Rop et al. (2012) reported that edible flowers of Chrysanthemum parthenium (Tanacetum parthenium) had a dry matter content (%w/w) of 9.86 %, crude protein of 6.77 g/kg and the following elements (mg/kg fresh mass (FM)): P 501.29 mg, K 3600.34 mg, Ca 341.32 mg, Mg 159.17 mg, Na 113.31 mg, Fe 5.83 mg, Mn 7.33 mg, Cu 2.35 mg, Zn 5.94 mg and Mo 0.31 mg. The flowers had total antioxidant capacity of 4.21 g ascorbic acid equivalents/kg FM, total phenolic content of 2.72 g gallic acid/kg FM and total flavonoid content of 1.29 g rutin/kg FM. Flowers of field-grown plants had higher concentration of parthenolide (3.8 % w/w dw) than those from hydroponic plants (1.2 % w/w dw) (Pedneault et al. 2002). A hydroalcohol solution was found to extract more melatonin from the flowers than the hot water extract (Ansari et al. 2010).

The oil yield obtained by SFE (supercritical fluid extraction) of feverfew-flowering heads was similar to that resulting from hexane extraction (5.4 and 4.92 %, respectively) (Kery et al. 1999). The yield of essential oil obtained by steam distillation was only approximately one tenth that obtained by SFE or hexane extraction. Chemical analysis of the volatile constituents of feverfew revealed the presence of 17 major components, 13 of which were identified. The main constituents of each product were camphor and chrysanthenyl acetate. Other minor volatile components identified were α-pinene, camphene, β-pinene, limonene, p-cymene, eucalyptol, γ-terpinene, linalool, α-thujone, borneol and α-terpineol.

The essential oil contents of T. parthenium based on the dry weight of wild and cultivated plants from Iran were 0.1 and 0.4 % (w/w), respectively (Mirjalili et al. 2007). In total, 33 and 30 constituents were identified and quantified in wild and cultivated samples, representing 95.7 and 97.5 % of the total oil, respectively. In the oil of the wild sample, camphor (50.5 %), germacrene-D (9.2 %), camphene (7.7 %), (E)-sesquilavandulol (4.8 %) and (E)-myrtanol (4.7 %) were the major compounds; the minor components were tricylene (1.1 %), α-pinene (0.5 %), dihydrosabinene (0.2 %), sabinene (0.2 %), β-pinene (0.4 %), α-phellandrene (0.1 %), p-cymene (0.5 %), limonene (0.5 %), γ-terpinene (0.4 %), filifolone (1.4 %), chrysanthenone (1.3 %), pinocarvone (tr), borneol (0.6 %), 4-terpineol (0.5 %), lavandulyl acetate (0.1 %), bornyl acetate (1.5 %), α-capaene (0.3 %), β-elemene (0.1 %), (E)-caryophyllene (0.3 %), (Z)-β-farnesene (2.1 %), γ-gurjunene (0.1 %), (Z,E)-α-farnesene (1.5 %), bicyclogermacrene (1.1 %), δ-cadinene (0.2 %), spathulenol (0.4 %), viridflorol (0.6 %), α-cadinol (1.5 %), valerarone (0.1 %) and (Z)-nucliferol acetate (1.2 %). In the oil of cultivated plant, the major components were camphor (57.6 %), (E)-chrysanthenyl acetate (25.1 %), camphene (4.6 %) and bornyl angelate (2.2 %); the minor components were tricylene (0.2 %), α-pinene (0.3 %), sabinene (tr), β-pinene (tr), p-cymene (1.1 %), limonene (0.3 %), γ-terpinene (0.3 %), terpinolene (tr), linalool (0.2 %), α-campholenal (0.4 %), α-cyclocitral (0.1 %), pinocarvone (tr), borneol (0.5 %), 4-terpineol (0.5 %), α-terpineol (tr), (E)-carveol (tr), bornyl acetate (1.4 %), neryl acetate (tr), β-terpinyl acetate (0.1 %), α-copaene (tr), (E)-caryophyllene (0.5 %), (Z)-β-farnesene (1.2 %), germacrene D (0.2 %), bornyl angelate (2.2 %), caryophyllene oxide (0.4 %), viridiflorol (0.1 %) and α-cadinol (0.2 %). It was found that (E)-chrysanthenyl acetate and bornyl angelate were only observed in the oil of the cultivated sample, and (E)-sesquilavandulol (4.8 %) and (E)-myrtanol (4.7 %) were completely absent in the oil of this sample. Oxygenated monoterpenes predominated in the oil of cultivated (85.9 %) and wild (60.6 %) samples. The oil of wild plants contained primarily of ten monoterpene hydrocarbons (11.6 %), nine oxygenated monoterpenes (60.6 %), eight sesquiterpene hydrocarbons (14.9 %) and six oxygenated sesquiterpenes (8.6 %), while the oil of cultivated plants consisted mainly of nine monoterpene hydrocarbons (6.8 %), 13 oxygenated monoterpenes (85.9 %), four sesquiterpene hydrocarbons (1.9 %) and four oxygenated sesquiterpenes (2.9 %).

