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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

Drug/Class Interaction Type	Mechanism and Significance	Management
Cyclosporine Allograft immunosuppressive agents	Theoretically, long-term concomitant use might require increased levels of immunosuppression in allograft patients. Inadvertent use without professional care may cause drug failure.	Avoid, except for short-term acute coadministration, with professional monitoring.
Cyclophosphamide / /	Immunotherapeutic outcomes of low-dose drug protocols ( not cytotoxic schedules) may be enhanced by concomitant administration. High-dose drug effects on myelosuppression may be reduced.	Adopt; coadminister only with integrative oncologist supervision.
Myelosuppressive Antineoplastic Chemotherapies /	Echinacea may help protect white blood cell (WBC) counts in chemotherapy-induced myelosuppression. Natural killer (NK) cell number and activity increased by long-term administration.	Adopt; coadminister with related myeloprotective agents. Continue herb after chemotherapy.
Interferon, interleukin-2 (IL-2) Immunotherapeutic BRMs /	Possible additive effects of herb and drug allow sparing of drug, reduction of drug side effects, and enhanced therapeutic responses.	Consider adopting; professional management required.
Tumor necrosis factor-alpha antagonists Immunosuppressive BRMs / /	Echinacea may theoretically be used to enhance cellular immunity during temporary drug withdrawal mandated by opportunistic infection.	Stop drug; administer herb short-term only, before recommencing drug therapy.
BRM s, Biological response modifiers.

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

Evidence: Cyclosporine (Ciclosporin, cyclosporin A, CsA; Neoral, Sandimmune, SangCya).

Extrapolated, based on similar properties: Azothioprine (asathioprine; Azamun, Imuran, Thioprine), cyclophosphamide (Cytoxan, Endoxana, Neosar, Procytox), prednisolone oral (Delta-Cortef, Orapred, Pediapred, Prelone), prednisone oral (Deltasone, Liquid Pred, Meticorten, Orasone), tacrolimus (FK-506, fujimycin; Prograf).

Potential or Theoretical Adverse Interaction of Uncertain Severity

Probability: 4. Plausible
Evidence Base:

Inadequate

Effect and Mechanism of Action

Enhancement of cell-mediated immunity by echinacea administration holds the potential to cause a shift in the level of immunosuppression required to maintain host-graft adaptation in transplant recipients. Arguably, this proposed phenomenon represents a “contraindication” rather than interaction.

Research

Studies have shown phagocytic activity of human peripheral blood monocytes can be stimulated by echinacea polysaccharide fractions. ^26-31 Resistance to systemic infection in immunosuppressed animals was enhanced by echinacea. ³² Natural killer (NK) cell activity from human peripheral blood monocytes drawn from immunodeficient patients (AIDS, CFIDS) compared with normal subjects showed that cell-mediated immune activity was significantly enhanced after echinacea administration to the immunodeficient groups. ³³ More controversially, a “melanin”-like compound from echinacea has been shown to activate NF-κB through a toll-like receptor (TLR) mechanism (involving TLR2), resulting in increased Th1 cytokine levels. ⁴ At this time the clinical role, if any, of plant melanins as immunomodulating agents remains to be established.

Integrative Therapeutics, Clinical Concerns, and Adaptations

Immunosuppressed allograft recipients are more vulnerable to minor infection than normal individuals. Acute use of echinacea at the onset of symptoms (e.g., common cold, acute URIs) is preferred by some allograft patients and practitioners to antibiotic therapies, because preexisting susceptibility to opportunistic infection (e.g., Candida) is likely to be exacerbated by antibiotics. Assuming prior stable immunosuppression within accepted safety margins, as reflected in serum immunosuppressive drug levels, there seems no reason to oppose the use of echinacea acutely for prophylaxis or treatment of mild infection. However, compelling reasons would be needed to extend echinacea treatment to chronic use in this patient population. Clinical features of graft rejection must be treated by aggressive intensification of immunosuppressive therapy.

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

Aldesleukin (IL-2, recombinant interleukin-2 (rIL-2); Proleukin), GCSF/filgrastim (Neupogen), GMCSF/sargramostim (Granulocyte-Macrophage Colony-Stimulating Factor), interferon alpha (IFN-α; Alferon N, Intron A, Roferon-A), interferon gamma-1b levamisole (Ergamisol), oprelevkin (Neumega), pegfilgrastim (PEG-filgrastim; Neulasta), pegylated interferon alfa-2b (PEG-Intron).

