€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****LANCET***** Murphy JJ Heptinstall S Mitchell JR Randomised double-blind placebo-controlled trial of feverfew in migraine prevention. In: Lancet (1988 Jul 23) 2(8604):189-92 ISSN: 0140-6736 The use of feverfew (Tanacetum parthenium) for migraine prophylaxis was assessed in a randomised, double-blind, placebo-controlled crossover study. After a one-month single-blind placebo run-in, 72 volunteers were randomly allocated to receive either one capsule of dried feverfew leaves a day or matching placebo for four months and then transferred to the other treatment limb for a further four months. Frequency and severity of attacks were determined from diary cards which were issued every two months; efficacy of each treatment was also assessed by visual analogue scores. 60 patients completed the study and full information was available in 59. Treatment with feverfew was associated with a reduction in the mean number and severity of attacks in each two-month period, and in the degree of vomiting; duration of individual attacks was unaltered. Visual analogue scores also indicated a significant improvement with feverfew. There were no serious side-effects. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****BIOCHEMICAL PHARMACOLOGY***** Sumner H Salan U Knight DW Hoult JR Inhibition of 5-lipoxygenase and cyclo-oxygenase in leukocytes by feverfew. Involvement of sesquiterpene lactones and other components. In: Biochem Pharmacol (1992 Jun 9) 43(11):2313-20 ISSN: 0006-2952 Leaves or infusions of feverfew, Tanacetum parthenium, have long been used as a folk remedy for fever, arthritis and migraine, and derived products are widely available in U.K. health food shops. Previous reports have suggested interactions with arachidonate metabolism. Crude chloroform extracts of fresh feverfew leaves (rich in sesquiterpene lactones) and of commercially available powdered leaves (lactone-free) produced dose-dependent inhibition of the generation of thromboxane B2 (TXB2) and leukotriene B4 (LTB4) by ionophore- and chemoattractant-stimulated rat peritoneal leukocytes and human polymorphonuclear leukocytes. Approximate IC50 values were in the range 5-50 micrograms/mL, and inhibition of TXB2 and LTB4 occurred in parallel. Isolated lactones (parthenolide, epoxyartemorin) treated with cysteine (to neutralize reactive alpha-methylene butyrolactone functions of the sesquiterpenes). Inhibition of eicosanoid generation appeared to be irreversible but not time-dependent. We conclude that feverfew contains a complex mixture of sesquiterpene lactone and non- sesquiterpene lactone inhibitors of eicosanoid synthesis of high potency, and that these biochemical actions may be relevant to the claimed therapeutic actions of the herb. Registry Numbers: 29552-41-8 (parthenolide) 4371-52-2 (Cysteine) 54397-85-2 (Thromboxane B2) 71160-24-2 (Leukotriene B4) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****BRITISH JOURNAL OF PHARMACOLOGY***** Hay AJ Hamburger M Hostettmann K Hoult JR Toxic inhibition of smooth muscle contractility by plant-derived sesquiterpenes caused by their chemically reactive alpha- methylenebutyrolactone functions. In: Br J Pharmacol (1994 May) 112(1):9-12 ISSN: 0007-1188 1. Previous studies have shown that extracts of feverfew (Tanacetum parthenium) and parthenolide, a sesquiterpene alpha- methylenebutyrolactone obtained from it, inhibit smooth muscle contractility in a time-dependent, non-specific and irreversible manner. 2. The hypothesis that this toxic effect is due specifically to the presence in the sesquiterpene lactone of the potentially reactive alpha-methylene function was tested on rabbit isolated aortic ring preparations. This was done (a) by comparing the effects of two plant-derived sesquiterpene lactones purified from yellow star thistle (Centaurea solstitialis): cynaropicrin (an alpha- methylenebutyrolactone) and solstitialin 13-acetate (lacking the alpha-methylene function), and (b) by chemically inactivating the alpha-methylene functions in cynaropicrin and parthenolide by reaction with cysteine. 3. The results show that the characteristic smooth muscle inhibitory profile is demonstrated by the two alpha- methylenebutyrolactones (parthenolide and cynaropicrin), but not by the compound lacking this functional group (solstitialin 13-acetate), or by those previously active compounds in which it has been inactivated with cysteine. 