Department of Health and Physical Education, Human Physiology Laboratory, Marywood University, Scranton, Pennsylvania, USA.
J Gerontol A Biol Sci Med Sci. 2012 Feb;67(2):158-67. doi: 10.1093/gerona/glr062. Epub 2011 Jul 11.
Basic science literature abounds with molecules that promise to ameliorate almost any disease, from curing cancer to slowing the aging process itself. However, most of these compounds will never even be evaluated in humans, let alone proven effective. Here, we use resveratrol as an example to highlight the enormous difficulties in understanding pharmacokinetics, determining side effects, and, ultimately, establishing mechanisms of action for a natural compound. Despite extensive interest and effort, and continuing promising results from basic science groups, very little is known even today about the effects of resveratrol in humans. Part of the problem is the unattractiveness of natural compounds to large, well-funded companies that could run clinical trials because developing their own molecules affords much greater protection for their intellectual property. In fact, selling unpatentable material motivates smaller nutraceutical companies to complicate the scientific problem even more--each creates its own proprietary blend, making it extremely difficult to compare their data with those of other companies, or of academic labs using pure compounds. But even beyond these problems lies a deeper one; resveratrol, and almost every natural compound, is likely to have many clinically relevant targets with different dose-response profiles, tissue distributions, and modifiers. Tackling this type of problem efficiently, and even beginning to address the spectrum of other molecules with claimed benefits, is likely to require the development of new paradigms and approaches. Examples include better molecular modeling to predict interactions, large-scale screens for toxic or other common effects, affinity-based methods to identify drug-interacting proteins, and better synthesis of existing data, including legislation to promote the release of trial results, and tracking of voluntary supplement usage. The evidence for benefits of resveratrol in humans remains too sparse to be conclusive; yet, the limited data that are available, combined with a growing list of animal studies, provide a strong justification for further study.
基础科学文献中充斥着各种分子，它们承诺可以改善几乎任何疾病，从治愈癌症到减缓衰老过程本身。然而，这些化合物中的大多数甚至都不会在人体中进行评估，更不用说证明其有效性了。在这里，我们以白藜芦醇为例，强调理解药代动力学、确定副作用以及最终确定天然化合物作用机制的巨大困难。尽管基础科学研究小组进行了广泛的研究和努力，并不断取得有希望的结果，但即使在今天，人们对白藜芦醇在人体中的作用也知之甚少。部分问题是，大型、资金充足的公司对天然化合物不感兴趣，因为开发自己的分子可以为其知识产权提供更大的保护。事实上，销售不可专利的材料促使较小的营养保健品公司使科学问题更加复杂——每个公司都创建自己的专利混合物，使得很难将其数据与其他公司或使用纯化合物的学术实验室的数据进行比较。但即使超越了这些问题，还有更深层次的问题；白藜芦醇，几乎每一种天然化合物，都可能有许多具有不同剂量反应特征、组织分布和修饰剂的临床相关靶点。有效地解决这类问题，甚至开始解决声称具有益处的其他分子的范围问题，可能需要开发新的范例和方法。例如，更好的分子建模以预测相互作用，大规模筛选毒性或其他常见作用，基于亲和力的方法来识别与药物相互作用的蛋白质，以及更好地合成现有数据，包括立法以促进试验结果的发布，以及跟踪自愿补充剂的使用。白藜芦醇对人体有益的证据仍然太少，无法得出结论；然而，现有的有限数据，加上越来越多的动物研究，为进一步研究提供了强有力的理由。
