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A Review on Pharmacological and Therapeutic Properties of Echinacea Mostafa Ganjuri1, Sara Darakhshan2,3* and Fereidoun Taghizad4 1Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran 2Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran 3Department of Pharmaceutics, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran 4Department of physiology, Faculty of veterinary medicine, Ferdowsi University of Mashhad, Mashhad, Iran

Received: July 28, 2016; Accepted: November 7, 2016; Published: November 11, 2016

*Corresponding author: Sara Darakhshan, Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran; Tel: +988334274545; Fax: +988334274545; E-mail: [email protected]

Kinase; MCP: Monocyte Chemotactic Protein; MDR: Multiple Abstract Drug Resistance; MHC: Major Histo Compatibility Complex; MIP-

The botanical Echinacea supplement market is growing at a rapid rate 1: Macrophage Inflammatory Protein-1; NF-κB: Nuclear Factor- and this trend is expected to continue to progress. In the world of Kappab; NK cells: natural killer cells; NO: Nitric Oxide; PARP: Poly- Nutraceuticals plant is widely used for medicinal and ADP-Ribose Polymerase; PBMCs: Peripheral Blood Mononuclear commercial purposes. This Native American herb has a remarkable Cells; PGE2: Prostaglandin E2; PI3K: Phosphatidylinositol-3- record of clinical and laboratory study, as Echinacea well a long history of medicinal use in the management of a variety of conditions. Kinase; PPAR-γ: Peroxisome Proliferator-Activated Receptor- Phytomedicinal preparations from the genus of areEchinacea widely Gamma; SOD: Superoxide Dismutase; sRBC: sheep Red Blood used for the prevention and the treatment of common cold and upper Cells; STAT: Signal Transducer and Activator of Transcription; respiratory tract infections.in However, vitro most of the uses of TBARs,: Thiobarbituric Acid-Reactive Substances; TGF-β: thatare based Echinacea on the reported immunological properties; there is a large Transforming Growth Factor-beta; TLR4: Toll-Like Receptor 4; body of evidence, based on and animal studies, demonstrating TNF-α: Tumor Necrosis Factor-Alpha; UGT1A: UDP-Glucuronysl possess anti-inflammatory, anti-oxidative, and anti- Introduction microbial properties. It has also been suggested that this plant is a Transferase 1A, URI: Upper Respiratory Infection Echinaceapotential therapeutic agent for cancer, diabetes and skin problems. From the other point of view, on the basis of the available safety data, has little adverse effects and is well tolerated. Echinacea Nowadays, the use of herbal/botanicalEchinacea products has become has agained best- growing acceptance by public due to the belief that they are This paper reviews the pharmacological properties of natural and, therefore, safe [1]. genusKeywords: and its individual Echinacea active components. Echinacea has selling medicinal herbal preparation of all time in North America ; Common Cold; Coneflower; Inflammation; and Europe [2]. Several species in the genus of Review been used for centuries, customarily as a remedy to treat a Abbreviations number of ailments including common cold, coughs, bronchitis, Upper Respiratory Infections (URI), abscesses, wound infections, gangrene, eczema, dizziness, sore eyes, snake bites, syphilis, ABTS: 2,2’-Azino-Bis(3-Ethylbenzothiazoline-6-Sulphonic typhoid, malaria, diphtheria, hemorrhoids, and tumors [3,4]. Acid); AP: Activator Protein; ATF-2: Activating Transcription Numerous pharmacological Echinacea investigations. Interest are in availableEchinacea inis Factor-2; cAMP: cyclic Adenosine Mono Phosphate; CB : literature and they are related to several kinds of preparations Cannabinoid Receptor; CCL: Chemokine (C-C motif) Ligand; obtained from the species of CCR: C-C Chemokine Receptor; CD: Cluster of Differentiation; focused on its immunomodulatory effects [5-9], and particularly C-EBP: CCAAT-Enhancer-Binding Protein; COX:Cyclooxygenase; several clinical trials have been done in the prevention and Echinacea CREB-1: cAMP Responsive Element Binding Protein-1; CYPs: treatment of common cold and URIs [10-14]. Cytochrome P450 Enzymes; ERK: Extracellular Signal-Regulated The beneficial effects of are also in a variety of Kinase; G-CSF: Granulocyte-Colony Stimulating Factor; GSPx: disease states, suchEchinacea as inflammation [15,16], oxidative conditions Glutathione Peroxidase; Gy: Gray; HO-1, heme oxygenase-1; hsp: [17,18], cancer [19-21], skin problems [22], and liver diseases Heat Shock Protein; H2O2: Hydrogen Peroxide; IFN-γ: Interferon- [23]. In addition, Echinacea exhibit anti-microbial [24-27] and Gamma; IL: Interleukin; iNOS: inducible Nitric Oxide Synthase; anti-diabetic properties [28-30]. This review focuses on the JNK: c-Jun N-terminal Kinase; LDL: Low-Density Lipoprotein; pharmacological benefits of and its active ingredients LPS: Lipopolysaccharide; MAPK: Mitogen-Activated Protein in the context of its therapeutic potentials (Figure 1). Symbiosis Group *Corresponding author email: [email protected] A Review on Pharmacological and Therapeutic Properties of Echinacea Copyright: © 2016 Darakhshan et al.

Table 1: Echinacea “Echinacea Echinacea All of the relevant databases were searched for the term KingdomScientific classificationPlantae of Characteristics” and information and Chemical on Compounds was collected via Order electronic search by using PubMed and Science Direct. Family Echinacea Asterales Genus AsteraceaeEchinacea (Compositae) , commonly called coneflower, is a genus of herbaceous perennial flowering plants in the daisy family, Species angustifolia,tennesseensis atrorubens, laevigata, pallida, AsteraceaeEchinacea and originates in eastern North America [2]. paradoxa, purpurea, sanguinea, simulata, Traditional taxonomic system has reported that nine species of exist in nature [31] (Table 1), however,Echinacea under a recentE. purpurea reclassificationE. angustifolia system, fourE. pallida species and eight varieties are categorized [32]. Among species of the genus, , , and have been the most widely used in medicine for their pharmacological properties [33] (Figure 2). Echinacea species The main bioactive compounds present in include alkylamides (alkamides), caffeic acid and its derivatives (caftaric, chlorogenic and cichoric acid, cynarin and echinacoside), polysaccharides, glycoproteins, lipoproteins, and acetylenes Figure 2: a) Echinacea purpurea, b) E. angustifolia E. pallida. (polyacetylenes and polyenes) [34,35]. There are trace elements , and c) including Ca, Echinacea Mg, Fe, Mn, Cu, Zn, Ni, and Li in root, stem, leaves, and flowers [36]. However the concentration of key compounds pallida in species of vary by plant age, plant parts used, growth conditions, geographical location, and method of extraction significantlyE. inhibited pallida Nitric Oxide (NO) production by [37]. In addition, the distribution of chemical compounds and Lipo Poly Saccharide (LPS)-activated the RAW 264.7 macrophage cells, among which was the most active. The enzymes Echinaceabiological activities differ within the same plant (root, stem, leaves and flowers) [38]. For example, the alkylamide content in Nitric Oxide Synthase (iNOS) and arginase metabolize a common species appears to be higher in roots, to increase with substrate, L-arginine, but produceEchinacea different biological effects. age and to differ with the geographical area of cultivation [38]. While iNOS is involved in inflammation, arginase contributes to Echinacea anti-inflammatoryE. pallida response. can modulate the iNOS/ Several forms of commercial preparations are available arginase balance due anti-inflammatory activation. The alcoholic that use different parts of the plant such as roots, extract of inhibited iNOS enzyme at protein level inE. seeds, flowers, and leaves. The most commonly used form is the angustifoliaLPS-treated RAWE. pallida 264.7 macrophages,E. purpurea whereas arginase activity tincture, which is a liquid ethanol-water extract. Other forms of the cells was significantly improved by alcoholic extracts of include powdered ethanol-water extract, freeze-dried ethanolic , and . The hydrophilic fraction or hydrophilic extracts, capsule and tablet, skin cream, ointment Anti-Inflammatory Effects containing caffeic acid derivatives enhanced arginaseEchinacea activity,- and gel, and pressed juice and tea. while the hydrophobic fraction containing alkamides inhibited iNOS expression and NO production [15].Echinacea The present at Currently special emphasis has been given to the role mediated decrease in NO production was generally associated of inflammation in the pathogenesis of diseases. For a long with decreased protein level of iNOS, E. time, medicinal plants have been used as remedies for various purpureathe onset of LPS-induced iNOS expression led to a stronger inflammatory conditions. E. angustifolia E. purpurea E. inhibitory effect on NO production. An alcoholic tincture of roots considerably inhibited the nuclear expression The alcoholic extracts of , and of pro-inflammatory transcriptionEchinacea factors commercial NF-κB and preparations STATs in rhinovirus-infected cells [39]. In a study using gene and proteinE. purpureaarray analysis the effects of E. purpurea (E1 was an aqueous expressed juice of the aerial parts, of , and E2 was a 50% ethanol tincture from roots) on rhinovirus infection was evaluated by BEAS-2B a line of human tracheobronchial epithelial cells. It found that rhinovirus E.infection purpurea would increase some inflammatory cytokines at mRNA and protein levels, and that these effects could be reversed by . Substantial increasesE. purpurea were observed about the pro- inflammatory cytokines IL-6 and IL-8 (CXCL8) at protein levels Figure 1: Echinacea plant. thatE. was angustifolia ameliorated by [40]. Pharmacological properties of preparation enriched fractions Bauer Citation: Echinacea. Int J