4. Thus the alpha-methylene function is critical for this aspect of the toxic pharmacological profile of the sesquiterpene butyrolactones, which are natural products widely distributed in the Compositae family of flowering plants. Registry Numbers: 22738-70-1 (solstitialin) 29552-41-8 (parthenolide) 35730-78-0 (cynaropicrin) 4371-52-2 (Cysteine) 59-42-7 (Phenylephrine) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF ETHNOPHARMACOLOGY***** Bejar E Parthenolide inhibits the contractile responses of rat stomach fundus to fenfluramine and dextroamphetamine but not serotonin. In: J Ethnopharmacol (1996 Jan) 50(1):1-12 ISSN: 0378-8741 The isolated rat stomach fundus preparation, a sensitive bioassay to evaluate serotonin-(5-HT) like activity, was used as a model to study the effects of parthenolide (PAR), a component to Tanacetum parthenium (feverfew), on 5-HT storage, release and stimulation of the 5-HT2B receptor. Cumulative-concentration response curves to 5-HT and the indirect-acting serotonergics fenfluramine (F) and dextroamphetamine (DA) on fundus were obtained in the presence and absence of 1 x 10(-6) to 1 x 10(-5) PAR. 5-HT release elicited by F and DA was indirectly assessed by comparing the contraction elicited by these compounds on tissues from reserpine-treated, L-p- chlorophenylalanine (l-PCPA)-treated and untreated rats. The observed order of agonist potencies on intact fundus was: 5-HT > DA > F and the order of intrinsic activity was: 5-HT > DA > F. PAR did not show agonist effects nor antagonism toward 5-HT on rat fundus at all concentrations used. However, PAR antagonized non-competitively the effects of F and DA. Contractile responses to 5-HT were not significantly different on mucosa-denuded fundus and tissue strips from untreated, l-PCPA- and reserpine-treated rats. PAR appears to inhibit 5-HT release mediated responses by the indirect-acting 5-HT agonists on fundal tissue. Registry Numbers: 19216-56-9 (Prazosin) 29552-41-8 (parthenolide) 458-24-2 (Fenfluramine) 50-67-9 (Serotonin) 51-64-9 (Dextroamphetamine) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF PHARMACY AND PHARMACOLOGY***** Hayes NA Foreman JC The activity of compounds extracted from feverfew on histamine release from rat mast cells. In: J Pharm Pharmacol (1987 Jun) 39(6):466-70 ISSN: 0022-3573 An extract of the plant feverfew (Tanacetum parthenium) produces a dose-dependent inhibition of histamine release from rat peritoneal mast cells stimulated with anti-IgE or the calcium ionophore A23187. Greater inhibition of anti-IgE-induced histamine release was achieved with feverfew compared with the inhibition of A23187-induced release. Inhibition of anti-IgE-induced histamine release by feverfew extract was observed when the drug was added simultaneously with anti-IgE and the inhibitory activity increased only slightly when the drug was preincubated with the cells for 5 min before anti-IgE stimulation. In this respect feverfew differs from cromoglycate and quercetin. Feverfew extract inhibited anti-IgE-induced histamine release to the same extent in the absence and presence of extracellular glucose. It is concluded that feverfew extract contains a novel type of mast cell inhibitor. Registry Numbers: 117-39-5 (Quercetin) 37341-29-0 (IgE) 52665-69-7 (Calcimycin) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Capasso F The effect of an aqueous extract of Tanacetum parthenium L. on arachidonic acid metabolism by rat peritoneal leucocytes. In: J Pharm Pharmacol (1986 Jan) 38(1):71-2 ISSN: 0022-3573 The effect of feverfew (Tanacetum parthenium L., Schultz Bip.) as a whole plant on an aqueous extract equivalent to 20 mg dried plant per ml, has been examined on both cyclo-oxygenase and lipoxygenase activity in rat leucocytes in-vitro. At 10-25 micrograms ml-1 feverfew had no effect on the formation of arachidonate metabolites while at highest concentrations (50-200 micrograms ml-1) it inhibited both cyclo-oxygenase and lipoxygenase metabolic products. Registry Numbers: EC 1.13.11.12 (Lipoxygenase) EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthase) 506-32-1 (Arachidonic Acid) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Barsby RW Knight DW McFadzean I A chloroform extract of the herb feverfew blocks voltage-dependent potassium currents recorded from single smooth muscle cells. In: J Pharm Pharmacol (1993 Jul) 45(7):641-5 ISSN: 0022-3573 We have studied the effects of a chloroform extract of fresh leaves from the herb feverfew (Tanacetum parthenium) on potassium currents in smooth muscle. The currents were recorded from single cells dissociated from the rat anococcygeus and the rabbit ear artery using the whole-cell patch-clamp technique. When applied to cells isolated from the rat anococcygeus, the extract reduced the inactivating voltage-dependent potassium current in a concentration-related manner, with an IC50 value (the concentration that