Phytochemicals & Chemoprevention el pt

Harvey's Chocolates

Date: May 2, 2024

by Chaya Venkat

Oral Absorption of EGCG

The Difficult Case of the Round-headed Kid;
The Continuing Saga of the Round-headed Kid;
Remission Management for the Round-headed Kid;
Rituxan Road Block;
Harvey Is Back;
Strategy and Tactics.

Harvey, our round-headed kid and strictly hypothetical patient-hero is doing very well (see: The Difficult Case of the Round-headed Kid  and The Continuing Saga of the Round-headed Kid). I will update his clinical response to the "RHK" protocol in the next few days. In the meanwhile, he ran into a small problem with his daily regimen of remission maintenance. We discussed how his girl friend had concocted a great recipe for transdermal green tea cream. All Harvey had to do was lather it on prior to working out on his treadmill. But after sticking to this approach pretty conscientiously for a couple of months, Harvey began to grumble. The green tea extract cream was a bother to put on, it stained his clothes, his skin started feeling uncomfortable if he left it on too long, what about the days he worked late at the office and didn't feeling like working out late evening, yada yada. No pleasing the man. But his girlfriend proved to be up to the challenge. Last time I met Harvey and his lady, she had worked out a whole new approach to the problem. Even Harvey cannot complain about this one!

Prior to telling me the secret of her solution, Serena (that is Harvey's girlfriend, decidedly his better half) made me sit down and learn all about the different ways in which drugs can be transported into the general blood circulation. The usual caveats apply, you have to make up your own mind on the validity of her approach. Serena is no more a doctor than I am: all she has going for her is a very stubborn personality that hates to accept failure, insatiable curiosity and the ability to learn what she needs to know to try and help the guy she loves. I thought I would share with you the results of her research, for what they may be worth.

Bioavailability of EGCG

The amount of polyphenols such as EGCG present in green tea leaves varies with respect to the climate, season, horticultural practices used in growing the stuff, and the position of the leaf on the harvested shoot. Tender leaves have more EGCG than the old leaves at the bottom of the shoot. On average, a cup of high quality brewed green tea contains about 25 milligrams of EGCG.

The problem with drinking green tea is that oral consumption is a very inefficient way of getting the EGCG into your blood. Most of it is not absorbed in your stomach and gut, and just goes for the ride. The small amount that is absorbed goes directly through the portal vein to the liver. The major function of the liver is to get rid of "toxins" in the food we eat, and it goes about converting and "detoxifying" the precious EGCG. The amount of EGCG that gets past all these hurdles and into general blood circulation is quite small. There is also a great deal of variability from one person to the next, depending on how your stomach and gut work, level of stomach acid, how recently you have eaten and what you have eaten, and finally the efficiency of your liver. All in all, no more than 5% of EGCG consumed orally gets into systemic blood circulation, may be even less. Let's see now: if you drink 6 cups of green tea per day, that is about 150 milligrams of EGCG consumed, but only about 5-10 milligrams of it actually make it into your blood circulation. You can learn more about green tea and oral availability by reading prior articles on the subject on our website. (CLL Topics articles: Do You Like Drinking Green Tea? and Methods of Drug Delivery.)

You could increase the amount of EGCG consumed by taking high potency green tea extract capsules instead, thereby increasing the amount of EGCG consumed. But be careful going overboard on that - too much green tea polyphenols working their way through the stomach and gut can lead to diarrhea and other unpleasant side effects. Besides, it is not a good idea to throw a lot of EGCG at the liver, increase its load of "toxins" to dispose. Cancer patients are particularly at risk of poor liver function and you do not want to make that worse by over working the liver. In any case, this method also suffers from the inevitable losses associated with oral consumption.

Intravenous injections of EGCG does the trick of getting EGCG directly into your blood circulation, no doubt about it. But this is hardly a patient-friendly way of getting the EGCG into your system on a daily basis. Since EGCG and the other tea polyphenols and catechins do not hang around too long in your body, regular dosing at frequent intervals is necessary to maintain a sufficient level in the blood.

The transdermal route by using a green tea extract body cream is a little bit better than the oral route, but that, too, has its drawbacks. Efficiency of transport across the skin differs among individuals, and it requires "excipients" such as d-limonene (a monoterpene found in oils from lemon and orange skins) to make the transport more efficient. Working out after applying the green tea transdermal rub helps, because it gets the lymphatic fluid moving at a nice clip, raises the body temperature, and all that sweating makes the pores of your skin open up. The drawbacks are that it can be messy, stain your clothes, and long term use may cause skin irritation. Furthermore, cancer patients are not always in the best of health and working out on a regular basis is often not possible.

