Echinacea for Upper Respiratory Viral Infections: Preparatory Differences Matter
Echinacea for Upper Respiratory Viral Infections: Preparatory Differences Matter
Abstract & Commentary
By Francis Brinker, ND. Dr. Brinker is Clinical Assistant Professor, Department of Medicine, College of Medicine, University of Arizona; he is a retained consultant for Eclectic Institute, Inc.
The confusion over what constitutes effective echinacea preparations for the treatment of colds and influenza is demonstrated in several recent reviews addressing this issue. Depending on inclusion criteria and methods of analysis, these reviews have arrived at different conclusions. A structured review of the treatment of the common cold suggested that the possible therapeutic efficacy of echinacea has not been established.1 A meta-analysis of echinacea for prevention and treatment of the common cold, as reflected in its incidence and duration, found that both were significantly improved; odds of developing a cold was decreased by 58% (P < 0.001); the duration was reduced by 1.4 days (P = 0.01). The significant reductions were maintained when analysis was limited to subgroups that excluded Jadad scores < 3, fixed method of cold exposure, or limited consideration to use of Echinacin/Echinaguard (E. purpurea; ie, above-ground, aerial plant juice).2
A systematic review noted that most trials had reasonable-to-good methodology based on the Jadad method, but the variety of echinacea preparations assessed contained different types and amounts of bioactive compounds, rendering comparisons inconclusive. Those based on E. purpurea aerial parts were found to possibly be effective in the early treatment of colds in adults, but results were inconsistent. Other preparations lacked adequate evidence for efficacy.3 Reviews and analyses of these sorts are telling, in that they generally combine results from studies on distinctively different types of products that are derived from several different echinacea species and plant parts, or their combinations, extracted by different methods and/or solvents and delivered in liquid or solid dosage forms in varying amounts.
In spite of this variety of different preparations and phytochemical contents and amounts, the reviews usually attempt to draw conclusions regarding a generic concept of superficially-related products called "Echinacea," whose equivalence only exists in the human imagination. The results of studies of different preparations must be considered separately regarding outcomes for that particular product or pharmaceutically-similar preparations. Extrapolation of results to other phytochemically different species, plant parts, extracts, and/or their combinations cannot be regarded as scientific. That two of the reviews took into account the fact that the preponderance of evidence is on behalf of preparations of E. purpurea aerial parts,2,3 is a step in the right direction, yet still fails to adequately analyze pertinent distinctions.
A major problem in many published clinical trials of echinacea and other botanical preparations is the inadequate characterization of the product by the research authors. Failure to sufficiently describe noncommercial preparations by providing species scientific Latin names, source, portion(s) used, drying technique, if used, solvent composition, extraction protocol, and/or phytochemical content renders information given on dosing difficult to interpret. Proprietary products likewise need to be characterized by their specific label claims, but these demand confirmation by assay, at least to the extent of identifiable phytochemical content, even (or especially) for products which claim to be standardized. Without establishing the botanical and chemical identity of the substance being studied, outcomes are rendered meaningless. Retaining botanical voucher specimens or samples of commercial products with the same lot number is also necessary, or future scientific validation of its identity cannot be achieved.4,5
The tendency to rely exclusively on established research protocols designed primarily for studying isolated drug compounds to determine research quality can misrepresent this aspect of credibility when assessing botanical research findings.6 A review of botanical product characterization in randomized, controlled trials found that only 9% (5/54) of "higher quality" studies with a Jadad score > 3 performed phytochemical content testing, compared to 26% (7/27) of those of lower Jadad scores.7
Good research begins by accurately identifying the preparation being studied. As the July 2007 conference of the American Society of Pharmacognosy emphasized, clarity and consistency in medicating is essential for validating and comparing outcomes.8 In using echinacea preparations for the common cold, for which there is a high placebo response,1 the need for consistent protocol can only go so far as the type of interaction between physician and patient,9 a potentially confounding factor in different settings of multi-clinic trials.