reduced the current by 50%) of 56 micrograms mL-1. Complete block of the current occurred at 1 mg mL-1. In addition to reducing the peak current, feverfew decreased the time to peak of the current and increased the rate of decay of the current. These effects can be explained by the feverfew extract blocking open potassium channels. In single cells isolated from rabbit ear artery the feverfew extract again reduced the voltage-dependent potassium current, whilst at the same time having no effect on the spontaneous transient outward currents which arise as a consequence of activation of calcium-dependent potassium channels. These results suggest that chloroform extracts of feverfew leaf contain an as yet unidentified substance capable of producing a selective, open-channel block of voltage-dependent potassium channels. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Barsby RW Salan U Knight DW Hoult JR Feverfew extracts and parthenolide irreversibly inhibit vascular responses of the rabbit aorta. In: J Pharm Pharmacol (1992 Sep) 44(9):737-40 ISSN: 0022-3573 Samples prepared from chloroform extracts of fresh leaves of feverfew (Tanacetum parthenium) strongly inhibited responses of rabbit aortic rings to phenylephrine, 5-hydroxytryptamine, thromboxane mimetic U46619 (9,11-dideoxy-11 alpha,9 alpha-epoxy-methano-PGF2 alpha), and angiotensin II, but the inhibition to contractions induced by potassium depolarization was much less. The inhibition was concentration- and time-dependent, non-competitive, and irreversible, and also occurred in endothelium-denuded preparations. The feverfew extracts also caused a progressive loss of tone of pre-contracted aortic rings and appeared to impair the ability of acetylcholine to induce endothelium-dependent relaxations of the tissue. These effects were mimicked by a purified preparation of an alpha- methylenebutyrolactone, parthenolide, obtained from the extract. Our results demonstrate a nonspecific and potentially toxic response to feverfew on the vasculature. Registry Numbers: 29552-41-8 (parthenolide) 51-84-3 (Acetylcholine) 59-42-7 (Phenylephrine) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Heptinstall S Awang DV Dawson BA Kindack D Knight DW May J Parthenolide content and bioactivity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.). Estimation of commercial and authenticated feverfew products. In: J Pharm Pharmacol (1992 May) 44(5):391-5 ISSN: 0022-3573 Three physicochemical methods (HPLC, NMR spectroscopy, and HPLC of a derivative) have been used to measure parthenolide in authenticated Tanacetum parthenium (feverfew) and in several commercial purported feverfew products. A bioassay based on inhibition of the secretory activity of blood platelets by extracts of feverfew in comparison with parthenolide was also used. Similar results were obtained for all three physicochemical assays and also for the bioassay. Thus different methodologies yield consistent values for parthenolide content of feverfew preparations. Parthenolide appears to be mainly responsible for the antisecretory effects of extracts of feverfew. Authenticated Tanacetum parthenium grown in the UK contained a high level of parthenolide in leaves, flowering tops and seeds but a low level in stalks and roots. The level of parthenolide in powdered leaf material fell during storage. The purported feverfew products varied widely in their parthenolide content and in some products parthenolide was not detected. Possible reasons for the variation in parthenolide content are discussed. Since therapeutic efficacy has only been demonstrated for preparations of feverfew that contain parthenolide, it is suggested that manufacturers of feverfew products should use measurements of parthenolide as a means of standardization and quality control. Registry Numbers: 29552-41-8 (parthenolide) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****PHYTOCHEMISTRY***** Williams CA Hoult JR Harborne JB Greenham J Eagles J A biologically active lipophilic flavonol from Tanacetum parthenium. In: Phytochemistry (1995 Jan) 38(1):267-70 ISSN: 0031-9422 A new lipophilic flavonol, 6-hydroxykaempferol 3,7,4'-trimethyl ether, called tanetin, has been characterized in the leaf, flower and seed of feverfew, Tanacetum parthenium. It co-occurs with the known 6- hydroxykaempferol 3,7-dimethyl ether, quercetagetin 3,7-dimethyl ether and quercetagetin 3,7,3'-trimethyl ether. Pharmacological tests indicate that tanetin could contribute to the anti-inflammatory properties of feverfew by inhibiting the generation of pro- inflammatory eicosanoids, although it is unlikely to be the only biologically active compound within the plant. Water soluble flavone glycosides were detected in the leaves and identified as apigenin 7- glucuronide, luteolin 7-glucuronide, luteolin 7-glucoside and chrysoeriol 7-glucuronide. