The European Agency for the Evaluation of Medicinal Products Veterinary Medicines Evaluation Unit EMEA/MRL/687/99-FINAL August 1999 COMMITTEE FOR VETERINARY MEDICINAL PRODUCTS ECHINACEA (use in veterinary homeopathy) SUMMARY REPORT 1. Echinacea species are plants of the Asteraceae family. Homeopathic preparations of Echinacea according to homeopathic pharmacopoeias are prepared by ethanolic extraction of the whole fresh (flowering) aerial parts and/or roots of the plant subspecies Echinacea angustifolia, Echinacea pallida or Echinacea purpurea. In the past a clear distinction between the species Echinacea angustifolia and Echinacea pallida has not always been made. Therefore data on constituents relate to either Echinacea angustifolia or Echinacea pallida or both. Constituents of the whole plant of Echinacea angustifolia and/or Echinacea pallida include caffeic acid derivatives as verbascoside, echinacoside (0.3 to 1.3% in the roots), cynarine, chlorogenic and isochlorogenic acid, flavonoids (such as rutin, kaempferol, quercetin), alkamides such as dodeca-2E,4E,8Z,10E-tetraenic acid isobutylamide as well as polysaccharides. The volatile oil (less than 0.1% in the roots of Echinacea angustifolia, up to 2% in the roots of Echinacea pallida, less in the leaves, more in certain parts of the blossoms) contain alkenes and alkanones such as dodeca-2,4-dien-1-yl-isovalerianate, pentadeca-1,8-Z-diene and ketoalkenines as well as epishyobunol, ß-farnesene, a- and ß-pinene, myrcene, carvomenthene, caryophyllene. In the roots the pyrrolizidine alkaloids tussilagin (0.006%) and isotussilagin with a saturated necine configuration have been demonstrated, as well as polyacetylenes (e.g. trideca-1- en-3,5,7,9,11-pentain and pontiacepoxid). Additionally, sesquiterpenes as germacrene-alcohol, betain, phytosterols, fatty acids and resins are found at low concentrations. Echinacea purpurea contains a similar spectrum of constituents: Caffeic acid derivatives (0.6 to 3.1% of cichorienic acid (2,3-O-dicaffeoyl-tartaric acid) in different parts of Echinacea purpurea) and other glycosides, flavonoids (such as rutin, kaempferol, quercetin), polyacetylenes, alkyamides and polysaccharides as well as pyrrolizidine alkaloids of the saturated type (approximately 0.006% in Echinacea purpurea). Other constituents are betaine, fatty acids, phytosterol, resin and volatile oil (less than 0.1% in all parts of Echinacea purpurea). Echinacea purpurea has previously been assessed by the Committee for Veterinary Medicinal Products (CVMP) in respect to its use in veterinary phytotherapy and is included in Annex II of Council Regulation (EEC) No 2377/90 as follows: Pharmacologically active Animal species Other provisions substance(s) Echinacea purpurea All food producing species For topical use only 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Switchboard (44-20-7) 418 8400 Fax (44-20-7) 418 8447 E-mail: [email protected] http://www.eudra.org/emea.html ãEMEA 2000 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged 2. This application relates to the hmoepathic mother tincture of Echinacea (Echinacea angustifolia, Echinacea pallida, Echinacea purpurea) and dilutions thereof, which are intended for use in all food-producing species. The maximum recommended parenteral dosage for large animals is 10 ml/animal. The use follows the principles of homeopathic therapy where animals are diagnosed on basis of the individual pattern of clinical signs. Treatment may be repeated but a fixed dose schedule is not common in homeopathy. The drug is also used in human homeopathy as the mother tincture as well as in lower concentrations. 3. Claimed pharmacodynamic effects of homeopathic formulations of Echinacea include immunomodulating activity, mainly immunostimulation via T-cell activation and enhancement of phagocytosis, leading to antiviral and antibacterial action, promotion of wound healing possibly induced by stimulation of fibroblast cell growth, and antihyaluronidase activity. After frequent treatment an inhibiting action on the immune system has also been reported. Antiphlogistic as well as tumorsuppressive effects have also been postulated. Several of these effects have been connected with the polysaccharide fraction of the plant; but individual caffeic acid derivatives such as echinacoside, the alkamide fraction, and the polyacetylene fraction have been related to the above activities as well as to antiviral, antibacterial and antifungal activity of the plant extracts. The fresh and the dried press sap of Echinacea purpurea cause a significant in vitro stimulation of cytokine production by human peripheral blood macrophages at concentrations as low as 0.012 mg/ml. A 1:10 dilution of the dry matter of an ethanolic root extract stimulated in vitro phagocytosis in human granulocytes. The polysaccharide extract of Echinacea was shown to have an antihyaluronidase activity. 