Mechanism of action
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Skip the menu of subheadings on this page.68. The exact mechanism by which Echinacea preparations exert their beneficial effect on the treatment and prevention of common cold is not known. Antiviral, immunomodulatory and anti-inflammatory effects of Echinacea were demonstrated in in vitro, in vivo and human studies referenced in the section below. However, the relevance of the in vitro and in vivo effects of Echinacea to clinical efficacy is not known and exact pharmacodynamic mechanism cannot be established (EMA, 2014).
In vitro and in vivo studies
Antiviral effects
69. The Echinacea antiviral mechanism of action is not fully elucidated, but it is thought to be due to prevention of viral entry into the cells rather than inhibition of viral replication (Pleschka et al., 2009; Sharma et al., 2009), suggesting that Echinacea treatment is effective only at the very early stages in the infection process (Pleschka et al., 2009). The use of different species, extraction methods and preparations make it difficult to attribute the antiviral activity of Echinacea to specific compounds. Echinacea has also been reported to inhibit the induction of pro-inflammatory cytokines IL-6, IL-8 and TNF-α in vitro (Sharma et al., 2009) and IL-10 and IFN-γ in vivo (Fusco et al., 2010), which can contribute to improved clinical outcomes of influenza infections by modulating the immune response (Fusco et al., 2010).
Immunomodulatory and anti-inflammatory effects
70. The immunomodulatory properties of Echinacea and its constituents have been extensively studied and reviewed in the literature. The studies reviewed in this statement reported that Echinacea stimulated the secretion of TNF-α (Burger et al., 1997; Rinninger et al., 2002; Goel et al., 2002), IL-1(Burger et al., 1997; Rinninger et al., 2002; Zhai et al., 2007) and IL-10 (Burger et al., 1997; Li et al., 2017) from macrophages and IFN-γ from lymphocytes (Li et al., 2017; Zhao et al. 2007). Echinacea has also been shown to increase the natural killer cells (NK) mediated cytotoxicity (See et al., 1997; Gan et al., 2003; Zhao et al. 2007), promote dendritic cells maturation (Li et al., 2017) and lead to changes in the percentage of immune cell populations, including T lymphocytes and NK cells (Zhao et al. 2007; Li et al., 2017; Gan et al., 2003). The immunomodulatory effects of Echinacea from in vitro and animal studies have been summarised in Table 2. The majority of the studies focused on E. purpurea preparations, with the exception of Zhao et al. (2007) where E. angustifolia and E. pallida were also tested.
Table 2: Summary of the immunomodulatory effects of Echinacea.
|
Echinacea preparation |
Concentration or dose |
Test system |
Summary of immune system effects |
Reference |
|
Fresh and dried juice from EchinaFresh (E. purpurea) standardized for a content of 2.4% soluble β-1,2-D-fructofuranosides. |
0.05-10 µg/mL fresh juice and 0.01-10 µg/mL dried juice. |
Human peripheral blood macrophages. |
Statistically significant increase in the production of IL-1, TNF-α, IL-6 and IL-10 by the macrophages at all concentrations of Echinacea. |
Burger et al., 1997 |
|
E. purpurea raw herb and root powders subjected to simulated digestion protocol in simulated gastric fluid.
|
5 – 320 µg/mL
|
RAW267.7 murine macrophages. |
Dose dependent induction of TNF-α, NO, IL-1α, IL-1β, and IL-6 with Echinacea treatment comparable to the results achieved with the LPS positive control. |
Rinninger et al., 2002 |
|
Plant parts extracted with aqueous ethanol, producing four different fractions with concentrations of chicoric acid, polysaccharide and alkylamides at basal level, 3, 20 and 50 times the basal level.
|
100 µL via oral gavage |
Male Sprague-Dawley rats. |
Echinacea fractions at 20 and 50 times the basal dose levels significantly increased the phagocytic index in alveolar macrophages compared to basal and 3 times basal level dose. TNF-α secretion from alveolar macrophages showed a dose-dependent rise with 3 and 20 times basal level doses. Similarly, spleen macrophages exhibited dose-dependent increases in TNF-α and IFN-γ release. |
Goel et al., 2002 |
|
Commercially available E. purpurea extracts with a defined chemical composition of chicoric acid (3.045%), caftaric acid (1.575%), chlorogenic acid (0.065%), dodeca-2E, 4E, 8Z, 10E/Z-tetraenoic acid isobutylamide (1.635%)
|
400 μg/mL |
Bone marrow-derived dendritic cells (BMDCs) derived from femur and tibia of 6–8-week-old female C57BL/6 mice. |
Echinacea treatment significantly increased percentage of CD40, CD80, CD83 and CD86 markers on BMDCs and increased the secretion of IFN-γ, IL-12, IL-10, and TGF-β1 by BMDCs. Endocytosis of fluorescently labelled dextran reduced by Echinacea treatment, similar to results observed with LPS control. |
Li et al., 2017 |
|
Dried, ground preparations of fresh E. purpurea herb homogenized, filtered and used fresh the same day.