Thirty compounds were identified in the flower-head essential oil, and the major compounds were camphor 48.4 %, chrysanthenyl acetate 26.3 % and camphene 8.76 % (Rateb et al. 2007). Other minor components included cis-2-octene, butyl acetate, tricylene, α-pinene, camphene, sabinene, β-pinene, p-cymene, limonene, 1,8-cineole, γ-terpinene, p-cymenene, borneol, terpin-4-ol, α-terpineol, linalool acetate, thymol, E-pinocarvyl acetate, E-caryophyllene, germacrene D, germacrene D-4-ol, Z-chrysanthenyl angelate, bornyl angelate, β-caryophyllene oxide, globulol, E,E-farnesol and E,E,-farnesyl acetate.

Seeds were found to be rich in parthenolide and to contain tanaparthin-α-peroxide (Kaplan et al. 2002). Majdi et al. (2011) found that the highest expression of germacrene A synthase (TpGAS) was in glandular trichomes which also contained the highest concentration of parthenolide, suggesting that glandular trichomes were the secretory tissues where parthenolide biosynthesis and accumulation occurred. Expressions of (E)-β-caryophyllene synthase (TpCarS), amorpha-4,11-diene synthase, were also observed.

Three pinene derivatives, two spiroketal enol ether polyines, four germacranolides and six guaianolides, two of them being endoperoxides and two secoguaianolides, were isolated from the aerial parts: germacranolide—parthenolide; eudesmolides reynosin and santamarin; guaianolides canin and artecanin; and non-lactone terpenes including camphor, β-farmesene and germacrene D, chrysanthenyl acetate, bornyl acetate, bornyl angelate, α-pinene derivatives and spiroketal enol ether polyines (Bohlmann and Zdero 1982). Compounds isolated from feverfew included sesquiterpene lactones, parthenolide, 3-β-hydroxyparthenolide, secotanapartholide A, canin and artecanin (Groenewegen et al. 1986); guaianolides, tanaparthin-α-peroxide, canin and secotanapartholide-A [major group] and the corresponding ‘β’ series [β-peroxide, artecanin and the seco-B derivative] (Begley et al. 1989); significant amounts of parthenolide, camphor and chrysanthenol acetate (Smith and Burford 1992); guaianolide 3,4-epoxy-8-deoxycumambrin B and the eudesmanolide epoxysantamarine (Milbrodt et al. 1997); flavonoids, 3,6,4′-trimethyl ether and quercetagetin 3,6,3′-trimethyl ether, methyl ethers of scutellarein and 6-hydroxyluteolin, chrysoeriol 7-glucuronide, quercetin 7-glucuronide and apigenin and luteolin 7-glucuronides (Williams et al. 1999a); (2-glyceryl)-O-coniferaldehyde as the major constituent of T. parthenium tissue culture (Laiking and Brown 1999); and flavonoids santin 3, jaceidin 2 and centaureidin 1 (Long et al. 2003). The lipophilic flavonol, 6-hydroxykaempferol 3,7,4′-trimethyl ether, called tanetin, was found in the leaf, flower and seed of feverfew together with the known 6-hydroxykaempferol 3,7-dimethyl ether, quercetagetin 3,7-dimethyl ether and quercetagetin 3,7,3′-trimethyl ether (Williams et al. 1995). The lipophilic flavonoids in leaf and flower were found to be methyl ethers of the flavonols 6-hydroxykaempferol and quercetagetin (Williams et al. 1999b). Apigenin and two flavone glucuronides were present in glandular trichomes on the lower epidermis of the ray florets. The structures of the four 6-hydroxyflavonol methyl ethers of T. parthenium were found to be 6- rather than 7-O-methylated, and tanetin was revised as 6-hydroxykaempferol 3,6,4′-trimethyl ether. The vacuolar flavonoids of feverfew were dominated by the presence of apigenin and luteolin 7-glucuronides; nine other glycosides were also present. Some rare compounds found in feverfew included guaianolides, 8α-hydroxystafiatin, endoperoxide tanaparthin-α-peroxide, canin, 10-epi-canin and secotanapartholide A and B (Todorova and Evstatieva 2001).

