Parthenolide Feverfew

Some studies have evaluated the quantity of a specific constituent in various herbal products by a thin-layer chromatography spectrophotometric method. Of 44 feverfew products that were evaluated, 14 (32%) did not contain the minimum of 0.2% parthenolide content (active ingredient) and 10 (22%) did not contain any detectable levels of parthenolide [30]. 

Heptinstall S, Awang DVS, Dawson BA, Kindack D, Knight DW, May J. Parthenolide content and bioactivity of feverfew (Tanacetum parthenium (1.) Schultz-Bip.). Estimation of commercial and authenticated feverfew products. J Pharm Pharmacol 44 391-395, 1992. 

The primary active chemical constituent in feverfew is parthenolide, a sesquiterpenoid lactone (figure 8.8) (Robbers et al. 1996). Levels of sesquiterpene lactones vary across different types of extracts ethanol extracts contain about 0.5%, whereas aqueous ones contain 0.3% (Gromek et al. 1991). The sesquiterpene lactones in feverfew inhibit the... 

Groenewegen WA, Heptinstall S. (1990). A comparison of the effects of an extract of feverfew and parthenolide, a component of feverfew, on human platelet activity in-vitro. J Pharm Pharmacol. 

Parthenolide was only the first of many sesquiterpene lactones to be isolated from feverfew. Two further compounds were isolated and named chrysartemin A (4) and B (5) [14]. The structure of chrysartemin B was later revised [15], Recently, several studies have shown that chrysartemin A and B are not present in feverfew as the structures shown in (4) and (5) but are in fact the isomeric canin (19) and artecanin (20), respectively (see... 

Sesquiterpene lactones are not exclusive to feverfew and most of the compounds extracted from the plant, including parthenolide [26], have also been... 

The ability of feverfew extract to inhibit 5HT-secretion in platelets was used to identify compounds responsible for the inhibitory effects on platelets [44], A crude feverfew extract was separated by chromatography and fractions were screened for antisecretory activity induced by adrenaline. In five active fractions compounds were identified as the sesquiterpene lactones parthenolide (1), canin (19), artecanin (20), secotanapartholide A (24) and 3 8-hydroxyparthenolide (2). The ability of parthenolide to affect platelet activity induced by other agents was confirmed in a study of direct comparison of crude feverfew extract with parthenolide [43], Parthenolide in the micromolar concentration range inhibited platelet 5HT-secretion. 

Agents that contain SH-groups such as cysteine or 2-mercaptopropionyl glycine were able to neutralize feverfew inhibitory activity on platelets [52]. Further, the same study demonstrated a dramatic reduction in the number of acid-soluble SH-groups, both by feverfew and parthenolide. These effects... 

There are only a few reports on the efficacy of feverfew in an in vivo situation. Inhibition of collagen-induced bronchoconstriction in an in vivo guinea-pig model was demonstrated [56] and it was concluded that this was consistent with in vivo phospholipase A2 inhibition. In a rat model of experimentally induced nephrocalcinosis, parthenolide was shown to protect the rats against this condition. Inhibition of prostaglandin biosynthesis may have been the mechanism of action of parthenolide in this case, as prostaglandins are thought to be involved in nephrocalcinosis [57]. 

As early as 1950, feverfew was reported to cause contact dermatitis in at least one patient [62] and parthenolide was found to cause an allergic reaction in patients with the same condition [63]. Since then there have been many reports [64-68] of feverfew-induced allergic reactions, the condition being worst in the summer months coinciding with the flowering season of the plant. The a-methylene butyrolactone group was found to be a partial requirement for activity in contact dermatitis [69]. 

The capsules contained a mean of 82 mg feverfew and thus the level of activity calculated as parthenolide can be estimated as 0.67%. Other studies quote 0.87% sesquiterpene lactones calculated as parthenolide [27] and 0.25-0.30% of active (antimicrobial) material [33]. Bohlmann s extraction of individual components from the dried plant yielded 116 mg sesquiterpene lactones/kg dried feverfew which amounts to less than 0.01 % [17]. Another extraction yielded 330 mg endoperoxides/kg and 56 mg canin/kg alone [19] which would amount to a level of sesquiterpene lactones of at least 0.04%. Thus, the level of sesquiterpene lactones appears to vary with different sources of the plant and this could have been due to a number of factors including the conditions in which feverfew was grown, the season in which it was picked and the way in which it was stored. Another important determinant of the parthenolide content of feverfew appears to be the geographical location. A recent survey of commercial preparations found that all the North American commercial products tested contained less that 0.1% parthenolide, wheras much higher values were obtained for British products. A minimum level of 0.2% parthenolide in commercial products has been proposed by the Health Protection Branch of Health and Welfare Canada [71]. 

