Synergy in Herbal Medicines
Eric Yarnell, ND, RH(AHG)
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Keywords

Artemisia annua
Coptis
Glycyrrhiza
Medicinal plants
Synergy
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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, qīng hāo), Ammi visnaga(khella), Glycyrrhiza glabra (licorice), G. uralensis (Chinese licorice, gān co), Panax ginseng (Asian ginseng, rén shēn), 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.

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References

Samuelsson G. Drugs of Natural Origin: A Textbook of Pharmacognosy, 4th edn. Stockholm: Apotekarsocieteten; 1999.
Evans WC. Trease and Evans’ Pharmacognosy, 13th edn. London: Baillière Tindall; 1989.
Tran QL, Tezuka Y, Ueda JY, et al. In vitro antiplasmodial activity of antimalarial medicinal plants used in Vietnamese traditional medicine. J Ethnopharmacol. 2003; 86(2–3):249–252.
Wagner H. Synergy research: approaching a new generation of phytopharmatceuticals. Fitoterapia. 2011; 82(1):34–37.
Yarnell E. Artemisia annua (sweet Annie), other Artemisia species, artemisinin, artemisinin derivatives, and malaria. J Restorative Med. 2014; 3(1):69–84.
Mueller MS, Runyambo N, Wagner I, et al. Randomized controlled trial of a traditional preparation of Artemisia annua L (annual wormwood) in the treatment of malaria. Trans R Soc Trop Med Hyg. 2004; 98(5):318–321.
Xie XY, Chen FF, Shi YP. Simultaneous determination of eight flavonoids in the flowers of Matricaria chamomilla by high performance liquid chromatography. J AOAC Int. 2014; 97(3):778–783.
Ezzat SM, Salama MM. A new α-glucosidase inhibitor from Achillea fragrantissima (Forssk) Sch Bip growing in Egypt. Nat Prod Res. 2014; 28(11):812–818.
Zhu XX, Yang L, Li YJ, et al. Effects of sesquiterpene, flavonoid and coumarin types of compounds from Artemisia annua L on production of mediators of angiogenesis. Pharmacol Rep. 2013; 65(2):410–420.
Kobayakawa J, Sato-Nishimori F, Moriyasu M, Matsukawa Y. G2-M arrest and antimitotic activity mediated by casticin, a flavonoid isolated from Viticis Fructus (Vitex rotundifolia Linne fil). Cancer Lett. 2004; 208(1):59–64.
Liu LP, Cao XC, Liu F, et al. Casticin induces breast cancer cell apoptosis by inhibiting the expression of forkhead box protein M1. Oncol Lett. 2014; 7(5):1711–1717.
Jiang L, Cao XC, Cao JG, et al. Casticin induces ovarian cancer cell apoptosis by repressing FoxM1 through the activation of FOXO3a. Oncol Lett. 2013; 5(5):1605–1610.
Ono M, Yanaka T, Yamamoto M, et al. New diterpenes and norditerpenes from the fruits of Vitex rotundifolia. J Nat Prod. 2002; 65(4):537–541.
Yang J, Yang Y, Tian L, et al. Casticin-induced apoptosis involves death receptor 5 upregulation in hepatocellular carcinoma cells. World J Gastroenterol. 2011; 17(38):4298–4307.
Ye Q, Zhang QY, Zheng CJ, et al. Casticin, a flavonoid isolated from Vitex rotundifolia, inhibits prolactin release in vivo and in vitro. Acta Pharmacol Sin. 2010; 31(12):1564–1568.
Lim EK, Mitchell PJ, Brown N, et al. Regiospecific methylation of a dietary flavonoid scaffold selectively enhances IL-1β production following Toll-like receptor 2 stimulation in THP-1 monocytes. J Biol Chem. 2013; 288(29):21126–21135.
Liou CJ, Len WB, Wu SJ, et al. Casticin inhibits COX-2 and iNOS expression via suppression of NF-κB and MAPK signaling in lipopolysaccharide-stimulated mouse macrophages. J Ethnopharmacol. 2014; 158PA:310–316.
Choudhary MI, Azizuddin , Jalil S, et al. Antiinflammatory and lipoxygenase inhibitory compounds from Vitex agnus-castus. Phytother Res. 2009; 23(9):1336–1339.
Sertié JA, Basile AC, Panizza S, et al. Anti-inflammatory activity and sub-acute toxicity of artemetin. Planta Med. 1990; 56(1):36–40.