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alkylamide 11 and Bauer ketone 23 showed anti-inflammatory oil-induced mouse ear dermatitis when applied topically. effect in LPS-induced RAW264.7 mouse macrophage cell line. Polysaccharidic fraction also reduced the leukocytic infiltration These treatments decreased Prostaglandin (PG)E2 production of the croton oil dermatitis, evaluated both from histological and Echinacea and inhibition of PGE2 production may be due to targeting ofE. peroxidase activity aspects [50]. Cyclooxygenase (COX)-2 enzyme activity [41]. In macrophages angustifolia These studies suggesting that influences subjected to Hydrogen Peroxide (H2O2), treatment by inflammatory pathways and may modulate pro-/ anti- extract reversed mRNA expression of COX-2, Echinacea as an Anti-Oxidant inflammatory ratio. Interleukin (IL)1-β, NF-κB1, NF-κB2, and Tumor Necrosis Factor (TNF)-α, alsoE. tennesseensis Peroxisome Proliferator-Activated Receptor (PPAR)-γ to normal levels [42]. In a study, 50% ethanolic The relationship between free radicals and the incidence tinctures of were prepared from roots, stems, of various types of diseases has led to considerable interest in leaves, and flowers ofin vitro the plant. Fresh root, leaf, and flower preventive medicine in assessing the free radical scavenging tinctures stimulated human Peripheral Blood Mononuclear Cells Echinacea alcoholic activity of Echinacea medicinal species. plants and other nutritional anti-oxidant (PBMC) proliferation , also fresh root tincture stimulated supplements. There have been several reports on anti-oxidative IL-10 production [43]. Oral administration of benefits of E. purpurea E. angustifolia extract to mice increased production of anti-inflammatory E. pallida cytokines IL-4 and IL-10, but decreased production of TNF-α and Methanolic extracts of freeze-dried , IL-1β in activated spleen cells [44]. and roots have anti-oxidant activities and were capable of scavenging Hydroxyl Radical (OH·). Similar scavenging In murine macrophages, the alkamides significantly inhibited threecapacities species for each extract were found for both 1,1-Diphenyl-2- COX-2 activity and suppressed the LPS-induced expression of Picrylhydrazyl (DPPH) radical and ABTS radical. Moreover all COX-2, iNOS, TNF-α, IL-1α, IL-6, and Monocyte Chemotactic were found to delay the formation of conjugated Protein (MCP)-1, but elevated Heme Oxygenase-1E. (HO-1) pallida protein each diene hydroperoxide-induced by the thermal decomposition of expression [16]. In RAW264.7 macrophage cells, chemically 2, 2’-azobis(2-amidinopropane) dihydrochloride and extend synthesized Bauer Ketones 21 and 23 from the lag phase of peroxidation of soybean liposomes.2+ Each significantly inhibited both PGE2 and NO production; as well root extract suppressed the oxidation of human Low-Density Bauer Alkylamide 11 repressed production of PGE2 and NO [45]. LipoproteinE. purpurea (LDL), following oxidative modification by Cu [17]. Other results showed that polyunsaturated alkamides, undeca- The efficacy of the extracts from the stems, leaves, and roots of 2Z-ene-8,10-diynoic acid isobutylamide (A5), dodeca-2E-ene- E. purpurea in the reaction with DPPH correlated well with the 8,10-diynoicE. angustifolia acid isobutylamide (A7), and dodeca-2E,4Z-diene- amount of cichoric acid present in the extracts. The alkamides 8,10-diynoic acid 2-methylbutylamide (A8), isolated from roots from alone showed no anti-oxidant effect; however, of wereE. paradoxa efficient inhibitors of COX-2 activity and alkamides present in the extract improved the anti-oxidative suppressed PGE2 formation in H4 human neuroglioma cells [46]. activity of cichoric acid in the peroxidating lipid emulsion [51]. Ethanolic extract of var. paradoxa, rich in polyenes/ CuIn 2+ another study the anti-oxidant activities of echinacoside polyacetylenes suppressed LPS-induced production of NO, and caffeic acid was compared by measuring their inhibition of PGE2, IL-1β and IL-6 in stimulated RAW264.7 macrophage cells.E. -catalyzed oxidation of human LDL. The efficiency of anti- Pentadeca-8Z-ene-11, 13-diyn-2-one (Bauer ketone 23) and paradoxa oxidant activity of the tested substances was: cichoricEchinacea acid had pentadeca-8Z, 13Z-dien-11-yn- 2-one (Bauer ketone 24) from the highest capacity, the second was echinacoside, and finally were found mainly responsible for inhibitory effects on caffeic acid. E. Synergistic purpurea anti-oxidative effects of NO and PGE2 production [47]. E. purpurea roots components wereE. pallida found whenE. angustifolia cichoric acid (major caffeic acid A polysaccharide from water extract of derivative in ) or echinacoside (major caffeic acid inhibited Pam3Csk4-stimulated release of TNF-α by human THP- derivative in and ) were combined with 1 acute monocytic leukemia cells. This anti-inflammatory activity a mixture of alkamides and/or an aqueous extract containing the E. highE. molecular purpurea weight polysaccharides [52]. waspurpurea shown to be mediated by the Phosphat Idylinositol-3-Kinase (PI3K)/Akt signaling pathway [48]. The cichoric acid from was given to mice at a dose of 30 mg/ kg body extract has anti-inflammatory activity in rheumatoid weight for 14 days before and after irradiation with 3 Gy of arthritis by collagen-induced arthritis rat model. Administration γ-rays. The results reflected the reduced effects of γ-rays on of cichoric acid for 4 weeks significantly decreased the paw peripheral blood hemoglobin and red blood cells, differential swelling, restored body weight gain, and decreased the organ white blood cells and bone marrow cells counts in γ-irradiated index of the thymus and spleen compared with that of the arthritis mice. The changes observed in Thiobarbituric Acid-Reactive group. The cichoric acid reduced the TNF-α, IL-1β and PGE-2 Substances (TBARs) level, SuperoxideE. purpurea Dismutase (SOD) levels in serum; also decreased the levels of NF-κB, TNF-α and E. and Glutathione Peroxidase (GSPx) activities, as E. well purpurea DNA angustifoliaCOX-2 in synovium root extract tissues of the ankle joint compared with the fragmentation were ameliorated by administration arthritis group [49]. A polysaccharidic fraction obtained from [18]. In a study the radio-protective properties of (0.5 mg/ kg) inhibited the carrageenan- tablets in a group of radiation workers who were identified as induced rat paw edema in intravenous injection and the croton carrying dicentric chromosomes in their lymphocytes were Citation: Echinacea. Int J

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Echinacea investigated. All radiation workers were taking two 275 mg MononuclearIL-10, and NO Cells secretion, asin well vitro as to significantly enhance tablets for two week treatment. At the end of period,E. the viability and/or proliferation of human Peripheral Bloodin lymphocytepurpurea chromosome aberrations frequency dropped vitro (PBMCs) [59]. Randolph, etEchinacea al. [60] significantly, and the number of apoptotic cells increased [53]. in a preliminary study in six healthy individuals found that administration had a suppressiveE. effect purpurea on radiation- exposure of THP-1 peripheral leukocytes to induced lymphocytopenia and monocytopenia, and resulted extract induced expression of the IL-1α, IL-1β, IL-8, TNF-α, in a faster recovery of blood cell counts. activated Intra Cellular Adhesion Molecule (ICAM), and IL-10 genes. macrophages to stimulate IFN-γ production in associationE. Serum and hematological values Echinacea were not different from® is purpureawith the secondary activation of T lymphocytes, and cytokines baseline, suggestingE. purpureathat liver or bone marrow responses were released from macrophages in mouse peripheral blood after not involved in acute responses to . Echinaforce administration activated helper T cells to proliferate. In exthe vivo standardized preparation from ® combined root addition, SOD activity_ in peripheral blood was increased because and aerial ethanolic extract, from Bioforce, Switzerland. In an of echinacoside and caffeic acid as anti-oxidants which eliminate study oral administration Echinaforce reduced the superoxide (O2 ) [54]. Echinacea pro-inflammatory mediators TNF-α and IL-1β, and increased anti-inflammatory IL-10 levels. Chemokines Macrophage® These results indicate that and its derivatives are a Inflammatory® Protein-1 (MIP-1)α and IL-8 were up-regulated good source of natural anti-oxidants and could be used to prevent Polinacea Immunomodulatory Activities in blood samples from subjects treated with Echinaforce [61]. the damaging effects of free-radicals. E. angustifolia is a standardized hydroethanolic extract obtained from ® roots containing echinacoside, the high Herbal medicine provides several remedies for strengthening molecular weight polysaccharide IDN 5405 and an isobutylamide the body’s resistance to illness by acting on various components fraction. Polinacea in 10 healthy subjects was administered as of the immune system. A class of medicinal plants, known as herbal syrup once a day for 30 days (containing 100 mg). Results showed the up-regulation of mRNA expression of IL-2 and IL-8 immunomodulators, alter the activityEchinacea of immune function through the regulation of molecules such as cytokines, and the down-regulation mRNA levels of the pro-inflammatory cytokines TNF-α and IL-6; these changes positively correlated chemokinesimmune responses. and immunoglobulins. is a wide-spectrum immunomodulator that regulates both innate and adaptive withE. the purpurea protein levels detected in the plasma [62]. Echinacea preparations ethanolic extract can regulate the differentiation In normal rats oral administration of of Dendritic Cells (DCs), which are known as professional (containing its components cichoric acid, polysaccharides and antigen-presenting cells. Alkylamide-rich root extract promoted alkylamides) two times/day for 4 days improved phagocytic maturation of human DCs in a similar manner as LPS; however, the stem plus leaf extract inhibited DC maturation. Down-regulation activity of alveolar macrophage, alsoEchinacea TNF-α and was NO apparent release by in the mRNA expression of chemokines MIP-1α, and MCP-2, and the LPS-stimulated alveolar macrophages. An enhancedEchinacea release aerial of TNF-α and IFN-γ in response to receptors CD191 (CCR1) and CDw199 (CCR9) were observed in spleen macrophages [55]. In a study, extract of stem plus leaf extract-treated DCs. Regulatory molecules MIP-1β parts (50 mg/ kg) was administered over an 8-week period to and MCP-1 involvedE. purpurea in the c-Jun pathway were found to be up- male Sprague-Dawley rats. This treatment significantly increased regulated in root extract-treated DCs [5]. The polysaccharide-rich root extract of increased the expression of MHC class Echinaceacirculating total white cell counts, and IL-2 level [56]. Normal II, CD86, and CD54 surface biomarkers after 48 hours of exposure, human peripheral blood macrophages cultured in E. presence purpurea of ethanolic extract produced higher amounts of IL- whereas the alkylamide-rich leaf extract inhibited the expression 1, TNF-α, IL-6 and IL-10 than unstimulated cells. of these molecules. Production of IL-6 and TNF-α increased with increased the number of cytotoxic T cells and suppressor T cells. exposure to the root, in contrast, the leaf extract inhibited COX-2 An increase was observed in IFN-γ levels which activated cell- activity. While both extracts decreased the uptake of ovalbumin by murine Bone Marrow-Derived Dendritic Cells (BMDCs), the mediated immune responses, such as proliferationE. and purpurea activation on of type I helper T (Th1) cells [57]. Sullivan, et al. [58] examined leaf extract inhibited the antigen-specific activation of naïve CD4+Echinacea T cells from OT II/Thy1.1 mice [7]. withthe effects of polysaccharides isolated from macrophages. Murine peritoneal macrophages were cultured is found to be a potent activator of Natural Killer E. purpurea (NK) cells; these cells are active in non-specific immunity against E. purpurea virus-mediated infections and tumors. Mice immunized with extract enrichedE. for purpurea polysaccharide. The results E. angustifolia, E. pallida, E. showed an extract stimulated production of IL-6, IL- sheeppurpurea Red. The Blood three Cells extracts (sRBC) were gavaged for 7 days with 12, and NO from macrophages. triggered a signaling each of the alcohol extracts from and cascade within macrophages through both TLR4-dependent increased percentages of CD49+ and and -independent mechanisms, involving ERK, p38 and c-Jun EchinaceaCD19+ lymphocytes in spleen and NK cell cytotoxicity. Antibody N-terminalE. purpurea Kinase (JNK), and ultimately the activation of NF-κB. response to sRBC was improved equally by extracts of all three- E. angustifolia-species. In addition,E. pallida each extract significantly increased whole herb and root powders were found to IFN-γ production, but inhibited the release of TNF-α and IL stimulate murine macrophage for TNF-α, IL-1α, IL-1β, IL-6, 1β. and -treated mice demonstrated Citation: Echinacea. Int J

