A Suter

Cytochrome P450 inhibitory action of Echinacea preparations differs widely and co-varies with alkylamide content.

Echinacea preparations are one of the best selling herbal medicinal products with a well established therapeutic use in the prophylaxis of upper respiratory tract infections. Their consumption is increasing, but information about their ability to inhibit cytochrome P450 enzymes (CYP) is fragmentary. The picture is further complicated by a lack of phytochemical characterization of previously tested preparations. Due to its well characterized immunomodulatory activity, the standardized Swiss registered Echinacea purpurea (L.) Moench Echinaforce extract was selected for detailed study. With the single baculovirus‐expressed CYP isoforms 1A2, 2C19, 2D9 and 3A4, inhibitory actions were measured by monitoring fluorescent metabolites derived from enzyme substrates (supersome assay). The Echinaforce extract induced mild inhibition of all these isoforms, with CYP 3A4 being the most, and CYP 2D6 the least sensitive enzyme. To assess whether CYP inhibition might be a general feature of Echinacea preparations, an additional nine commercially available preparations were screened using CYP 3A4. All tested preparations were able to inhibit CYP 3A4, but inhibitory potencies (expressed as median inhibitory concentration, IC50) varied by a factor of 150. The alkylamides are thought to be responsible for the immunomodulatory activity of Echinacea, and so the concentration of 2E,4E,8Z,10E/Z‐tetranoic acid isobutylamide (1) and total alkylamide content were determined in all preparations, and the latter was found to be associated with their CYP 3A4 inhibitory potency. The chemically pure alkylamides dodeca‐2E,4E,8Z,10E/Z‐tetranoic acid isobutylamide (1) and dodeca‐2E,4E‐dieonoic acid isobutylamide (2) showed inhibitory activity on CYP 2C19, 2D6 and 3A4. However, unlike the Echinaforce extract, the alkylamides did not induce CYP 1A2 inhibition. Thus, other, as yet unidentified constituents also contribute to the overall weak inhibitory effects seen with Echinacea preparations in‐vitro.

Metabolomic Profiling of Liquid Echinacea Medicinal Products with In Vitro Inhibitory Effects on Cytochrome P450 3A4 (CYP3A4)

ECHINACEA is a popular and widely used herbal medicinal product and consequently, studies of its interactions with conventional drugs are of particular importance. We have shown that ECHINACEA preparations and some common alkylamides weakly inhibit several cytochrome P450 (CYP) isoforms, with considerable variation in potency. We now report a detailed analysis of six commercial ECHINACEA liquid preparations, with emphasis on the metabolomic characterisation of the ECHINACEA compounds responsible for inhibiting CYP3A4. We separated each preparation into its ethanol- and water-soluble components, and then used (1)H-NMR together with multivariate data analysis and partial least square regression analysis to investigate the nature of the compounds responsible for CYP3A4 inhibition. The results implicated alkylamides in the CYP3A4 inhibitory activity of ECHINACEA. One of the commercial preparations (Echinaforce(R)) was further fractionated using solid phase extraction. Analysis by (1)H-NMR and mass spectroscopy (LC/MS, tandem MS, accurate mass) identified dodeca-2 E,4 E,8 Z,10 E/Z-tetraenoic acid (alkylamide 1) and a new compound (putative molecular formula C (18)H (36) NO (+)) as major components of the inhibitory fractions. In addition, the alkylamide content of all six preparations was determined by reverse phase HPLC. Levels of alkylamides 1 and 3 (undeca-2 E,4 E/ Z-diene-8,10-diynoic acid isobutylamide), correlated well with CYP3A4 inhibition. The acetylene tetradeca-8 Z-ene-11,13-diyn-2-one was shown to be present in the E. PURPUREA as well as the E. PALLIDA extracts. E. PURPUREA unlike E. PALLIDA was thought to not contain significant amounts of acetylenes. Our results directly confirm the role of alkylamides in the inhibition of CYP3A4 by ECHINACEA and uncovered a new compound which may also be involved. Extensive differences in the composition of the commercially available preparations were found. This will inevitably impact on the product efficacy, safety and pharmacological effects, especially since the differences involve alkylamides, an important class of ECHINACEAs active constituents. The metabolomic approach presented here may prove valuable as a screening or quality control tool.