Three flavones, 3-hydroxyflavone, kaempferol (3,4′,5,7-tetrahydroxyflavone) and fisetin (3,3′,4′,7-tetrahydroxyflavone), and a flavanone naringenin (4′,5′,7-trihydroxyflavanone) were isolated from the aerial parts (Shafaghat and Salimi 2008).

Antioxidant phenolic acid compounds 3,5-, 4,5- and 3,4-di-O-caffeoylquinic acids (DCQAs) were purified from feverfew (Wu et al. 2007). Polyphenolic compounds (g/kg dry matter) in the aerial feverfew plant parts were determined as follows: chlorogenic acid 6.45 g, 3,5-DCQA (dicaffeoylquinic acid) 30.08 g, 4,5, DCQA 5.61 g, total caffeoyl derivatives 42.14 g, total dihydroxycinnamic acid derivatives 57.21 g, total flavonoids 13.97 g, total dihydroxycinnamic acid derivatives + flavonoids 71.18 g and total polyphenolic compounds 81.12 g (Fraisse et al. 2011).

Feverfew essential oil was found to increase from the beginning of stem formation (0.30 %, v/w) until full bloom (0.83 %, v/w) (Hendriks et al. 1996). During the development of the plant, the content of camphor rose from 28 to 48 %, whereas the amount of chrysanthenyl acetate decreased from 30 to 22 %. In none of the oil samples investigated could the potentially toxic monoterpenes α- or β-thujone be detected. They found that the yield of parthenolide per individual plant gradually increased from about 10 mg at study commencement to about 20 mg when the plant was in full bloom (Hendriks et al. 1997). Parthenolide was present in the leaves and flower heads, but not in the stems. Drying at ambient temperature and lyophilization had no negative influence on the yield of parthenolide per individual plant.

Twenty components were identified in the essential oil of aerial parts of T. parthenium in the eastern region of Kosova, constituting 885 of the oil (Haziri et al. 2009). The major components were camphor 63 % and camphene 9.6 %, indicating the occurrence of camphor/camphene chemotype in Kosova. Other components included p-cymene 3.3 %, bornyl acetate 3 %, chrysanthenone 1.3 % and the remainder all <1 %: tricylene, α-thujene, α-pinene, β-pinene, α-phellandrene, α-terpinene, pinocarvone, borneol, terpinene-4-ol, p-cymen-8-ol, α-terpineol, myrtenal, eugenol, trans-myrtenolacetate, isobornyl-2-methylbutanoate and caryophyllene oxide. The volatile fraction of the essential oil of feverfew grown in Belgium was characterized by high camphor (44 %) and trans-chrysanthenyl acetate (23 %) contents (de Pooter et al. 1989).