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Echinacea E. purpurea higher productionE. purpureaof IL-4 and increased IL-10 production [44]. cell production of IL-4 and IL-10 suggesting that may be capable of stimulating non-specific immunity stimulation of both Th-2 and Th-1Echinacea cytokine production improved in the elderly. after two weeks of administration B cell function and increased antibody formation [44]. A diet had the capacity to increase the number of NK cells in aging supplemented with 1% w/ w for 28 days can enhance mice, reflecting increased new NK cell production in their bone immune function by increasing antibody production which marrow generation site, leadingE. purpurea to an increase in the absolute resulted from augmenting bothEchinacea Th1 and Th2 cytokine production. numbers of NK cells in the spleen, their primary origin [63]. Production amount of IgA, IgG, and IgME. was pallida higher in the splenic Administering root extract of daily for 50 days from lymphocytesE. of purpurea rats fed with [70]. Arabino Galactan- the onset of leukemia in mice augmented NK cells and prolonged Proteins (AGPs) purified from roots of and suspension life span. Treatment had an increasing effect on theE. purpurea absolute- culture of induced the IgM-production of mouse numbers of NK cells in spleens in 9 days (intermediate stage lymphocytes and stimulated IL6-productionE. in angustifolia alveolar mouse root leukemia). Three months after leukemia beginning, macrophage culture [71]. A study by Rehman and colleagues treated leukemic mice had 2-3 times the normal numbers of NK [6] demonstrated that oral administration cells in their spleens, also all the major hemopoietic and immune extract of rats for a period of 6 weeks which were injected cell lineages in their bone marrow origin site were recorded at with the antigen Keyhole Limpet Hemocyanin (KLH) and re- Echinacea normal numbers [64]. exposed to KLH after theE. initial purpurea exposure, showed a significant Echinacea augmentation of their primary and secondary IgG response to increased the frequency of NK target conjugates the antigen. Extract of enhanced cellular immune and activated the programming for lysis of NK cells. ei function of PBMC both from normal individuals and patients with resulted in the activation of CD69 expression and increase in mean ther the chronic fatigue syndrome or the Acquired Immuno fluorescence intensity in both the CD16+ and CD56+ NK subsets. Echinacea. There was recruitment Deficiency Syndrome (AIDS). The addition of herb significantly As well, the frequency of CD56+ killer cells in the conjugates was increased both antibody-dependent and NK-mediated activities also significantly increased by against cells infected with herpes E.virus purpurea [72]. of non-conjugated CD56+ cells into CD16+ NK-target conjugates and activation of the NK-target non-killer conjugates into killer Polysaccharides isolated from activatedE. peritoneal purpurea- cells [65]. E. purpurea macrophages after administration of cyclophosphamide or Cyclosporin A (CsA) in immunodeficient mice. Water-soluble extract from fresh aerial parts treated macrophages exhibited increased production of TNF-α (containing 80% polysaccharides, phenolic compounds, cynarin, well as against the intracellular Leishmania enrietti and higher cytotoxicity against tumor target WEHI-164 as cichoric and caftaric acids) strongly enhanced T-cell production . After a of IL-2 and IFN-γ in response to Phorbol 12-Myristate 13-Acetate E. angustifolia cyclophosphamide-mediated reduction of leukocytes in the (PMA) plus ionomycin stimulation [66]. The addition of cichoric E. purpurea E. purpurea peripheral blood, the polysaccharides induced an earlier acid from a root extract (prepared from both and - influx of neutrophil granulocytes. treatment after ) and 2,4-diene alkylamide-derived from combination Listeria cyclophosphamide or CsA restored their resistance against lethal of both species induced NF κB expression after PMA stimulation monocytogenes infections with the macrophage-dependent® pathogen of Jurkat T-cell line [67]. In a study by Sasagawa et al. Jurkat Candida albicans Echinacea and predominantly granulocyte-dependentC. albicans cells were treatedE. purpurea with ethanolic extract prepared from dried [73]. Polinacea administered orally showed an leaves and flowers of with alkylamides or caffeic acid immune-stimulating activity by reducing the -induced derivatives. 95:5 ethanol/water extract inhibited mortality both in normal and in CsA-treated mice. It enhanced phytohemagglutinin-dependent production of E. IL-2, purpurea and this T-cell function and proliferation by stimulating IFN-γ production Glycyrrhizainhibitory activity glabra correlated with® the presence of alkylamides in anti-CD3-treated murine T-cell cultures [74]. but not caffeic acid derivatives [9]. A mixture of and Echinacea-derived alkamides have a structural similarity to root (Revitonil tablets) showed a stimulatory effect on human granulocytes, and notable stimulating activity anandamide, an endogenous ligand of cannabinoid receptors; was observed in the T-lymphocyte CD69 bioassay [68]. It found consequently, it was found that alkamides bind to Cannabinoid that decreased number and function of regulatory T cells (Tregs) Receptor (CB) type-1 and -2, therefore suggested as a new class of cannabinomimetics [75]. CB2 receptor is abundantly in association with the enhancedE. purpurea feeder function of Antigen- Presenting Cells (APCs) may contribute to the improvement expressed in some of inflammatory and immune cells, and there of immune function by . The CD4+FoxP3+ and is evidence that the CB2 receptor plays aE. role purpurea in inflammatoryE. also immune responses, as well as related pathophysiological CD4+CD25+ Tregs incidence was attenuated and CD4+CD25+E. purpurea angustifolia Tregs function was decreased, while the feeder function of APCs conditions [76]. N-alkylamides from and was enhanced in the mice spleens administered with preparations are capable of stimulating IL-10, and for 3Echinacea weeks [69]. inhibiting expression of TNF-α protein. N-alkylamides exerted pleiotropic effects modulating the endocannabinoid system Echinacea has the potential for enhancement of humoral by activating the CB2 receptor, endocannabinoid transport immune responses as well as innate immunity. An alcohol extract and degradation [77]. Alkylamides dodeca-2E,4E,8Z,10E/Z- of improved the T cell-dependent antibody response tetraenoic acid isobutylamides (1/2), trienoic (3) and dienoic to immunization with sRBCs in mice and increased splenic T acid (4) derivatives induced synthesis of TNF-α mRNA in primary Citation: Echinacea. Int J

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E. purpurea human monocytes/macrophages. This up-regulation was found cells [80]. Ethanolic extract of flowers and its major to be mediated by CB2 receptors, increased cAMP, p38/MAPK compound cichoric acid showed a significant inhibitory effect and JNK signaling, as well as NF-κB and ATF-2/CREB-1 activation on proliferation of human colon cancer cells Caco-2 and HCT- [78]. 116 in a dose- and time-dependent manner. Cichoric acid was E. purpurea able to decrease telomerase activity in HCT-116 cells. Moreover, A controversy result showed that cynarin isolated from cichoric acid effectively induced apoptosis in colon cancer cells, down-regulated immune responses by binding which were characterized by DNA fragmentation, activation of to CD28, a receptor of T-cells on T-lymphocytes, and this caspase-9, cleavage of Poly-ADP-Ribose Polymerase (PARP) and interaction is stronger than the binding between CD28 and CD80, E. pallida down-regulation of β-catenin [19]. An acetylenic constituent of a co-stimulated receptor of antigen presenting cells. Cynarin’s roots, namely pentadeca-(8 Z,13 Z)-dien-11-yn-2-one, function was proved by its ability to down-regulate CD28- Echinacea revealed a concentration-dependent cytotoxicity on leukemia dependent IL-2 expression in a T-cell culture line. It is believed Jurkat and HL-60, breast carcinoma MCF-7, and melanoma MeWo that the immunomodulatory effects of depend on the E. purpurea cell lines. This component arrested the cell cycle in the G1 phase combined action of alkamides, polysaccharides, and chicoric humoral immunity as well as innate immune responses. It on HL-60 cells [20]. When a commercially extract of acid. These components are potentially effective in stimulating Echinacea root was administered to mice immunized with killed leukemia multiple pathways. Echinacea cells in an erythroleukemic mouse model for 3 months the appears likely that stimulates the immune system via Echinacea Echinacea number of NK cells was elevated compared to animals without can affect non-specific immune receiving the . In the group fed with product response, activate innate immune cells such as macrophages, in the early phase of the tumor development the number of T- polymorphonuclear leukocytes and NK cells, stimulate E. purpurea and B lymphocytes in the spleen was markedly enhanced [21]. phagocytosis, and inhibit the production of inflammatory had suppressive effects on spontaneously occurring mediatorsThe results by white about blood Echinaceacells. leukemia causedE. purpurea by endogenous recombinant Murine Leukemia Echinacea immunomodulation seem Viruses (MuLV). Female AKR/J mice were given oral 7.5 mg/ inconclusiveimmunesuppressor. and controversial, It is noteworthy some to mention studies that express immunity that week dose of leaves powder for 8 weeks.E. Mortalitypurpurea is an immunostimulator and some of them state it is an from thymic lymphoma was delayed and enlargement of thymic lymphoma in experimental mice was suppressedE. purpurea with is a two-edgedEchinacea blade that the body keeps under tight control; preparation. Proliferation of MuLV in the thymus was markedly excessively strong immune reactions can be precarious. Based on inhibited after oral administration of the . Production this concern, should be used withEchinacea caution by can individuals stimulate of endogenousE. purpurea IFN-γ in mice was also effectively augmented by with autoimmune disorders such as rheumatoid arthritis and the oral treatment with herb [81]. The administration of 50 mg/ multiple sclerosis. On the other side, kg extract to rats with Benign Prostate Hyperplasia immunity and may be harmful where immunosuppression (BPH) for 4 and 8 weeks gradually and considerably reduced could be vital in some people such as in Echinaceaorgan transplantation. the prostate mass and reversed the degenerative changes in the Furtherimmune studiessystem. are needed to clarify the mechanisms which are structure of the prostate [82]. responsible for the beneficial effect of observed in Anti-Cancer Effects Gastrointestinal mucositis® is a common complication of chemotherapeutic drugs and there is currently no effective long- termVaccinium treatment. myrtillus SAMITALMacleayais cordata an oral suspensionE. formulationangustifolia Interest in herbal medicine for cancer therapy has dramatically based on the combination of three standardized extracts from , fruits and Echinaceagrown over the past years. Cancer patients may wish to use natural botanicals to inhibit tumor growth and development. roots designed for the relief of oral mucositis-induced by and its compounds have shown promising anti-tumor chemotherapy ® and/or radiotherapy in cancer patients. 20 effects. E. purpurea E. angustifolia pediatric patients undergoing® chemotherapy initially received E. pallida oral SAMITAL to treat gastrointestinal mucositis® and were Hexanic root extract of the , and then given SAMITAL prophylactically to prevent recurrences reduced cell viabilityE. pallida in human pancreatic MIA PaCa- with successive cycles of chemotherapy. SAMITAL significantly 2 and colonic COLO320 cancer cell lines in a concentration- and decreased gastrointestinal® mucositis grade, reduced pain, time-dependent manner. extract induced apoptosis mucosal erosions, bleeding and dysphagia [83]. Phase II trials by increasing caspase-3 activity and the internucleosomal with SAMITAL as part of an overall clinical development degradation of DNA, without evidence of necrotic cell death program are currently ongoing [84]. [79]. Five compounds, two polyacetylenes (namely, 8-hydroxy- Echinacea pentadeca-(9E)-ene-11,13-diyn-2-one and pentadeca-(9E)-ene- These results represent scientific evidence on the possible 11,13-diyne-2,8-dione) and three polyenes (namely, 8-hydroxy- role of species in medical oncology. Because theEchinacea agents used for cancer chemotherapy are known to be highly toxic pentadeca-(9E,13Z)-dien-11-yn-2-one, pentadeca-E. pallida (9E,13Z)- dien-11-yne-2,8-dione and pentadeca-(8Z,13Z)-dien-11-yn-2- area.towards normal cells, immune-enhancing activities by one) isolated from the n-hexane extract of roots induced is looked into with interest and more research is needed in this apoptosis in pancreatic MIA PaCa-2 and colonic COLO320 cancer Citation: Echinacea. Int J