Traditional uses of different echinacea species/parts/ extracts
Echinacea was first professionally manufactured for doctors in 1894 by Lloyd Brothers Pharmacists in Cincinnati as an alcoholic liquid extract of E. angustifolia root. In 1912, a survey by this company, with responses from over 10,000 doctors, ranked it 11th (5065 listings) in importance of all botanical drugs. In 1921-1922, it was, by far, the best selling remedy sold by the Lloyd Brothers. In 1923, they reported on results of a survey soliciting information on it use from hundreds of doctors. Over one in five applied it as a dilution locally to bites, stings, wounds, and skin infections. It was also simultaneously taken internally, as well as being employed orally for serious sore throats and other infectious conditions, but its application for colds and flu was not emphasized. A high alcohol content was necessary to preserve the isobutylamide (alkamide) components noted for their tingling effect on the tongue. The 65% ethanolic fluid extract of E. angustifolia root, and later E. pallida root that lacked these "tongue-tingling" isobutylamides, were officially recognized in the National Formulary until 1946. Both of these species contain echinacoside, a caffeic acid conjugate, as a major marker compound.10
E. purpurea was seldom employed until 1939 when the German pharmacist Gerhard Madaus mistakenly obtained the seeds for this species. Subsequently, he produced the expressed juice of the aerial plant containing high molecular weight polysaccharides and preserved with 22% alcohol (proprietary name: Echinacin).9 After laboratory and clinical research established its local and internal applications for wound healing, colds, and other respiratory and urinary infections, the German Commission E approved this preparation or its equivalent for these uses in 1989.9,10 In 1992, the German Commission E also approved E. pallida root 50% ethanol liquid extract at 1:5 strength (root:solvent) for influenza-like infections. Other echinacea preparations lacked sufficient evidence at that time for approval.11
In 1992, a published placebo-controlled, double-blind study in Germany showed that a 1:5 strength tincture of E. purpurea root extracted with 55% ethanol was effective at a daily dose of 180 drops (900 mg root), but not at half this amount. It significantly reduced duration and severity of flu-like symptoms compared to placebo after 3-4 days (P < 0.05) and 8-10 days (P < 0.0001).12 E. purpurea root yields alkamides like E. angustifolia root, but contains the caffeic acid conjugate cichoric acid, rather than echinacoside.10 This extension of clinically-confirmed effective preparations of echinacea for viral upper respiratory infections (URIs) would be further expanded in following years. To evaluate which forms appear to be most preferable, we will consider those URI studies published in English since then, but limited to adult treatment effects, not prevention or pediatric studies.
Clinical echinacea studies of different species, parts, and extracts
In 1993, a randomized, placebo-controlled, double-blind (RPCDB) trial in Germany, published in English in 1997, studied 115 viral URI patients with flu-like symptoms. The treatment for 70 subjects was a liquid E. pallida root hydroalcoholic extract (dose = 900 mg root). It reduced viral infections to 9.1 days, compared to 13 days for the 45 patients given placebo, a statistically significant reduction (P < 0.0001). The reduction of overall symptom score for cold, weakness, extremity pain, and headache by the extract was likewise statistically significant (P < 0.0004). The extract group also had a more rapid return to normal lymphocyte count.13 This study confirmed the Commission E approval of this preparation.11
Two RPCDB studies, with 200 adults total, treated early common cold symptoms with E. purpurea aerial-plant juice preserved with 22% ethanol, taken in doses of either 1 mL every two hours on day one, then three times daily for up to ten days (Echinagard),14 or 5 mL twice daily for ten days (Echinacin).15 No increase in adverse effects occurred, but significant reductions were shown in median duration of the colds compared to placebo (P < 0.000114 and 0.011215), likewise confirming Commission E approval of this form.11 However, another RPCDB study with 128 early cold patients with comparable backgrounds used 100 mg of the freeze-dried juice from E. purpurea aerial plant in capsules three times daily for seven days. Use began the first day of the cold, on average 15 hours after first symptoms. This solid form, standardized to 2.4% soluble beta-1,2-D-fructofuranosides, failed to produce benefit compared to placebo for all 15 scored symptoms (P range, 0.29-0.90) or individual symptoms (P range, 0.09-0.93). Symptom resolution was of same duration (P = 0.73).16 Though theoretically "equivalent" to the approved liquid form, this solid preparation form failed in practice.