There remains one further way of getting the EGCG into your system. Have you seen the recent ads for nicotine chewing gum, sold as an aid to smokers trying to quit? Have you ever wondered why they don't sell nicotine capsules that can be swallowed? Here again the problem with swallowing a capsule is that very little of the nicotine gets into the blood, and in any case it takes too long to get there. Smokers need a quick and immediate 'hit' of nicotine to get them over the intense craving. A transdermal patch works by gradual and prolonged release of nicotine. The nicotine chewing gum works by rapid and efficient drug transport through the mucosal lining of your mouth and salivary glands and into your blood circulation. This is also the method of delivery of heart medications such as nitroglycerine, where it is important to get the drug into the blood stream efficiently and quickly, and a drug delivery method that the patient can employ for himself at short notice. Below is a link that gives a very nice and detailed review of drug delivery using the mucosal ("buccal") lining of your mouth. You might find it interesting reading.

Abstract:

Review Article from the Journal of Pharmacy and Pharmaceutical Sciences (Full-text)

Buccal Mucosa As A Route For Systemic Drug Delivery: A Review

Amir H. Shojaei, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada

Within the oral mucosal cavity, the buccal region offers an attractive route of administration for systemic drug delivery. The mucosa has a rich blood supply and it is relatively permeable. It is the objective of this article to review buccal drug delivery by discussing the structure and environment of the oral mucosa and the experimental methods used in assessing buccal drug permeation/absorption. Buccal dosage forms will also be reviewed with an emphasis on bioadhesive polymeric based delivery systems.
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In fact, transport of EGCG and other polyphenols is so efficient across the lining of your mouth that tea drinkers who hold the tea for a few minutes in their mouth as opposed to gulping it down right away have much higher uptake of the EGCG and polyphenols into their saliva. Moral of the story, sip your green tea, swish it around your mouth, savor the aroma and drink it slowly. You can read the full length article of the abstract below by clicking on the link given at the bottom of the abstract. The authors conclude that "drinking tea slowly or using a tea mouthwash or lozenge would be effective ways to deliver tea catechins to the target tissues". Hmmm....

Abstract:

Article from Cancer Epidemiology Biomarkers & Prevention (Full-text)

Cancer Epidemiology Biomarkers & Prevention Vol. 8, 83-89, January 1999

Human salivary tea catechin levels and catechin esterase activities: implication in human cancer prevention studies.

Yang CS, Lee MJ, Chen L.

College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ.

Because of the possible application of tea in the prevention of oral and esophageal cancers, the salivary levels of tea catechins were determined in six human volunteers after drinking tea. Saliva samples were collected after thoroughly rinsing the mouth with water. After drinking green tea preparations equivalent to two to three cups of tea, peak saliva levels of (-)-epigallocatechin (EGC; 11.7-43.9 microg/ml), EGC-3-gallate (EGCG; 4.8-22 microg/ml), and (-)-epicatechin (EC; 1.8-7.5 microg/ml) were observed after a few minutes. These levels were 2 orders of magnitude higher than those in the plasma. The elimination half-life (t(1/2)) of the salivary catechins was 10-20 min, much shorter than that of the plasma. Holding a tea solution in the mouth for a few minutes without swallowing produced even higher salivary catechin levels, but taking tea solids in capsules resulted in no detectable salivary catechin level. Holding an EGCG solution in the mouth resulted in EGCG and EGC in the saliva and, subsequently, EGC in the urine. The results suggest that EGCG was converted to EGC in the oral cavity, and both catechins were absorbed through the oral mucosa. A catechin esterase activity that converts EGCG to EGC was found in the saliva. The enzyme was likely of human origin, but the activity was not inhibited by common human esterase inhibitor. The present results suggest that slowly drinking tea is a very effective way of delivering rather high concentrations of catechins to the oral cavity and then the esophagus.

PMID: 9950244
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Harvey's Chocolates

That last quote in the paper about tea mouthwash or lozenges was all that Serena needed to get her creativity into high gear. She broke open a couple of capsules of green tea extracts that Harvey had bought earlier and tasted the brown powder. Ughh! It was way too bitter. Since pure EGCG was supposed to be almost white and without any taste, clearly the bitter taste and brown color came from all the other tea catechins and polyphenols in the mixture. Serena had a few friends from college days, a couple of them had contacts among ingredient suppliers to pharmaceutical companies. A couple of weeks later, she had what she wanted. The accompanying certificate of analysis guaranteed EGCG content was 94%, it had next to zero caffeine, it was very high purity stuff. The powder was almost white, just a barely almond tinge to it. A quick taste test confirmed it had no bitter taste, but there was a clear astringent after-taste characteristic of tea. So far so good, she just wished it was not so darned expensive!