Ganjuri M, Darakhshan S, Taghizad F (2016) A Review on Pharmacological and Therapeutic Properties of Page 6 of 18 Pharmacovigil 1(1): 18. A Review on Pharmacological and Therapeutic Properties of Echinacea Copyright: © 2016 Darakhshan et al.

Anti-Microbial Properties 10 production, diminished IL-2 production, and had no effect on IFN-γ production [88]. Several anti-microbial agents are available but have some Echinacea side effects. To overcome this problem, many natural sources Results indicated that rhinovirusE. infection purpurea of epithelial cells particularlyE. pallida medicinalE. plants purpurea can be considered as alternatives. treated with led to profound effects on numerous mediators. An alcohol tincture from roots increased and inhibitedSalmonella NO production enterica and the expression of several transcription factors in non-activated TNF-α release from LPS-stimulated RAW 264.7 macrophage human bronchial epithelial BEAS-2B cell line, but inhibited the cells in response to infection Echinacea of . Upon expression of these when the cells were infected with rhinovirus. bacterial infection, RAW 264.7 cells produced high levels of NO; The BEAS-2B cells were used as the model, and nuclear extracts of however, alcoholic extract of administered orally E. purpurea extract. It was E. purpurea uninfected cellsEchinacea and rhinovirus-14 infected cells were examined for one week decreased NOPseudomonas production inaeruginosa a dose-dependent with and without treatment with Emanner. purpurea [85]. The use of extract had prophylactic found that increased the nuclear content of several effect on the development of infection. transcription factors, including the pro-inflammatory factors feeding resultedEchinacea in diminishing bacterial number such as Activator Protein (AP)-1, AP-2, NF-κB, and STATs 1-6. in livers of C57Bl/6 (susceptible strain) and B6C3F1 (relative Infection by rhinovirus resultedEchinacea in a more dramatic increase in resistant strain) mice. feeding of the second relative these transcription factors; however, when rhinovirus-infected resistant strain Echinacea (BALB/c x C3H) F1 resulted in stimulation of cells were treated with , transcription factor levels granulocytes chemiluminescent and lymphocytes proliferative were reduced to low levels [39]. Preparations include juice from response [86]. could inactivate certain® respiratory the aerial parts of the plant (which contain polysaccharides) and Streptococcusbacteria and could pyogenes also reverse inflammatory effects caused alcoholic tinctures from roots (containing caffeic acid derivatives by these bacteria in epithelial cells. Echinaforce inactivated and alkylamides) stimulated the release of pro-inflammatory Hemophilus influenzae(Group A streptococcus),Legionella pneumophila which is factors from uninfected BEAS-2B bronchial epithelial cells. often associated with sore throat and more severe pulmonary Exposure to Rhinovirus 14 stimulated the release ofEchinacea several infections. and Staphylococcus aureus chemokines known to attract inflammatory cells, and most these were also readily inactivated, and their cellular pro-inflammatory Mycobacterium effects wereEchinacea reversed by introduction either of the two smegmatisresponse completely reversed. Moreover ® extracts [89]. These results could explain the anti-inflammatory (methicillin-resistant and sensitive strains) and effects of . The rhinovirus type 1A (RV1A) resulted in were also sensitive to Echinaforce [24]. increased mucopolysaccharide inclusions in the goblet cells of Echinacea by Echinacea Influenza infection is an important clinical problem. normal human airwayEchinacea epithelial cells; this change was reversed extracts® and active components have the potential for treatment. MucusEchinacea production treatment. during colds Echinacea could be being used in improving the pathology of influenza infections. ameliorated by because mucin secretion stimulated Echinaforce has potent anti-viral activity against the IV strains, by RV1A is reversed by human Victoria (H3N2) and PR8 (H1N1), avian strains KAN- also inhibited secretion of substantial amounts of the pro- E. pallida 1 (H5N1) and FPV (H7N7), and the pandemic S-OIV (H1N1). inflammatory cytokines IL-6 and IL-8 in RV-infected tissues [90]. Human H1N1-type IV, highly pathogenic ® avian. Haemagglutination IV (HPAIV) of The hydroalcoholic extract also pressed juice of the H5 and H7 types, as well as® swine origin IV (H1N1) were exhibited anti-viral activity against herpes simplex virus types inactivated in treatment by Echinaforce 1 and 2 (HSV-1, HSV-2) in a Echinacea dose-dependent manner. Plaque assays showed that Echinaforce inhibited the receptor bindingin vitro formation was significantly reduced by more than 99% or activity of the virus, suggesting that the extract® restricted the completely absent. In addition juice revealed anti-viral viral entry into cells. In sequential passage studies under activity during all phases of the viral replication cycle, protected treatment with the H5N1 virus no Echinaforce -resistant variants cells against viral infection by interferingE. with purpurea virus attachment appeared, in contrast to Tamiflu, which® produced resistant and could interact with herpes virus inside and outside the viruses upon passaging. In addition, the Tamiflu-resistant cell [91]. Polysaccharide isolated from promoted viruses were susceptible to Echinaforce as well as the wild immune response, leading to a reduced latency phase, and it has type viruses [26]. The alkylamides undeca-2Z,4E-diene-8,10- a promising effect on latency prevention in HSV-1 when supplied diynic acid isobutylamide, dodeca-2E,4E,8Z,10E/Ztetraenoic prior to infection [92]. The rhinoviruses 1A and 14, influenza acid isobutylamide, dodeca-2E,4E-dienoic acid isobutylamide, virus, Respiratory Syncytial Virus (RSV), adenovirus types 3 and and undeca-2E-ene-8,10-diynoic acid isobutylamide suppressed 11, and HSV-1® induced secretion of IL-6 E. purpurea and IL-8, preparation in addition production of TNF-α and PGE2 from RAW 264.7 macrophage to several other chemokines, depending on the virus; and cells-infected with the H1N1 influenza A strain PR/8/34. Dodeca- Echinaforce inhibited this induction. 2E,4E-dienoic acid isobutylamide especially inhibited production effectively inhibited the virus-induced cytokine secretion and of these mediators and also strongly suppressed production of pro-inflammatory responses induced by all the viruses tested in Granulocyte-Colony Stimulating Factor (G-CSF), MCP-1, MIP- BEAS-2B human bronchial epithelial cells. This preparation also 1α and CCL5 (RANTES)E. tennesseensis [87]. In the context of influenza virus- showed potent virucidal activity against viruses with membranes stimulated human PBMCs from older individuals vaccinated such as RSV, HSV, and influenza virus, at the oral recommended against influenza, root tinctures augmented IL- dose [93]. Citation: Echinacea. Int J

Ganjuri M, Darakhshan S, Taghizad F (2016) A Review on Pharmacological and Therapeutic Properties of Page 7 of 18 Pharmacovigil 1(1): 18. A Review on Pharmacological and Therapeutic Properties of Echinacea Copyright: © 2016 Darakhshan et al.

