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 Echinacea: Fact and Fiction, Part Two By Kerry Bone, BSc (hons.), Dip. Phyto Editor's note: Click here to read part one of Dr. Bone's article. The Importance of Liver Metabolism As previously noted, only alkylamides were found in human plasma after ingestion of echinacea root tablets, but the levels were quite variable and first-pass liver metabolism was suspected to be influencing this observation. (First-pass metabolism is the rapid degradation by the liver as the products from digestion first pass through the liver on their way to the general circulation.) The alkylamides mainly found in E. purpurea were rapidly degraded by human liver microsomes. In contrast, the alkylamides mainly found in E. angustifolia were much more slowly degraded. Interestingly, it was discovered that the latter type of alkylamide actually slowed down the rate of degradation of the former type of alkylamide. This protective effect of the E. angustifolia alkylamide is a highly novel finding, and it was deduced that the presence of only relatively small proportions of this compound would result in a product with enhanced bioavailability. This is a strong justification for the combination of E. angustifolia root with E. purpurea root.13 Liquid Extracts Versus Tablets One question that often is asked is whether herbs work better as liquid extracts or tablets. Well-made tablets likely are to work just as well as liquids because they are made using extracts (not the powdered herb) and are formulated to pharmaceutical standards to ensure rapid disintegration. This was verified in a clinical study that compared equivalent doses of a commercial echinacea product in liquid or in tablet form. The total amount of alkylamides absorbed into the bloodstream was essentially the same for both products.14 To the author's knowledge, this is the first study of this kind (comparing the bioavailability of equivalent doses of a herbal liquid extract against a tablet) ever undertaken. Immune Activity of Alkylamides Research has established that alkylamides are the only phytochemicals that are bioavailable from traditional lipophilic extracts of echinacea root. In addition, combining E. angustifolia with E. purpurea will enhance the alkylamide bioavailability. This research poses the question as to whether alkylamides have any effect on the immune system. This can be answered in part by test tube research to investigate such activity. The key findings of preliminary studies are that echinacea alkylamides do not activate the immune system in the absence of any immunological challenge. Echinacea alkylamides tended to modulate the immune responses of macrophages and T-cells, toning the response down in the face of a strong stimulus, thus helping the immune system to operate more efficiently.15,16 CB2 Receptors A significant recent discovery, first presented at a major international conference in 2004, was the observation by two separate research teams that some of the immune effects of echinacea may be mediated by the interaction of echinacea alkylamides with cannabinoid receptors. Gertsch found that an in vitro immune-modulating effect of a lipophilic echinacea extract (and individual alkylamides) on monocytes/macrophages could be neutralized by the presence of agents which block CB2 cannabinoid receptors.17 Bauer, et al., found that alkylamides from echinacea bind to both CB1 and CB2 cannabinoid receptors.18 In particular, certain alkylamides exhibited selectivity for CB2 receptors. Taken together, these developments (the pharmacokinetic trials and the CB2 receptor studies) suggest the hypothesis that the alkylamides largely are responsible for the systemic immune effects of echinacea lipophilic extracts. This immune-modulating activity is partly due to the interaction of alkylamides with cannabinoid receptors, specifically CB2. CB1 receptors are highly localized in the central nervous system (CNS) and are believed to primarily modulate behavior, while CB2 receptors predominate in immune tissues outside the CNS, especially the spleen, and are believed to modulate immune function.19 Cannabinoid receptors are remarkably preserved across the animal kingdom, which suggests they play an important developmental and physiological role.20,21 Much of the immune activity of the cannabinoid system appears to be mediated by the cytokine network. Cytokines include the interleukins (IL-3, IL-6, etc.), tumor necrosis factor alpha (TNFα) and the interferons (IFN). Gertsch et al., have followed on from this groundbreaking research and shown that certain echinacea alkylamides bind strongly to CB2 receptors.22 In addition, they have shown that alkylamides also exert additional effects on immune cells which are independent of CB2.22 Their research has been particularly insightful into one aspect of the mode of action of echinacea alkylamides.23 A lipophilic extract of E. purpurea strongly stimulated TNFα mRNA synthesis in peripheral monocytes, but not TNFα protein production. In other words, the echinacea-induced new TNFα transcripts (mRNA) were not translated into TNFα itself. When monocytes are treated with LPS (lipopolysaccharide or endotoxin, a powerful stimulator of the immune system) TNFα protein production is substantially increased. However, co-incubation of monocytes with lipopolysaccharide (LPS) and echinacea root extract resulted in a strong inhibition of this effect of