGCG has been eNOS, endothelial nitric oxide synthase; MMP, matrix metalloproteinase; shown to effectively reduce the amount of platelet aggre- NO, nitric oxide; PAF, platelet-aggregating factor; PDGF, platelet-derived gation by inhibiting certain events at the molecular level.
growth factor; SMC, smooth muscle cell; TIMP-2, tissue inhibitor metallo-proteinase; VEGF, vascular endothelial growth factor; VLDL, very low- Green tea's actions on the vasomotor tone as a lipid regulator, and in SMC proliferation and migration canenhance these cardiovascular protective effects. Studies necessary to fully elucidate and better understand green have also shown that through several means EGCG ef- tea's method of action, particularly at the cellular level.
fectively prevents angiogenesis, causing cessation of cer- In this manner, we can determine the active components tain types of tumor growth. It has been reported that tea involved in this process, perhaps with the goal of prepar- can improve gastrointestinal function, ethanol metabo- ing extracts specifically for those individuals who cannot lism, kidney, liver, and pancreatic function, stomach in- drink tea or simply dislike it. The evidence is strong that juries, skin and eye protection, and alleviation of arthri- green tea consumption is a useful dietary habit to lower tis. It has also been used in the management and the risk and treat a number of chronic diseases. Prevention prevention of allergies, diabetes, bacterial and viral in- is by far the best cure. The consumption of 6 to 10 cups of fections, dental caries, to improve neurologic and psy- tea per day might constitute an aid to increased health, chological health, and to ameliorate or cure other dis- longevity, and quality of life. Tea is becoming a popular eases that have an inflammatory component.
drink and, to some extent, it seems to be a potential solu- Despite the plethora of information, more studies are tion to some of the major health problems of the elderly Green Tea and Cardiovascular Disease J Am Coll Surg and society. It is important to reveal its role and mechanism dant flavonoids and risk of coronary heart disease: the Zutphen of action in today's lifestyle-related diseases.
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A prescription for change: how the medicare act revises hatch-waxman to speed market entry of generic drugs

3/25/2005 4:38 PM A Prescription for Change: How the Medicare Act Revises Hatch-Waxman to Speed Market Entry of Generic Drugs Stephanie Greene* The Drug Competition and Patent Term Restoration Act of 1984, commonly known as the Hatch-Waxman Act ("Hatch-Waxman" or "Hatch-Waxman Act"), was passed to bring generic drugs to market more quickly. While recognizing the need to maintain incentives for pioneer research and innovation in the pharmaceutical industry, Hatch-Waxman greatly benefits the generic drug industry by providing a method for expedited review and approval of generic products by the Food and Drug Administration (FDA). Although Hatch-Waxman has been successful in substantially increasing generic competition, evidence suggests that manufacturers of brand-name drugs have discovered loopholes in the Act and have engaged in tactics to "game the system" to prolong the life of patents, thereby delaying the market entry of generic competitors. Generic manufacturers have also been accused of abusing provisions of Hatch-Waxman to the detriment of competitors and consumers. Provisions of the Act may tempt generic manufacturers to enter into collusive agreements with brand-name manufacturers. In December of 2003, President Bush signed into law the Medicare Prescription Drug and Modernization Act of 2003. Title XI of the Act amends Hatch-Waxman, in an effort to close loopholes that delay the market entry of generic drugs. The new legislation implements two major changes in the Hatch-Waxman process of generic drug approval and patent challenges. First, the law prevents the innovator drug patentee from filing multiple patents with the FDA, in the hopes of triggering Hatch-Waxman's thirty-month stay provision. When a generic applicant seeks FDA approval of its product and claims that its product will not infringe a patent or that the patent is invalid, an innovator that files a patent infringement suit is granted an automatic thirty-month stay of FDA approval. This provision has enticed innovators to list with the FDA those patents that may not properly claim the drug in question. The improper listing of patents has allowed innovators to stack successive thirty-month stays to delay market entry of generic competition. The new legislation allows an innovator the benefit of only one thirty-month stay per generic applicant per drug. Second, the law prevents collusive agreements between innovator and generic manufacturers as well as such agreements between generic manufacturers that might delay market entry of generic products. The first generic applicant that challenges an innovator's patent and receives FDA approval is entitled to 180 days of market exclusivity under Hatch-Waxman. Subsequent generic applicants may not receive FDA approval for their products until this 180-day exclusivity period has run. New provisions in the law subject agreements that relate to the 180-day exclusivity period to FTC scrutiny. Furthermore, new provisions ensure timely market entry of generic products by specifically enumerating incidents that trigger the

Microsoft word - vc_japan2.doc

A Technology Review on Virtual Colonoscopy Virtual Colonoscopy: An Alternative Approach to Examination of the Entire Colon Jerome Z. Liang Departments of Radiology, Computer Science and Biomedical Engineering State University of New York, Stony Brook, NY 11794, USA We have developed a virtual colonoscopy system aiming toward mass screening for polyps through the entire colon. This work reviews the key technical components of the system. Introduction Colorectal carcinoma is the second leading cause of cancer-related deaths among men and women in the United States, following lung cancer, with 56,000 deaths reported in 1998 and an estimated over 130,000 new cases per year [21]. Unfortunately the symptoms of colon cancer, such as anemia and change in bowel habits, are neither sensitive nor specific. Diagnosed cancers are often in the later stage of development, resulting in a high mortality incidence. Most colon cancer probably arises from polyps, which can take 5 to 15 years for malignant transformation. Recent studies have shown that screening of colonic polyps can reduce the mortality rate from the cancer. Optical colonoscopy and barium enema are the two most commonly used diagnostic procedures. Other tools include fecal occult blood testing (which detects only 30-40% of colorectal cancer and 10% of adenomas) and sigmoidoscopy (which fails to detect lesions in the proximal colon, where 40% of all cancers occurs, and misses 10-15% sigmoid colon carcinomas [5, 10, 15, 37]). While optical colonoscopy is accurate and can biopsy detected polyps, it is expensive ($1,800), invasive (requires scope insertion), uncomfortable (colon washing and sedation required), time consuming (hours), and carries a small risk of perforation and death (colonic perforation in one in 500 to 1000 cases and death in one in 2,000 to 5,000 cases [29]). It fails to demonstrate the entire colon in 10-15% of the cases and thus misses 10-20% of the lesions [10, 15]. Barium enema is less expensive ($400) and non-invasive, but it is less accurate (less than 78% sensitivity in detecting polyps of size from 5 to 20 mm diameter [28]), more time consuming, and requires a good deal of patient positioning and cooperation when X-ray radiographs of the colon are taken at various views. An accurate, cost-effective, non-invasive, comfortable procedure for mass screening of colonic polyps with a size less than 1 cm in diameter is extremely valuable, since the detection and removal of these small polyps will totally cure the patient. Since 1994, several pilot studies [16, 19, 23, 31, 34, 39] evaluating the feasibility of virtual colonoscopy as an alternative means for colon screening have motivated a great amount of research interests ranging from image formation, and segmentation, to visualization [1, 3, 10, 11, 13, 20, 22, 26, 27, 32, 33, 38]. This alternative means utilizes computer virtual-reality techniques to navigate inside the reconstructed three-dimensional (3D) colon model created from computed tomography (CT) or magnetic resonance (MR) images, looking for polyps. It starts with a bowel cleansing procedure, similar to that used in conventional optical colonoscopy, and is followed by inflating the colon with room air or CO2 gas --- if CT modality is utilized --- introduced through a rectal insert.