Harvey came home from work that night to find the house redolent of delicious caramel aroma. There was a pan of chocolate caramel cooling on the counter. Serena had to chase him away from digging into it right away. The next day Harvey worked out after popping into his mouth one of the small chocolate caramels. Serena watched him like a hawk to make sure he did not eat it up right away, just kept it in his cheek to melt away gradually. Sure, it had an astringent taste to it that plain caramel does not have, but Harvey liked it better that way. The good quality Belgian chocolate Serena used in her recipe made the caramels delicious. At 100 milligrams of EGCG per piece, and with much more efficient transfer of the EGCG compared to drinking brewed green tea, each chocolate was the equivalent of drinking about 10 cups of tea! As far as Harvey was concerned, the only problem is that Serena would not let him eat more than a couple each day.

Below is the recipe I got from Serena. I thought "Harvey's Chocolates" tasted pretty good! As for the effectiveness of Harvey's Chocolates in combating CLL, I will leave that up to you to judge. Hey, there are far less pleasant things one can do to fight cancer, than enjoying a high quality bitter-sweet chocolate caramel.

Ingredients
Serena's Recipe

Item/Quantity	Weight
2 cups sugar	420 grams
1 cup sweetened condensed milk	220 grams
3/4 cup light corn syrup	210 grams
1 tablespoon unsalted butter	20 grams
Semi-sweet chocolate	120 grams
Pinch of salt	-
Green tea extract (EGCG 94%)	10 grams
Weight of caramel	1,000 grams
Yield	100 pieces
EGCG content	100 milligrams/piece.

Line a 8X8 inch shallow baking sheet with aluminum foil. Coat the aluminum foil evenly with a very small amount of melted butter.

Melt the chocolate in a double boiler over hot but not boiling water, (or zap it in a microwave oven, carefully, stopping to stir frequently. Don't let the chocolate burn!). Blend in the EGCG powder, working the mixture till it is completely smooth and well mixed. Keep the chocolate-EGCG mixture warm so that it does not harden. Set it aside.

Mix the sugar, condensed milk, corn syrup, butter and salt in a sturdy thick-bottomed pan. Make sure pan is tall enough to contain splatters as caramel bubbles, it can cause nasty burns. Heat over medium heat with constant stirring and scraping down the sides of the pan. Use a candy thermometer to monitor the temperature carefully. Turn the heat off when temperature reaches 235 F. Keep stirring the caramel till the temperature drops to 205 F. Add the chocolate-EGCG mixture and blend thoroughly till the chocolate caramel is silky smooth and glossy. If you wish, this is the time to add any other flavors you might like, such as a dash of Grand Marnier, perhaps? You will have to experiment with the flavors that work best for you.

Turn the mixture out on to the lined baking sheet and spread evenly. You have to work quickly before the mixture cools down, otherwise it will be too stiff to spread.

Wait until the EGCG chocolate caramel is completely cool, preferably overnight. Lift the caramel out of the pan by using the excess aluminum foil around the edges. Using a sharp and heavy knife, cut the caramel into ten even sized strips, then cut each strip into ten pieces, yielding a total of 100 pieces. Wrap individual pieces in wax paper, or place them between layers of wax paper without touching each other, then store in a cool place (not refrigerator) in an airtight container.

Notes:

1. If the caramel sets up too hard, the final temperature was too high. If it is not hard enough, the temperature was too low. Adjust accordingly the next time, experiment till you get the caramel consistency you like. Kitchen thermometers do not all work exactly the same.
2. It is important to add the chocolate-EGCG mixture to the hot caramel only after the temperature is well below 212 F, the boiling point of water. Since EGCG is traditionally consumed by drinking green tea which is brewed by steeping in boiling water, Serena reasonably assumed the compound is chemically unaltered below this temperature.
3. The chocolate helps hide the slightly bitter astringent after-taste of EGCG. Why not splurge and get really good Belgian chocolate, or some other type you like?
4. The higher the purity of the EGCG you use in your recipe, the less the bitter taste. If you only have access to the 50% EGCG variety, you may have to cut back on the 10 grams green tea extract per kilogram of EGCG-chocolate-caramel, to make the end product palatable.
5. Remember, this is not a candy, it is certainly not meant for children. Each piece contains approximately 100 milligrams of EGCG. The idea is to keep the caramel between your gums and cheek for a while, at least 5-10 minutes, and not gobble it up right away. The transport of the EGCG across the mucosal linings of the inside of your mouth is facilitated the longer you keep it there. Compared to simply drinking green tea or swallowing capsules, since EGCG is absorbed so much more effectively across the lining of your mouth (especially the area under the tongue or inside of your cheeks), each piece of EGCG caramel is the equivalent of 4-5 cups of green tea. Start with only one piece per day, graduate to two pieces if it seems to agree with you, and you see no adverse effects. It may also be a good idea to check out the whole thing with your doctor first. In fact, that would be my strong recommendation in any case.
6. EGCG is a pretty strong appetite suppressant. You might not feel hungry for a while after eating one of these EGCG chocolates. Each piece is about 10 grams of almost pure sugar, about 50 calories. If sugar is a problem for you, try to experiment with non-sugar alternatives for making the base caramel.