4. The acute toxicity of Echinacea angustifolia preparations is generally reported to be low. LD50 values, however, are not available. The LD50 of the Echinacea purpurea fresh pressed juice (aerial parts only) was above 5 and 10 g/kg bw after intravenous injection and 15 and 30 g/kg bw after oral administration in rats and mice, respectively. 5. Information on the repeated dose toxicity of Echinacea purpurea fresh pressed juice (aerial parts only) indicated that the daily administration of doses of 800, 2400 or 8000 mg/kg bw for four weeks did not induce changes in clinical chemistry values or at necropsy in comparison to the control group (no details available). 6. No information on the reproductive toxicity, including embryotoxicity and teratogenicity was submitted. 7. No information was provided on the mutagenic and genotoxic properties of Echinacea angustifolia or its constituents. Echinacea purpurea (fresh pressed juice from aerial parts) was not mutagenic in the Salmonellamicrosomal asssay with and without metabolic activation at concentrations up to 5000 mg/plate. It also had no effect in a gene mutation test in L5178 Y mouse lymphoma cells at the HPRT locus, with and without metabolic activation, in a cytogenetic assay in primary human lymphocyte culture, in the cell transformation assay in Syrian hamster embryo cells and in an in vivo micronucleus test in male and female mice. Some of the caffeic acid derivatives, such as cynarin, chlorogenic and cichoric acid, have been reported to exert mutagenic effects in certain bacterial or mammalian mutagenicity tests. However, most of these compounds, as secondary metabolites in plants, are natural ingredients of the human diet. In addition, they have been connected with antimutagenic and anticarcinogenic effects in humans via antioxidant properties. 8. No information on the carcinogenicity of Echinacea was submitted. The pyrrolizidine alkaloids tussilagin and isotussilagin reported to occur at low concentrations in the roots are saturated in necine moiety, and therefore do not possess structural alerts as regards liver toxicity and neoplasia reported for pyrrolizidine compounds with unsaturated necine configuration. 2/3 ãEMEA 2000 9. In human medicine preparations of Echinacea purpurea are used by dermal and oral administration. Indications include common colds and infections of the respiratory tract for oral administration, and wound healing for dermal administration. Oral doses are 6 to 9 ml/day of the freshly pressed plant juice and may be taken up to 8 weeks. With the exception of allergic reactions, no adverse effects in humans after oral or dermal treatment have been reported. However, parenteral administration is reported to cause as nausea, fever. The parenteral administration of homeopathic preparations of Echinacea in lower dilutions than 1:10000 is contraindicated in cases of autoimmune diseases, progredient inflammatory processes, leukaemia and diabetes mellitus. 10. In view of the similarity of the constituent profile of the different subspecies of Echinacea the previous assessment of Echinacea purpurea by the CVMP also applies to the topical use of Echinacea in medicinal products used in veterinary homeopathy, in all concentrations including the mother tincture. The use of Echinacea in veterinary homeopathy was further considered in a preliminary risk evaluation procedure by the CVMP, considering all defended old substances used in veterinary homeopathy in concentrations greater than 1:10 000. Apart from the above reported information on toxicity, further information made available and systematic search of published literature did not provide any further evidence for pharmacological or toxicological properties of Echinacea and its constituents alerting to specific health risks, which may result from residues in food producing animals following the intended uses. Special emphasis was put on identification of suspicion pointing to genotoxicity or other potential of serious health effects of plant constituents. It was concluded, that for all other routes of administration homeopathic dilutions of Echinacea resulting in concentrations in the veterinary medicinal product not exceeding 1 part per 10 may be used, as they can be considered as not giving rise to any specific consumer health concerns and provide a sufficient margin of safety. Conclusions and recommendation Having considered the criteria laid down by the Committee for the inclusion of substances in Annex II of Council Regulation (EEC) No 2377/90 and in particular that: · the subspecies Echinacea