Michielin EM, Salvador AA, Riehl CA, et al. Chemical composition and antibacterial activity of Cordia verbenacea extracts obtained by different methods. Bioresour Technol. 2009; 100(24):6615–6623.
de Souza P, Gasparotto A Jr, Crestani S, et al. Hypotensive mechanism of the extracts and artemetin isolated from Achillea millefolium L (Asteraceae) in rats. Phytomedicine. 2011; 18(10):819–825.
Sridevi VK, Chouhan HS, Singh NK, Singh SK. Antioxidant and hepatoprotective effects of ethanol extract of Vitex glabrata on carbon tetrachloride-induced liver damage in rats. Nat Prod Res. 2012; 26(12):1135–1140.
Dugas AJ Jr, Castañeda-Acosta J, Bonin GC, et al. Evaluation of the total peroxyl radical-scavenging capacity of flavonoids: structure-activity relationships. J Nat Prod. 2000; 63(3):327–331.
Ortet R, Prado S, Regalado EL, et al. Furfuran lignans and a flavone from Artemisia gorgonum Webb and their in vitro activity against Plasmodium falciparum. J Ethnopharmacol. 2011; 138(2):637–640.
Elford BC, Roberts MF, Phillipson JD, Wilson RJ. Potentiation of the antimalarial activity of qinghaosu by methoxylated flavones. Trans R Soc Trop Med Hyg. 1987; 81(3):434–436.
Liu KCS, Yang SY, Roberts MF, et al. The contribution of flavonoids to the antimalarial activity of Artemisia annua. Planta Med. 1989; 55(7):654–655.
Liu KC, Yang SL, Roberts MF, et al. Antimalarial activity of Artemisia annua flavonoids from whole plants and cell cultures. Plant Cell Rep. 1992; 11(12):637–640.
Weathers PJ, Towler MJ. The flavonoids casticin and artemetin are poorly extracted and are unstable in an Artemisia annua tea infusion. Planta Med. 2012; 78(10):1024–1026.
Ferreira JF, Peaden P, Keiser J. In vitro trematocidal effects of crude alcoholic extracts of Artemisia annua, A. absinthium, Asimina triloba, and Fumaria officinalis: trematocidal plant alcoholic extracts. Parasitol Res. 2011; 109(6):1585–1592.
Mouton J, Jansen O, Frédérich M, van der Kooy F. Is artemisinin the only antiplasmodial compound in the Artemisia annua tea infusion? An in vitro study. Planta Med. 2013; 79(6):468–470.
Wright CW, Linley PA, Brun R, et al. Ancient Chinese methods are remarkably effective for the preparation of artemisinin-rich extracts of Qing Hao with potent antimalarial activity. Molecules. 2010; 15(2):804–812.
Wan YD, Zang QZ, Wang JS. Studies on the antimalarial action of gelatin capsule of Artemisia annua. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi. 1992; 10(4):290–294 [in Chinese].
De Donno A, Grassi T, Idolo A, et al. First-time comparison of the in vitro antimalarial activity of Artemisia annua herbal tea and artemisinin. Trans R Soc Trop Med Hyg. 2012; 106(11):696–700.
Favero F de F, Grando R, Nonato FR, et al. Artemisia annua L: evidence of sesquiterpene lactones’ fraction antinociceptive activity. BMC Complement Altern Med. 2014; 14:266.
Huang L, Liu JF, Liu LX, et al. Antipyretic and anti-inflammatory effects of Artemisia annua L. Zhongguo Zhong Yao Za Zhi 1993; 18:44–48, 63–64 [in Chinese].
Melillo de Magalhães P, Dupont I, Hendrickx A, et al. Anti-inflammatory effect and modulation of cytochrome P450 activities by Artemisia annua tea infusions in human intestinal Caco-2 cells. Food Chem. 2012; 134(2):864–871.
Stermitz FR, Scriven LN, Tegos G, Lewis K. Two flavonols from Artemisa annua which potentiate the activity of berberine and norfloxacin against a resistant strain of Staphylococcus aureus. Planta Med. 2002; 68(12):1140–1141.
Rasoanaivo P, Wright CW, Willcox ML, Gilbert B. Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions. Malar J. 2011; 10(Suppl 1):S4.
Gathirwa JW, Rukunga GM, Njagi EN, et al. The in vitro anti-plasmodial and in vivo anti-malarial efficacy of combinations of some medicinal plants used traditionally for treatment of malaria by the Meru community in Kenya. J Ethnopharmacol. 2008; 115(2):223–231.
Eder M, Mehnert W. Plant excipients–valuable pharmaceutical aids or superfluous ballast? Pharm Unserer Zeit. 2000; 29(6):377–384 [in German].
