Echinacea Abstracts

Design & Setting
Three-armed, randomized, double-blind, placebo-controlled trial. Four military institutions and 1 industrial plant.

Participants & Interventions
Three hundred two volunteers without acute illness at time of enrollment.

Ethanolic extract from Echinacea Purpurea Roots, Echinacea Angustifolia Roots, or placebo, given orally for 12 weeks.

Main Outcome Measure
Time until the first Upper Respiratory Tract Infection (time to event).

Secondary outcome measures were the number of participants with at least 1 infection, global assessment, and adverse effects.

Results
The time until occurrence of the first Upper Respiratory Tract Infection was 66 days (95% confidence interval [CI], 61-72 days) in the E Angustifolia group, 69 days (95% CI, 64-74 days) in the E Purpurea group, and 65 days (95% CI, 59-70 days) in the placebo group (P = .49).

In the placebo group, 36.7% had an infection. In the treatment groups, 32.0% in the E Angustifolia group (relative risk compared with placebo, 0.87; 95% CI, 0.59-1.30) and 29.3% in the E Purpurea group (relative risk compared with placebo, 0.80; 95% CI, 0.53-1.31) had an infection.

Participants in the treatment groups believed that they had more benefit from the medication than those in the placebo group (P = .04).

Adverse effects were reported by 18 subjects in the E Angustifolia group, 10 in the E Purpurea group, and 11 in the placebo group.

Conclusion
In this study a prophylactic effect of the investigated Echinacea extracts could not be shown.

However, based on the results of this and 2 other studies, one could speculate that there might be an effect of Echinacea products in the order of magnitude of 10% to 20% relative risk reduction.

Future studies with much larger sample sizes would be needed to prove this effect.

Herbal medicinals are being used by an increasing number of patients who typically do not advise their clinicians of concomitant use. Known or potential drug-herb interactions exist and should be screened for.

If used beyond 8 weeks, Echinacea could cause HepatoToxicity and therefore should not be used with other known Hepatoxic drugs, such as Anabolic Steroids, Amiodarone, Methotrexate, and Ketoconazole.

However, Echinacea lacks the 1,2 saturated necrine ring associated with hepatoxicity of Pyrrolizidine Alkaloids.

NonSteroidal anti-inflammatory drugs may negate the usefulness of Feverfew in the treatment of Migraine headaches.

Feverfew, Garlic, Ginkgo, Ginger, and Ginseng may alter bleeding time and should not be used concomitantly with Warfarin Sodium.

Additionally, Ginseng may cause Headache, Tremulousness, and Manic episodes in patients treated with Phenelzine Sulfate. Ginseng should also not be used with Estrogens or CorticoSteroids because of possible additive effects.

Since the mechanism of action of St John Wort is uncertain, concomitant use with MonoAmine Oxidase Inhibitors and Selective Serotonin Reuptake Inhibitors is ill advised.

Valerian should not be used concomitantly with Barbiturates because excessive sedation may occur.

Kyushin, Licorice, Plantain, Uzara Root, Hawthorn, and Ginseng may interfere with either Digoxin pharmacodynamically or with Digoxin monitoring.

Evening Primrose Oil and Borage should not be used with AntiConvulsants because they may lower the Seizure threshold. Shankapulshpi, an Ayurvedic preparation, may decrease Phenytoin levels as well as diminish drug efficacy.

Kava when used with Alprazolam has resulted in Coma. ImmunoStimulants (eg, Echinacea and zinc) should not be given with ImmunoSuppressants (eg, CorticoSteroids and Cyclosporine).

Tannic Acids present in some herbs (eg, St John wort and Saw Palmetto) may inhibit the absorption of Iron.

Kelp as a source of Iodine may interfere with Thyroid replacement therapies. Licorice can offset the pharmacological effect of Spironolactone.

Numerous herbs (eg, Karela and Ginseng) may affect blood Glucose levels and should not be used in patients with Diabetes Mellitus.

Patients who self-medicate with herbs for preventive and therapeutic purposes may assume that these products are safe because they are "natural," but some products cause adverse effects or have the potential to interact with prescription medications.

The United States lacks a regulatory system for herbal products.

Although only limited research on herbs has been published, St John's Wort shows promise as a treatment for Depression.