Twenty-three components were identified in the essential oil of T. parthenium aerial plant parts from Turkey representing 90.1 % of the oil (Akpulat et al. 2005). The main constituents were camphor (56.9 %), camphene (12.7 %), p-cymene (5.2 %) and bornyl acetate (4.6 %). Other components identified include tricylene, α-thujene, α-pinene, β-pinene, α-phellandrene, α-terpinene, γ-terpinene, chrysantheone, pinocarvone, borneol, terpinen-4-ol, ρ-cymen-8-ol, α-terpineol, myrtenal, carvacrol, eugenol, trans-myrtenol acetate, isobornyl 2-methyl butanoate and caryophyllene oxide. Twenty-nine components were identified in feverfew essential oil from Iran (Mohsenzadeh et al. 2011). The highest yield was extracted at the flowering stage, and the major components were camphor (18.94 %), bornyl acetate (18.35 %), camphene (13.74 %), bornyl isovalerate (3.15 %), borneol (10.93 %), juniper camphor (6.23 %) and β-eudesmol (2.65 %).

Tissue cultures of T. parthenium afforded significant amounts of two coumarins, scopoletin and isofraxidin together with stigmasterol and sitosterol (Banthorpe and Brown 1989). These two coumarins were either absent or were very minor compounds in the parent plant.

Water-soluble flavone glycosides detected in the leaves were identified as apigenin 7-glucuronide, luteolin 7-glucuronide, luteolin 7-glucoside and chrysoeriol 7-glucuronide (Williams et al. 1995). Murch et al. (1997) reported minute amount up to 2.45 μg/g of melatonin (N-acetyl-5-methoxytryptamine) in the leaves which was lower than that found in the flowers of St. John’s wort (4.39 μg/g) and Scutellaria baicalensis (7.11 μg/g). The following flavonoids were detected in feverfew leaves: flavones, luteolin, scutellarein-6-methyl ether (hispidulin), scutellarein-6-4′-dimethyl ether (pectolinarigenin), 6-hydroxyluteolin 6-methyl ether (nepetin), 6-hydroxyluteolin 6,3′ -dimethyl ether (jaceosidin); flavonol, quercetagetin 3,6-dimethoxy ether (axillarin) (Ivancheva et al. 1998).

Parthenolide, tanaparthin-α-peroxide, tanaparthin-β-peroxide, 3-β-hydroxycostunolide and canin (Kaplan et al. 2002); parthenolide and epoxyartemorin (Sumner et al. 1992) were isolated from the leaves. Leaves of field-grown plants had higher concentration of parthenolide (1.85 % w/w dw) than those from hydroponic plants (0.38 % w/w dw) (Pedneault et al. 2002). From the leaves, isolated sesquiterpene lactones were identified as parthenolide, epoxysantamarin, 3β-hydroxyparthenolide and secotanapartholide A, and flavonoids identified as santin, apigenin, luteolin and quercetin (Rateb et al. 2007). Forty compounds were identified in the leaf essential oil, and the major compounds were camphor 37.7 %, chrysanthenyl acetate 33.8 % and terpin-1-ol 5.14 % (Rateb et al. 2007). Other minor components included butyl acetate, tricylene, α-pinene, camphene, sabinene, β-pinene, β-myrcene, p-cymene, limonene, β-phellandrene, 1,8-cineole, γ-terpinene, terpinolene, p-cymenene, pinocarvone, borneol, terpin-4-ol, α-terpineol, linalool acetate, bornyl acetate, citronellal hydrate, thymol, E-pinocarvyl acetate, carvacrol, α-copaene, E-caryophyllene, α-humulene, E-β-farnesene, germacrene D, Ar-curcumene, isobornyl-2-methyl butyrate, Σ-cadinene, Z-chrysanthenyl angelate, bornyl angelate, β-caryophyllene oxide, globulol, viridiflorol, E,E-farnesol and E,E,-farnesyl acetate. Shafaghat et al. (2009) found that feverfew leaf oil was characterized by a high amount of camphor (56.4 %), whereas in the stem oil, camphor (26.0 %), trans-β-ocimene (23.6 %) and germacrene-D (15.0 %) were the major constituents.