	Interaction Likely but Uncertain Occurrence and Unclear
	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Probability: 4. Plausible
Evidence Base:

Inadequate

Effect and Mechanism of Action

Echinacea may increase endogenous interferon production by leukocytes and potentiate the effects of therapeutic recombinant interferon administration. It also increases NK cell number and activity, a target of IL-2 treatment.

Research

Research on the coadministration of echinacea and interferon is lacking, although preliminary positive data exist for astragalus, another interferon-enhancing herb (see also Astragalus monograph, aldesleukin/IL-2 discussion). However, in vitro, ex vivo, and in vivo evidence indicates that echinacea extracts increase IFN-α, which is consistent with its antiviral effect. ^41,42 Miller ¹⁹ has used murine models to compare echinacea effects on NK cells to IL-2.

Integrative Therapeutics, Clinical Concerns, and Adaptations

Combining immunomodulating BRMs with echinacea has not been studied. At this time, extrapolations from echinacea pharmacology merely suggest the possibility of an additive enhancement (or sparing); data are insufficient to make clear recommendations.

Myelosuppressive Antineoplastic Chemotherapy

Alkylating agents:Busulfan (Myleran), carboplatin (Paraplatin), chlorambucil (Leukeran), cisplatin ( cis-diaminedichloroplatinum, CDDP; Platinol, Platinol-AQ), cyclophosphamide (Cytoxan, Endoxana, Neosar, Procytox), dacarbazine (DIC, DTIC, DTIC-Dome, imidazole carboxamide), ifosfamide (Ifex, Mitoxana), mechlorethamine (Mustargen, nitrogen mustard), melphalan (Alkeran), oxaliplatin (Eloxatin), phenylalanine mustard (Melphalan), pipobroman (Vercyte), streptozocin (Zanosar), temozolomide (Temodar), thiotepa (Thioplex), uracil mustard (uramustine).

Cytotoxic antibiotics:Bleomycin (Blenoxane), dactinomycin (Actinomycin D, Cosmegen, Cosmegen Lyovac), mitomycin (Mutamycin), plicamycin (Mithracin).

Antimetabolites:Agalsidase beta (Fabrazyme), capecitabine (Xeloda), cladribine (Leustatin), cytarabine (ara-C; Cytosar-U, DepoCyt, Tarabine PFS), floxuridine (FUDR), fludarabine (Fludara), fluorouracil (5-FU, Adrucil, Efudex, Efudix, Fluoroplex), gemcitabine (Gemzar), lometrexol (T64), mercaptopurine (6-mercaptopurine, 6-MP, NSC 755; Purinethol), methotrexate (Folex, Maxtrex, Rheumatrex), pentostatin (Nipent), pemetrexed (Alimta), raltitrexed (ZD-1694; Tomudex), thioguanine (6-thioguanine, 6-TG, 2-amino-6-mercaptopurine; Lanvis, Tabloid), ZD9331.

Mitotic inhibitors:Docetaxel (Taxotere), paclitaxel (Paxene, Taxol), paclitaxel, protein-bound (Abraxane), vinblastine (Alkaban-AQ, Velban, Velsar), vincristine (Leurocristine, Oncovin, Vincasar PFS), vinorelbine (Navelbine).

Similar natural compounds.

	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Probability: 3. Possible
Evidence Base:

Preliminary

Effect and Mechanism of Action

Echinacea may help support and protect bone marrow myelopoiesis during chemotherapy, thereby ameliorating toxic effects of these agents on white blood cell counts.

Research

In animal studies, echinacea has proliferative effects at both spleen and bone marrow levels in rodents, although this study was confined to examining elevations in NK cells. ⁴³ The same group examined the effects of echinacea on myeloid progenitor cells in spleen and marrow and found that echinacea did not significantly increase granulocyte precursors. ⁴⁴ Weight loss was reduced and recovery from cisplatin administration was increased in rodents pretreated with E. pallidaextracts intraperitoneally. ⁴⁵ A German study on 70 breast cancer patients post-chemoradiotherapy found that a formula containing extracts of E. angustifoliaand E. purpurearoot with Thuja occidentalisand Baptisia tinctoriaexhibited a limited ability to protect peripheral blood counts, although the doses of preparation were low at 1.25 mL of the formula per day. ⁴⁶ A subsequent study involving 15 patients with advanced gastric cancer undergoing palliative chemotherapy with 5-FU, leucovorin, and etoposide received 2 mg daily of intravenous E. purpureapolysaccharide extract for 10 days total (3 days before chemotherapy) showed significant increases in leukocyte numbers compared with controls. ⁴⁷