Safety of Herbal Medicinal Products: Echinacea and Selected Alkylamides Do Not Induce CYP3A4 mRNA Expression

A major safety concern with the use of herbal medicinal products (HMP) is their interactions with conventional medicines, which are often mediated via the cytochrome P450 (CYP) system. Echinacea is a widely used over-the-counter HMP, with proven immunomodulatory properties. Its increasing use makes research into its safety an urgent concern. Previously, we showed that Echinacea extracts and its alkylamides (thought to be important for Echinaceas immunomodulatory activity) mildly inhibit the enzymatic activity of the main drug metabolising CYP isoforms, but to this date, there is insufficient work on its ability to alter CYP expression levels. We now report for the first time the effect of a commercial Echinacea extract (Echinaforce) and four Echinacea alkylamides on the transcription of the major drug metabolizing enzyme CYP3A4. HepG2 cells were exposed for 96 h to clinically relevant concentrations of Echinaforce (22, 11.6 and 1.16 μg mL−1) or the alkylamides (1.62 and 44 nM). CYP3A4 mRNA levels were quantified using real-time reverse transcription polymerase chain reaction (RT-PCR). Neither Echinaforce nor the alkylamides produced any significant changes in the steady-state CYP3A4 mRNA levels, under these conditions. In contrast, treatment with 50 μM rifampicin resulted in a 3.8-fold up-regulation over the vehicle control. We conclude that Echinaforce is unlikely to affect CYP3A4 transcriptional levels, even at concentrations which can inhibit the enzymatic activity of CYP3A4. Overall, our data provides further evidence for the lack of interactions between Echinacea and conventional drugs.

A phytochemical comparison of saw palmetto products using gas chromatography and 1H nuclear magnetic resonance spectroscopy metabolomic profiling

Preparations containing saw palmetto berries are used in the treatment of benign prostatic hyperplasia (BPH). There are many products on the market, and relatively little is known about their chemical variability and specifically the composition and quality of different saw palmetto products notwithstanding that in 2000, an international consultation paper from the major urological associations from the five continents on treatments for BPH demanded further research on this topic. Here, we compare two analytical approaches and characterise 57 different saw palmetto products.

Alteration of anti-inflammatory activity of Harpagophytum procumbens (devil's claw) extract after external metabolic activation with S9 mix

Extracts of the tubers of Harpagophytum procumbens (devils claw, DC) inhibit different proinflammatory mediators important in the pathophysiology of osteoarthritis. Many plant‐derived preparations interfere with cytochrome P450 liver enzymes, which influence their different biological activities. Therefore, the present study was designed to investigate the influence of an external metabolic activation of a DC extract on the cytotoxicity and the release of proinflammatory cytokines.

The interaction potential of herbal medicinal products: a luminescence-based screening platform assessing effects on cytochrome P450 and its use with devil's claw (Harpagophyti radix) preparations

Objectives  Potential interactions between herbal medicinal products and the cytochrome (CYP) P450 system are an important safety concern. We set out to develop a screening panel for assessing such interactions and use it to evaluate the interaction potential of devils claw.

Union schweizerischer komplementärmedizinischer ärzteorganisationen

Verschiedene Ärz t e o rganisationen der Komplementärm e d i zin haben sich im Jahr 1996 zu einer Dachorganisation, der «Union schweizerischer komplementärmedizinischer Ärzteo rganisationen», zusammengeschlossen. Die UNION vere i n t heute rund 2’000 Ärztinnen und Ärzte. ■ Die UNION ist mitspracheberechtigte Ärz t e o rganisation bei der Verbindung der Schweizer Ärztinnen und Ärzte (FMH). ■ Die UNION wird regelmässig zu Stellungnahmen bei Vernehmlassungen im Bereich Gesundheitswesen und Krankenversicherung eingeladen. ■ Die Unterstellung der Akupunktur/Chinesischen Medizin, A n t h roposophischen Medizin, Homöopathie, Neuraltherapie und Phytotherapie unter die obligatorische Krankenpflegeversicherung geht auf einen Antrag der Union an die Eidgenössische Kommission für allgemeine Leistungen zurück. ■ Für ärztliche Fachrichtungen der Komplementärmedizin, die unter die Zusatzversicherung fallen, hat die UNION einen Fertigkeitsausweis geschaffen. ■ Ab dem Jahr 2000 wird alle zwei Jahre ein Fachkongress durchgeführt. ■ Die UNION hat eine Ombudsstelle für den Bereich der ärz tlichen Komplementärmedizin und Krankenversicherung eingerichtet. ■ Im Jahr 2001 erfolgte die Gründung der Forschungsstiftung Komplementärmedizin. Diese Stiftung wird sich der Förderung der Forschung im Bereich der ärztlichen Komplementärmedizin annehmen.