Date: February 5, 2006
by Chaya Venkat
Very often I get emails from patients asking about my recommendation for a good brand of green tea extract, as well as the dosage they should be taking. I then go into my song and dance routine about how I am not a medical doctor and I am not about to prescribe drugs without a license, and how you really should talk to your doctor before you take green tea extract or any other drug / herbal product. I am sure my response has ticked off some of you in the past, and I regret that. It is not meant to be coy or unhelpful. After reading this article I hope you will agree with me that caution is not only a good thing but essential when it comes to over-the-counter medications, brand names and dosages.
I am sure most of you know that Project Alpha, the clinical trial we are sponsoring at Mayo Clinic, uses Polyphenon E, a defined grade, decaffeinated green tea polyphenol mixture, a brand name product of Mitsui Norin. As we have reported in August 2005, the trial is up and running. Patients have been recruited for the dose escalation phase of the trial. While I am not at liberty to disclose any clinical results before their time, let’s say I am not disappointed with what I am hearing thus far. Bear in mind, green tea extract / EGCG is a far cry from potent chemotherapy drugs. You would be foolish to expect it would be as potent as, say, fludarabine. The good news, and that is what attracted us to EGCG in the first place, is that it may have reasonable efficacy in slowing down the CLL in a certain percent of the patient population, without significant risk of toxicity. There it is again, that fundamental truth of all cancer therapy, the balance between risks and rewards! Today I would like to bring to your attention some new information that I have just received regarding the potential liver toxicity of EGCG. We discussed this risk in prior articles (Harvey's Chocolates), but it bears repeating in light of this new information.
Exolise is a green tea extract that has been sold over-the-counter in Europe as a weight loss drug. Over a period of time, 13 patients who took Exolise demonstrated elevated liver enzymes (ALT and AST http://www.rnceus.com/lf/lfast.html). The estimated frequency of this adverse effect is 1 case per 100,000 boxes of Exolise sold over that period of time. In 12 of these patients this problem was resolved when they quit taking the drug. However, in the one remaining patient the problem did not resolve and developed into full blown liver toxicity. (There were some unresolved side issues with this single patient, and it was not clear if these contributed to the liver toxicity). DHHD (Department of Health and Human Services) says “the relevance of these findings to Polyphenon E, in any, is not clear". However, I believe Exolise is no longer allowed to be marketed in at least two European countries (France & Spain).
Recently the NCI has sponsored a 13 week study of toxicology of Polyphenon E (the same proprietary brand name green tea extract that is used in the Mayo Clinical trial) in Beagle dogs. I know, I too cringed when I read that bit. I am a big fan of Snoopy! The dogs were given a range of 200 to 600mg per kg body weight of the drug, each day for 13 weeks. (If you want to convert that dosage range to a typical human of 80 kg, it would be 16 to 48 grams of the drug each day! The present dosage of Polyphenon E used in the Mayo trial is 1.6 grams per day, which is ten times less than the lowest dosage the dogs got). This dog study saw no clinical or physical signs of toxicity. In another NCI study, 4 dogs were fed 250 mg/kg EGCG for just under a month. In this study side effects were limited to nausea, diarrhea, weight loss and discolored stool. When the dogs were “sacrificed” (don’t you just love these euphemisms used in animal research?) at the end of the study, no gross abnormalities were observed. So far, so good.
However, more recently in another Beagle dog study, Polyphenon E was given at escalating doses of 250 mg/kg to a whopping 1,000 mg/kg, administered daily in a fasting state. Some of the dogs died. This has sent alarm bells ringing through the FDA and DHHS. Rightly so, that is the whole point of doing dose escalation studies in mice, followed by larger mammals such as the poor Beagles in these studies, so that we can better judge the potential for toxicity in humans. It is also the reason why I thought I should write this detailed article to bring you up to speed on the latest information.
Below are two abstracts of human studies. You can get the full text of both of them for free, just click on the links given with each abstract. I have highlighted the portions that might be of interest to us, but I do urge you to read the whole abstract as well as the full text article if possible, especially if you are considering EGCG as part of your maintenance regimen. For those of you inclined to do your own research, it is easy enough to log onto PubMed, type in the keywords “green tea; cancer”, and browse through the hundreds of article citations.
Clin Cancer Res. 2003 Aug 15;9(9):3312-9.
Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals.
Chow HH, Cai Y, Hakim IA, Crowell JA, Shahi F, Brooks CA, Dorr RT, Hara Y, Alberts DS.
Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724, USA.