Integrative Therapeutics, Clinical Concerns, and Adaptations

Many classes of antineoplastic agents exhibit dose-limiting toxicities on myelopoiesis, involving some or all cell lines, to the extent that leukopenia, thrombocytopenia, and anemia may prevent continued administration of chemotherapy. Nutritional status and general health of patients undergoing myelosuppressive chemotherapy are recognized as important factors in successful treatment toleration. A number of herbal and nutritional agents have been used as myeloprotective influences during chemotherapy, including echinacea extracts. These agents are often combined with other herbs directed at minimizing related chemotherapy-induced toxicities. Chinese medicine has explored these strategies more fully than Western herbal medicine to date, although echinacea can be incorporated into Western formulae for this purpose. Additionally, anecdotal clinical experience suggests that use of recombinant agents such as granulocyte colony-stimulating factor (G-CSF) would not be compromised by such approaches, and concomitant administration may potentially be beneficial. The additional effects of Th1 cytokine promotion (cell-mediated immunity) further support the rationale of using echinacea, particularly in combination formulae, in this context. ⁴⁸

Tumor Necrosis Factor-Alpha (TNF-α) Antagonists

Adalimumab (Humira), infliximab (Remicade), etanercept (Enbrel).

	Interaction Likely but Uncertain Occurrence and Unclear
/	Bimodal or Variable Interaction, with Professional Management

Probability: 6. Unknown
Evidence Base:

Preliminary

Effect and Mechanism of Action

At this time, the interaction is a theoretical concern but with important implications. Approved BRMs targeting the cytokine TNF-α reduce chronic inflammatory processes but increase susceptibility to infection. Echinacea extracts, administered short-term in acute doses, upregulate cell-mediated immunity to enhance drug-induced depression in mounting endogenous immune responses to pathogenic agents.

Research

Some experimental pharmacological in vitro and in vivo evidence suggests that fresh-pressed juice extracts of echinacea may increase TNF-α. ^28-30,38,41 These results have not been replicated with hydroethanolic echinacea root extracts (which lack in polysaccharides) or with oral administration to healthy human subjects. ^42,49,50 Immunosuppressed animals (with cyclophosphamide or cyclosporine) given echinacea respond to opportunistic infection more effectively than untreated animals. ³²

Integrative Therapeutics, Clinical Concerns, and Adaptations

Despite their common ability to inhibit cytokine bioactivity, the molecular structures and mechanisms of action of the various anti–TNF-α drugs currently approved for different conditions are in turn significantly different. For example, the TNF-binding moiety of etanercept is derived from soluble TNF receptor subunits; infliximab is a chimeric (mouse-human) monoclonal antibody to TNF, and adalimumab is a fully human anti-TNF monoclonal antibody. ⁵¹ A significant side effect of these agents is an increase in susceptibility to opportunistic infections, including by potentially ominous pathogenic agents such as tuberculosis. ⁵²

Current manufacturer recommendations suggest the cessation of TNF-α antagonists at the onset of self-limiting infections such as influenza, to allow for resolution of the infection, before recommencing drug therapy. The shortest half-life among this class of drug is etanercept (5 days). This window would be a time to use echinacea as a short-term immunostimulant, in acute doses, to enhance cell-mediated immune responses to accelerate resolution of infection before resumption of the anti-inflammatory therapy. The kinetics of echinacea effects on immune cells is known to be rapid. At this time, use of echinacea and other herbal immunomodulators in patients using BRMs as chronic anti-inflammatories remains problematic due to lack of data, partly because of the novelty of the TNF-α antagonist drugs, but is likely to become an increasingly important therapeutic concern for integrative practitioners with the increasing adoption of such agents.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

Antimicrobials Such as Antibiotic, Antifungal, Antimycobacterial, and Antiretroviral Agents

Evidence:
Econazole (Ecostatin, Spectazole).

Because of its ability to stimulate nonspecific immunity, echinacea, when taken alone, can be beneficial in a wide range of infectious conditions. Echinacea may also be helpful when coadministered with many antimicrobial drugs. Studies specifically examining the possible benefits of coadministration are rare. Coeugniet and Kuhnast ¹⁸ compared topical econazole nitrate in 60 patients with recurrent candidiasis with econazole and E. purpureagiven orally, subcutaneously, or intravenously. Rate of recurrence dropped from 60.5% with econazole alone to 15% to 16% for the echinacea plus econazole groups (oral and parenteral), and Candidarecall antigen sensitivity was increased two to three times for all echinacea groups. Although some authors describe this as an echinacea-econazole interaction, there would appear to be reasonable grounds, derived from the known immunostimulating pharmacology of echinacea, for regarding it as one example of how echinacea may be beneficially combined with antimicrobial agents. Trials combining nonspecific immunomodulating herbs such as echinacea with different antimicrobials are required for evidential support of such a generic interaction claim. Well-designed and adequately powered clinical trials using combination botanicals and drugs methodology are, unfortunately, likely to remain the exception rather than the rule in the short term because of the limited interest in such integrative strategies. However, this may change with the increasing concerns over issues such as the rise of drug-resistant strains, hospital-acquired infections, and high drug development costs.