Ginkgo Biloba extract is possibly effective for CerebroVascular Insufficiency and Dementia.

Feverfew is used extensively in Canada for Migraine prophylaxis but needs more rigorous study.

Ephedrine has been regulated by many states because its misuse has been associated with several deaths.

Echinacea is being tried as an agent for Immune stimulation, and Garlic is under study for Cholesterol-lowering properties, but both require more study.

Physicians should educate themselves and their patients about the efficacy and adverse interactions of herbal agents and the limitations of our present knowledge of them.

Comment in: Am Fam Physician 1998 Oct 1;58(5):1064-5

Echinacea Purpurea, a plant originally used by native Americans to treat respiratory infections, was evaluated for its ability to stimulate the production of Cytokines by normal human peripheral blood Macrophages in vitro.

Commercial preparations of Echinacea fresh pressed juice and dried juice were tested at concentrations ranging from 10 micrograms/ml to 0.012 microgram/ml and compared to EndoToxin stimulated and unstimulated controls.

Cytokine production was measured by ELISA after 18 h of incubation for IL-1 and 36 and 72 h for TNF-, IL-6, and IL-10.

Macrophages cultured in concentrations of Echinacea as low as 0.012 microgram/ml produced significantly higher levels of IL-1, TNF-, IL-6 and IL-10 (P < 0.05) than unstimulated cells.

The high levels of IL-1, TNF-, and IL-10 induced by very low levels of Echinacea are consistent with an Immune activated AntiViral effect.

Echinacea induced lower levels of IL-6 in comparison to the other Cytokines measured.

These results demonstrate the Immune stimulatory ability of the unpurified fresh pressed juice of Echinacea Purpurea and offer some insight into the nature of the resulting Immune Response as compared to EndoToxin.

This article describes and discusses five placebo-controlled randomized studies investigating the ImmunoModulatory activity of preparations containing extracts of Echinacea in healthy volunteers.

A total of 134 (18 female and 116 male) healthy volunteers between 18 and 40 years of age were studied.

Two studies tested intravenous homeopathic complex preparations containing Echinacea Angustifolia D1 (study 1) and D4 (study 5).

Two studies (2 and 3a) tested oral alcoholic extracts of roots of E. Purpurea, one study an extract of E. Pallida Roots (study 3b), and one study an extract of E. Purpurea Herb (study 4).

Test and placebo preparations were applied for four (study 5) or five (studies 1-4) consecutive days.

The primary outcome measure for ImmunoModulatory activity was the relative Phagocytic activity of PolyMorphoNuclear Neutrophil Granulocytes (PNG), measured in studies 1 and 2 with a microscopic method and in studies 3, 4, and 5 with two different cytometric methods.

The secondary outcome measure was the number of Leukocytes in peripheral venous blood. Safety was assessed by a screening program of blood and other objective parameters as well as by documentation of all subjective side effects.

In studies 1 and 2 the Phagocytic activity of PNG was significantly enhanced compared with placebo [maximal stimulation 22.7% (95% confidence interval 17.5-27.9%) and 54.0% (8.4-99.6%), respectively], while in the other studies no significant effects were observed.

Analysis of intragroup differences revealed significant changes in Phagocytic activity during the observation periods in five test and three control groups.

Leukocyte number was not influenced significantly in any study. Side effects due to the test preparations could not be detected.

Our studies provide evidence for ImmunoModulatory activity of the homeopathic combination tested in study 1 and the E. Purpureae radix extract tested in study 2.

The negative results of the other three studies are difficult to interpret due to the different methods for measuring Phagocytosis.

The relevant changes in Phagocytic activity within most placebo and treatment groups during the observation period, and the small sample sizes.

Future studies should be performed on patients rather than healthy volunteers and use standardized or chemically defined monopreparations of Echinacea.

Extracts of Echinacea Purpurea and Panax Ginseng were evaluated for their capacity to stimulate Cellular Immune function by Peripheral Blood Mononuclear Cells (PBMC) from normal individuals and patients with either the Chronic Fatigue Syndrome or the Acquired ImmunoDeficiency Syndrome.

PBMC isolated on a Ficoll-hypaque density gradient were tested in the presence or absence of varying concentrations of each extract for Natural Killer Cells (NK Cells) activity versus K562 cells and Antibody-Dependent Cellular CytoToxicity (ADCC) against Human HerpesVirus 6 infected H9 cells.