The roots of Tanacetum parthenium transformed with Agrobacterium rhizogenes afforded, in addition to the known coumarin isofraxidin, a new isofraxidin drimenyl ether which was elucidated as 9-epipectachol B (Kisiel and Stojakowska 1997). Twenty components (92 % of essential oil) were identified in the essential oil of T. parthenium roots and rhizomes (Mojab et al. 2007). Camphor (30.2 %), (Z)-chrysanthenyl acetate (26.5 %), α-farnesene (11.1 %) and spathulenol (8.2 %) were the major components. Other components included bornyl angelate (3.3 %), bornyl acetate (3.1 %), ethyl myristate (1.8 %), fenchone (1.5 %),1-hexanol (1.7 %), 7-benzofuranol (1.3 %), hexanal (1.1 %), β-myrcene (0.8 %), β-caryophyllene (0.4 %), α-pinene (0.3 %), p-cymene (0.3 %), carvacrol (0.2 %), borneol (0.1 %), isobornyl formate (0.1 %), isothujyl acetate (0.1 %) and β-bisabolene (0.1 %). The main components of the root oil were α-pinene (50.0 %), trans-β-farnesene (13.8 %) and bicyclogermacrene (11.0 %) (Shafaghat et al. 2009).

In feverfew hairy root cultures treated with methyl jasmonate (MJ) increased accumulation of spiroketal enol ether type diacetylenes of known deterrent activity about twofolds (Stojakowska et al. 2002). Salicylic acid (SA) transiently reduced a content of constitutive spiroketal enol ethers, common for all root clones, but selectively enhanced accumulation of cis-C13-spiroketal enol ether epoxide ((E)-3,4-epoxy-2-(2,4-hexadiynylidene)-1,6-dioxaspiro[4.4]nonane) (2), present in clone M2. The maximum total acetylene content (≈2.5 and 1.1 % dry weight in clones M2 and I2, respectively) was observed after 72–96 hours MJ treatment. Simultaneous addition of SA and MJ to the culture medium increased accumulation of the epoxide in clone M2 (up to sixfold increase compared with the control).

In the European Patent Specification EP 1 367 993 B1 titled ‘Use of a feverfew extract for regulating skin ageing factors’, Martin and Salio (2002) the inventors stated that to-date, the chemical constituents of whole feverfew extract include, but are not limited to apigenin-7-glucoside, apigenin-7-glucuronide, 1-β-hydroxyarbusculin, 6-hydroxykaempferol-3,7-4′-trimethylether (tanetin), 6-hydroxykaempferol-3,7-dimethyl ether, 8-β-reynosin, 10-epicanin, ascorbic acid, β-carotene, calcium, chromium, chrysanthemolide, cosmosine, chrysanthemum, chrysarten-A, chrysarten-C, chrysoeriol-7-glucuronide, cobalt, β-costunolide, epoxyartemorin, luteolin-7-glucoside, luteolin-7-glucuronide, mangnoliolide, tanaparthin, parthenolide, reynosin, quercetagentin-3,7,3′-trimethylether, quercetagetin-3′7- dimethylether, 3,7,3′-trimethoxyquercetagetin, tanaparthin-1α,4α-epoxide and tanaparthin-1β,4β-epoxide3-β-hydroxyparthenolide. In the US Patent US 6224875 B1, entitled ‘Tanacetum parthenium extract and method of obtaining same’, the inventors Bombardelli and Morazzoni (2001) stated that Tanacetum parthenium contained various volatile oils having mono- and/or sesquiterpene components, flavonoids, tannins and pyrethrin, as well as terpenoids of the family of sesquiterpene lactones known as germacranolides, guaianolides and eudesmanolides. These latter compounds were found to be characterized by an α-unsaturated γ-lactone structure and to comprise in particular the compounds known as parthenolide, 3-β-hydroxy-parthenoide, costunolide, 3-β-hydroxy-costunolide, artemorin, 8-α-hydroxy-estafiatin and chrysanthemum. The presence of these sesquiterpene lactones had been considered necessary for the extracts to achieve pharmacological activity in commercial and authenticated feverfew products by (Heptinstall et al. 1992). Heptinsatll et al. (1992) found authenticated Tanacetum parthenium grown in the United Kingdom 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 declined during storage and purported feverfew products varied widely in their parthenolide content and in some products parthenolide was not detected.