In an open-label, fixed-sequence study, 50 patients infected at early onset of cold or flu symptoms was effective for relieving® can be by human immunodeficiency virus (HIV) received anti-retroviral these symptoms in a shorter period [11]. The results from a containingtherapy including E. purpurea 400 mg etravirine (a non-nucleoside reverse clinical study suggested® that treatment with Echinaforce transcriptase inhibitor of HIV) once daily for 4 weeks. Capsules recommended as a prophylactic treatment. Long-term treatment root extractE. were purpurea added to the anti- with Echinaforce was associated with a significant reduction retroviral treatment (500 mg every 8 h) for two weeks. Results in both total number and severity of cold episodes, whereas it showed that the co administration of with etravirine did not induce any health risk above that reported with the was safe and well tolerated in HIV-infected patients [94]. Cichoric placebo treatment ®[99].E. purpurea In a double-blind trial, 246 healthy adult acid has beenin vitro shown to inhibit the HIV-type 1 integrase, improved volunteers with recent onset of a respiratory infectionE. purpurea were given the anti-HIV-1 effect of Zidovudine and protease inhibitor either Echinaforce , concentrate (same preparation ® (AG1350) [95]. at 7 times higher concentration),® special radix Leishmania donovani Leishmania major preparation or placebo until they felt healthy again but not longer Echinaforce inhibited growth of three species of Echinacea extract Trypanosoma brucei. L. donovani than 7 days. Echinaforce and its concentrated preparation were trypanosomatids: , , and significantly more effective than the special stimulated the production® Echinacea or placebo. All treatments were well tolerated, and among the of the pro-inflammatory IL-6 and IL-8 cytokines in human groups, the frequency of adverse events was not bronchial epithelial cells and in skin fibroblasts, but Echinaforce significantly higher than in the placebo group [100]. E.eradicated purpurea this stimulation by anti-inflammatory effect [96]. withBy application the parasite of purified Leishmania polysaccharides enriettii from cell culturesCandida of In a randomized, double-blind, placebo-controlled trial, 282 albicans , peritoneal macrophagesEchinacea killed cells infected either subjects with a history of two or more colds in the previous Saccharomyces cerevisiae, or withCandida yeast shehata year, but otherwiseE. purpurea in good health, were recruited. They were C. kefyr [97].C. albicans ExtractsC. from steatulytica inhibitedC. tropicalis the growth of instructed to start Echinilin (a formulation prepared from freshly several yeasts suchEchinacea as , , harvested and standardized on the basis of active , , and [25]. The components alkamides, cichoric acid and polysaccharides) or alkamides from S. cerevisiae acted synergistically to disrupt the placebo at the onset of the first symptom related to a cold for seven fungal cell wall and cell membrane, a target for Echinaceaspecific inhibition extract days. The total daily symptom scores were found lower in the of fungal pathogens. cells exposed to sub-inhibitory Echinilin group,Echinacea and the response rate to treatments was greater concentrations of synthetic alkamides and in the treated group. Early intervention with a standardized exhibit increased frequencies of cell wall damage and death, formulation of resulted in reduced symptom severity which were comparable to caspofungin and significantly greater in subjects with naturally acquired upper respiratory tract than hygromycin and nourseothricin, which inhibit protein infection [101]. In a study, Echinilin was administered to 150 synthesis [98]. adults at the onset of their cold for one week, with eight doses Echinacea (5 ml/dose) on day 1 and three doses on the subsequent days. These results provide evidence that bacterial, viral, and Common Cold and Upper Respiratory Infections Researchers observed decreased daily symptomatic scores and fungal infections could be halted by administration. Echinacea sustained increase in the number of circulating total white blood cells, monocytes, neutrophils, and NK cells in the The common cold is one of the most prevalent illnesses group versus placebo group. These results suggest that Echinilin, by enhancing the non-specific immune response and stimulating worldwide, coupled withEchinacea a lack of specific treatment options which invites to evaluate alternative therapies such as herbal free radical scavenging properties, may have led to a faster resolution of the cold symptoms [102]. remedies. Nowadays,Echinacea is possibly the most recognized herbal supplement for prevention and treatment of colds. Many In one double-blind placebo-controlled study, a total of 95 people believe that can boost the immune system and Echinacea subjects with early symptomsEchinacea of cold or flu (runny nose, scratchy reduce the severity and the frequency of cold symptoms. This throat, fever) were randomly assigned to receive an plant is widely used to fight the common cold and other upper Echinacea herbal tea preparation ( Plus) 5-6Echinacea cups/day titrating to respiratory infections in United States and Europe, nevertheless,Echinacea is 1 over 5 days or placebo, the study period was 3 months. There some studies of for the common cold have not found was a significant difference between the and placebo that it real helps. The clinical effectiveness of group, also there were no negative effects reported by any of the controversial because clinical trials have had mixed results, some subjects in either group [10]. 473E. patients purpurea with early influenza studies have shown clinical benefit, whereas others have not symptoms randomized to either 5 days of oseltamivir followed by Echinacea (summarized in Table 2). 5 days of placebo, or 10 days of an -based formulation called Echinaforce Hot drink (Switzerland). According to the Some studies showed that E. couldpurpurea reduce duration, severity and frequency of symptoms of cold and URIs. Hoheisel results, Echinaforce Hot drink is as effective as oseltamivir in the early treatment of influenza infections with a reduced risk of et al. in a double-blind studyE. purpurea found that or a placebo as pressedsoon as juicethey complications and adverse events [103]. reduced the duration and the severity of colds. In thisEchinacea study, 120 people were given In a prospective, double-blind, randomized study, 62 patients started showing signs of getting a cold. Treatment with with symptoms of the common cold were treated with a natural Citation: Echinacea. Int J

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Table 2: Echinace Type of Dosage/Treatment period InterventionClinical trials and humanStudy studies population on efficacy of Comparatora against common cold and upper respiratory tractOutcome infections References study

patients with parts of E. purpurea E. earliest symptoms RCT Placebo angustifoliaTea preparation fromE. purpurea aerial and 5 to 6 cups day 1, titration to root Positive Lindenmuth [10] , and one cup on day 5/ 5 days patientsof a cold with E. purpurea ® RCT Placebo herb (Echinacin ) 20 drops every 2 h on day 1 Pressed juice of symptoms of a followed by 3 × 20 drops/ day/ Positive Hoheisel [11] Echinaforce® cold 10 days (alcoholic RCT Placebo E. purpurea with for illness prevention: 3 × 0.9 extraction from freshly healthy adults ml/ day; in case of cold: 5 × Positive Jawad et al. [101] harvested ® E. 0.9ml/ day/ 4 months 95% herb and 5% roots) purpurea RCT Placebo Echinaforce tablets ( 2 × 3 (40.68 mg/ day)/ Brinkeborn et al. crude extract based healthy volunteers Positive E. purpurea maximum one week [102] on 95% herb/5% roots) freshly harvested RCT Placebo and standardized on the 10 × 4 ml the first day, then 4 x basis of active components® healthy adults Positive Goel et al. [103] 4 ml/ 7 days alkamides, cichoric acid and E.polysaccharides purpurea (Echinilin® ) RCT Placebo adults at the onset 8 × 5 ml for day 1, then 3 × 5 ml (Echinilin ) Positive Goel et al. [104] E. purpurea herb of their cold RCT Placebo for 6 days/ one week 3.75 ml twice a day for ages 2-5 Syrup of healthy children years and 5 ml twice a day for Negative Taylor et al. [109] harvestedEchinacea at flowering RCT Placebo ages 6-11 years/ 10 days fresh capsule E. purpurea 3 × 1 capsule/ day/ maximum (freeze-dried pressed juice patients with cold Negative Yale & Liu [110] patients with 14 days from E.) purpurea ® RCT Placebo Pressed juice of Grimm & Müller symptoms of a 2 × 4 ml daily/ 8 weeks Negative (Echinacin ) [111] E. purpurea cold RCT Placebo E. plant 3 × 2 capsules/ day (1 Capsules of dried purpurea healthy adults capsule containing 300 mg Negative O'Neil et al. [112] Tablets containing E. purpurea RCT Placebo )/ 8 weeks root E. angustifolia root 4 × 2 tablet during first day, individuals with Barrett et al. then 4 × 1 tablet per day for the Negative and cold symptoms [113] next 4 days/ 5 days E. angustifolia root % patients with Capsules containing 50% RCT Placebo E. purpurea root E. 6 × 4 capsules in the first day, , 25 Barrett et al. purpurea herb then 3 x 4 capsules up to 10 Negative , 25% active cold [114] E. Purpurea/ E. angustifolia Melchart et al. RCT Placebo days/ 10 days root alcoholic extract healthy volunteers 50 drops twice a day/ 12 weeks Negative [115]

RCT = Double-blind, Randomized, Controlled trial m Echinacea Nigella sativa Panax ginseng extract plus ® Junior ultiherbal formula Immumax (containing extract, or otitis media. Almost all children after six months reported garlic powder, oil, and a reduction in frequency of acute episodes. Imoviral vitamin C and zinc) for the duration of their symptoms or a can improve the quality of life in pediatric patients affected by maximum of 2 weeks. The results indicated that Immumax was recurrent pharyngotonsillitis and otitis media without adverse helpful in reducing the duration and severity of common cold effects [105]. URIs frequently cause exacerbations of Chronic- symptoms, and the symptoms resolved faster in the Immumax Obstructive Pulmonary E. Disease purpurea (COPD). along with In amicronutrients double-blind randomized placebo-controlled trial in COPD patients with acute group than in the placebo group. The median timeE. to angustifolia resolution URI, the combination of of all symptoms was 8 days in the placebo group and 4 days® in the zinc, selenium and vitamin C may alleviate COPD exacerbations Immumax group [104]. An herbal compound of s, Arabinogalactan, Vitamin C, Beta- Glucan e Zinc (Imoviral Junior) caused by acute URI [106]. was given to 37 children affected by recurrent pharyngotonsilliti In contrast to abovementioned results, some studies have Citation: Echinacea. Int J

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Echinacea reported no statistically significant improvementE. purpurea with withliterature Echinacea search; and based on the analysis, the likelihood of for the common cold. Taylor, et al. [107] using a large randomized experiencingEchinacea a clinical cold was 55% higher with placebo than controlledEchinacea trial found no evidence of help in children . This meta-analysis exhibited standardized suffering from URIs. Results of this trial do not support a benefit extracts of were effective in the prevention of symptomsEchinacea of in the treatment of common cold symptoms in of the common cold after clinical inoculation, compared with children, and its useEchinacea was associated with an increased risk of placebo [12]. Shah et al. did meta-analysis reviewed rash. However, Echinacea the authors concluded that their findings are clinical trialsEchinacea that examined both prevention and treatment not transferable to use in adults or to other species/ in the incidence and duration of the common cold. The results E.preparations purpurea of . In another randomized double-blind supported ’s benefit in decreasing the incidence placebo-controlled design, 128 adults received either 100 mg of and duration of the common coldEchinacea [13]. Evidence from another a maximum (freeze-dried pressed juice from the aerial parts) or meta-analysis with a total of 2458 participants by Schapowal, placebo 3 times daily until cold symptoms were relieved up to et al. [14] indicated that use of Echinacea potently reduced the of two weeks. The time to resolution of symptoms risk of recurrent respiratory infections and development of was not statistically different and no significant difference was complications. Ethanolic extracts from appeared to be observed between treatment groups for symptoms including more effective than pressed juices, and increased dosing during sneezing, nasal discharge, nasal congestion, headache, sore acute episodes further enhanced these effects. or scratchy throat, hoarseness, muscle pain, and cough [108]. Echinacea A Cochrane review by Karsch-Völk, et al. [114] compared the A total of 109 patients with a history of more than three colds E. purpurea effect of to placebo, in the treatment and the prevention or respiratory infections in the previous year were randomly E. purpurea of the common cold. They reviewed twenty-four double-blind assigned to receive 4 ml fluid extract twice a day Echinacea controlled clinical trials with 4631 participants investigating in a double-blind study. Treatment with did not the effectiveness of several different preparations for significantly decrease the incidence, duration or severity of Echinacea Echinacea preventing and treating common colds or induced rhinovirus colds and respiratory infections compared to placebo. Adverse infections. The authors concluded that products have events were observed in 20% of patients in the Echinacea not proved statistically significant in reducing illness occurrence, group compared with 13% patients in the placebo group [109]. Echinacea although there might be a weak benefit from some In a randomized, double-blind clinical trial 58 subjects were Echinacea group products. Echinacea assigned to survey the effects of on the frequency of Echinacea upper respiratory symptoms. Individuals in the Studies of for the common cold have had mixed reported 9 sick days during 8 weeks, whereas the placebo group results, andEchinacea whether or not helps prevent or treat the reported 14 sick days. No differenceEchinacea was found in the frequency common cold remains under debate. There are many variables in of upper respiratory tract symptoms and total symptom days studying for the common cold and URIs. All studies to forthat patientsEchinacea taking prophylactic for 8-week period date have had essential limitations, including differences in trial compared with those taking parsley capsules. The findings suggest design, use of different species and/or plant parts (containing does not have a meaningful effect on E.respiratory purpurea different constituents), various routes of administration, sample tractE. infection angustifolia symptoms [110]. In a large randomized study on size, monitoring responses of healthy subjects, analytical 713 patients, Barrett, et al. [111] found that dried methodology, and choice of biomarker and placebo.Echinacea These and root (10.2 g for the first 24 h of a cold and differences make it hard to compare the results; consequently 5.1 g for the next 4 days) did not improve symptoms more than Hepatoprotectivethese data do not allow Effects clear conclusions whether placebo or no treatment. Change in IL-8 levels and neutrophil might be effective for this purpose or not. counts were also not statistically significant in the E.no-pill angustifolia group . Barret,E. purpurea et al. [112] in another randomized double-blind placebo- controlled study on adults with colds concluded Chicoric acid may reduce acute alcohol-induced steatosis in mice through interfering with the induction of iNOS and and does not have an expressiveE. effect. purpurea In a double-E. blind trial by Melchart, et al. [113] 302 healthy volunteers were iNOS-dependent signaling pathways in the liver. Acute angustifolia alcohol administration caused a significant increase in hepatic giventhat E. an purpurea alcohol tinctureE. angustifoliacontaining either root, root, or placebo for 12 weeks. The results showed triacylglycerols accumulation, which was associated with and decreased the number of increase in 4-hydroxynonenal protein adducts, and iNOS and people who got sick; however, the difference was not statistically active plasminogen activator inhibitor 1 protein level in the significant. Echinacea on liver; pretreatment with chicoric acid for 4 days before ethanol ingestion significantly attenuated these alcohol effects on the Three meta-analyses evaluated the effect of liver. In RAW264.7 macrophages, treatment with chicoric acid (4 incidence, duration and prevention of the common cold and mg/ kg body weight) suppressed LPS-induced TNF-α and iNOS at induced rhinovirus infections [12-14]. Schoop et al. performed a mRNA expression level [23]. E. purpurea extract had a protective meta-analysis of experimental rhinovirus infection studies with role on kidney and liver against Diethylnitrosamine (DEN) toxicity humans to determine whether the negative results obtained in in rats. One month administration of DEN caused elevation in previous studies were a consequence of efficacy or of inadequate serum Alanine Transaminase (ALT), Aspartate Transaminase sample size. A total of 234 articles were identified through the (AST), and Alkaline Phosphatase (ALP), creatinin and total and Citation: Echinacea. Int J