Quantitative analysis of feverfew with regards to sesquiterpene lactone content has been carried out by TLC [72,73] and HPLC [71,74,75] and H-NMR spectroscopy [75]. Measurements of parthenolide by HPLC correlated well with measurements by bioassays based on 5HT-secretion from platelets [75]. The availability of several techniques for quantitation of parthenolide levels in feverfew, makes some standardization of commercial preparations possible. 

The importance of NF-kB to inflammation, apoptosis resistance and tumour progression has resulted in the development of unique NF-kB inhibitors as part of cancer therapeutic regimens for GI and other cancers. Efforts are also being made to understand the efficacy of using natural substances obtained from plants, such as feverfew (e.g. parthenolide), bee glue (e.g. caffeic acid phenylethyl ester), tea (e.g. EGCG), spices (e.g. curcumin from turmeric) and mulberry figs (e.g. morin, a flavone) for the prevention both of persistent NF-kB activation and of the development of inflammatory pre-neoplastic lesions. 

Parthenolide inhibits serotonin release, an action that is thought to be a likely source of its effectiveness in migraine. Extracts have also been shown to reduce the production of prostaglandins (another possible mechanism) and leukotrienes. Interestingly, melatonin has been identified in feverfew, a possibly significant observation, since chronic migraines have been associated with low melatonin levels. 

Double-blind withdrawal of feverfew leaf from migraine sufferers who were regular users led to a significant increase in the frequency and severity of headaches (see Chapter 30). A prospective, randomized, double-blind, placebo-controlled trial subsequently found that feverfew was an effective prophylactic migraine agent. The sesquiterpene lactone parthenolide is considered to be an important constituent, but other constituents may also play a significant role. 

Parthenolide, a constituent of feverfew, inhibits the release of certain chemicals, including the hormone serotonin, which is produced during a migraine attack, and certain inflammatory mediators, including the hormone prostaglandin, which regulates inflammation. Feverfew is used for prevention of migraines and headaches (see Chapter 30). 

Feverfew is widely consumed in England as a remedy for arthritis and migraine. Feverfew contains parthenolide, which is a member of sesquiterpene. Parthenolide inhibits the activity of prostaglandin synthetase. It also inhibits platelet aggregation and alter serotonin release (Figure 25.2). 

Feverfew contains flavonoid glycosides, monoterpenes (eg, camphor, other pinene derivatives), and sesquiterpene lactones. The most prevalent sesquiterpene is parthenolide, which is primarily found in the seeds and leaves of the plant, with concentrations ranging from 1% to 3%. 

Feverfew is most often used as a prophylactic remedy for migraine headache. This action has been related to the serotonin hypothesis for migraine causation (see also Chapter 16 Histamine, Serotonin, the Ergot Alkaloids). In vitro, feverfew and parthenolide inhibit platelet aggregation and serotonin release from platelets. 

Kwok, B.H. et al., The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase, Chem. Biol., 8, 759, 2001. 

More than 11,000 Sesquiterpenes have been isolated from natural sources [3]. Feverfew (Tanacetum parthenium (L.) Sch. Bip.,. Compositae) is a common herb utilized for fever, arthritis and migraine. The leaves of feverfew contain large amounts of sesquiterpene lactones. The chloroform extracts of fresh leaves and a commercial leaf product show dose-dependent inhibiting the production of throboxane B2 (TXB2) and leukotriene B4 (LTB4) in rat and human leukocytes. Sesquiterpene lactones isolated from the leaves of feverfew, such as parthenolide and tanaparthin-a-peroxide, demonstrate potent dual inhibitions of COX and LOX pathways with IC50 for COX at 6 17 pg/ml, and for LOX at 12 17 pg/ml, respectively [135],... 

Feverfew 1. Antimigraine drugs, e.g. sumatriptan t risk of episodes of tachycardia and hypertension (may be dangerous) The parthenolide constituent of feverfew has been shown to inhibit the release of serotonin and prostaglandins. Sumatriptan is an SSRI Avoid concomitant use... 

As Tanacetum parthenium is rich in allergenic sesquiterpene lactones, such as parthenolide, it is not surprising that contact dermatitis has been observed (SEDA-11, 426). The most common adverse effect of oral feverfew is mouth ulceration. A more widespread inflammation of the oral mucosa and tongue, swelhng of the lips, and loss of taste have also been reported. 

---