Major polyphenolic acid compounds in feverfew with potent DPPH* scavenging activities were characterized as 3,5-, 4,5- and 3,4-di-O-caffeoylquinic acids (DCQAs) (Wu et al. 2007). Total antioxidant capacity (%) (DPPH scavenging activity) of feverfew aerial plant parts was 7.89 %, and contribution from the main caffeoyl derivatives was as follows: chlorogenic acid 8.49 %, 3,5- DCQA (dicaffeoylquinic acid) 48.92 %, 4,5-DCQA 9.12 % and total caffeoyl derivatives 66.53 % (Fraisse et al. 2011).

A parthenolide-depleted extract of feverfew (PD-Feverfew), which was free of sensitization potential, was found to possess free radical scavenging activity against a wide range of reactive oxygen species and with greater activity than vitamin C (Martin et al. 2008). PD-Feverfew had a fivefold greater scavenging activity for oxygen and hydroxyl radicals than ascorbic acid and threefold greater scavenging activity for ferric radicals than ascorbic acid. PD-Feverfew had the greatest scavenging activity against ferric radicals followed by oxygen, hydroxyl and peroxynitrate radicals, respectively. PD-Feverfew was also effective in scavenging superoxide anion as measured by using a superoxide dismutase (SOD) assay kit. The IC₅₀ of SOD scavenging activity for PD-Feverfew was 2.74 μg/ml and that for ascorbic acid was 34.8 μg/ml. Thus, the SOD activity of PD-Feverfew was 13-fold greater than that of ascorbic acid. In-vitro, PD-Feverfew restored cigarette smoke-mediated depletion of cellular thiols, attenuated the formation of UV-induced hydrogen peroxide and reduced proinflammatory cytokine release. PD-Feverfew was also found to protect keratinocytes from cigarette smoke-induced ROS formation. Cellular toxicity as measured by lactate dehydrogenase (LDH) release was also dose-dependently reversed by PD-Feverfew treatment. In-vivo, topical PD-Feverfew reduced UV-induced epidermal hyperplasia, DNA damage and apoptosis. In a clinical study PD-Feverfew treatment significantly reduced erythema versus placebo 24 hours post-UV exposure. The study showed that parthenolide-depleted extract of feverfew may protect skin from the numerous external aggressions encountered daily by the skin and reduce the damage to oxidatively challenged skin.

Feverfew was one of 32 plant herbs that exhibited inhibitory activity against Epstein–Barr virus early antigen (EBV-EA) activation in Raji cells promoted by phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) (Kapadia et al. 2002). Studies showed that parthenolide inhibited the growth of the Epstein–Barr virus (EBV)-positive Burkitt lymphoma cell line, Raji, and activated the transcription of BZLF1 and BRLF1 by inhibiting NF-κB activity (Li et al. 2012). Further, when parthenolide was used in combination with ganciclovir (GCV), the cytotoxic effect of parthenolide was amplified, suggesting that the induction of lytic EBV infection with parthenolide in combination with GCV may be a viral-targeted therapy for EBV-associated Burkitt lymphoma.

The exact mechanism of migraine pathophysiology is still uncertain. Based on therapeutic and triggered migraine studies, serotonin receptors, nitric oxide, calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide and prostanoids have been demonstrated to be specific chemical mediators of migraine Charles (2013). Numerous mechanisms have been proposed for the action of feverfew in migraine and include inhibition of inflammation, inhibition of serotonin release, inhibition of prostaglandin synthesis, inhibition of platelet aggregation and secretion, inhibition of polymorphonuclear leucocyte degranulation, inhibition of phagocytosis of human neutrophils, inhibition of mast cell release of histamine minimizing damage to endothelium and inhibition of VSMC and modulating vasoconstriction (Biggs et al. 1992; Kemper 1999; Colodny et al. 2003). According to Rodriguez-Sainz et al. (2013) migraine, epilepsy and stroke are highly prevalent neurological disorders, often comorbid. They share diverse pathophysiological mechanisms that explain the use of similar drugs on certain occasions.