PURPOSE: Green tea and green tea polyphenols have been shown to possess cancer preventive activities in preclinical model systems. In preparation for future green tea intervention trials, we have conducted a clinical study to determine the safety and pharmacokinetics of green tea polyphenols after 4 weeks of daily p.o. administration of epigallocatechin gallate (EGCG) or Polyphenon E (a defined, decaffeinated green tea polyphenol mixture). In an exploratory fashion, we have also determined the effect of chronic green tea polyphenol administration on UV-induced erythema response.
EXPERIMENTAL DESIGN: Healthy participants with Fitzpatric skin type II or III underwent a 2-week run-in period and were randomly assigned to receive one of the five treatments for 4 weeks: 800 mg EGCG once/day, 400 mg EGCG twice/day, 800 mg EGCG as Polyphenon E once/day, 400 mg EGCG as Polyphenon E twice/day, or a placebo once/day (8 subjects/group). Samples were collected and measurements performed before and after the 4-week treatment period for determination of safety, pharmacokinetics, and biological activity of green tea polyphenol treatment.
RESULTS: Adverse events reported during the 4-week treatment period include excess gas, upset stomach, nausea, heartburn, stomach ache, abdominal pain, dizziness, headache, and muscle pain. All of the reported events were rated as mild events. For most events, the incidence reported in the polyphenol-treated groups was not more than that reported in the placebo group. No significant changes were observed in blood counts and blood chemistry profiles after repeated administration of green tea polyphenol products. There was a >60% increase in the area under the plasma EGCG concentration-time curve after 4 weeks of green tea polyphenol treatment at a dosing schedule of 800 mg once daily. No significant changes were observed in the pharmacokinetics of EGCG after repeated green tea polyphenol treatment at a regimen of 400 mg twice daily. The pharmacokinetics of the conjugated metabolites of epigallocatechin and epicatechin were not affected by repeated green tea polyphenol treatment. Four weeks of green tea polyphenol treatment at the selected dose and dosing schedule did not provide protection against UV-induced erythema.
CONCLUSIONS: We conclude that it is safe for healthy individuals to take green tea polyphenol products in amounts equivalent to the EGCG content in 8-16 cups of green tea once a day or in divided doses twice a day for 4 weeks. There is a >60% increase in the systemic availability of free EGCG after chronic green tea polyphenol administration at a high daily bolus dose (800 mg EGCG or Polyphenon E once daily).
J Clin Oncol. 2001 Mar 15;19(6):1830-8.
Phase I trial of oral green tea extract in adult patients with solid tumors.
Pisters KM, Newman RA, Coldman B, Shin DM, Khuri FR, Hong WK, Glisson BS, Lee JS.
Department of Thoracic/Head & Neck Medical Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, USA.
PURPOSE: This trial was designed to determine the maximum-tolerated dose, toxicity, and pharmacology of oral green tea extract (GTE) once daily or three times daily.
PATIENTS AND METHODS: Cohorts of three or more adult cancer patients were administered oral GTE with water after meals one or three times daily for 4 weeks, to a maximum of 6 months, depending on disease response and patient tolerance. Pharmacokinetic analyses were encouraged but optional.
RESULTS: Dose levels of 0.5 to 5.05 g/m(2) qd and 1.0 to 2.2 g/m(2) tid were explored. A total of 49 patients were studied. Patient characteristics: median age, 57 years (range, 27 to 77 years); 23 patients were women (47%); 98% had a Zubrod PS of 1%; 98% had PS of 1; and 21 had non-small-cell lung, 19 had head & neck cancer, three had mesothelioma, and six had other. Mild to moderate toxicities were seen at most dose levels and promptly reversed on discontinuation of GTE. Dose-limiting toxicities were caffeine related and included neurologic and gastrointestinal effects. The maximum-tolerated dose was 4.2 g/m(2) once daily or 1.0 g/m(2) three times daily. No major responses occurred; 10 patients with stable disease completed 6 months of GTE. Pharmacokinetic analyses found accumulation of caffeine levels that were dose dependent, whereas epigallocatechin gallate levels did not accumulate nor appear dose related.
CONCLUSION: A dose of 1.0 g/m(2) tid (equivalent to 7 to 8 Japanese cups [120 mL] of green tea three times daily) is recommended for future studies. The side effects of this preparation of GTE were caffeine related. Oral GTE at the doses studied can be taken safely for at least 6 months.
The death of the Beagle dogs in the new study is worth thinking about. What does it mean for consumers like us who want to try EGCG? Here are some of my thoughts on the subject.
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