A recent trial on echinacea in the treatment of the common cold in children failed to account for a substantial proportion of the children in both the placebo and the echinacea group taking a variety of over-the-counter (OTC) medications, as well as various dietary supplements, presumably assuming that these would not have any effect when combined with the echinacea. ⁵³ The trial has also been criticized on other methodological grounds. ^54,55 Meanwhile, although integrative practitioners might find that coadministration has multiple benefits, this sweeping generic interaction is classified here as “speculative.”

Cytochrome P450 1A2 Substrates, Including Clozapine and Related Atypical Antipsychotics, Cyclobenzaprine, Tacrine, and Tertiary Tricyclic Antidepressants

Atypical antipsychotics:
Aripiprazole (Abilify, Abilitat), clozapine (Clozaril), olanzapine (Symbyax, Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ziprasidone (Geodon).

Cyclobenzaprine (Flexeril), tacrine (tetrahydroaminoacridine, THA; Cognex).

Tertiary tricyclic antidepressants:
Amitriptyline (Elavil), combination drug: amitriptyline and perphenazine (Etrafon, Triavil, Triptazine), clomipramine (Anafranil), doxepin (Adapin, Sinequan), imipramine (Janimine, Tofranil), trimipramine (Surmontil).

Recent in vivo human pharmacokinetic data suggest that echinacea may inhibit CYP1A2. ²⁵ (See Strategic Considerations earlier.) Interactions between echinacea and 1A2 substrates have not been reported to date. A low-affinity, high-throughput CYP450 isoform, 1A2 is subject to induction by a range of environmental and dietary factors, including caffeine, brassicaceous vegetables, charbroiled foods, and tobacco smoking. Theoretically, the predominant patterns of echinacea prescription (i.e., short-term acute dosing for URIs) may mitigate any tendency to generate significant interactions caused by CYP450 effects. Until further data are available, however, a few critical substrates of 1A2 should be noted for potential interactions with prolonged echinacea use. These include the cholinesterase inhibitor tacrine (also a 1A2 inhibitor), the methylxanthines theophylline and caffeine, cyclobenzaprine, clozapine, and related antipsychotics. Tertiary tricyclics are cosubstrates of 1A2 and 3A4, which may be relevant if 3A4 is also inhibited by echinacea.

Cytochrome P450 3A4 Substrates

At present, interactions between narrow-therapeutic-index CYP3A4 drugs and echinacea have not been reported. Budzinski et al. ²¹ originally reported in vitro evidence for inhibition of 3A4. Gorski et al. ²⁵ found that echinacea inhibited intestinal 3A4 and induced hepatic 3A4 in a manner that tended to offset the net effects on availability of 3A4 substrates. Yale and Glurich ²³ found that in vitro, E. purpureaextracts moderately inhibited one 3A4 model substrate but did not affect another. This suggests that predicting the effect of echinacea on 3A4 substrates is likely to be complex, and that the actual effects will be variable. Further research is required to clarify whether echinacea administration will in lead to any significant 3A4 substrate drug interactions.

Warfarin

Coumadin, Marevan, Warfilone.

Warfarin is metabolized by both CYP1A2 (the R-enantiomer) and 2C9 (the S-enantiomer). The Gorski study on echinacea inhibition of P450 enzymes found a significant inhibition of 1A2 and a moderate inhibition of 2C9. ²⁵ Yale and Glurich ²³ confirmed 2C9 inhibition in vitro. This suggests that warfarin levels may theoretically be increased in susceptible individuals (2C9-poor metabolizers) because of lowered clearance after coadministration with echinacea; however, this interaction has not been reported clinically. Theoretically, normal monitoring and adjustment of warfarin levels would preclude the potential for increased risk of bleeding resulting from elevated drug levels.