LPS. Investigation over a longer time span revealed that the lipophilic echinacea extract, via interaction with CB2 receptors, modulated and prolonged TNFα production following immune stimulation. The results of this study suggest echinacea works more as a modulator or facilitator of the immune response, rather than as an immune stimulant. In resting monocytes it prepares them for a quicker immune response by inducing TNFα mRNA. However, in overstimulated monocytes (as in the case of LPS) it first reduces and then extends their response in terms of TNFα production. In particular, these key findings challenge the mythology that traditional echinacea extracts will "overstimulate and wear out" the immune system if taken continuously. Echinacea and Innate Immunity In an extraordinarily titled paper, "Echinacea: A Miracle Herb Against Aging and Cancer?" Dr. Sandra Miller reviewed her research on echinacea, specifically E. purpurea root.24 Dr. Miller's interest in echinacea was triggered by her team's research on the drug indomethacin, which is a cyclo-oxygenase inhibitor that reduces the endogenous suppressors of natural killer (NK) cells, namely the prostaglandins.25,26 The drug resulted in statistically significant increases in NK cell numbers and function in leukemic mice. This led to the search for a safe agent without dangerous side effects that might function in the same way. The observation that alkylamides in echinacea can inhibit prostaglandin production in vitro,27 and the general reputation of echinacea as an immune herb, led to the investigation of the potential of echinacea in NK cell enhancement using in vivo laboratory models. In healthy young-adult mice, oral doses of E. purpurea root (0.45 mg per 25 g body weight, similar to human dose rates) stimulated NK cell production by bone marrow in the first seven days, which resulted in significantly higher levels (around 25 percent more) of NK cells in the spleen by two weeks.28 In addition, the "helper" or accessory cells for NK cells, the monocytes, were also around 25 percent more numerous in both the bone marrow and spleens of mice consuming echinacea. The echinacea treatment influenced no other white blood cell counts, and polysaccharides, even by injection, were found to be not responsible for this effect.29 NK cells decline in number and function with age, and this is thought to be one factor behind the increase of various cancers and infections with age. Experiments conducted in healthy, elderly mice found that two weeks of oral doses of echinacea returned NK cell numbers in bone marrow and spleen to the levels of young adults and also resurrected the functional capacity (target cell binding, lysis) of these cells.30 On this result, Dr. Miller writes: "These observations appear to apply uniquely to this herb since we could never rejuvenate the NK cell-mediated component of the immune system in elderly mice by any of the other typical NK cell enhancers." As discussed, one of the persistent controversies about echinacea is whether it is safe to be taken consistently for long periods of time. According to Dr. Miller's findings, the answer, at least in mice, is definitely in the affirmative. Mice were fed E. purpurea root from seven weeks of age to 13 months at the dose previously described.31 Long-term use of echinacea was not only not detrimental, but distinctly beneficial. By 13 months of age, 46 percent of the control mice fed the standard chow were still alive, compared to 74 percent of those consuming echinacea. As might be expected from previous experiments, the NK cell levels in the echinacea-fed mice were considerably elevated compared to controls. On this, Miller writes: "Given that the key immune cells acting as the first line of defence against developing neoplasms in mice and humans are NK cells, it is not difficult to conclude that sustained enhancement of NK cells alone, throughout life, could readily account for the reduced frequency in deaths with advancing age. Spontaneous neoplasms, clinically undetectable, are well known to increase with advancing age in humans and mice. Thus, the logical corollary from this study indicates that chronic daily intake of Echinacea, is clearly not detrimental to the immune system, but rather prophylactic." Finally, Miller set out to answer the question of whether echinacea still will be effective once a cancer is in progress. In particular, leukemias and lymphomas are well-known as targets for NK cell attack and are established as the first line of defense against these types of malignancies. Leukemia-induced mice typically died after 3.5 weeks, whereas one-third of mice additionally fed echinacea survived until 3 months after leukemia onset and went on to live a normal lifespan.32 References
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All Rights Reserved, Naturopathy Digest, 2011.
Date Last Modified - Friday, 17-Oct-2008 12:11:12 PDT
About the Author: Kerry Bone was an experienced research and industrial chemist before studying herbal medicine full-time in the UK, where he graduated from the College of Phytotherapy and joined the National Institute of Medical Herbalists. He is a practicing herbalist; co-founder and head of research and development at MediHerb; and principal of the Australian College of Phytotherapy. Kerry also is the author of several books, including Principles and Practice of Phytotherapy and The Essential Guide to Herbal Safety.
