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Echinacea

Botanical Names: The three principal species used commercially are Echinacea angustifolia DC, Echinacea purpurea (L.) Moench, and Echinacea pallida (Nutt.) Nutt.
Pharmacopoeial Names: Echinaceae radix, Echinaceae herba.
Common Names: Echinacea; E. angustifolia: narrow-leaved coneflower, Western echinacea; E. purpurea: purple coneflower, purple echinacea; E. pallida: pale coneflower echinacea, pale echinacea.

Summary Table
herb description

Family

Asteraceae.

Related Species

The Echinacea genus contains about 12 species, depending on the taxonomic authority consulted, although three major species ( E. angustifolia, E. purpurea, E. pallida ) are used in commerce. The minor taxa are sometimes classed as variants of the principal species. The minor species are confined to relatively small wild populations and include Echinacea paradoxa, E. simulata, and E. atrorubens; the Eastern species E. tenneseensis and E . laevigata are endangered.

Habitat and Cultivation

Echinacea angustifolia is native to the Great Plains and Atlantic drainage areas of the United States (U.S.) and Canada. Echinacea purpurea was introduced from the U.S. to Germany by Dr. Madaus before World War II and became cultivated on a large scale in Western Europe, where it is the dominant species of commerce.

Parts Used

Root and aerial flowering herb; commercially, the roots of Western echinacea (E. angustifolia) are preferred in the U.S.; aerial parts of purple echinacea (E. purpurea) are the principal part used in Europe.

Common Forms

  • Dried:   Root powder and aerial parts.

  • Fluid Extract or Tinctures:   Any of the above, 45% ethanol.

  • Fresh Stabilized Juice:   Echinacin is a German preparation (Madaus AG) that consists of E. purpurea flowering tops’ succus stabilized in 22% ethanol.

  • Solid Extracts, Tableted, or Encapsulated:   Combinations of the above in different concentrations are available.

  • Standardized Extracts:   In the U.S., echinacosides have been used as a marker; however, agreement on standardization is lacking, and manufacturers’ preparations may vary.

herb in clinical practice

Overview

The medicinal use of echinacea derived from indigenous Native American medicine. Widely used in the U.S. in the preantibiotic era for infectious diseases of all types, the modern view of the herb is narrower in focus, corresponding to the influence of European phytotherapy. An influential German clinical literature primarily employed aerial parts of E. purpurea, usually the stabilized fresh-juice preparation, administered both orally and parenterally. Historically, this resulted from the widespread cultivation of E. purpurea in Germany, which lacks native populations of echinacea. The roots of E. angustifolia are the preferred medicinal species in North American use. Modern clinical trials of echinacea focus largely on its use in prophylaxis and treatment of common colds and flu, whereas other therapeutic aspects of the herb remain underinvestigated by clinical researchers.

In popular use, echinacea is usually associated with prophylaxis and self-treatment of mild respiratory infections such as the common cold. However, the trial evidence for echinacea's efficacy for this indication remains conflicting and is perennially controversial in part because of the different Echinacea spp., different plant parts used in preparations, and different dosing regimens, as well as varying study design, methodology, and power. 1,2The debate regarding the efficacy of echinacea in relation to the common cold has unfortunately become emblematic of divisions between advocates of natural medicine and those of conventional medicine. Arguably, this detracts from issues of more practical concern to clinicians, who likely are more focused on the general immunomodulating properties of the herb rather than on whether a trial shows “it works” for the common cold.

The detailed pharmacological mechanisms of action of echinacea remain to be fully characterized. It is well established, however, that the herb enhances cell-mediated immunity, particularly phagocytosis, and has moderate anti-inflammatory as well as beneficial wound-healing and connective tissue effects. Different constituent groups are thought to act in concert to affect immune parameters. Although there have been many studies of the herb, variations in the form of preparation, including differing plant parts and plant species used, as well as dose ranges and routes of administration, have contributed to a surprising lack of cohesive understanding of the pharmacology of echinacea. Novel discoveries about the immunological properties of echinacea emerge as research into this complex herb continues; recent examples include the discovery of a “melanin”-like constituent that activates nuclear factor kappa B (NF-κB) via a toll-like receptor (TLR2) mechanism, as well as a cannabinoid receptor–dependent pathway of immunoactivation unique to the alkylamide fraction. 3,4