Duration of Use, Hepatotoxicity, Autoimmunity, and Interactions with Hepatotoxic Drugs, Including Anabolic Steroids, Amiodarone, Methotrexate, and Ketoconazole

Duration of Use, Hepatotoxicity, Autoimmunity, and Interactions with Hepatotoxic Drugs, Including Anabolic Steroids, Amiodarone, Methotrexate, and Ketoconazole

It has been asserted that echinacea administration exceeding 8 weeks induces hepatotoxicity, which leads to adverse interactions with a variety of hepatotoxic drugs, including anabolic steroids, amiodarone, methotrexate, and ketoconazole. ⁵⁶ This assertion may be based on the presence of trace amounts of pyrrolizidine alkaloids (PAs) (∼0.0006% of tussilagine and isotussilagine) in the roots of E. pallidaand E. angustifolia. ⁵⁷ These PAs in fact lack the necessary necine macrocyclic ring structure of the hepatotoxic PAs that are metabolized into intermediate compounds, which form covalent adducts in hepatocytes, leading to the characteristic veno-occlusive disease toxicity.

The issue of limits to duration of use originated from Commission E, who stated that oral preparations of E. purpureaherb and E. pallidaroot should be consumed for no longer than 8 weeks. ¹³ No evidence exists for imposing restrictions on duration of use, either from adverse effects, suppression of immune function, or tachyphylaxis, and this assertion has been refuted in recent literature. ^16,58 Miller ¹⁹ used a murine model to demonstrate that long-term administration actually increaseshealth and longevity, with sustained improvements in immunological parameters.

Echinacea was also stated by Commission E “in principle” to be contraindicated in “progressive systemic diseases” such as tuberculosis, “leucosis” (sic), collagenosis, multiple sclerosis, acquired immunodeficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection, and other autoimmune diseases. In fact, phytotherapists regularly use echinacea in several autoimmune conditions, with studies on its use in HIV infection and AIDS, as well as a report of extended administration in chronic lymphocytic leukemia. ^59,60

Historically, Eclectic physicians used echinacea to treat thousands of patients with tuberculosis. Among professional herbalists and naturopathic physicians, possible aggravations of autoimmune disease have been extensively discussed, and although the consensus is that a blanket contraindication is generally unsupported, isolated incidents of symptom flare-up in patients with systemic lupus erythematosus (SLE) associated with echinacea use have been informally reported.

Given the heterogenous and multifactorial mechanisms of autoimmunity and the currently available data, a prudent conclusion at this time would be to approach echinacea use with caution in patients with serious or progressed autoimmune disease, especially those who are susceptible to symptom flare, as in lupus (SLE) and some forms of multiple sclerosis.

Allergenicity

A review by Parnham ⁶¹ of echinacea adverse event data in Germany from 1989 to 1995 found 13 adverse drug reactions (ADRs) possibly related to oral Echanacin use, of which four were attributed to echinacea exposure. All were allergic reactions with skin manifestations. In the study period, an unknown number of doses of echinacea were consumed in Germany, but Dr. Bauer, an acknowledged echinacea expert, estimates that 10 million doses are sold annually in Germany; allowing for a degree of underreporting of herbal ADRs, frequency of allergic response would appear to be low.

An Australian report of an atopic female patient who experienced allergic symptoms requiring emergency room attention was followed by a review of Australian safety data by the investigator. ⁶² The author concluded that 26 patients, of whom more than half were known to be atopic, had experienced echinacea-related allergic symptoms, and that IgE-mediated ADRs are possible from echinacea exposure among susceptible individuals. ⁶³ The national usage data for echinacea in Australia were not given, but if the figures are of the same order of magnitude as in Europe and the U.S., the risk/benefit ratio would appear to be lower rather than higher. This is corroborated by a skin test study of sensitivity to various herbal preparations involving more than 1000 subjects, in which echinacea caused dermatological reactions in only two subjects. ⁶⁴

Probiotics

In a 10-day randomized trial involving 15 healthy adults, Hill et al. ⁶⁵ observed potentially problematic changes in intestinal microbiota after Echinaceaadministration. Standardized E. purpurea(1000 mg daily) stimulated the growth of certain Bacteroidesspp. of intestinal bacteria, which may act as pathogens, particularly when the gut ecology has been disrupted. In stool samples, Echinaceause was associated with increased counts for three groups of organisms: the total group of aerobic bacteria, the anaerobic Bacteroidesin general, and Bacteroides fragilisin particular. The authors concluded that the “health consequences associated with this change are unknown.” ⁶⁵ Notably, reports of potentially related adverse events associated with Echinaceause are lacking, such as irritable bowel syndrome or other pathological responses that might be predicted to result from such unfavorable alterations.

Although similar findings for echinacea or other herbs (e.g., goldenseal, isatis) often used as antimicrobial or immunostimulant agents are generally absent in the scientific literature, such effects from chronic use at high doses would not necessarily be unexpected. Further research and judicious pharmacovigilance are appropriate and necessary as the use of botanical medicine grows within the consumer self-care market and professional therapeutic application.

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