A fresh whole plant E. purpurea liquid extract has recently been developed and clinically tested. Echinilin contains alkamides, cichoric acid, and polysaccharides standardized to concentrations of 0.25, 2.5, and 25 mg/mL, respectively. This 40% ethanol liquid extract from fresh parts E. purpurea was studied in a RPCDB trial for common cold with 111 patients. Ten 4 mL doses were taken first day at the onset, then four doses daily for next six days. Daily symptom scores were 23% lower for extract group than for placebo group (P < 0.01). Except for cough, the overall mean severity scores of symptoms was less for those taking echinacea (P < 0.05). By day seven, symptom reduction was 95% for extract vs 63% for placebo. Duration of sore throat and nasal congestion was less for Echinilin (P < 0.05).17 This same extract or placebo were given to 150 subjects in eight 5 mL doses on the first day of their cold, then three doses for the next six days. The decrease in total daily symptomatic score was greater in the extract group than for placebo (P < 0.05). This was accompanied by an increase in neutrophil count on days 3 and 8 compared to placebo (P < 0.05).18
Another form of fresh E. purpurea extract has been popular in Europe since the 1960s. The Swiss naturopath Alfred Vogel began using the tincture of the whole fresh plant to strengthen the immune response to infectious conditions.19 This extract is called Echinaforce. The solid native extract from the whole plant (95% herb, 5% root) was given in a RPCDB study of the common cold at doses of 6.78 mg or 48.27 mg; these were compared to 29.6 mg of concentrated E. purpurea root extract and placebo tablets. Dosage was 2 tablets of each three times daily for up to 7 days in 246 total patients. Overall effect on 12 cold symptoms showed Echinaforce was effective in the doctor's record of relative reduction of symptoms over placebo at low dose (P = 0.020) and high dose (P = 0.003). The solid root extract was not better than placebo.20 While the dried fresh plant tincture retained its efficacy against colds after being converted to a solid form, the root extract did not.
What about E. angustifolia root tincture? A RPCDB study with 250 subjects in the treatment phase used three noncommercial 1:5 strength extracts of E. angustifolia 2-year-old fresh roots (made with supercritical carbon dioxide (CO2), 60% ethanol or 20% ethanol) at a dose of 1.5 mL three times daily (900 mg root) for six days after a viral challenge with the rhinovirus 39. There was no significant effect on symptom severity compared to placebo (P = 0.46, 0.28, 0.89, respectively). The CO2 extract was made up of 74% alkamides; the 60% ethanol extract had 2% alkamides and 49% polysaccharides, and the 20% ethanol extract was 0.1% alkamides and 42% polysaccharides. No echinacoside was detected.21 Only the 60% ethanol solvent is in the common range of commercially-available products. However, the phytochemical assays suggest that the German-cultivated roots were not representative of roots traditionally wild-crafted from the American Great Plains.
Conclusions and discussion
The current popularity of echinacea products in the treatment of viral URIs has focused research on this use, but medical and media assessments typically fail to distinguish between the multitude of available products. The majority of clinical evidence on E. purpurea preparations for viral URIs appear to indicate that this readily-cultivated species is preferable for colds and/or influenza. Liquid preparations from E. purpurea aerial plant juice or hydroalcoholic extracts of the whole fresh plant appear most effective for directly exposing the local oropharyngeal lymphatic tissue to its potential immunomodulatory, antiviral, and/or anti-inflammatory influences. However, tinctures of its root or the root of E. pallida also share limited evidence of efficacy at a dosage equivalency of 900 mg daily, while those of E. angustifolia root at this time do not. Aside from solid extracts derived from tinctures of the whole fresh plant, tablets or encapsulated preparations have not been shown to be effective.
Numerous factors can determine the outcome of clinical trials with echinacea preparations, not the least of which is the dose and dosing schedule. Beginning dosing early (at least within the first day of symptoms) is a hallmark of most studies.14-18,20,21 Frequent dosing early, followed by reduced frequency on the following days, is a standard approach for taking echinacea products, as was demonstrated with the liquid hydroalcoholic extract of whole fresh E. purpurea.17,18 However, both small and large infrequent doses of whole fresh plant extract tablets have produced benefit.19 In studies of the aerial plant liquid juice using frequent and early but small doses14 or larger infrequent doses of the juice,15 positive effects have been achieved, but not with regular moderate doses of the dried juice. Early dosing with liquid extracts of fresh E. purpurea (aerial plant and/or root) appears preferable.