Historical/Ethnomedicine Precedent

Echinacea was used by Native American peoples as a medicinal agent for a wide variety of ailments, both topically and internally, including for snakebites, enlarged glands, and septic conditions. It was introduced into mainstream herbal medicine as a component of “Meyer's Blood Purifier” in the 1870s, where it came of the attention of the Eclectics, particularly John Uri Lloyd and John King. In the 1880s, Eclectic physicians started using echinacea, and the herb rapidly became a mainstay of their practice. Eclectic indications included carbuncles, furunculosis, abscesses, nasopharyngeal and respiratory catarrh, dysentery, syphilis, snakebites, sepsis, and cancer; their empirical reports constitute detailed, comprehensive, and authoritative contributions to the literature on echinacea. 5,6Echinacea was official in the National Formulary from 1916 to 1946. Brinker 7 has systematically detailed the divergent historical, cultural, and pharmacological aspects of the two major medicinal Echinacea species, E. angustifolia and E. purpurea, in the U.S. and Europe.

Known or Potential Therapeutic Uses

  • Internal:   Immunomodulation and promotion of cell-mediated immunity, particularly increasing phagocytosis by macrophages and monocytes, in a wide range of bacterial and viral conditions; chemotherapy-induced immunosuppression; recurrent candidiasis, sinusitis, etc.; upper respiratory tract infections (URIs); prophylaxis of URIs and infection in general.

  • Topical:   Wound healing and connective tissue repair, venomous bites, including snakebites and spider bites.

Key Constituents

Caffeic acid derivatives, alkylamides, flavonoids, polyacetylenes, essential oil, polysaccharides, alkaloids. Echinacea angustifolia root contains isobutylamides; E. pallida lacks these compounds but contains polyacetylenes, which appear to have similar pharmacological effects on immune parameters. Constituent profiles also vary according to part used (root vs. herb) and the method of extraction; for example, immunoactive polysaccharides are not present in most hydroethanolic preparations because of their insolubility in ethanol. “Melanin” has recently been identified in phenolic extractions. 4

Therapeutic Dosing Range

Suggested therapeutic dose ranges of the herb vary widely. Western echinacea root preparations are often administered at lower doses than E. purpurea aerial parts. Acute and chronic dose ranges also widely vary, as do posological approaches, which include the homeopathic through supraphysiological. The following are composite figures based on several sources. 8-13

Chronic Dose Range

  • Dried Root:   1 to 5 g/day

  • Dried Aerial Parts:   2.5 to 6 g/day

  • Fluid Extract (1:1)   3 to 5.5 mL/day

  • Fresh Juice:   8 to 9 mL/day

Acute Dose

The chronic doses may be significantly increased for short-term administration in acute conditions; 10 to 15 g/day or equivalent in liquid preparations is common.

interactions review

Strategic Considerations

Authoritative monographs for Echinacea spp. generally list no known interactions. 10,11,13,14The German Commission E listed certain contraindications “in principle” that have been challenged as speculative (see Theoretical, Speculative, and Preliminary Interactions Research). Because the mechanisms of action of different constituents of echinacea are not fully characterized, extrapolations from the available data to in vivo interactions involve a degree of speculation, although consideration of specific clinical contexts of herb/drug administration can clarify potential interaction issues.

Self-prescribing consumers may administer echinacea for more serious conditions than colds and flu, as shown by a recent survey of nonconventional therapy use by cancer patients. 15 Echinacea is anecdotally used by herbalists as an immune stimulant for various indications, including immunosuppressive or immunosupportive pharmacotherapies, and for patients with immunodeficiency or autoimmune conditions and cancer. Possible interactions in these contexts are addressed later, despite lack of published data and inherent problems of extrapolating from limited experimental data to in vivo clinical practice. Echinacea in these settings is established in herbal practice, however, and this implies a wider concept of the therapeutic value of echinacea than the cold and flu treatment that dominates mainstream perceptions and publications among conventional health care professionals and the lay public. 16,17

As a nonspecific cell-mediated immunomodulator, echinacea has been combined with anti-infective pharmacotherapies, either to increase net antimicrobial effect or to provide a similar degree of antimicrobial action at a lower drug dose. Few studies support this type of strategic interaction, although a study showing that a combination of E. purpurea intravenously with econazole was more efficacious than econazole alone in preventing recurrent candidal infection over a 6-month period is an often-cited example. 18 Some secondary sources evaluate this single study as evidence for a specific econazole-echinacea interaction. However, it is probably more appropriate to consider it as a specific instance of a general additive combination with converging antimicrobial effects leading to an enhancement of T helper cell type 1 (Th1) immunity; this interaction could arguably be extrapolated to several classes of anti-infective drugs for which evidence is not currently available.