Both Echinacea and Ginseng, at concentrations > or = 0.1 or 10 micrograms/kg, respectively, significantly enhanced NK-function of all groups. Similarly, the addition of either herb significantly increased ADCC of PBMC from all subject groups.

Thus, extracts of Echinacea Purpurea and Panax Ginseng enhance Cellular Immune Function of PBMC both from normal individuals and patients with depressed Cellular Immunity.

We measured the levels of the Cytokines IL-1alpha, IL-1-beta, IL-2, IL-6, TNF-, and IFN- in culture supernatants of stimulated whole blood cells.

Derived from 23 Tumor patients undergoing a 4-week oral treatment with a spagyric extract from Echinacea Angustifolia, Eupatorium perfoliatum, and Thuja occidentalis (Echinacea complex).

All patients had had curative surgery for a localized solid malignant Tumor. Blood was taken before treatment and after 2 and 4 weeks of therapy.

Twelve untreated Tumor patients at the same clinical stage, also after curative surgery, served as a control group.

In the blood cell cultures of all patients, a rather wide range of Cytokine levels was found.

After therapy with Echinacea complex, no significant alteration in the production of the Cytokines could be seen in comparison to the controls, and also the Leukocyte populations remained constant.

We conclude that at this application and dosage, the therapy with Echinacea complex has no detectable effect on Tumor patients' Lymphocytes activity as measured by their Cytokine production.

Background
Phytomedicinal preparations from members of the genus Echinacea are popular worldwide and frequently used to treat Upper Respiratory Infections.

With the increasing popularity of herbal medicines, many people are making their own Echinacea extracts at home and storing them at refrigerator (4 degrees C) temperatures.

We tested the hypothesis that Echinacea extracts made using homemade methods change in ImmunoModulatory efficacy with storage at 4 degrees C over a 4-day period.

Methods
Three extract types (50% ethanol tincture, cold water infusion, hot water infusion) from 5 different species (Echinacea Angustifolia, E. Pallida, E. Purpurea, E. Sanguinea, E. Tennesseensis) were prepared.

Four in vitro Immune assays (Monocyte secretion of TNF-, IL-10, and IL-12; and Peripheral Blood Mononuclear Cell proliferation) using human blood were used to test extract efficacy at Days 1 and 4 post-extraction.

Two statistical analyses, traditional ANOVA and several statistical models that account for EndoToxin effects, were used.

Results
EndoToxin was found to significantly impact Immune outcomes only in 4-day old cold water infusions and not in all assays. Extracts showed the greatest stimulation in TNF- assays.

By extract type, 50% Ethanol tinctures produced the most Immune stimulation. By species, extracts from E. Angustifolia extracts were the most efficacious in our assays; extracts from E. Sanguinea showed the least activity overall.

Conclusions
Taken together, these results suggest that:

1. Homemade Echinacea extracts are efficacious in modulating Immune Cell activity in vitro but that their properties change with time during storage at 4 degrees C; and
2. EndoToxin effects from extracts may be important considerations in the analysis of ImmunoBiological data.

Echinacea purpurea, a plant originally used by native Americans to treat respiratory infections, has also been shown to exert ImmunoModulatory activities both in vivo and in vitro.

However, the mechanism underlying Echinacea-induced ImmunoModulation remains largely unknown. This study examined in vitro the effects of soluble extracts of E. purpurea on Natural Killer (NK) Cells present in human Peripheral Blood Mononuclear Cells (PBMC).

Flow cytometric methods were used to examine activation, CytoToxicity, NK-target binding, and Killer Cell frequency.

Treatment of PBMC with Echinacea overnight resulted in the activation of CD69 expression and increase in mean fluorescence intensity in both the CD16⁺ and CD16⁺CD56⁺ NK subsets.

However, the frequency of CD16⁺ Cells was decreased as well as the mean fluorescence intensity was down-regulated. NK CytoToxicity was augmented 100% at the concentration of 0.1 microg/ml of Echinacea in a short time (4-h) assay.

Examination at the single cell level revealed augmentation of the frequency of CD56⁺ NK-target conjugates and a plateau was reached after 30-60 min of incubation.