Though referring to a preparation merely as "echinacea" is usually meaningless, combinations of different parts from several species may be legitimately described by this generic term. Several RPCDB studies of different combinations of Echinacea species and parts have shown both the tea (Echinacea Plus® with E. purpurea whole plant and E. angustifolia leaves) and tablets (Esberitox® with 30% alcoholic extracts of E. purpurea roots and E. pallida roots) used as lozenges, or swallowed in larger doses, to be effective for symptoms of the flu and common cold.22,23,24 Unfortunately, the variable contents and/or auxiliary botanical ingredients makes it impossible to assess the value of the individual echinacea components in these studies.
Studies of dried powdered parts of individual Echinacea species have not been performed. The one RPCDB study evaluating a combination of the dried powdered whole E. purpurea plant with the dried powdered root of E. angustifolia for treating colds was marred by the use of alfalfa (Medicago sativa) herb as a placebo.25 A subsequent laboratory study revealed that strong in vivo immune-enhancing effects of the melanin component found in high concentrations both in Echinacea species and alfalfa26 renders the strong "placebo effect" and lack of statistically significant echinacea benefits in the outcome unsurprising.
Though melanin is not extracted by commercial solvents, it is conceivably available in the expressed juice products. Its action on toll-like receptors of the intestinal tract and Peyer's Patches cells indicates that absorption may not be necessary to increase interferon- and IgA secretion.26 A similar mechanism may also explain activity of non-absorbable, high molecular weight polysaccharides that are precipitated out of solution by over 30% alcohol.10 Pharmacokinetic studies show that alkamides present in E. purpurea and E. angustifolia root extracts are well-absorbed,27 and their absorption is more rapid from liquid than solid extracts.28 These components enhance phagocytosis by macrophages in vivo and bind to cannabinoid-2 receptors, decrease pro-inflammatory cytokines, and inhibit COX-2 formations of prostaglandin E2.29
Caffeic acid conjugates are not well-absorbed.27 In addition, cichoric acid is rapidly degraded by enzymes when administered in fresh juice,29 even in the presence of 22% ethanol.30 However, preparations with over 30% ethanol preserve the caffeoyl conjugates,31 and the in vitro antiviral activity of E. purpurea's cichoric acid and the echinacoside in E. angustifolia and E. pallida,32 suggest that absorption may not be necessary, if local exposure to viral-affected tissues is assured.
Failure to differentiate results from echinacea preparations disregards their distinctive contents and bioactivity. Pharmacological effects of herbal products are functions of active phytochemical content, dosage, and bioavailability, as influenced by form. As processing changes the content and form, the therapeutic effect can also be changed, explaining the different outcomes documented when treating URIs with various echinacea preparations. The species, plant parts, extract solvent, local and systemic exposures, and dosages all should be taken into account when selecting a product, based upon clinical preferences.
While both liquid and solid extract preparations may be advantageous for their systemic immunomodulating effects, oral exposure to liquid forms seems additionally advantageous as a local treatment of pharyngeal lymphatic tissue in URIs. Local exposure of lymphatic tissue to liquid extracts provides direct therapeutic effects. Faster absorption with liquid extracts is also preferred for acute and/or febrile conditions. Solid dosing forms, including the dried herb and/or root that require initial digestion, may theoretically serve a greater advantage in prevention by providing slower and steadier absorption that maintains a more consistent serum titer to enhance systemic resistance to infections. Capsules and tablets also allow the patient to avoid having to regularly taste what some may consider distasteful botanical liquid extracts. Unfortunately, published research studies on preparations of single echinacea species for the prevention of respiratory infections, thus far, have invariably utilized liquid dosing forms. Practicing the art of botanical medicine requires taking individual factors regarding the patient, condition, and remedy into consideration when selecting the most suitable preparation.
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32. Cheminat A, et al. Caffeoyl conjugates from Echinacea species: Structures and biological activity. Phytochem 1988;27:2787-2794.The confusion over what constitutes effective echinacea preparations for the treatment of colds and influenza is demonstrated in several recent reviews addressing this issue.
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