|
0.001 to 1000 pg/mL |
Human peripheral blood mononuclear cells (PBMC) from healthy patients or patients with chronic fatigue syndrome (CFS) or acquired immunodeficiency syndrome (AIDS). |
Significant increase in the NK cell activity from healthy patients and those with CFS and AIDS was observed following Echinacea treatment in a concentration dependent manner. A similar concentration dependent response was observed for the antibody dependent cell-mediated cytotoxicity in all three patient groups following E. purpurea treatment. |
See et al., 1997 |
|
E. purpurea dissolved in water and filtered to prepare a water soluble extract. |
Concentrations up to 10 µg/mL |
Human peripheral blood mononuclear cells (PBMC). |
Increase in the NK-mediated cytotoxic activity was observed with E. purpurea treatment in a concentration dependent manner. Echinacea treatment reduced CD16 expression (frequency and intensity) by lymphocytes, while increasing CD69 expression within CD16⁺ populations, with over 90% CD16⁺ cells expressing CD69 at the highest concentration. |
Gan et al., 2003 |
|
Ground E. purpurea aerial parts and freeze dried into a powder. The preparation contained cichoric and caftaric acids, as well as cynarin, but not alkylamide. |
Concentrations of up to 250 μg/mL |
Human T-cell line Jurkat E6-1. |
E. purpurea induced a dose-dependent increase in IL-2 secretion and a five-fold rise of IFN-γ secretion by high-density T cells. |
Fonseca et al., 2014 |
|
Alcohol extracts of Echinacea. E. purpurea contained chicoric acid and caftraic acid, no echinacoside. E. angustifolia contained echiancoside, cynarin, chlorogenic acid. E. pallida contained echinacoside, chlorogenic acid and caftaric acid. |
130 mg/kg bw/day by gavage |
Eight-week-old male BALB/c mice |
All three Echinacea species increased IFN-γ production in mitogen-stimulated splenocytes, suppressed IL-1β and TNF-α. In non-stimulated splenocytes, E. purpurea significantly increased IL-1β secretion. E. purpurea increased the percentage of CD49⁺ and CD19⁺ splenic cells, while E. angustifolia only increased CD49⁺; E. pallida had no effect on either. Only E. pallida significantly enhanced NK cell cytotoxicity. |
Zhai et al., 2007 |
71. Echinacea extracts have also been reported to exhibit anti-inflammatory properties due to their ability to inhibit cyclooxygenases (COX) I and COX II (Clifford et al., 2002) and 5-lipoxygenase (5-LOX) (Merali et al., 2003). Clifford et al. (2002) found that alkylamides from E. purpurea roots inhibited COX-I and COX-II by 36–60% and 15–46%, respectively, at 100 µg/mL, compared to higher inhibition by standard non-steroidal anti-inflammatory drugs (NSAIDs). Merali et al. (2003) reported 5-LOX inhibition by root extracts of E. angustifolia, E. purpurea, and E. pallida attributing the activity to the presence of alkylamides in the extracts.
Human Studies
72. A meta-analysis (Schapowal et al., 2015) of six randomised control trials (RCTs) reported that Echinacea significantly reduced the relative risk (RR) of recurrent respiratory tract infections (RR = 0.649; 95% CI: 0.545–0.774; p < 0.0001). In individuals with high susceptibility to recurrent respiratory tract infections (e.g., stress, smoking, poor sleep, low T4/T8 ratio), the risk reduction was greater (RR = 0.501; 95% CI: 0.380–0.661; p < 0.0001). Echinacea treatment also halved the incidence of complications such as pneumonia, sinusitis, and bronchitis (RR = 0.503; 95% CI: 0.384–0.658; p < 0.0001), with pneumonia showing the greatest reduction (64.9%). The study concluded that Echinacea is an effective option for the management of recurrent respiratory tract infections and their related complications and that people with presumed lower immune function and high susceptibility to infection may benefit most. The authors attributed the increased resistance to viral infections observed in the human studies to the reported immunomodulatory effects of Echinacea in in vitro and in vivo studies.
73. Melchart et al. (1995) summarized the results of five placebo-controlled, randomized studies investigating the immunomodulatory activity of Echinacea extracts in a total of 134 healthy volunteers (18 females and 116 males) aged 18–40 years. The primary outcome measure was the relative phagocytic activity of polymorphonuclear neutrophil granulocytes (PNG). Two studies reported a significant increase in PNG phagocytic activity with Echinacea compared to placebo, while the remaining three found no significant effect. Peripheral blood leukocyte counts were unchanged across all studies. The review authors concluded that it was difficult to draw firm conclusions regarding Echinacea’s effect on PNG activity due to methodological differences in measuring phagocytosis, small sample sizes, and the absence of chemically defined, standardised Echinacea preparations.
74. A human study with 10 healthy subjects (5 male and 5 female) evaluated the immunomodulatory effect of a standardised E. angustifolia root extract (Polinacea) by measuring the mRNA and protein levels of the cytokines IL-2, IL-8, IL-6 and TNF-α in plasma samples (Dapas et al., 2014). The subjects took 10 mL, equal to 100 mg E. angustifolia root extract containing 4.7 mg/10 mL of echinacoside and 8.0 mg/10 mL of high molecular weight polysaccharides, daily for 4 weeks. The study reported upregulated expression levels of IL-2 and IL-8 and downregulation of the pro-inflammatory cytokines TNF-α and IL-6 following Echinacea treatment. The maximal differential gene expression for the cytokines was observed after 14 days of Echinacea treatment. The authors acknowledge the study limitations such as small sample size and the lack of comparison to other Echinacea preparations.