Likewise, the frequency of CD56⁺ Killer Cells in the conjugates was also significantly increased by Echinacea.

There was recruitment of non-conjugated CD56⁺ Cells into CD16⁺ NK-target conjugates and activation of the NK-target Non-Killer conjugates into Killer Cells.

These findings demonstrate that Echinacea extracts are potent activators of NK CytoToxicity. Echinacea augments the frequency of NK target conjugates and activates the programming for lysis of NK Cells.

Alkylamides present in Echinacea species have reported ImmunoModulatory actions, yet their direct effects on T-Lymphocytes, key mediators of AntiViral Immunity, are poorly understood.

We hypothesized that constituents present in ethanolic extracts of Echinacea species exert direct ImmunoModulatory effects on human Jurkat T-Cells.

Modulation of IL-2 production by submaximally stimulated Jurkat cells was determined in response to treatment with extracts prepared from dried aerial parts of Echinacea purpurea.

Cells were treated with the extracts, with Alkylamides or Caffeic Acid derivatives isolated from Echinacea species, or with corresponding ethanol vehicle.

In the absence or presence of Phytohemagglutinin and phorbal ester. E. purpurea extracted in a solvent mixture of 95:5 ethanol/water dose-dependently inhibited IL-2 production.

This IL-2 inhibitory activity correlated with the presence of Alkylamides but not Caffeic Acid derivatives, as determined by high performance liquid chromatography/electrospray ionization-mass spectrometry analysis.

Simultaneous measurement of secreted IL-2 by ELISA and cell viability by the XTT assay showed that the 95:5 ethanol/water extract of E. purpurea was both IL-2 suppressive and CytoToxic at 50 and 100 microg/mL.

Lower concentrations from 6.25 to 25 microg/mL significantly decreased IL-2 production but not cell viability.

Alkylamides at concentrations found in a 50 microg/mL extract decreased IL-2 production by approximately 50%.

Two Echinacea-derived Alkylamides significantly depressed IL-2 production but not cell viability in a dose-dependent manner.

Thus, Alkylamides present in E. purpurea suppress the ability of activated Jurkat T-Cells to produce IL-2 independently of direct, CytoToxic effects.

Among the different species belonging to the Echinacea family, largely used in traditional medicine, Echinacea pallida, Echinacea purpurea and Echinacea angustifolia were investigated.

These different species, due to their difficult identification, were commonly confused in the past and probably used indifferently for the same therapeutic purposes.

In fact, the three species have in common, some pharmacological activities, based on the presence of active compounds that act additively and synergistically.

Nevertheless, the composition of each species has slight variation in the amount of each active component.

In particular, Echinacoside, a Caffeoyl derivative, is present in E. pallida and only in traces in E. angustifolia. It seems to have protective effects on skin connective tissue and to enhance wound healing.

The AntiInflammatory and wound healing activities of Echinacoside, compared with the ones of the total root extract of E. pallida and E. angustifolia, were examined in rats, after topical application.

The tissues of the treated animals were evaluated after 24, 48 and 72 h treatment and excised for histological observation at the end of the experiment.

Results confirm the good AntiInflammatory and wound healing properties of E. pallida and of its constituent Echinacoside, with respect to E. purpurea and control. This activity probably resides in the AntiHyaluronidase activity of Echinacoside.

We have investigated the ImmunoStimulatory, AntInflammatory, and AntiOxidant activities of various Echinacea raw materials and commercially available products on murine Macrophages and human Peripheral Blood Mononuclear Cells (PBMCs).

To emulate oral dosing, a simulated digestion protocol was employed as a means of sample preparation.

Echinacea-induced Macrophage activation was used as a measure of ImmunoStimulatory activity determined via quantitative assays for Macrophage-derived factors including Tumour Necrosis Factor-, InterLeukin (IL-1alpha), IL-1beta, IL-6, IL-10, and Nitric Oxide.

Echinacea herb and root powders were found to stimulate murine Macrophage Cytokine secretion as well as to significantly enhance the viability and/or proliferation of human PBMCs in vitro.

In contrast, Echinacea extracts chemically standardized to Phenolic Acid or Echinacoside content and fresh pressed juice preparations were found to be inactive as ImmunoStimulatory agents but did display, to varying degrees, AntiInflammatory and AntiOxidant properties.