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Effects On Skin Problems direct bilirubin levels in serum; however these factors decreased in E. purpurea administration. In addition, histopathological Echinacea contains Several plants with effective properties may offer better investigation revealed proliferation of hepatic stellate cells alternative treatments for skin complications. [115]. It was found that alkamide dodeca-2E,4E,8Z,10Z(E)- E. purpurea many valuable constituents for protection of skin from oxidative tetraenoic acid isobutylamides isolated from E. purpurea root stress and for improving skin health. In a survey has hepatoprotective effect against acute fulminant hepatitis extract was incorporated into cream and gel bases and the induced by lipopolysaccharide/D-galactosamine (LPS/D-GalN) in effect of those formulations on skin irritation, hydration level mice. This dose-dependently induced HO-1 protein expression in E. purpurea and wrinkle reduction was evaluated in 10 healthy volunteers. LPS-stimulated murine macrophages that was regulated through According to results cream and gel were effective increase in JNK phosphorylation, c-jun protein expression in improving skin hydration and reducing wrinkle, also both and phosphorylation, and transcription factor AP-1 binding formulations showedPropionibacterium no irritation to skin acnes [118]. Acne is a ®chronic might consensus DNA activity. Besides, this alkamide suppressed serum inflammatory disorder of skin follicles caused by the gram- aminotransferase activities, TNF-α expression, and damages to positive bacterium . Echinaforce hepatocytes of LPS/d-GalN-treated mice [116]. Cadmium (Cd provide a useful safe treatment in the control of acne diseasein 2+) is toxic to a wide range of tissues. Prolonged intraperitoneal vitroby preventingP. acne proliferation of the organism and inhibiting the injection of E. purpurea extract combined with Cd(2+)Cl(2) bacterial-induced inflammation. In human skin fibroblasts ® decreased the mitotic activity induced by Cd 2+, also increased , induced the secretion of considerableEchinacea amounts of is apoptotic activity of hepatocytes of mice [117]. These data pro-inflammatory cytokines IL-6 and IL-8; however, Echinaforce suggests a new application of Echinacea as a hepatoprotective completely reversedE. pallida their level to normal [22]. agent,Echinacea however against further investigationdiabetes is needed. purported to be beneficial for wound healing. It revealed that root extract of and its constituent echinacoside has good wound healing properties in excision wounds treated Diabetes is a debilitating and often life-threatening problem topically. ThisE. pallidaactivity probably related to the anti-hyaluronidase with increasing incidence throughout the world. A scientific and anti-inflammatory activities of echinacoside [119]. Alcoholic investigation of herbal remediesEchinacea for diabetes may provide extract of accelerated cutaneousEchinacea wound closure in valuable alternative drugs and therapeutic strategies. Recent the stressed mice, but had no curing effect for the non-stressed studies have indicated that could have anti-diabetic mice. The wound healing effect of in stressed mice is activities. withnot mediatedEchinacea through modulation of glucocorticoid signaling because plasma glucocorticoid in restraint stressed mice treated Adipogenesis has been used to study the insulin signaling Effects On Nervous System didn’t change [120]. pathway and to screen anti-diabetic compounds. When adipocyte differentiation was induced with insulin plus 3-isobutyl-1- methylxanthine and E. dexamethasone, purpurea the accumulation of lipid Excitatory synaptic transmissionEchinacea extract;in the hippocampus, but no change a brain in droplets and the cellular triglyceride content were increased by region that is involved in anxiety and anxiety-related behaviors, ethanolic extract of . The expression of PPAR-γ and was suppressed by an CCAAT-Enhancer-Binding Protein (C-EBP)α in 3T3-L1 adipocytes- inhibitoryEchinacea synaptic transmission could be detected upon treated with dodeca-2(E),4(E)-dienoic acid isobutylamide were application of this extract. In addition, at low concentration the extract reduced the spiking activity of CA1 pyramidal increased, as well as triglyceride content of adipocytesE. purpurea and were fat accumulation were improved [28]. The isomeric C12-alkamides cells, while at high concentration increased it, this was parallel isolated from a dichloromethane root extract of Echinaceato the reduction in the magnitude of the h-current-mediated found to activate PPAR-γ, to increase basal and insulin-dependent voltage responses in pyramidal cells [121]. Anxiolytic potency of glucose uptake in 3T3-L1 adipocytes in a dose-dependent manner, preparations were consistently seen in three different laboratory tests of anxiety, the elevated plus-maze, social and to exhibit characteristics of a PPAR-γ partialE. purpurea agonist [29]. Echinacea preparations The alkamide hexadeca-2E,9Z,12Z,14E-tetraenoic acid isobutyl interaction and shock-induced social avoidance tests; these effects amide isolated from an n-hexane extract of flowers are comparable with chlordiazepoxide.E. angustifolia was shown to increase insulin-stimulated glucose uptake and to had a considerable anxiolytic potential and it decreased anxiety- like behavior in all tests [122]. extract decreased Echinaceaactivate PPAR-γ without stimulating adipocyte differentiation [30]. In Non-Obese Diabetic (NOD) mice, supplementation with anxiety in the elevated plus-maze and ameliorated contextual conditioned fear. No lethality or behavioral signs of discomfort resulted in a significant increase in the absolute E. angustifolia were noticed in rats treated with intragastric administration numbers of NK cells in the spleen, irrespective of feeding E. angustifolia of 1000 and 3000 mg/kg . A pharmacological duration, moreover, it actually stimulated NK cell production in formulation based on the same extract was tested their bone marrow origin site. What’s more, consumption of herb in healthy volunteers. One or two tablets (each contained 20 mg by NOD mice has led to no negative consequences with respect to Echinacea of the plant extract) per day were administered for 7 days to the hemopoietic and immune lineages. These data suggest that subjects scoring high on the State-Trait Anxiety Inventory (STAI). contain compounds with potential to manage insulin The high dose (2 tablets/ day) decreased STAI scores within resistance and diabetes. Citation: Echinacea. Int J