Haug KG, Weber B, Hochhaus G, Butterweck V. Pharmacokinetic evaluation of visnagin and Ammi visnaga aqueous extract after oral administration in rats. Planta Med. 2012; 78(17):1831–1836.
Schimmer O, Rauch P. Inhibition of metabolic activation of the promutagens, benzo[a]pyrene, 2-aminofluorene and 2-aminoanthracene by furanochromones in Salmonella typhimurium. Mutagenesis. 1998; 13(4):385–389.
Vanachayangkul P, Chow N, Khan SR, Butterweck V. Prevention of renal crystal deposition by an extract of Ammi visnaga L and its constituents khellin and visnagin in hyperoxaluric rats. Urol Res. 2011; 39(3):189–195.
Vanachayangkul P, Byer K, Khan S, Butterweck V. An aqueous extract of Ammi visnaga fruits and its constituents khellin and visnagin prevent cell damage caused by oxalate in renal epithelial cells. Phytomedicine. 2010; 17(8–9):653–658.
Xie S, Zhang G, Sun G, et al. Detoxication experimental study on different compatibility proportion of Aconiti Lateralis Radix Praeparata and glycyrrhizae radix et rhizoma. Zhongguo Zhong Yao Za Zhi. 2012; 37(15):2210–2214 [in Chinese].
Li Y, Fu CM, Ren B, et al. Study on attenuate and synergistic mechanism between aconiti lateralis praeparata radix and glycyrrhizae radix for toxicity reduction based on metabonomic of MI-RI mouse cardiomyocytes. Zhongguo Zhong Yao Za Zhi. 2014; 39(16):3166–3171 [in Chinese].
Zhao MQ, Wu WK, Zhao DY, et al. Protective effects of sini decoction on adriamycin-induced heart failure and its mechanism. Zhong Yao Cai. 2009; 32(12):1860–1863 [in Chinese].
Liu J, Peter K, Shi D, et al. Traditional formula, modern application: Chinese medicine formula sini tang improves early ventricular remodeling and cardiac function after myocardial infarction in rats. Evid Based Complement Alternat Med. 2014; 2014:141938.
Zhang G, Zhu L, Zhou J, et al. Effect of aconiti laterlis radix compatibility of glycyrrhizae radix on CYP3A4 in vivo. Zhongguo Zhong Yao Za Zhi. 2012; 37(15):2206–2209 [in Chinese].
Shen H, Wu J, Di LQ, et al. Enhancement by Glycyrrhizae Radix of hepatic metabolism of hypaconitine, a major bioactive and toxic component of Aconiti Laterlis Radix, evaluated by HPLC-TQ-MS/MS analysis. Biomed Chromatogr. 2013; 27(5):556–562.
Zhang JM, Li L, Gao F, et al. Chemical ingredient analysis of sediments from both single Radix Aconiti Lateralis decoction and Radix Aconiti Lateralis – Radix Glycyrrhizae decoction by HPLC-MS. Yao Xue Xue Bao. 2012; 47(11):1527–1533 [in Chinese].
Yang Y, Yin XJ, Guo HM, et al. Identification and comparative analysis of the major chemical constituents in the extracts of single fuzi herb and fuzi-gancao herb-pair by UFLC-IT-TOF/MS. Chin J Nat Med. 2014; 12(7):542–453.
Zhang W, Zhang H, Sun S, et al. Comparative pharmacokinetics of hypaconitine after oral administration of pure hypaconitine, Aconitum carmichaelii extract and sini decoction to rats. Molecules. 2015; 20(1):1560–1570.
Ma L. Studies on the Changes of the Main Compounds in Co-boiling Extracts, Pooled Individual Boiling Extracts in Dioscorea bulbifera L and Glycyrrhiza uralensis Fisch Decoction (Thesis, Fujian University of Traditional Chinese Medicine), 2011.
Li YS, Tong PJ, Ma HZ. Toxicity attenuation and efficacy potentiation effect of liquorice on treatment of rheumatoid arthritis with Tripterygium wilfordii. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2006; 26(12):1117–1119 [in Chinese].
Wang X, Zhang H, Chen L, et al. Liquorice, a unique ‘guide drug’ of traditional Chinese medicine: a review of its role in drug interactions. J Ethnopharmacol. 2013; 150(3):781–790.
Nie RL, Tanaka T, Miyakoshi M, et al. A triterpenoid saponin from Thladiantha hookeri var pentadactyla. Phytochemistry. 1989; 28(6):1711–1715.
