Elsevier

Phytomedicine

Volume 18, Issue 10, 15 July 2011, Pages 826-831
Phytomedicine

Effects of Echinaforce® treatment on ex vivo-stimulated blood cells

https://doi.org/10.1016/j.phymed.2011.05.011Get rights and content

Abstract

The herb Echinacea purpurea, also called purple coneflower, is regarded as an immune modulator. This study examined changes in cytokine production in blood samples from 30 volunteers before and during 8-day oral administration with an ethanolic extract of fresh Echinacea purpurea (Echinaforce®). Daily blood samples were ex vivo stimulated by LPS/SEB or Zymosan and analysed for a series of cytokines and haematological and metabolic parameters. Treatment reduced the proinflammatory mediators TNF-α and IL-1β by up to 24% (p < 0.05) and increased anti-inflammatory IL-10 levels by 13% (p < 0.05) in comparison to baseline. This demonstrated a substantial overall anti-inflammatory effect of Echinaforce® for the whole group (n = 28). Chemokines MCP-1 and IL-8 were upregulated by 15% in samples from subjects treated with Echinaforce® (p < 0.05). An analysis of a subgroup of volunteers who showed low pre-treatment levels of the cytokines MCP-1, IL-8, IL-10 or IFN-γ (n = 8) showed significant stimulation of these factors upon Echinaforce® treatment (30–49% increases; p < 0.05), whereas the levels in subjects with higher pre-treatment levels remained unaffected. We chose the term “adapted immune-modulation” to describe this observation. Volunteers who reported high stress levels (n = 7) and more than 2 colds per year experienced a significant transient increase in IFN-γ upon Echinaforce® treatment (>50%). Subjects with low cortisol levels (n = 11) showed significant down-regulation of the acute-phase proteins IL1-β, IL-6, IL-12 and TNF-α by Echinaforce® (range, 13–25%), while subjects with higher cortisol levels showed no such down-regulation. This is the first ex vivo study to demonstrate adapted immune-modulation by an Echinacea preparation. While Echinaforce® did not affect leukocyte counts, we speculate that the underlying therapeutic mechanism is based on differential multi-level modulation of the responses of the different types of leukocytes. Echinaforce® thus regulates the production of chemokines and cytokines according to current immune status, such as responsiveness to exogenous stimuli, susceptibility to viral infection and exposure to stress.

Introduction

Virally transmitted respiratory tract infections are the most common diseases in Western countries. On average, adults suffer from 2 to 4 colds per year, whereas children can be affected up to 12 times annually (Fendrick, 2003).

Echinacea purpurea, also known as purple coneflower, is a medicinal plant. Echinacea extracts are currently used to prevent and treat influenza infections as well as the common cold (Blumenthal et al., 2007, Woelkart et al., 2008). A meta-analysis of Echinacea studies concluded that it is clinically beneficial (Schoop et al., 2006a, Shah et al., 2007, Linde et al., 2006), and various pharmacodynamic actions have been proposed (Gertsch et al., 2004). However, current knowledge about the mechanism of action of Echinacea is based mainly on in vitro research, and studies have reported different effects due to the use of different preparations from the same plant species (Gertsch et al., 2004, Rininger et al., 2000). In vitro studies have limited usefulness, as they do not reflect the bioavailability of phytochemical compounds, which are often investigated at non-physiological concentrations. In addition, a single dose of the test compound is commonly used in in vitro cultures, making this an inadequate model for investigating the effects of multiple dosing to simulate prophylactic intake of the compound. Ex vivo studies are better models for investigating drug actions, as they better reflect the effects of digestion, resorption and metabolism. Notably, the combined use of different plant parts may enhance synergistic activity: when investigating the effects of complex plant extracts, it is necessary to investigate the effect of the extract of the whole plant during and after administering the extract to the whole organism. To date, few studies have investigated the effects of repeated oral administration of Echinacea purpurea extracts on a series of chemokines and cytokines in humans using an ex vivo model.

Clinical investigations have reported the immunomodulatory effects of extracts of (mainly) freshly harvested Echinacea purpurea: prolonged 14-day treatment with single daily doses has an anti-inflammatory effect via regulation of TNF-α, interleukins, leucocytes and hsp70 as well as via superinduction of superoxide during some viral infections (i.e. common colds) (Randolph et al., 2003, Woelkart et al., 2006, Goel et al., 2004, Goel et al., 2005, Guitto et al., 2008, Agnew et al., 2005). Jurcic et al. (1989) observed increased phagocytosis after oral administration of an alcoholic extract of Echinacea purpurea, with peak induction of 120% after 5 days compared to placebo. Some preparations increased the number of leucocytes, neutrophils and monocytes, as well as the percentage of natural killer cells (Goel et al., 2005, Agnew et al., 2005); others induced no changes, and so the data remain inconclusive.

The trials cited above involved small cohorts and, in many cases, only single time point measurements i.e. before and after treatment with Echinacea. Some studies investigated isolated immune mediators in serum, while others employed ex vivo stimulation protocols to investigate the effects of Echinacea on immune cell response.

The aim of this study was to investigate the effects of repeated daily doses of a commercial Echinacea extract, Echinaforce®, on the production of several immune mediators in a heterogeneous group of subjects using an ex vivo stimulation model. Adapted effects were also observed in a subanalysis of subjects with a higher susceptibility to colds and exposure to stress and who were classified as either “strong” or “weak” immune producers based on their production of immune mediators. Sampling time points, nutritional and stress status and the presence of infections and adverse events were taken into account when assessing the effects of Echinaforce®.

Section snippets

Study design and patients

After study approval (Eudract number 2005-004013-15) by the appropriate ethics committees (Bute Medical School, University of St. Andrews and Fife and Forth Valley Local Research Ethics Committee, NHS Five) and by the Medicines and Healthcare Products Regulatory Agency (MHRA), healthy subjects (n = 30) were enrolled in the study after providing written informed consent. The age range of the 12 women and 18 men was 18–57 years, and each reported ≥2 colds per year. The subjects were studied once

Results

A total of 30 subjects were included in the study. The mean age was 24.1 ± 11.7 years, the mean mass was 67.7 ± 13.8 kg, the mean height was 171.4 ± 9.5 cm and the mean body mass index was 23 ± 3.7. Results from 28 subjects were used in the per protocol analysis: compliance could not be calculated in one subject, and one subject dropped out of the study due to difficulty in providing blood samples.

Evaluation of individual stress levels showed a mean PSS-10 score of 19.1 ± 7.6 in the first period (during

Discussion

Cytokines and chemokines play critical roles in the immune response and contribute to symptoms during respiratory tract illness. Local production of immune mediators like IL-1β, IL-6, IL-8 and TNF-α increases during the common cold and during influenza infections in normal and asthmatic subjects (de Kluijver et al., 2003). Modulation of these mediators and of leukocyte activity might represent an effective strategy for the prevention and treatment of respiratory tract diseases and their

Disclosure

This research has been founded by A. Vogel Bioforce AG, Switzerland.

Funding

This study was funded by Bioforce, Switzerland.

Acknowledgements

The authors thank Mr. Vincent Wong, Mr. Alisdair Gilmour and Miss Sarah Gates, medical students at St. Andrews University, for their outstanding assistance.

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