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3 days in human subjects, an effect that remained stable for the potently inhibit the expression of CYP3A1 and CYP3A2, also duration of the one week treatment and for the 2 weeks that CYP2D2 and CYP2C6 activitiesE. purpurea [130]. CYP3A4 and CYP2C9 Echinaceafollowed treatment [123]. The endocannabinoid system involves enzymes have been reported to metabolizeE. purpurea one of the main many pathophysiological activities including analgesic action. alkamide constituents of extract in human liver E. angustifolia-isolated alkamides appear to exert psychoactive microsomes [131]. Administration root extract for activities through the endocannabinoid system [77]. Alkamides 8 days to healthy volunteersE. significantlypurpurea decreased CYP1A2 from roots showed psychoactive properties by activity, increased hepatic CYP3A4 activity, and there was little binding to CB1 receptors predominantly expressedEchinacea in the brain decrease in CYP2C9 activity. E. root purpurea reduced cause the herb- oral tissue [124]. The finding about the interaction of alkamides with clearance of substrates of CYP1A2 but not the oral clearance of CB receptors may help explain the traditional use of for substrates of CYP2C9 and CYP2D6 [132]. woundEffects healing, On Reproductive pain relief and improvementSystem of cold symptoms drug interaction by up-regulating CYP1A2, CYP3A4 and MDR1 [125]. expression via Pregnane X Receptor (PXR) activation in human liver carcinoma HepG2 cells [133]. Echinacea Alkylamide® undeca-2 E,4 E/ Z-diene-8,10-diynoic acid Two study raised questionsE. purpurea about possible anti-fertility E. effects of . The histological changes were found after purpureaisobutylamide correlated well with inhibition of CYP3A4 by 4 or 8 weeks of using 50 mg/kg in Wistar male rats. EchinaforceE purpurea[134]. In a clinical study, no significant effect of on midazolam pharmacokinetics was reported in healthy Results of the study showed significantE. purpurea reduction in the testicle E. purpurea whole mass and the body mass, as well as changes in histological volunteers. selectively altered the catalytic activity of structures after eight weeks of administration. CYP3A in the liver vs. intestine, conversely, Consumption of the preparation for 8 weeks caused anti- plant extract administration didE. purpurea not significantly alter CYP3A metabolic serum ratios of 1-hydroxymidazolam: midazolam androgenicin vitro variations in cells of spermatogenic epithelium of E.a in healthy volunteers [135]. significantly induced purpuratesticle duct and consequently inhibited spermatogenesis [126]. cytochrome CYP3A activity but does not alter lopinavir-ritonavir possiblyAn the investigation Echinacea by fresh sperm specimens exhibited at high-concentration interfered with sperm enzymes, exposure inE. healthypurpurea subjects. Neither lopinavir nor ritonavir (400/100 mg) pharmacokinetics were significantly altered by Echinacea treatmentEchinacea may prevent sperm from E. purpurea fertilizing the oocytes. The beat cross frequencies were higher for 2 weeks of co administration in healthy volunteers. treatment group [127]. extract can be useful induced CYP3AE. activity purpurea but did not alter lopinavir medication for treatment of Benign Prostate Hyperplasia (BPH). concentrations, most likely due to the presence of ritonavir as a potent CYP3A inhibitor. is unlikely to alter the Results of a work showedE. apurpurea significant decrease of prostate pharmacokinetics of ritonavir-boosted protease inhibitors but E.weight angustifolia of BPH in rats, and reversed changes in the structure of the prostate gland after using extract for 8 weeks [82]. may cause a decreaseE. purpurea in plasma concentrations of other CYP3A extract enhanced cell viability and proliferation substrates [136]. In an open-label, fixed-sequence study the interaction of with etravirine, a non-nucleoside in mammary epithelial cells, HC11 mouse cell line and BME-UV Echinacea reverse transcriptase inhibitor of HIV was investigated. Fifteen bovine cell line. This effectEchinacea may be modulated by MAPK and Akt E. purpurea activation and by a reduction of caspase-3 activity in HIV-infected patients receiving etravirine (400 mg once daily) for 4 week, and root extract (500 mg every 8 h) treatment. MoreoverE. angustifolia extract was able can tostimulate increase mammary β-casein E. purpurea expression in association with prolactin (5 mg/ml). These data was added to the anti-retroviral treatment for 14 days. Results demonstrate that showed that the coadministration of with etravirine epithelial cell physiology and may be considered a candidate was safe and well tolerated in HIV-infected patients [94]. Metabolismto support mammary and Pharmacokinetics gland activity during mammogenetic and The multidrug transporter P-glycoprotein (P-gp), the lactogenetic states [128]. product of the ABCB1 gene, involved in cancer Multi Drug Resistance (MDR) and in herb-drug or drug-drug interactions. their components at the same time with substances that are Concomitant administration of medicinal herbs with drugs that It is found that application of herbal medicinal products and are P-gp substrates may produce clinically significant herb- drug interactions. P-glycoprotein is responsible for exporting Cytochrome P450 (CYP) enzymes substrates may cause herb- E. angustifolia xenotoxins including pharmaceutical medicines from the cell. drug interactions. Since the use of herbal supplements continues Alkamides isolated from inhibited P-gp-mediated to increase throughout the world, the potential for drug-herbal calcein transport a major constituent of the blood-brain barrier interactions also rises. Modified expression of CYP enzymes will E. pallida E. angustifolia E. inpurpurea isolated porcine brain capillary endothelial cells [137]. The affect drug metabolism in three different ways. It can alter drug n-hexane root extracts from , and elimination, pro-drugEchinacea activation, or drug bioactivation (such as reduced the efflux of the P-gp probe calcein-AM from conversion to toxic metabolites), all of which can have serious human proximal tubuleE. HK-2 pallida cells (that constitutively expresses consequences [129]. is a widely used herbal medicinal ABCB1). Pentadeca-(8 Z,13 Z)-dien-11-yn-2-one isolated from product and consequently, studies of its interactions with the n-hexane extract of roots was an efficient compound E. purpurea ethanolic extract can E. purpurea with P-gp transporter conventional drugs are of particular importance. that reduced P-gp activity and decreased the calcein-AM efflux It was demonstrated [138]. The interaction of Citation: Echinacea. Int J

Ganjuri M, Darakhshan S, Taghizad F (2016) A Review on Pharmacological and Therapeutic Properties of Page 12 of 18 Pharmacovigil 1(1): 18. A Review on Pharmacological and Therapeutic Properties of Echinacea Copyright: © 2016 Darakhshan et al.

was studied in human adenocarcinoma colonic cell line Caco- significantly greater than those received only phenytoin [144]. 2, as a standard rapid, reliable, and low-cost model for study The teratogenic effect of phenytoin on cleft palate is associatedE. the absorption of drugsE. purpurea by the intestine. In a study digoxin was purpureawith inhibition of cell proliferation and increase in cell apoptosis used as a substrate and verapamil as a control inhibitor. At high of Mouse Embryonic Palatal Mesenchymal (MEPM) cells, and concentrations of E. purpurea, a significant linear decrease was extract had the reverse effect [145]. observed in the net digoxin flux, indicating a dose-dependent On the other side of safety, there are rare cases of adverse inhibitory effect of on P-gp [139]. Echinacea effects. Such side effects include nausea, abdominal pain, diarrhea, Commonly used herbal supplements wereEchinacea screened for their itch, andEchinacea rash. has also been linked to allergic reactions, potential to inhibit UDP-Glucuronysl Transferase 1A1 (UGT1A1) including asthma, shortness of breath, and one case of anaphylaxis activity using human liver microsomes. showed [146]. can be associated with allergic reactions that inhibition of UGT1A1 activity [140]. Alkamides and cinnamic may be severe or exacerbate asthma [146]. Moreover,Echinacea it has also acid have been shown to have good permeability through human been incriminated in causing contact dermatitis and anaphylactic Caco-2 cells, although caftaric acid, echinacoside and cichoric reactionsEchinacea associated with the consumption of [147]. acid permeated poorly through the EchinaceaCaco-2 monolayers [141]. In clinical trials, gastrointestinal symptoms were common. supplementation has altered the gastrointestinal tract These findings suggest that and components E. purpurea are also to microbiota. In a study 50 human subjects consumed 1000 mg may influence metabolism of different drugs also alter their Echinacea of standardized for 10 days. Significant increases pharmacokinetics. However, further studies needed E. purpurea were found for total aerobic bacteria, Bacteroides group and confirm the potential of interactions between and Safety and Toxicity Bacteroides fragilis after exposure [148]. other conventional drugs. Echinacea There are concerns that by stimulating immune function, could potentially exacerbate autoimmune diseases The increasing use of medicinal herbs among the populations thanand/or human decrease analyses. the effectiveness Its immunostimulatory of immunosuppressive property drugs, may has created the need for scientific research to determine the but this warning is based on theoretical considerations rather safety of herbs. Herbal remedies and dietary supplements are Echinacea not classified as drugs by the US Food and Drug Administration lead to interference with immunosuppressant agents; therefore (FDA); therefore, although the 1994 Dietary Supplement Health a general consensus exists about the avoidance of and Education Act allows manufacturers to make claims intended in patients who are being administered immunosuppressive to influence public opinion regarding the benefits of these drugs, especially in patients undergoing organ transplantation. products, herbs and supplements are excepted from the rigorous However, despite the immunostimulatory effect that may be Echinacea Echinacea regulations required for drugs. seen with short-term use, chronic long-term use (>6-8 weeks) E. purpurea has an excellent safety record and is well tolerated of may be immunosuppressive [149] which increases by most consumers. Oral administration of the the risks of poor wound healing and opportunistic infections. Consequently its use in AIDS or autoimmune disorders such as expressed juice for 4 weeks proved virtually non-toxic to rats andE. multiple sclerosis and rheumatoid arthritis is controversial. angustifoliamice, even in doses many times greater than human therapeutic Echinacea in combination Furthermore, there are also concerns about its potential doseE. angustifolia [142]. There are reports of anti-apoptotic activity of extract on noncancerous cells. The biological effect hepatotoxicity, probably the use of of extract on cell viability and cell differentiation in with other drugs metabolized by the liver can cause possible mammary epithelial cells have been observed in two different cell unwanted effects; thus this plant should be used carefully in lines HC11 and BME-UV. This herb activated MAPK/Akt pathway patients with pre-existingEchinacea hepatic dysfunctions. involved in cell viability and proliferation and prevention of Echinacea EchinaceaSo altogether, while administration appears to be caspase-3 accumulationE. pallida that indicates an anti-apoptotic effect Conclusionswithout significant adverse effects, the full toxicological profile of of extract [130]. Moreover hydroalcoholic extract and remains to be assessed. pressed juice from exhibited a low cytotoxic effect on Echinacea monkey kidney cell cultures [143]. E. purpurea is one of the most important medical herbs. In Cleft palate is one of the most common birth defects. Echinacea a 2007 National Center for Complementary and Alternative extract had prophylactic effect on incidence of Echinacea Medicine survey, was the third most commonly used phenytoin-induced cleft palate. In a study the prophylactic non-vitamin, non-mineral natural product among adults, and the effects of levamisole and extract on teratogenic effects Echinacea purpurea, E. fifth highest selling herbal dietary supplement [150]. At present, of phenytoin was compared. This study was performed on angustifolia E. pallida E. purpurea extracts and plant products made from pregnant mice that received phenytoin at 10th day of gestation, , and comprise one of the largest parts of the extract were administrated at dose of 360 mg/ kg herbalEchinacea medicine market, in North America as well as in Europe. intraperitoneally, along withEchinacea and 12 extract; hours also after mean phenytoin weight injection. Cleft palate incidence decreased in fetusesEchinacea of mice were that is widely used as one of the treatments chosen received phenytoin with by consumers with the belief that it will reduce the severity and length of fetuses of the ones that received and duration of the common cold and because of its supposed Citation: Echinacea. Int J