Wantanabe K, Fujino H, Morita T, et al. Solubilization of saponins of bupleuri radix with ginseng saponins: cooperative effect of dammarane saponins. Planta Med. 1988; 54(5):405–409.
Kimata H, Sumida N, Matsufuji N, et al. Interaction of saponin of bupleuri radix with ginseng saponin: solubilization of saikosaponin-a with chikusetsusaponin-V (=ginsenoside Ro). Chem Pharm Bull. 1985; 33(7):2849–2853.
Zhou X, Kasai R, Yoshikawa M, et al. Solubilization of saponins of Bupleuri radix with Ginseng saponins: effect of malonyl-ginsenosides on water solubility of saikosaponin-b. Chem Pharm Bull. 1991; 39(5):1250–1252.
Guo J, Shang E, Zhao J, et al. Data mining and frequency analysis for licorice as a ‘two-face’ herb in Chinese formulae based on Chinese Formulae Database. Phytomedicine. 2014; 21(11):1281–1286.
Chen L, Yang J, Davey AK, et al. Effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism. Xenobiotica. 2009; 39(12):955–963.
Nabekura T, Hiro T, Kawasaki T, Uwai Y. Effects of natural nuclear factor-kappa B inhibitors on anticancer drug efflux transporter human P-glycoprotein. Biomed Pharmacother. 2015; 70:140–145.
Bhattacharjee A, Majumder S, Majumdar SB, et al. Co-administration of glycyrrhizic acid with the antileishmanial drug sodium antimony gluconate (SAG) cures SAG-resistant visceral leishmaniasis. Int J Antimicrob Agents. 2015; 45(3):268–277.
Cao J, Chen X, Liang J, et al. Role of P-glycoprotein in the intestinal absorption of glabridin, an active flavonoid from the root of Glycyrrhiza glabra. Drug Metab Dispos. 2007; 35(4):539–553.
Yao HW, Fu XY, Xie QD, et al. Effect of liquorice decoction on rat intestinal P-glycoprotein. Nan Fang Yi Ke Da Xue Xue Bao. 2009; 29(8):1571–1573 [in Chinese].
Zhang J, Zhou F, Wu X, et al. 20(S)-Ginsenoside Rh2 noncompetitively inhibits P-glycoprotein in vitro and in vivo: a case for herb-drug interactions. Drug Metab Dispos. 2010; 38(12):2179–2187.
Huang BB, Li GF, Ren F, et al. Effect of Glycyrrhiza inflata and Daphne genkwa on permeabilities of rhodamine 123, a P-glycoprotein substrate across rat jejunum membranes in vitro. Zhongguo Zhong Yao Za Zhi. 2008; 33(21):2521–2526 [in Chinese].
Sun YB, Li GF, Tang ZK, Wu BY. Modulation on the P-glycoprotein in the jejunum by combined use of Glycyrrhiza inflata and kansui. Yao Xue Xue Bao. 2010; 45(4):510–516 [in Chinese].
Shen J, Mo X, Tang Y, et al. Analysis of herb-herb interaction when decocting together by using ultra-high-performance liquid chromatography-tandem mass spectrometry and fuzzy chemical identification strategy with poly-proportion design. J Chromatogr A. 2013; 1297:168–178.
Cantelli-Forti G, Maffei F, Hrelia P, et al. Interaction of licorice on glycyrrhizin pharmacokinetics. Environ Health Perspect. 1994; 102(suppl 9):65–68.
Wang Z, Nishioka M, Kurosaki Y, et al. Gastrointestinal absorption characteristics of glycyrrhizin from Glycyrrhiza extract. Biol Pharm Bull. 1995; 18(9):1238–1241.
Kamei J, Saitoh A, Asano T, et al. Pharmacokinetic and pharmacodynamic profiles of the antitussive principles of Glycyrrhizae radix (licorice), a main component of the Kampo preparation Bakumondo-to (Mai-men-dong-tang). Eur J Pharmacol. 2005; 507(1–3):163–168.
Zani F, Cuzzoni MT, Daglia M, et al. Inhibition of mutagenicity in Salmonella typhimurium by Glycyrrhiza glabra extract, glycyrrhizinic acid, 18α- and 18β-glycyrrhetinic acids. Planta Med. 1993; 59(6):502–507.
Kobayashi S, Miyamoto T, Kimura I, Kimura M. Inhibitory effect of isoliquiritin, a compound in licorice root, on angiogenesis in vivo and tube formation in vitro. Biol Pharm Bull. 1995; 18(10):1382–1386.
