Synergy in Herbal Medicines: Part 1
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Synergy in Herbal Medicines: Part 1 Eric Yarnell, ND, RH(AHG)a ©2015, Eric Yarnell, ND, RH(AHG) Journal Compilation ©2015, AARM DOI 10.14200/jrm.2015.4.0104 ABSTRACT In the following paper, we will review the available literature on synergy and additive effects involving medicinal herbs and herbal extracts. Several types of synergistic interactions are discussed, including apparently inactive constituents enhancing the effects of apparently active constituents within and between herbal medicines, various herbal compounds altering the absorption of others, reduction in toxicity of some herbal constituents by others, and direct synergistic therapeutic effects when active constituents are combined within and between many medicinal herbs. Species discussed include Artemisia annua (sweet Annie, q ng h o), Ammi visnaga (khella), Glycyrrhiza glabra (licorice), G. uralensis (Chinese licorice, g n c o), Panax ginseng (Asian ginseng, rén sh n), Mahonia aquifolium (Oregon grape), Berberis aetnensis (Mt. Etna barberry), B. trifoliolata (algerita), B. fendleri (Colorado barberry), and Coptis chinensis (goldthread, huáng lián). Part 2 of this article will continue this review on other medicinal herb species. Keywords: Synergy; Medicinal plants; Artemisia annua; Glycyrrhiza; Coptis aCorresponding author: Associate Professor, Department of Botanical Medicine, Bastyr University, 14500 Juanita Dr NE, Kenmore, WA 98028, USA. Chief Medical Officer, Northwest Naturopathic Urology, 3670 Stone Wy N, Seattle, WA 98103, USA. Tel.: +1 425-602-3289; E-mail: [email protected] Journal of Restorative Medicine 2015; 4: page 60 Herbal Synergy INTRODUCTION Medicinal plants contains hundreds if not thousands including those involving multiple herbs. Many of unique compounds. Models based on single instances are reviewed where various types of molecular entities do not accurately describe or synergy have been studied with both supportive and capture the complexity of interactions among the some negative results. The term synergy will be constituents in medicine plants and multiconstituent used loosely in this review to include effects greater extracts made from them. than the sum of the parts (true synergy) and simple additive effects. Overall, however, the current In the mainstream pharmaceutical view, there is research on many important medicinal herbs under- a single active constituent in a plant that explains appreciates the value of complex mixtures compared its activity and which can be isolated and used as with single isolated constituents.4 a conventional drug. This idea is reinforced by the fact that many widely-used drugs are either single molecules isolated from plants or semisynthetic variants of natural molecules.1, 2 However, this ARTEMISIA ANNUA (SWEET still does not prove that the single compounds are ANNIE) superior to complex mixtures, particularly when possible beneficial effects of various compounds The prolific and widespread weed Artemisia annua that indirectly support the main desired action have (sweet Annie, q ng h o) illustrates the problem of not been assessed. activity-guided research overlooking useful effects In many studies, an assay (such as receptor activa- beyond the “active” constituents. The sesquiter- tion or inhibition, or killing of a microbe or cancer pene lactone artemisinin (Figure 1) from A. annua cell in vitro) can be used to identify a single mol- is a potent antimalarial schizonticide.5 Artemisinin ecule or several molecules that appear to provide (qinghaosu in Chinese) and various semisynthetic most or all the effect of a crude plant extract for derivatives of it are among the most widely-used that assay. For example, one fractionation assay antiplasmodial drugs in the world. It seems to be ultimately determined that berberine was the single largely assumed in mainstream medicine that this most active antimalarial constituent found in 14 is the beginning and ending of the sweet Annie different Vietnamese medicinal plants.3 This would story: artemisinin is the silver bullet, and there is seem on the face of it to support the conventional nothing else worth investigating further in the herb. pharmacological model for medicinal plants. However, a clinical trial showing a crude decoction However, these assays do not evaluate the complex of A. annua that effectively eliminated symptoms activities of other compounds in the plant that could and dramatically lowered parasite burden in adults in directly affect the outcome being assessed. This can the Democratic Republic of the Congo with chronic lead to severe oversights and a failure to recognize malaria, with cure rates on average of 74%, despite “inactive” constituents as providing important func- providing far