The emerging use of pharmaceutical biological response modifiers (BRMs) that target different molecular aspects of the inflammatory process constitutes a challenging and complex scenario for clinicians considering the use of immunomodulating herbs. Several such agents are approved in a variety of chronic inflammatory conditions, including psoriasis, inflammatory bowel disease, and rheumatoid arthritis, as well as spondylosing arthropathies. Currently, the most frequently used class of these drugs targets tumor necrosis factor alpha (TNF-α) through a variety of mechanisms. Although necessarily speculative at this stage, the interactions between echinacea and these important emerging agents are considered later. A related consideration that should not be overlooked is that herbs influence human physiology differently than drugs, even when the apparent effects are convergent, as with echinacea and recombinant interleukin-2 (rIL-2). 19

Incorporation of echinacea as an ingredient in Western botanical formulae for bone marrow recovery after myelosuppressive chemotherapies is consistent with known pharmacology of the herb. At this time, coadministration with pharmaceutical colony-stimulating factors such as Neupogen lacks published support, although adverse event reports from concomitant administration are lacking. Related botanical strategies for protection of white blood cell (WBC) counts during chemotherapy are found in both Chinese and Western botanical integrative oncological settings. 19,20

Effects on Drug Metabolism and Bioavailability

Until recently, data on the effects of echinacea on drug-metabolizing systems were unavailable. An in vitro fluorometric screening study by Budzinski et al. 21 suggested moderate in vitro inhibition of cytochrome P450 (CYP450) 3A4 by echinacea extracts, implying a potential for pharmacokinetic interactions with substrates of this drug-metabolizing enzyme, but such interactions have not been reported to date in the clinical literature. No other potentially significant pharmacokinetic interactions with drug absorption, distribution, metabolism, and excretion (ADME) parameters have been reported. An in vitro study using a Ca-co cell membrane model examined differential transport of the caffeic acid derivatives and alkylamides, the principal components of hydroethanolic extracts of echinacea, and found that the apparent intestinal permeability for the alkyl amides was significantly greater than that for the caffeic acid compounds. 22 Another in vitro study found no inhibition of CYP2D6 and mild to moderate inhibition of CYP3A4 that was, unusually, dependent on the substrate, but marked inhibition of CYP2C9. 23 Currently, minimal data exist on echinacea and drug-transporter proteins. An experimental model of the human organic anion-transporting polypeptide-B (OATP-B) revealed a moderate inhibitory effect on estrone-3-sulfate uptake after echinacea addition. However, the number of known OATP-B substrates in humans is limited at present, although it does include DHEA-S and estrone. 24 The in vivo relevance of these data remains to be established.

A clinical study by Gorski et al. 25 used in vivo CYP450 substrate specific probe techniques to examine the effect of echinacea on several drug-metabolizing enzymes in healthy volunteers. After a washout period following baseline probe administration, using as probe drugs caffeine (1A2), tolbutamide (2C9), dextromethorphan (2D6), and midazolam (hepatic and intestinal 3A4), echinacea was administered at 400 mg of dried root four times daily for 8 days; the probes then were readministered and blood samples taken. The echinacea appeared to have no effect on 2D6 but exerted moderate inhibition on 2C9 and 1A2 and a complex effect on 3A4 involving a near–self-canceling inhibition of intestinal 3A4 with induction of hepatic 3A4 (see Theoretical, Speculative, and Preliminary Interactions Research). Notably, the Gorski study used powdered E. purpurea root for 8 days, although aerial herb is the more typical form of purple coneflower preparation, and the healthy volunteers were not phenotyped for polymorphisms of the P450 enzymes studies, which is particularly relevant for 2C9. A wide range of intersubject variability in pharmacokinetic responses was noted, in line with predictable levels of individual variation known to be partly associated with genetic, genomic, and metabolomic differences.