Feng YC, Wang KC, Chiang LC, et al. Water extract of licorice had anti-viral activity against human respiratory syncytial virus in human respiratory tract cell lines. J Ethnopharmacol. 2013; 148(2):466–473.
Stermitz FR, Lorenz P, Tawara JN, et al. Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5’-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci. 2000; 97(4):1433–1437.
Stermitz FR, Tawara-Matsuda J, Lorenz P, et al. 5’-Methoxyhydnocarpin-D and pheophorbide a: Berberis species components that potentiate berberine growth inhibition of resistant Staphylococcus aureus. J Nat Prod. 2000; 63(8):1146–1149.
Stermitz FR, Beeson TD, Mueller PJ, et al. Staphylococcus aureus MDR efflux pump inhibitors from a Berberis and a Mahonia (sensu strictu) species. Biochem Syst Ecol. 2001; 29(8):793–798.
Musumeci R, Speciale A, Costanzo R, et al. Berberis aetnensis C Presl extracts: antimicrobial properties and interaction with ciprofloxacin. Int J Antimicrob Agents. 2003; 22(1):48–53.
Ivanovska N, Philipov S. Study on the anti-inflammatory action of Berberis vulgaris root extract, alkaloid fractions and pure alkaloids. Int J Immunopharmacol. 1996; 18(10):553–561.
Iauk L, Costanzo R, Caccamo F, et al. Activity of Berberis aetnensis root extracts on Candida strains. Fitoterapia. 2007; 78(2):159–161.
Chen HY, Ye XL, Cui XL, et al. Cytotoxicity and antihyperglycemic effect of minor constituents from Rhizoma Coptis in HepG2 cells. Fitoterapia. 2012; 83(1):67–73.
Zhu J, Xin FQ, Chen X, et al. Synergism of alkaloids from Coptis Rhizoma. Shi Zhen Med Mater Med Res. 2010; 21:2282–2284 [in Chinese].
Yi J, Ye X, Wang D, et al. Safety evaluation of main alkaloids from Rhizoma Coptidis. J Ethnopharmacol. 2013; 145(1):303–310.
Ma BL, Ma YM, Shi R, et al. Identification of the toxic constituents in Rhizoma Coptidis. J Ethnopharmacol. 2010; 128(2):357–364.
Feng Y, Wang N, Ye X, et al. Hepatoprotective effect and its possible mechanism of Coptidis rhizoma aqueous extract on carbon tetrachloride-induced chronic liver hepatotoxicity in rats. J Ethnopharmacol. 2011; 138(3):683–690.
Ye X, Feng Y, Tong Y, et al. Hepatoprotective effects of Coptidis rhizoma aqueous extract on carbon tetrachloride-induced acute liver hepatotoxicity in rats. J Ethnopharmacol. 2009; 124(1):130–136.
Yan R, Wang Y, Shen W, et al. Comparative pharmacokinetics of dehydroevodiamine and coptisine in rat plasma after oral administration of single herbs and Zuojinwan prescription. Fitoterapia. 2011; 82(8):1152–1159.
Jia X, Jiang J, Chen B, et al. Progress in research of processing of fructus Evodiae-Rhizoma Coptidis and research thoughts and methods of its processing mechanism. Zhongguo Zhong Yao Za Zhi. 2009; 34(10):1314–1317 [in Chinese].
Ma BL, Yao MK, Han XH, et al. Influences of Fructus evodiae pretreatment on the pharmacokinetics of Rhizoma coptidis alkaloids. J Ethnopharmacol. 2011; 137(3):1395–1401.
Dharmananda S. Evodia: Traditional and Modern Uses. Institute for Traditional Medicine, Portland, OR. http://www.itmonline.org/articles/evodia/evodia.htm [accessed 19 Feb 2015] , 2010.
Zhao FR, Mao HP, Zhang H, et al. Antagonistic effects of two herbs in Zuojin Wan, a traditional Chinese medicine formula, on catecholamine secretion in bovine adrenal medullary cells. Phytomedicine. 2010; 17(8–9):659–668.
Shi HL, Wu XJ, Liu Y, Xie JQ. Berberine counteracts enhanced IL-8 expression of AGS cells induced by evodiamine. Life Sci. 2013; 93(22):830–839.
Wang XN, Han X, Xu LN, et al. Enhancement of apoptosis of human hepatocellular carcinoma SMMC-7721 cells through synergy of berberine and evodiamine. Phytomedicine. 2008; 15(12):1062–1068.

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