ABSTRACT

All herbal medicines are by denition “phytocomplexes” and the use of such mixtures has always been considered, by advocates of herbal medicine, to be one of their main advantages, and the same principles apply whether the phytocomplex is a single extract or a mixture of different plant extracts. There is a great variation in products that comply with this description, and these include simple “crude” extracts like herbal teas, “rened” extracts containing a narrow range of compounds, such as soya iso¤avones, and “special” extracts where an unwanted compound or group of compounds have been removed or greatly reduced, for example, Ginkgo biloba extract

8.1 Introduction .................................................................................................. 147 8.1.1 Denitions and Implications ............................................................. 148 8.1.2 Multifactorial or Polyvalent Effects ................................................. 150

8.2 Mechanisms of Interaction ........................................................................... 150 8.2.1 Pharmacodynamic Interactions ........................................................ 150

8.3 Opposing Effects by Different Compounds within a Single Extract ........... 152 8.3.1 Rheum palmatum .............................................................................. 153 8.3.2 Calendula of•cinalis ........................................................................ 153 8.3.3 Saussurea lappa ............................................................................... 153 8.3.4 Pterospartum tridentatum ................................................................ 154

8.4 Enhancement of an Active Constituent by Other Components of an Extract.................................................................................................. 154

8.4.1 Cannabis sativa ................................................................................ 154 8.5 Pharmacokinetic Interactions ....................................................................... 154 8.6 Dietary Effects: Combinations of Plant Extracts with Food ........................ 156 8.7 Discussion: Implications of Synergy and Multifactorial Effects .................. 156

8.7.1 Discovery of New Active Compounds ............................................. 156 8.7.2 Predicting the Overall Effects of a Complex Extract ....................... 156 8.7.3 Development of New Nutraceutical and Herbal Supplements .......... 157 8.7.4 Establishing the “Active Pharmaceutical Ingredient” ...................... 157

8.8 Conclusion .................................................................................................... 158 References .............................................................................................................. 159

with low levels of ginkgolic acids or Petasites hydridus extract with most of the pyrollizidine alkaloids removed. Single compounds isolated from natural products are no different therapeutically from single chemical entities produced by any other means, including chemical synthesis, and the effect of a single substance acting at a single target is sometimes referred to as the “silver bullet” approach, in contrast to the “herbal shotgun” effect where multiple constituents interact with different targets. One of the basic tenets of herbal medicine, as practiced in all cultures, is that a whole plant extract is more effective and produces fewer side effects than those of a single “active” substance. Although this is intuitive rather than proven, it is increasingly being supported by experimental studies. Clinical evidence is available to show the efcacy of some herbal medicines and combination formulae, but clinical studies are expensive and time-consuming, require ethical approval, and do not really provide a suitable method of proving or disproving synergy and multifactorial effects, neither do they usually give many clues as to mechanisms of action. For these reasons, most evidence in support of synergistic and multifactorial effects of herbal medicines comes from animal and cell culture experiments, some of which have been previously reviewed (Williamson, 2001; Gilani and Rahman, 2005; Wagner, 2005, 2006; Kimura, 2006; Spelman et al., 2006; Wagner and Ulrich-Merzenich, 2009). Although a threshold concentration is required for a pharmacological effect, it is not known whether (or why) apparently subtherapeutic concentrations can still produce synergistic effects. Such effects could explain why the concentration of an “active” within a herbal extract may appear to be too low to produce any effect, even though the phytocomplex has demonstrable efcacy at this concentration. An example of this is shown by willow bark, Salix alba, which is usually assumed to be effective due to the salicin content, or rather its metabolite, salicylic acid (also the active metabolite of aspirin, acetylsalicylic acid). A randomized, placebo-controlled trial of a standardized extract of willow bark for osteo-arthritis of the hip and knee conrmed efcacy at a dose equivalent to 240 mg salicin daily (Schmid et al., 2001). However, the usual dose of aspirin given to control pain is 600 mg taken three times a day, so it seems inexplicable that only 240 mg of salicin can be therapeutically equivalent to 1800 mg of aspirin-unless the other components of the extract are contributing to the effect in some way of course.