More research with larger populations is required to examine the in vivo effects of echinacea on drug-metabolizing systems. Inhibition of drugs metabolized by CYP2C9 may be a potential risk. Principal among these would be the S-warfarin isomer, phenytoin, and the sulfonylureas. These interactions have not been observed or reported to date.

herb-drug interactions
Cyclosporine and Related Immunosuppressants
Cyclophosphamide
Cyclophosphamide (Cytoxan, Endoxana, Neosar, Procytox).
Interaction Likely but Uncertain Occurrence and Unclear Implication
/ Bimodal or Variable Interaction, with Professional Management

Probability: 4. Plausible
Evidence Base: Preliminary

Effect and Mechanism of Action

This complex interaction may depend on the dose of drug and the clinical context. In cancer, low doses of cytotoxic agents such as cyclophosphamide have been found to have “paradoxical” immunostimulatory effects despite their myeloablative effects at high dose levels. Echinacea appears to increase the immunity-dependent anticancer effects of low-dose cyclophosphamide when given concurrently. In autoimmune disease, cyclophosphamide may be used at noncytotoxic doses to achieve immunosuppression, in which context echinacea would be theoretically contraindicated.

Research

Emerging interest in the anticancer effects of nontoxic doses of cyclophosphamide and other agents (e.g., vinca alkaloids) has established an immunity-dependent mechanism of action. Although not fully understood, it is considered that T-regulatory cells are effectively disabled by low doses of the drug. Interleukin-10 (IL-10) and TNF-α have also been implicated as possibly mediating the effect in animal studies. 34-37 Echinacea administration is associated with increases in interleukin-1 (IL-1), IL-10, and TNF-α by macrophages, although other mechanisms may be, and likely are, involved in echinacea effects. 28,38 Cytokine and chemokine cascades are interrelated, complex, and difficult to study, in that they occur rapidly and are often confined to a small cellular compartment and not reflected in serum levels of these compounds. At the current level of scientific knowledge, such interactions are best gauged clinically, although continued research is essential to improving our ability to understand, predict, and utilize the potential value of this botanical-pharmaceutical interaction.

Lersch et al. 39,40 investigated the effects of combining echinacea in the form of intramuscularly administered Echinacin and concurrent thymostimulin (a thymic peptide preparation) with low-dose cyclophosphamide (300 mg/m 2 intravenously, every 28 days) in two small groups of patients, one with advanced hepatocellular carcinoma and the other with advanced colorectal carcinoma. Numbers of CD4+ and NK cells as well as lymphokine-activated killer (LAK) cell activity increased significantly in the hepatoma patients. In the colorectal patients, all of whom had previous surgery and progressive disease, partial regression was noted in one patient and stabilization in six others, with a decrease in tumor markers and tumor volume (by ultrasonography).

Steinmuller et al. 32 used a rodent model of cyclophosphamide-induced immunosuppression and found that resistance to opportunistic infection by Candida albicansor Listeria monocytogeneswas restored in echinacea polysaccharide–treated animals compared with controls. They also found an increase in TNF-α and enhanced cytotoxic activity in macrophages from the echinacea polysaccharide–treated animals.

Integrative Therapeutics, Clinical Concerns, and Adaptations

Although published data are tentative, the possibility of strategic enhancement of responsiveness to immunotherapeutic agents (e.g., low-dose Cytoxan) and recombinant agents (e.g., IL-2, interferons) by concurrent echinacea administration will be of interest to integrative practitioners attempting to address modulation of immunoreactivity. 19 Although parenteral preparations were used in the studies, as typical in Germany, most intravenous echinacea effects apply also to oral administration. (See also Astragalus monograph, as well as following section on myelosuppressive chemotherapy.) Because the therapeutic objectives of cyclophosphamide treatment vary in different situations and the effects may vary with different doses (biphasic responses), experienced professional management is required for coadministration of cyclophosphamide with echinacea.

Interferon Alpha (IFN-α), Interleukin-2, and Other Immunotherapeutic Biological Response Modifiers
Myelosuppressive Antineoplastic Chemotherapy
Tumor Necrosis Factor-Alpha (TNF-α) Antagonists
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Antimicrobials Such as Antibiotic, Antifungal, Antimycobacterial, and Antiretroviral Agents
Cytochrome P450 1A2 Substrates, Including Clozapine and Related Atypical Antipsychotics, Cyclobenzaprine, Tacrine, and Tertiary Tricyclic Antidepressants
Cytochrome P450 3A4 Substrates
Warfarin
Duration of Use, Hepatotoxicity, Autoimmunity, and Interactions with Hepatotoxic Drugs, Including Anabolic Steroids, Amiodarone, Methotrexate, and Ketoconazole
Allergenicity
Probiotics
Citations
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