lower levels of artemisinin than are tions. As cited below in depth, flavonoids found used as an isolated drugs, suggesting that there is in the same plant as berberine have been shown to more to A. annua than just artemisinin.6 inhibit resistance to berberine in microbes. Thus, Polymethoxylated flavonoids in A. annua also while berberine may be the most important anti- have physiological activity (Table 1), though they microbial, removing the flavonoids could result in are supposedly not directly antiplasmodial (note microbial resistance developing toward berberine that at least one in vitro study did find artemetin and its failure as an antimicrobial. Activity-guided directly antiplasmodial).24 These flavonoids have modeling misses the benefit of other plant con- been shown to decrease resistance of Plasmodium stituents on the overall outcome, as well as other spp. to artemisinin by inhibiting efflux pumps in the outcomes not being assessed. parasite.25 Chrysosplenol D (see Figure 1), chryso- This article will review the evidence on synergy of splenitin, circilineol, casticin, and artemetin have multiple compounds in complex herbal extracts, all been shown to significantly lower (by 20%–50% Journal of Restorative Medicine 2015; 4: page 61 Herbal Synergy OH OH O O H3CO O O H O H3CO OCH3 Artemisinin O OH O Chrysosplenol D Figure 1: Artemisinin and chrysosplenol D. depending on the compound) the half minimal aqueous crude extracts of A. annua are antiplas- inhibitory concentration (IC50) of artemisinin modial, and an absence of evidence of synergy in against Plasmodium spp. in vitro.26, 27 These A. annua aqueous extracts in vitro.29, 30 It is also flavonoids did not reduce Plasmodium resistance confusing given the human research on aqueous to chloroquine.26, 27 infusions of A. annua which shows they are effec- tive.6 It should be noted that traditional methods While artemisinin is readily and stably extracted of preparation of A. annua in Chinese medicine by aqueous decoction, flavonoids are best by soaking combined with wringing or pounding extracted by alcohol.28 This is interesting in light followed by juicing lead to extracts with 20 times of in vitro evidence that only ethanolic and not Table 1: Select other actions reported for polymethoxylated flavonoids found in Artemisia annua. Flavonoid Action Model References Chrysosplenol D Antioxidant In vitro Xie et al., 20147 α-Glucosidase inhibitor In vitro Ezzat and Salama, 20148 Antiangiogenic In vitro Zhu et al., 20139 Casticin Antiangiogenic In vitro Zhu et al., 20139 Growth inhibition by mitotic spindle Cervical cancer cells Kobayakawa et al., 200410 disruption in vitro Antineoplastic and pro-apoptotic by many Breast, ovarian, lung, Liu et al., 201411; Jiang mechanisms colon, liver cancer cells et al., 201312; Ono et al., in vitro 200213; Yang et al., 201114 Inhibit prolactin secretion by inhibiting Metoclopramide-treated Ye et al., 201015 ERα and stimulating ERβ rats Co-stimulates IL-1β secretion In vitro Toll-like Lim et al., 201316 receptor 2-activated cells Cyclooxygenase-2 inhibition, iNOS In vitro Liou et al., 201417 inhibition, NF-κB inhibition Lipoxygenase inhibition In vitro Choudhary et al., 200918 Artemetin Lipoxygenase inhibition In vitro Choudhary et al., 200918 Anti-inflammatory Carageenan-induced Sertié et al., 199019 edema in rat paws Antibacterial against Gram positive bacteria In vitro Michielin et al., 200920 Angiotensin converting enzyme inhibition In vitro; normotensive de Souza et al., 201121 rats Hepatoprotective Carbon tetrachloride- Sridevi et al., 201222 treated rats Antiperoxidative In vitro Dugas et al., 200023 ER, estrogen receptor; IL, interleukin; iNOS, inducible nitric oxide synthase; NF, nuclear factor. Journal of Restorative Medicine 2015; 4: page 62 Herbal Synergy higher levels of artemisinin than just infusion.31 and inflammation-modulating effects of A. annua in Artemisinin content alone did not explain the another report.35 Cinnamic acid derivatives (ros- antimalarial activity of these traditional juiced marinic and chlorogenic acids in particular) from extracts in vitro; the IC50 concentrations were up A. annua inhibited the pro-inflammatory cytokines to 18 times lower for the crude juices than pure IL-6 and -8 in vitro.36 artemisinin. One mouse study found that a crude Polymethoxylated flavonoids from A. annua ethanol extract of A. annua had a median effective reduce resistance to other natural antimicrobials. dose (ED ) of 35 mg/kg vs. 122 mg/kg for pure 50 Combining chrysosplenol D or chrysosplenetin artemisinin.32 Short-term (3 day) use of this prod- from A. annua with subinhibitory concentrations uct in an open human trial was as effective, if not of the isoquinoline alkaloid berberine was effec- more so, than chloroquine, though only 217 mg of tive in killing