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Echinacea on beneficial effects on the immune system. There are multiple 10. Lindenmuth GF, Lindenmuth EB. The efficacy of echinacea scientific studies published to evaluate the effects of compound herbal tea preparation on the severity and duration of upper respiratory and flu symptoms: a randomized, double-blind commonEchinacea cold and immunity; however, results are controversial placebo-controlled study. J Altern Complement Med. 2000;6(4):327- and inconclusive. It is well known that the effectiveness of 34. distinct products differ considerably, mainly due to 11. Hoheisel O, Sandberg M, Bertram S, Bulitta M, Schaffer M. Echinagard the use of different parts of the plant (including leaves, flowers, treatment shortens the course of the common cold: a double blind, root or rhizome), extraction protocols, and the addition of other placebo-controlled clinical trial. Euro J Clin Res 1997; 9:261-268. components. These all have made their outcomes difficult to 12. Schoop R, Klein P, Suter A, Johnston SL. Echinacea in the prevention of induced rhinovirus colds: a meta-analysis. Clin Ther. interpret and compare. e2006;28(2):174-83. Different commercial products are likely to contain different 13. Shah SA, Sander S, White CM, Rinaldi M, Coleman CI. Evaluation of relative concentrations of active constituents, and there are chinacea for the prevention and treatment of the common cold: a meta-analysis. Lancet Infect Dis 2007; 7:473-80. currently no regulated manufacturing standards for the amount 14. Schapowal A, Klein P, Johnston SL. Echinacea reduces the risk of of individual chemical compounds in commercial preparations. recurrent respiratory tract infections and complications: a meta- In addition, the dose and timing of administration also needs to analysis of randomized controlled trials. Adv Ther. 2015;32(3):187- be evaluated extensively. 200. doi: 10.1007/s12325-015-0194-4. in Echinacea 15. Zhai Z, Solco A, Wu L, Wurtele ES, Kohut ML, Murphy PA, et al. Results show that among the bioactive compounds present Echinacea increases arginase activity and has anti-inflammatory , alkylamides, cichoric acid and polysaccharides properties in RAW 264.7 macrophage cells, indicative of alternative have most effects. However the biological effects of unidentified macrophage activation. J Ethnopharmacol. 2009;122(1):76-85. doi: compounds in this herb should be also investigated. Despite many 10.1016/j.jep.2008.11.028. Echinacea 16. Hou CC, Chen CH, Yang NS, Chen YP, Lo CP, Wang SY, et al. pharmacological and clinical studies, the molecular mechanisms Comparative metabolomics approach coupled with cell- and gene- for which exert its effects are not well understood. based assays for species classification and anti-inflammatory ConflictsAdditionally, of more interest scientific research is required regarding its bioactivity validation of Echinacea plants. J Nutr Biochem. safety and adverse effects. 2010;21(11):1045-59. doi: 10.1016/j.jnutbio.2009.08.010. 17. Hu C, Kitts DD. Studies on the antioxidant activity of Echinacea root extract. J Agric Food Chem. 2000;48(5):1466-72. ReferencesNone declared. 18. Abouelella AM, Shahein YE, Tawfik SS, Zahran AM. Phytotherapeutic effects of Echinacea purpurea in gamma-irradiated mice. J Vet Sci. 2007;8(4):341-51. 1. Brenes A and Roura E. Essential oils in poultry nutrition: main 19. Tsai YL, Chiu CC, Yi-Fu Chen J, Chan KC, Lin SD. Cytotoxic effects and modes of action. Anim Feed Sci Technol, 2010; 158:1-14. effects of Echinacea purpurea flower extracts and cichoric acid 2. Barnes J, Anderson LA, Gibbons S, Phillipson JD. Echinacea species on human colon cancer cells through induction of apoptosis. (Echinacea angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt., J Ethnopharmacol.2012;143(3):914-9. doi: 10.1016/j. Echinacea purpurea (L.) Moench): a review of their chemistry, jep.2012.08.032. pharmacology and clinical properties. J Pharm Pharmacol. 20. Chicca A, Adinolfi B, Pellati F, Orlandini G, Benvenuti S, Nieri P. 2005;57(8):929-54. Cytotoxic activity and G1 cell cycle arrest of a Dienynone from 3. Percival SS. Use of echinacea in medicine. Biochem Pharmacol. Echinacea pallida. Planta Med. 2010;76(5):444-6. doi: 10.1055/s- 2000; 60(2):155-8. 0029-1186224. 21. Currier NL, Miller SC. The effect of immunization with killed 4. Press.Newall, C.A., Anderson, L.A., Phillipson, J.D., 1996. Herbal medicine: a guide for health care professionals, London: The Pharmaceutical tumor cells, with/without feeding of Echinacea purpurea in an erythroleukemic mouse model. J Altern Complement Med. 2002;8(1):49-58. 5. Wang CY, Chiao MT, Yen PJ, Huang WC, Hou CC, Chien SC, 22. Sharma M, Schoop R, Suter A, Hudson JB. The potential use of et al. Modulatory effects of Echinacea purpurea extracts Genomics. 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Echinacea purpurea extracts modulate murine dendritic cell extract (Echinaforce): dual actions against respiratory fate and function. Food Chem Toxicol. 2010;48(5):1170-7. doi: bacteria. Phytomedicine. 2010;17(8-9):563-8. doi: 10.1016/j. 10.1016/j.fct.2010.02.007. phymed.2009.10.022. 8. Roesler J, Emmendörffer A, Steinmüller C, Luettig B, Wagner H, 25. Binns SE, Purgina B, Bergeron C, Smith ML, Ball L, Baum BR, et al. Lohmann-Matthes ML. Application of purified polysaccharides from Light-mediated antifungal activity of Echinacea extracts. Planta cell cultures of the plant Echinacea purpurea to test subjects mediates Med. 2000;66(3):241-4. activation of the phagocyte system. Int J Immunopharmacol. 26. Pleschka S, Stein M, Schoop R, Hudson JB. Anti-viral properties and 1991;13(7):931-41. mode of action of standardized Echinacea purpurea extract against 9. Sasagawa M, Cech NB, Gray DE, Elmer GW, Wenner CA. Echinacea highly pathogenic avian influenza virus (H5N1, H7N7) and swine- alkylamides inhibit interleukin-2 production by Jurkat T cells. Int origin H1N1 (S-OIV). Virol J. 2009;6:197. doi: 10.1186/1743-422X- Immunopharmacol. 2006;6(7):1214-21. 6-197. Citation: Echinacea. Int J

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27. Moltó J, Valle M, Miranda C, Cedeño S, Negredo E, Barbanoj MJ, et al. nitric oxide production in cultured macrophages. J Agric Food Chem. Herb-drug interaction between Echinacea purpurea and darunavir- 2009;57(19):8820-30. doi: 10.1021/jf901202y. ritonavir in HIV-infected patients. Antimicrob Agents Chemother. 46. Hinz B, Woelkart K, Bauer R. Alkamides from Echinacea inhibit 2011;55(1):326-30. doi: 10.1128/AAC.01082-10. cyclooxygenase-2 activity in human neuroglioma cells. Biochem 28. Shin DM, Choi KM, Lee YS, Kim W, Shin KO, Oh S, et al. Echinacea Biophys Res Commun 2007; 360:441-6. purpurea root extract enhances the adipocyte differentiation of 47. Zhang X, Rizshsky L, Hauck C, Qu L, Widrlechner MP, Nikolau BJ, et 3T3-L1 cells. Arch Pharm Res. 2014;37(6):803-12. doi: 10.1007/ al. Bauer ketones 23 and 24 from Echinacea paradoxa var. paradoxa s12272-013-0251-y. inhibit lipopolysaccharide-induced nitric oxide, prostaglandin E2 29. Kotowska D, El-Houri RB, Borkowski K, Petersen RK, Fretté XC, and cytokines in RAW264.7 mouse macrophages. Phytochemistry. Wolber G, et al. Isomeric C12-alkamides from the roots of Echinacea 2012;74:146-58. doi: 10.1016/j.phytochem.2011.10.013. purpurea improve basal and insulin-dependent glucose uptake 48. Fast DJ, Balles JA, Scholten JD, Mulder T, Rana J. Echinacea purpurea in 3T3-L1 adipocytes. Planta Med. 2014 ;80(18):1712-20. doi: root extract inhibits TNF release in response to Pam3Csk4 in a 10.1055/s-0034-1383252. phosphatidylinositol-3-kinase dependent manner. Cell Immunol. 30. Christensen KB, Petersen RK, Petersen S, Kristiansen K, 2015;297(2):94-9. doi: 10.1016/j.cellimm.2015.07.003. Christensen LP. Activation of PPARgamma by metabolites from 49. Jiang L, Li W, Wang Y, Zhang X, Yu D, Yin Y, et al. Effects of cichoric the flowers of purple coneflower (Echinacea purpurea). 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Food Chem 2007; 101:74-81. chromatography analysis of polyacetylenes and polyenes in 52. Dalby-Brown L, Barsett H, Landbo AK, Meyer AS, Mølgaard P. Synergistic antioxidative effects of alkamides, caffeic acid Echinacea pallida by using a monolithic reversed-phase silica derivatives, and polysaccharide fractions from Echinacea purpurea column. J Chromatogr A. 2007;1149(1):56-65. on in vitro oxidation of human low-density lipoproteins. J Agric 35. Cheminant A, Zawatzky R, Becker H, Brouillard R. Caffeoyl Food Chem. 2005;53(24):9413-23. conjugates from Echinacea species: structures and biological 53. Joksić G, Petrović S, Joksić I, Leskovac A. Biological effects of activity. Phytochemistry 1988; 27:2787-94. Echinacea purpurea on human blood cells. Arh Hig Rada Toksikol. 36. Dong GC, Chuang PH, Forrest MD, Lin YC, Chen HM. Immuno- 2009;60(2):165-72. doi: 10.2478/10004-1254-60-2009-1920. suppressive effect of blocking the CD28 signaling pathway in 54. 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Pharm Biol 2009; 47:500-508. 2008;30(3):553-74. doi: 10.1080/08923970802135534. 41. Lalone CA, Huang N, Rizshsky L, Yum MY, Singh N, Hauck C, et 59. Rininger JA, Kickner S, Chigurupati P, McLean A, Franck Z. al. Enrichment of Echinacea angustifolia with Bauer alkylamide Immunopharmacological activity of Echinacea preparations 11 and Bauer ketone 23 increased anti-inflammatory potential following simulated digestion on murine macrophages and human through interference with cox-2 enzyme activity. J Agric Food Chem. peripheral blood mononuclear cells. J Leukoc Biol. 2000;68(4):503- 2010;58(15):8573-84. doi: 10.1021/jf1014268. 10. 42. Pomari E, Stefanon B, Colitti M. Effect of plant extracts on H2O2- 60. Randolph RK, Gellenbeck K, Stonebrook K, Brovelli E, Qian Y, induced inflammatory gene expression in macrophages. J Inflamm Bankaitis-Davis D, et al. Regulation of human immune gene Res. 2014;7:103-12. doi: 10.2147/JIR.S61471. expression as influenced by a commercial blended Echinacea 43. Senchina DS, McCann DA, Flinn GN, Wu L, Zhai Z, Cunnick JE, et al. product: preliminary studies. Exp Biol Med (Maywood). Echinacea tennesseensis ethanol tinctures harbor cytokine- and 2003;228(9):1051-6. proliferation-enhancing capacities. Cytokine. 2009;46(2):267-72. 61. Ritchie MR, Gertsch J, Klein P, Schoop R. Effects of Echinaforce® doi: 10.1016/j.cyto.2009.02.007. treatment on ex vivo-stimulated blood cells. Phytomedicine. 44. Zhai Z, Liu Y, Wu L, Senchina DS, Wurtele ES, Murphy PA, et al. 2011;18(10):826-31. doi: 10.1016/j.phymed.2011.05.011. Enhancement of innate and adaptive immune functions by multiple 62. Dapas B, Dall’Acqua S, Bulla R, Agostinis C, Perissutti B, Invernizzi Echinacea species. J Med Food. 2007;10(3):423-34. S, et al. Immunomodulation mediated by a herbal syrup containing 45. LaLone CA, Rizshsky L, Hammer KD, Wu L, Solco AK, Yum M, et a standardized Echinacea root extract: a pilot study in healthy al. Endogenous levels of Echinacea alkylamides and ketones are human subjects on cytokine gene expression. Phytomedicine. important contributors to the inhibition of prostaglandin E2 and 2014;21(11):1406-10. doi: 10.1016/j.phymed.2014.04.034. Citation: Echinacea. Int J

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