It is clear that there are a number of interesting possible pharmaceutical applications for green tea catechins. However, there are a number of practical and scientific issues that are yet to be resolved. What is particularly attractive about these compounds is that are safe at very high doses. Once shown to be active against a particular target, it is logical to hope that one might expect to be able to move to clinical trials relatively quickly. Certainly, the low toxicity is highly advantageous in being able to rapidly test in-situ and in animal models. However, there are a number issues that impede using the catechins as pharmaceuticals. These highly soluble and reactive compounds are poorly absorbed in the gut and quickly eliminated by the liver. This can only be partially compensated by administering larger doses of material. On the more practical side, the wide array of targets makes it difficult to demonstrate a specific mode of action and to obtain approval for a particular use. In addition, the large number of false starts in their application has jaded the community. Pharmaceutical companies are similarly skeptical, with the added problem in that it is nearly impossible to protect the application of such freely available compounds from patent challenges. These issues have certainly plagued our work on using EGCG to treat HHS. Since HHS is an orphan disease, we had hoped that such a non-toxic compound could be rapidly used in the clinic to help treat this multi-organ disease. However, for all of these reasons, being able to get support for this application has been difficult. Nevertheless, in unpublished results, we have the atomic structure of the GDH/EGCG complex and evidence that they are working in-vivo in HHS transgenic mouse models. Therefore, we still are hopeful that either these compounds or their mimics might still be applicable for a number of diseases.
Whether the green tea polyphenols can be considered to be a success or failure is dependent upon whether the end application is a nutritional additive or a traditional pharmaceutical with a specific target and dosing regime. With regard to their use as a nutraceutical, a number of studies have suggested that they may be effective as prophylactics or as synergistic compounds with other treatment regimes. Used in this manner, these compounds have offered modest benefits with a number of different disorders. As pharmaceutical agents, these compounds have been highly successful in controlled experiments but have not resulted in clinical application. Tea polyphenols hold such great promise with regard to safety and ability to cross the blood-brain barrier. However, even with modifications to make them more stable pro-drugs, it seems unlikely that the stability and bioavailability issues can be sufficiently overcome. Therefore, as use as targeted pharmaceutical agents, these polyphenols cannot be considered a success at this time. However, they have been extremely useful in identifying new ligand binding sites on target proteins and their low toxicity allows for rapid confirmation of activity in-situ and in-vivo. In the end, perhaps this is how these catechins have lived up to expectations; by providing scaffolds for further drug design.