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****PLANTA MEDICA***** Barsby RW Salan U Knight DW Hoult JR Feverfew and vascular smooth muscle: extracts from fresh and dried plants show opposing pharmacological profiles, dependent upon sesquiterpene lactone content. In: Planta Med (1993 Feb) 59(1):20-5 ISSN: 0032-0943 Preparations of fresh or dried feverfew (Chrysanthemum parthenium) are widely consumed in the U.K. as a remedy for arthritis and migraine, but the pharmacological basis for this has not been established. We have, therefore, compared the properties of extracts of fresh plants with those of dried powdered leaves available commercially from health food shops. The two extracts differed radically in their content of alpha-methylbutyrolactones and in their pharmacological profile when tested in vitro on the rabbit aortic ring and rat anococcygeus preparations. Extracts of fresh leaves caused does- and time-dependent inhibition of the contractile responses of aortic rings to all receptor-acting agonists so far tested; the effects were irreversible and may represent a toxic modification of post-receptor contractile function in the smooth muscle. The presence of potentially -SH reactive parthenolide and other sesquiterpene alphamethylenebutyrolactones in these extracts, and the close parallelism of the actions of pure parthenolide, suggest that the inhibitory effects are due to these compounds. In contrast , chloroform extracts of dried powdered leaves were not inhibitory but themselves elicited potent and sustained contractions of aortic smooth muscle that were not antagonised by ketanserin (5- HT2 receptor antagonist). These extracts did not contain parthenolide or butyrolactones according to a chemical-HPLC assay, We conclude that there are marked differences in the pharmacological potency and profiles between preparations from fresh and dried feverfew and that this may relate to their lactone content. As the effects of the lactones are potentially toxic, it will be necessary to compare the clinical profiles and side effects of preparations obtained from the two sources. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****POLISH JOURNAL OF PHARMACOLOGY AND PHARMACY***** Gromek D Kisiel W Stojakowska A Kohlmunzer S Attempts of chemical standardizing of Chrysanthemum parthenium as a prospective antimigraine drug. In: Pol J Pharmacol Pharm (1991 May-Jun) 43(3):213-7 ISSN: 0301-0244 A quantitative analysis of biologically active sesquiterpene lactones in ethanol and aqueous extracts of Chrysanthemum parthenium and its form flosculosum was carried out. The sesquiterpene lactone contents in the extracts were comparable, although the contents of ethanol extracts (ca. 0.5%) were higher than of aqueous ones (ca. 0.3%). Parthenolide was found to be the main constituent of the lactones. The applied IR and TLC/FID methods for quantitative determination of the total sesquiterpene lactones and parthenolide, respectively, may be used for chemical standardizing of the raw material and its preparations. Registry Numbers: 29552-41-8 (parthenolide) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****PROSTAGLANDINS, LEUKOTRIENES AND MEDICINE***** Makheja AN Bailey JM A platelet phospholipase inhibitor from the medicinal herb feverfew (Tanacetum parthenium). In: Prostaglandins Leukot Med (1982 Jun) 8(6):653-60 ISSN: 0262-1746 Feverfew has been used since antiquity to treat fevers and other inflammatory conditions. Feverfew extracts were found to inhibit ADP, thrombin, or collagen-induced aggregation of human platelets, but significantly, did not affect aggregation induced by arachidonic acid. Synthesis of thromboxane B2 from exogenous 14C-arachidonic acid was also not inhibited. Washed platelets prelabelled with 14C-AA responded normally to thrombin by releasing 14C-TXB2. This was completely blocked by feverfew. A purified platelet phospholipase A2 was inhibited by the material with an I50 of 0.1 antiplatelet units. The pharmacological properties of feverfew may thus be due to an inhibitor of cellular phospholipases, which prevents release of arachidonic acid in response to appropriate physiological stimuli. Registry Numbers: EC 3.1.- (Phospholipases) EC 3.4.21.5 (Thrombin) 506-32-1 (Arachidonic Acid) 50683-78-8 (12-hydroxy-5,8,10-heptadecatrienoic acid) 54397-85-2 (Thromboxane B2) 58-64-0 (Adenosine Diphosphate) 59985-28-3 (12-Hydroxy-5,8,10,14-eicosatetraenoic Acid) 9007-34-5 (Collagen) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€